WO2009039135A1 - N-phenyl-dioxo-hydropyrimidines useful as hepatitis c virus (hcv) inhibitors - Google Patents

N-phenyl-dioxo-hydropyrimidines useful as hepatitis c virus (hcv) inhibitors Download PDF

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Publication number
WO2009039135A1
WO2009039135A1 PCT/US2008/076594 US2008076594W WO2009039135A1 WO 2009039135 A1 WO2009039135 A1 WO 2009039135A1 US 2008076594 W US2008076594 W US 2008076594W WO 2009039135 A1 WO2009039135 A1 WO 2009039135A1
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Prior art keywords
group
substituted
independently selected
alkyl
optionally
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PCT/US2008/076594
Other languages
French (fr)
Inventor
Pamela L. Donner
John T. Randolph
Allan C. Krueger
David A. Betebenner
Douglas K. Hutchinson
Dachun Liu
Yaya Liu
Kenton L. Longenecker
Clarence J. Maring
John K. Pratt
Todd W. Rockway
Kent D. Stewart
Rolf Wagner
David M. Barnes
Shuang Chen
Thaddeus S. Franczyk Ii
Yi Gao
Anthony R. Haight
John E. Hengeveld
Rodger F. Henry
Brian J. Kotecki
Xiaochun Lou
Geoff G. Z. Zhang
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Abbott Laboratories
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Priority to MX2010002904A priority Critical patent/MX2010002904A/en
Priority to CN200880116208.2A priority patent/CN101918369B/en
Priority to PL08831558T priority patent/PL2203430T3/en
Priority to JP2010525104A priority patent/JP5726527B2/en
Priority to EP08831558A priority patent/EP2203430B1/en
Priority to AT08831558T priority patent/ATE512954T1/en
Priority to DK08831558.5T priority patent/DK2203430T3/en
Priority to RU2010114826/04A priority patent/RU2542099C2/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to SI200830377T priority patent/SI2203430T1/en
Priority to CA2699989A priority patent/CA2699989C/en
Publication of WO2009039135A1 publication Critical patent/WO2009039135A1/en
Priority to ZA2010/02690A priority patent/ZA201002690B/en
Priority to HK11100075.5A priority patent/HK1145839A1/en
Priority to HR20110632T priority patent/HRP20110632T1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • This invention is directed to: (a) compounds and salts thereof that, inter alia, are useful as hepatitis C virus (HCV) inhibitors; (b) intermediates useful for the preparation of such compounds and salts; (c) compositions comprising such compounds and salts; (d) methods for preparing such intermediates, compounds, salts, and compositions; (e) methods of use of such compounds, salts, and compositions; and (f) kits comprising such compounds, salts, and compositions.
  • HCV hepatitis C virus
  • Hepatitis C is a blood-borne, infectious, viral disease that is caused by a hepatotropic virus called HCV.
  • HCV genotype Ia predominates, followed by HCV genotypes Ib, 2a, 2b, and 3a.
  • HCV genotypes 1, 2, and 3 are the most common, with about 80% of the hepatitis C patients having HCV genotype 1.
  • HCV genotype Ib is predominant, followed by HCV genotypes 2a, 2b, 2c, and 3 a.
  • HCV genotypes 4 and 5 are found almost exclusively in Africa.
  • the patient's HCV genotype is clinically important in determining the patient's potential response to therapy and the required duration of such therapy.
  • HCV infection can cause liver inflammation (hepatitis) that is often asymptomatic, but ensuing chronic hepatitis can result in cirrhosis of the liver (f ⁇ brotic scarring of the liver), liver cancer, and/or liver failure.
  • the World Health Organization estimates that about 170 million persons worldwide are chronically infected with HCV, and from about three to about four million persons are newly infected globally each year. According to the Centers for Disease Control and Prevention, about four million people in the United States are infected with HCV. Co-infection with the human immunodeficiency virus (HFV) is common, and rates of HCV infection among HIV positive populations are higher.
  • HBV human immunodeficiency virus
  • ribavirin does not effectively suppress HCV levels, but an interferon/ribavirin combination is more effective than interferon alone.
  • hepatitis C is treated with a combination of pegylated interferon alpha and ribavirin for a period of 24 or 48 weeks, depending on the HCV genotype.
  • the goal of treatment is sustained viral response — meaning that HCV is not measurable in the blood after therapy is completed.
  • sustained cure rates sustained viral response
  • Treatment may be physically demanding, particularly for those with prior history of drug or alcohol abuse, because both interferon and ribavirin have numerous side effects.
  • Common interferon- associated side effects include flu-like symptoms, extreme fatigue, nausea, loss of appetite, thyroid problems, high blood sugar, hair loss, and skin reactions at the injection site.
  • Ribavirin-associated side effects include anemia, fatigue, irritability, skin rash, nasal stuffiness, sinusitis, and cough. Ribavirin can also cause birth defects, so pregnancy in female patients and female partners of male patients must be avoided during treatment and for six months afterward.
  • R 1 is selected from the group consisting of hydrogen, methyl, and nitrogen-protecting group
  • R 2 is selected from the group consisting of hydrogen, halo, hydroxy, methyl, cyclopropyl, and cyclobutyl;
  • R 3 is selected from the group consisting of hydrogen, halo, oxo, and methyl;
  • R 4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein:
  • the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, and alkylsulfonyl optionally are substituted with one or more substituents independently selected from the group consisting of halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl, and heterocyclyl, wherein: the amino optionally is substituted with:
  • substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl, or
  • the carbocyclyl and heterocyclyl optionally are substituted with up to three substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl, and heterocyclyl, wherein: the amino optionally is substituted with:
  • substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl, or
  • R 5 is selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, carbocyclylsulfonyloxy, haloalkylsulfonyloxy, and halo;
  • R A and R B are independently selected from the group consisting of hydrogen, Ci-C 6 -alkyl, Q-C 6 - alkyloxy, C 3 -C 8 -cycloalkyl, and halo, wherein: the C r C 6 -alkyl optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, halo, hydroxy, nitro, oxo, amino, cyano, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, and heterocyclyl;
  • R 6 is selected from the group consisting of C 5 -C 6 -carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl, wherein each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ ; each R E is independently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, cyano, amino, imino, azido, and aldehydo, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl; each R r is independently selected from the group consisting of alkyl, alkenyl, and alkynyl, wherein: each such substituent optionally is substituted with one or more substituents independently
  • alkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl optionally are substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, and (b) the aminocarbonyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxyalkyl, carbocyclyl, heterocyclyl, alkylsulfonyl, and alkylsulfonyl, and
  • the amino portion of such substituents optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkenyl, alkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
  • the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido, oxo, and amino, and
  • amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl,
  • the alkyl, alkenyl, and alkynyl portion of such substituents optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, and alkynyloxy, wherein: the alkyl optionally is substituted with one or more hydroxy;
  • the carbocyclyl and heterocyclyl portions of such substituents optionally are substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido, and amino, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl; and each R ⁇ is independently selected from the group consisting of aminosulfonyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl, wherein:
  • alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl optionally are substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl; and
  • aminosulfonyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl.
  • This invention also is directed to the salts (including pharmaceutically acceptable salts) of the compounds of the invention.
  • compositions including pharmaceutical compositions that comprise one or more compounds and/or salts of the invention, and, optionally, one or more additional therapeutic agents.
  • kits that comprise one or more compounds and/or salts of the invention, and, optionally, one or more additional therapeutic agents.
  • This invention also is directed to methods of use of the compounds, salts, compositions, and/or kits of the invention to, for example, inhibit replication of an RNA virus (including HCV), treat a disease treatable by inhibiting HCV ribonucleic acid (RNA) polymerase (including hepatitis C).
  • RNA virus including HCV
  • RNA polymerase including hepatitis C
  • This invention also is directed to a use of one or more compounds and/or salts of the invention to prepare a medicament.
  • the medicament optionally can comprise one or more additional therapeutic agents.
  • the medicament is useful for treating hepatitis C.
  • Figure 1 shows an illustrative PXRD pattern for the disodium salt nonahydrate of compound IB- Ll-1.1.
  • Figure 2 shows an illustrative PXRD pattern for the disodium salt tetrahydrate of compound IB- Ll-1.1.
  • Figure 3 shows an illustrative TGA profile of the disodium salt tetrahydrate of compound IB-Ll- 1.1.
  • Figure 4 shows an illustrative PXRD pattern for the dipotassium salt tetrahydrate of compound IB-Ll-1.1.
  • Figure 5 shows an illustrative PXRD pattern for the monopotassium salt trihydrate of compound IB-Ll-1.1.
  • Figure 6 shows an illustrative PXRD pattern for the monopotassium salt dihydrate of compound IB-Ll-1.1.
  • Figure 7 shows an illustrative TGA profile of the monopotassium salt dihydrate of compound IB- Ll-1.1.
  • Figure 8 shows an illustrative PXRD pattern for the 1/7 potassium salt of compound IB-Ll-1.1.
  • Figure 9 shows an illustrative PXRD pattern for the monodiethylamine salt tetrahydrate of compound IB-Ll-1.1.
  • Figure 10 shows an illustrative TGA profile of the monodiethylamine salt tetrahydrate of compound IB-Ll-1.1.
  • Figure 11 shows an illustrative PXRD pattern for the pattern A polymorph of compound IB-Ll- 1.1.
  • Figure 12 shows an illustrative DSC profile of the pattern A polymorph of compound EB-Ll-1.1.
  • Figure 13 shows an illustrative PXRD pattern for the pattern B polymorph of compound IB-Ll- 1.1.
  • Figure 14 shows an illustrative PXRD pattern for the pattern C polymorph of compound EB-Ll- 1.1.
  • Figure 15 shows an illustrative PXRD pattern for the pattern D polymorph of compound IB-Ll- 1.1.
  • Figure 16 shows an illustrative PXRD pattern for the pattern A hydrate of compound IB-Ll-1.1.
  • Figure 17 shows an illustrative TGA profile of the pattern A hydrate of compound IB-Ll-1.1.
  • Figure 18 shows an illustrative PXRD pattern for the pattern B hydrate of compound IB-Ll-1.1.
  • Figure 19 shows an illustrative TGA profile of the pattern B hydrate of compound IB-Ll-1.1.
  • Figure 20 shows an illustrative PXRD pattern for the pattern C hydrate of compound IB-Ll-1.1.
  • Figure 21 shows an illustrative TGA profile of the pattern C hydrate of compound IB-Ll-1.1.
  • Figure 22 shows an illustrative PXRD pattern for the pattern D hydrate of compound EB-Ll-1.1.
  • Figure 23 shows an illustrative PXRD pattern for the pattern E hydrate of compound IB-Ll-1.1.
  • alkyl (alone or in combination with another term(s)) means a straight-or branched- chain saturated hydrocarbyl substituent typically containing from 1 to about 20 carbon atoms, more typically from 1 to about 8 carbon atoms, and even more typically from 1 to about 6 carbon atoms.
  • substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, pentyl, iso-amyl, and hexyl.
  • alkenyl (alone or in combination with another term(s)) means a straight- or branched- chain hydrocarbyl substituent containing one or more double bonds and typically from 2 to about 20 carbon atoms, more typically from about 2 to about 8 carbon atoms, and even more typically from about 2 to about 6 carbon atoms.
  • substituents examples include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1 ,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, and 3-butenyl.
  • alkynyl (alone or in combination with another term(s)) means a straight- or branched- chain hydrocarbyl substituent containing one or more triple bonds and typically from 2 to about 20 carbon atoms, more typically from about 2 to about 8 carbon atoms, and even more typically from about 2 to about 6 carbon atoms.
  • substituents include ethynyl, 2-propynyl, 3-propynyl, 2-butynyl, and 3-butynyl.
  • carbocyclyl (alone or in combination with another term(s)) means a saturated cyclic (i.e., “cycloalkyl"), partially saturated cyclic (i.e., “cycloalkenyl”), or completely unsaturated (i.e., "aryl”) hydrocarbyl substituent containing from 3 to 14 carbon ring atoms ("ring atoms” are the atoms bound together to form the ring or rings of a cyclic substituent).
  • a carbocyclyl may be a single ring, which typically contains from 3 to 6 ring atoms.
  • Examples of such single-ring carbocyclyls include cyclopropyl (cyclopropanyl), cyclobutyl (cyclobutanyl), cyclopentyl (cyclopentanyl), cyclopentenyl, cyclopentadienyl, cyclohexyl (cyclohexanyl), cyclohexenyl, cyclohexadienyl, and phenyl.
  • a carbocyclyl alternatively may be 2 or 3 rings fused together, such as naphthalenyl, tetrahydronaphthalenyl (tetralinyl), indenyl, indanyl (dihydroindenyl), anthracenyl, phenanthrenyl, and decalinyl.
  • cycloalkyl (alone or in combination with another term(s)) means a saturated cyclic hydrocarbyl substituent containing from 3 to 14 carbon ring atoms.
  • a cycloalkyl may be a single carbon ring, which typically contains from 3 to 6 carbon ring atoms. Examples of single-ring cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • a cycloalkyl alternatively may be 2 or 3 carbon rings fused together, such as, decalinyl.
  • aryl (alone or in combination with another term(s)) means an aromatic carbocyclyl containing from 6 to 14 carbon ring atoms. Examples of aryls include phenyl, naphthalenyl, and indenyl.
  • the number of carbon atoms in a hydrocarbyl substituent is indicated by the prefix “C x -C y -", wherein x is the minimum and y is the maximum number of carbon atoms in the substituent.
  • C x -C y - refers to an alkyl substituent containing from 1 to 6 carbon atoms.
  • Cs-C ⁇ -cycloalkyl means a saturated hydrocarbyl ring containing from 3 to 6 carbon ring atoms.
  • hydrogen (alone or in combination with another term(s)) means a hydrogen radical, and may be depicted as -H.
  • hydroxy (alone or in combination with another term(s)) means -OH.
  • nitro (alone or in combination with another term(s)) means -NO 2 .
  • cyano (alone or in combination with another term(s)) means -CN, which also may be depicted as -C ⁇ N.
  • amino (alone or in combination with another term(s)) means -NH 2 .
  • halogen or "halo" (alone or in combination with another term(s)) means a fluorine radical (which may be depicted as -F), chlorine radical (which may be depicted as -Cl), bromine radical
  • a substituent is "substitutable" if it comprises at least one carbon or nitrogen atom that is bonded to one or more hydrogen atoms.
  • hydrogen, halogen, and cyano do not fall within this definition.
  • a sulfur atom in a heterocyclyl containing such atom is substitutable with one or two oxo substituents.
  • a non-hydrogen radical is in the place of hydrogen radical on a carbon or nitrogen of the substituent.
  • a substituted alkyl substituent is an alkyl substituent in which at least one non-hydrogen radical is in the place of a hydrogen radical on the alkyl substituent.
  • monofluoroalkyl is alkyl substituted with a fluoro radical
  • difluoroalkyl is alkyl substituted with two fluoro radicals. It should be recognized that if there are more than one substitution on a substituent, each non-hydrogen radical may be identical or different (unless otherwise stated).
  • a substituent is described as being “optionally substituted", the substituent may be either (1) not substituted or (2) substituted. If a substituent is described as being optionally substituted with up to a particular number of non-hydrogen radicals, that substituent may be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen radicals or by up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for example, if a substituent is described as a heteroaryl optionally substituted with up to 3 non-hydrogen radicals, then any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non- hydrogen radicals as the heteroaryl has substitutable positions.
  • tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non-hydrogen radical.
  • an amino nitrogen is described as being optionally substituted with up to 2 non- hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to 2 non- hydrogen radicals, whereas a secondary amino nitrogen will be optionally substituted with up to only 1 non-hydrogen radical.
  • haloalkyl means an alkyl substituent in which at least one hydrogen radical is replaced with a halogen radical.
  • haloalkyls include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1,1,1-trifluoroethyl. It should be recognized that if a substituent is substituted by more than one halogen radical, those halogen radicals may be identical or different (unless otherwise stated).
  • the prefix "perhalo" indicates that every hydrogen radical on the substituent to which the prefix is attached is replaced with independently selected halogen radicals, i.e., each hydrogen radical on the substituent is replaced with a halogen radical. If all the halogen radicals are identical, the prefix typically will identify the halogen radical. Thus, for example, the term “perfluoro” means that every hydrogen radical on the substituent to which the prefix is attached is substituted with a fluorine radical. To illustrate, the term “perfluoroalkyl” means an alkyl substituent wherein a fluorine radical is in the place of each hydrogen radical.
  • carbonyl (alone or in combination with another term(s)) means -C(O)-.
  • aminocarbonyl (alone or in combination with another term(s)) means -C(O)-NH 2 .
  • oxy (alone or in combination with another term(s)) means an ether substituent, and may be depicted as -O- .
  • alkoxy (alone or in combination with another term(s)) means an alkylether substituent, i.e., -O-alkyl.
  • alkylether substituent i.e., -O-alkyl.
  • substituents include methoxy (-0-CH 3 ), ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.
  • alkylcarbonyl (alone or in combination with another term(s)) means -C(O)-alkyl.
  • aminoalkylcarbonyl (alone or in combination with another term(s)) means -C(O)- alkyl-NH 2 .
  • alkoxycarbonyl (alone or in combination with another term(s)) means -C(O)-O-alkyl.
  • Carbocyclylcarbonyl (alone or in combination with another term(s)) means -C(O)- carbocyclyl.
  • heterocyclylcarbonyl (alone or in combination with another term(s)) means
  • heterocyclylalkylcarbonyl (alone or in combination with another term(s)) means -C(O)-alkyl-heterocyclyl.
  • thio or "thia” (alone or in combination with another term(s)) means a thiaether substituent, i.e., an ether substituent wherein a divalent sulfur atom is in the place of the ether oxygen atom. Such a substituent may be depicted as -S-.
  • alkyl-thio-alkyl means alkyl-S- alkyl (alkyl-sulfanyl-alkyl).
  • thiol or "sulfhydryl” (alone or in combination with another term(s)) means a sulfhydryl substituent, and may be depicted as -SH.
  • (thiocarbonyl) (alone or in combination with another term(s)) means a carbonyl wherein the oxygen atom has been replaced with a sulfur. Such a substituent may be depicted as -C(S)-.
  • sulfonyl (alone or in combination with another term(s)) means -S(O) 2 -.
  • aminosulfonyl (alone or in combination with another term(s)) means -S(O) 2 -NH 2 .
  • heterocyclyl (alone or in combination with another term(s)) means a saturated (i.e.,
  • heterocycloalkyl partially saturated (i.e., “heterocycloalkenyl”), or completely unsaturated (i.e., “heteroaryl”) ring structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
  • heteroatom i.e., oxygen, nitrogen, or sulfur
  • a heterocyclyl may be a single ring, which typically contains from 3 to 7 ring atoms, more typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms.
  • single-ring heterocyclyls include furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl (thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, oxazolyl, oxazolidinyl, isoxazolidinyl, isoxazolidinyl, isoxazolidinyl, isoxazolyl, thiazolyl, isothi
  • a heterocyclyl alternatively may be 2 or 3 rings fused together, such as, for example, indolizinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl (including pyrido[3,4-b]- pyridinyl, pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl.
  • indolizinyl pyranopyrrolyl
  • 4H-quinolizinyl purinyl
  • naphthyridinyl pyridopyridinyl (including pyrido[3,4-b]- pyridinyl, pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl)
  • fused- ring heterocyclyls include benzo-fused heterocyclyls, such as indolyl, isoindolyl (isobenzazolyl, pseudoisoindolyl), indoleninyl (pseudoindolyl), isoindazolyl (benzpyrazolyl), benzazinyl (including quinolinyl (1 -benzazinyl) or isoquinolinyl (2-benzazinyl)), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (1,2-benzodiazinyl) or quinazolinyl (1,3-benzodiazinyl)), benzopyranyl (including chromanyl or isochromanyl), benzoxazinyl (including 1,3,2-benzoxazinyl, 1,4,2- benzoxazinyl, 2,3,1 -benzoxazinyl,
  • 2-fused ring heterocyclyl (alone or in combination with another term(s)) means a saturated, partially saturated, or aryl heterocyclyl containing 2 fused rings.
  • 2-fused-ring heterocyclyls include indolizinyl, quinolizinyl, purinyl, naphthyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotri
  • heteroaryl (alone or in combination with another term(s)) means an aromatic heterocyclyl containing from 5 to 14 ring atoms.
  • a heteroaryl may be a single ring or 2 or 3 fused rings.
  • heteroaryl substituents include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, pyridazinyl, and 1,3,5-, 1,2,4- or 1,2,3-triazinyl; 5-membered ring substituents such as imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4- oxadiazolyl and isothiazolyl; 6/5-membered fused ring substituents such as benzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-membered fused rings such as benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolin
  • alkylcycloalkyl contains two components: alkyl and cycloalkyl.
  • Q-C6- prefix on Q-C ⁇ -alkylcycloalkyl means that the alkyl component of the alkylcycloalkyl contains from 1 to
  • haloalkoxyalkyl indicates that only the alkoxy component of the alkoxyalkyl substituent is substituted with one or more halogen radicals. If halogen substitution may alternatively or additionally occur on the alkyl component, the substituent would instead be described as "halogen-substituted alkoxyalkyl” rather than "haloalkoxyalkyl.” And finally, if the halogen substitution may only occur on the alkyl component, the substituent would instead be described as "alkoxyhaloalkyl.”
  • the rightmost-described component of the substituent is the component that has the free valence.
  • the leftmost dash of the substituent indicates the portion of the substituent that is bound to the left element in the depicted structure.
  • the rightmost dash indicates the portion of the substituent that is bound to the right element in the depicted structure.
  • ChemDraw software has been used to generate the compound names in this patent application.
  • amorphous refers to a solid-state in which the compound molecules are present in a disordered arrangement and do not form a distinguishable crystal lattice or unit cell. When subjected to X-ray powder diffraction, an amorphous compound does not produce any characteristic crystalline peaks.
  • crystalline form refers to a solid-state in which the compound molecules are arranged to form a distinguishable crystal lattice (i) comprising distinguishable unit cells, and (ii) yielding diffraction pattern peaks when subjected to X-ray radiation.
  • purity means the chemical purity of a compound according to conventional HPLC assay.
  • phase purity means the solid-state purity of a compound with regard to a particular crystalline or amorphous form of the compound as determined by X-ray powder diffraction analytical methods.
  • phase pure refers to purity with respect to other solid-state forms of the compound, and does not necessarily imply a high degree of chemical purity with respect to other compounds.
  • PXRD means X-ray powder diffraction
  • thermogravimetric analysis means thermogravimetric analysis.
  • DSC differential scanning calorimetry
  • This invention is directed, in part, to compounds that are phenyl-uracil derivatives that correspond in structure to formula I:
  • the compounds of formula I correspond in structure to the following formula (i.e., formula IB):
  • R 1 is selected from the group consisting of hydrogen, methyl, and nitrogen-protecting group. [00108] In some embodiments, R 1 is hydrogen. [00109] In some embodiments, R 1 is methyl.
  • R 1 is selected from the group consisting of hydrogen and methyl.
  • R 1 is a nitrogen-protecting group.
  • the compounds are useful as intermediates for the preparation of compounds of formula I. Nitrogen-protecting groups suitable for preparing compounds of formula I are known to those skilled in the art.
  • R 2 is selected from the group consisting of hydrogen, halo, hydroxy, methyl, cyclopropyl, and cyclobutyl.
  • R 2 is hydrogen
  • R 2 is halo. In some such embodiments, R 2 is selected from the group consisting of fluoro and chloro. In other such embodiments, R 2 is fluoro. In yet other such embodiments, R 2 is chloro. In yet other such embodiments, R 2 is bromo. In further such embodiments, R 2 is iodo. [00115] In some embodiments, R 2 is hydroxy. [00116] In some embodiments, R 2 is methyl.
  • R 2 is cyclopropyl
  • R 2 is cyclobutyl
  • R 2 is selected from the group consisting of hydrogen, methyl, hydroxy, and halo. In some such embodiments, R 2 is selected from the group consisting of hydrogen, methyl, hydroxy, fluoro, and chloro. In other such embodiments, R 2 is selected from the group consisting of hydrogen, methyl, hydroxy, and fluoro. In yet other such embodiments, R 2 is selected from the group consisting of hydrogen, methyl, hydroxy, and chloro. In yet other such embodiments, R 2 is selected from the group consisting of hydrogen, methyl, hydroxy, and bromo. In further such embodiments, R 2 is selected from the group consisting of hydrogen, methyl, hydroxy, and iodo.
  • R 2 is selected from the group consisting of hydrogen, methyl, and halo. In some such embodiments, R 2 is selected from the group consisting of hydrogen, methyl, fluoro, and chloro. In other such embodiments, R 2 is selected from the group consisting of hydrogen, methyl, and fluoro. In yet other such embodiments, R 2 is selected from the group consisting of hydrogen, methyl, and chloro. In yet other such embodiments, R 2 is selected from the group consisting of hydrogen, methyl, and bromo. In further such embodiments, R 2 is selected from the group consisting of hydrogen, methyl, and iodo.
  • R 2 is selected from the group consisting of hydrogen and halo. In some such embodiments, R 2 is selected from the group consisting of hydrogen, fluoro, and chloro. In other such embodiments, R 2 is selected from the group consisting of hydrogen and fluoro. In yet other such embodiments, R 2 is selected from the group consisting of hydrogen and chloro. In yet other such embodiments, R 2 is selected from the group consisting of hydrogen and bromo. In further such embodiments, R 2 is selected from the group consisting of hydrogen and iodo.
  • R 3 is selected from the group consisting of hydrogen, halo, oxo, and methyl. In some such embodiments, R 3 is selected from the group consisting of hydrogen, fluoro, oxo, and methyl. In other such embodiments, R 3 is selected from the group consisting of hydrogen, chloro, oxo, and methyl. In yet other such embodiments, R 3 is selected from the group consisting of hydrogen, bromo, oxo, and methyl. In yet other such embodiments, R 3 is selected from the group consisting of hydrogen, iodo, oxo, and methyl.
  • R 3 is selected from the group consisting of hydrogen, halo, and oxo. In some such embodiments, R 3 is selected from the group consisting of hydrogen, fluoro, and oxo. In other such embodiments, R 3 is selected from the group consisting of hydrogen, chloro, and oxo. In yet other such embodiments, R 3 is selected from the group consisting of hydrogen, bromo, and oxo. In yet other such embodiments, R 3 is selected from the group consisting of hydrogen, iodo, and oxo.
  • R 3 is selected from the group consisting of hydrogen and methyl.
  • R 3 is hydrogen
  • R 3 is methyl
  • R 3 is oxo
  • R 3 is halo. In some such embodiments, R 3 is fluoro. In other such embodiments, R 3 is chloro. In yet other such embodiments, R 3 is bromo. In further such embodiments,
  • R 3 is iodo.
  • R 4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein:
  • the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, and alkylsulfonyl optionally are substituted with one or more substituents independently selected from the group consisting of halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl, and heterocyclyl, wherein: the amino optionally is substituted with:
  • substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl, or
  • the carbocyclyl and heterocyclyl optionally are substituted with up to three substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl, and heterocyclyl, wherein: the amino optionally is substituted with:
  • substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl, or
  • R 4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein: the amino, aminocarbonyl, and aminosulfonyl optionally are substituted with:
  • R 4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein: the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, and alkylsulfonyl, optionally are substituted with one or more substituents independently selected from the group consisting of halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl, and heterocyclyl, wherein: the amino optionally is substituted with:
  • substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl, or
  • R 4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein: the carbocyclyl and heterocyclyl optionally are substituted with up to three substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl, and heterocyclyl, wherein: the amino optionally is substituted with: (1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, carbocycl
  • R 4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein:
  • the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyl, carbocyclyl, and heterocyclyl optionally are substituted with up to three substituents independently selected from the group consisting of halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, carbocyclyl, and heterocyclyl, wherein the amino optionally is substituted with:
  • substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl, or,
  • R 4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein: the amino, aminocarbonyl, and aminosulfonyl optionally are substituted with:
  • R 4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein: the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyl, carbocyclyl, and heterocyclyl optionally are substituted with up to three substituents independently selected from the group consisting of halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, carbocyclyl, and heterocyclyl, wherein the amino optionally is substituted with:
  • substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl, or,
  • R 4 is selected from the group consisting of halo, Ci-Q-alkyl, C 2 -C 4 - alkenyl, C 2 -C 4 -alkynyl, amino, C]-C 4 -alkylsulfonyl, C 3 -C 6 -carbocyclyl, and 5-6-membered heterocyclyl, wherein:
  • amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl,
  • Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, and C 2 -C 4 -alkynyl optionally are substituted with one or more substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and
  • the C 3 -C6-carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with up to three substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, and amino, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl.
  • R 4 is selected from the group consisting of Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 - C 4 -alkynyl, amino, Q-G t -alkylsulfonyl, C 3 -C 6 -carbocyclyl, and 5-6-membered heterocyclyl, wherein:
  • amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl,
  • Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, and C 2 -C 4 -alkynyl optionally are substituted with one or more substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and
  • R 4 is selected from the group consisting of halo, C r C 4 -alkyl, C 3 -C 6 - carbocyclyl, and 5-6-membered heterocyclyl, wherein:
  • the C r C 4 -alkyl optionally is substituted with up to three substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and
  • the C 3 -C 6 -carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, halo, and alkylsulfonylamino.
  • R 4 is selected from the group consisting of halo, Ci-C 4 -alkyl, C 3 -C 6 - carbocyclyl, and 5-6-membered heterocyclyl, wherein:
  • Ci-C 4 -alkyl optionally is substituted with one or two substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and
  • the C 3 -C 6 -carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with a substituent selected from the group consisting of alkyl, halo, and alkylsulfonylamino.
  • R 4 is selected from the group consisting of Ci-C 4 -alkyl, C 3 -C 6 - carbocyclyl, and 5-6-membered heterocyclyl, wherein:
  • Ci-C 4 -alkyl optionally is substituted with up to three substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and
  • the C 3 -C 6 -carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, halo, and alkylsulfonylamino .
  • R 4 is selected from the group consisting of halo, tert-butyl, C 3 -C 6 - carbocyclyl, and 5-6-membered heterocyclyl, wherein: the C 3 -C 6 -carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with a substituent selected from the group consisting of alkyl, halo, and alkylsulfonylamino.
  • R 4 is selected from the group consisting of tert-butyl, C 3 -C 6 -carbocyclyl, and 5-6-membered heterocyclyl, wherein: the C 3 -C 6 -carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with a substituent selected from the group consisting of alkyl, halo, and alkylsulfonylamino.
  • R 4 is selected from the group consisting of halo, alkyl, haloalkyl, carboxyalkyl, hydroxyalkyl, alkyloxyalkyl, trimethylsilylalkynyl, alkylcarbocyclyl, carbocyclyl, alkylheterocyclyl, heterocyclyl, halocarbocyclyl, alkylsulfonylamino, and alkylsulfonyl.
  • R 4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl.
  • R 4 is selected from the group consisting of halo, Ci-C 4 -alkyl, C 2 -C 4 - alkenyl, C 2 -C 4 -alkynyl, amino, Ci-C 4 -alkylsulfonyl, C 3 -C 6 -carbocyclyl, and 5-6-membered heterocyclyl.
  • R 4 is selected from the group consisting of halo, Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, amino, Q-Q-alkylsulfonyl, C 6 -carbocyclyl, and 5-6-membered heterocyclyl.
  • R 4 is selected from the group consisting of halo, C r C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 - alkynyl, amino, C]-C 4 -alkylsulfonyl, phenyl, and 5-6-membered heteroaryl.
  • R 4 is selected from the group consisting of CpC 4 -alkyl, C 2 -C 4 -alkenyl, C 2 - C 4 -alkynyl, amino, C r C 4 -alkylsulfonyl, C 3 -C 6 -carbocyclyl, and 5-6-membered heterocyclyl.
  • R 4 is selected from the group consisting of C]-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, amino, Q-Q-alkylsulfonyl, C 6 -carbocyclyl, and 5-6-membered heterocyclyl.
  • R 4 is selected from the group consisting of C r C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, amino, C t -C 4 - alkylsulfonyl, phenyl, and 5-6-membered heteroaryl.
  • R 4 is selected from the group consisting of halo, Ci-C 4 -alkyl, C 3 -C 6 - carbocyclyl, and 5-6-membered heterocyclyl. In some such embodiments, R 4 is selected from the group consisting of halo, C]-C 4 -alkyl, C 6 -carbocyclyl, and 5-6-membered heterocyclyl. In other such embodiments, R 4 is selected from the group consisting of halo, Ci-C 4 -alkyl, phenyl, and 5-6-membered heteroaryl.
  • R 4 is selected from the group consisting of Ci-C 4 -alkyl, C 3 -C 6 - carbocyclyl, and 5-6-membered heterocyclyl. In some such embodiments, R 4 is selected from the group consisting of C r C 4 -alkyl, C 6 -carbocyclyl, and 5-6-membered heterocyclyl. In other such embodiments, R 4 is selected from the group consisting of Q-Q-alkyl, phenyl, and 5-6-membered heteroaryl.
  • R 4 is selected from the group consisting of halo, tert-butyl, C 3 -C 6 - carbocyclyl, and 5-6-membered heterocyclyl. In some such embodiments, R 4 is selected from the group consisting of halo, tert-butyl, C 6 -carbocyclyl, and 5-6-membered heterocyclyl. In other such embodiments, R 4 is selected from the group consisting of halo, tert-butyl, phenyl, and 5-6-membered heteroaryl.
  • R 4 is selected from the group consisting of tert-butyl, C 3 -C 6 -carbocyclyl, and 5-6-membered heterocyclyl. In some such embodiments, R 4 is selected from the group consisting of tert-butyl, C 6 -carbocyclyl, and 5-6-membered heterocyclyl. In other such embodiments, R 4 is selected from the group consisting of tert-butyl, phenyl, and 5-6-membered heteroaryl. [00151] In some embodiments, R 4 is selected from the group consisting of C 3 -C 6 -carbocyclyl and 5-6- membered heterocyclyl.
  • R 4 is selected from the group consisting of C 6 - carbocyclyl, and 5-6-membered heterocyclyl. In other such embodiments, R 4 is selected from the group consisting of phenyl and 5-6-membered heteroaryl.
  • Suitable carbocyclyls for the above embodiments include, for example, cyclopropyl and phenyl.
  • Suitable heterocyclyls for the above embodiments include, for example, furanyl, thienyl, and pyridinyl.
  • R 4 is selected from the group consisting of halo, alkyl, and alkyloxy.
  • R 4 is alkyl
  • R 4 is tert-butyl
  • R 5 is selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, carbocyclylsulfonyloxy, haloalkylsulfonyloxy, and halo.
  • R 5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy, and halo.
  • R 5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy, and fluoro.
  • R 5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy, and fluoro.
  • R 5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy, and chloro.
  • R 5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy, and bromo.
  • R 5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy, and iodo.
  • R 5 is selected from the group consisting of hydrogen, hydroxy, methoxy, and halo. In some such embodiments, R 5 is selected from the group consisting of hydrogen, hydroxy, methoxy, and fluoro. In other such embodiments, R 5 is selected from the group consisting of hydrogen, hydroxy, methoxy, and chloro. In yet other such embodiments, R 5 is selected from the group consisting of hydrogen, hydroxy, methoxy, and bromo. In further such embodiments, R 5 is selected from the group consisting of hydrogen, hydroxy, methoxy, and iodo.
  • R 5 is selected from the group consisting of hydrogen, hydroxy, and alkyloxy. hi some such embodiments, R 5 is selected from the group consisting of hydrogen, hydroxy, methoxy, and ethoxy.
  • R 5 is s hydrogen. [00162] In some embodiments, R 5 is hydroxy. [00163] In some embodiments, R 5 is alkyloxy. [00164] In some embodiments, R 5 is methoxy. [00165] hi some embodiments, R 5 is ethoxy.
  • the compounds correspond in structure to formula IA-Ll:
  • the compounds correspond in structure to formula IB-Ll:
  • the compounds of formula I-Ll are more potent if R 6 and the phenyl-uracil are on opposite sides of the double bond (i.e., in trans configuration in relation to the double bond).
  • L is ethylene.
  • the compounds of formula I correspond in structure to I-L5-2:
  • the compounds correspond in structure to formula IA-L5-2:
  • L is cyclopropyl-l,2-ene.
  • the compounds of formula I correspond in structure to formula I-L8:
  • the compounds correspond in structure to formula IA-L8:
  • the compounds correspond in structure to formula IB-L8:
  • R A and R B are independently selected from the group consisting of hydrogen, Ci-C 6 -alkyl, Q- C 6 -alkyloxy, C 3 -Cg-cycloalkyl, and halo, wherein: the Ci-C 6 -alkyl optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, halo, hydroxy, nitro, oxo, amino, cyano, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, and heterocyclyl.
  • one of R A and R B is hydrogen, and the other is selected from the group consisting of C]-C 6 -alkyl, C]-C 6 -alkyloxy, C 3 -C 8 -cycloalkyl, and halo, wherein: the Ci-C ⁇ -alkyl optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, halo, hydroxy, nitro, oxo, amino, cyano, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, and heterocyclyl.
  • R A and R B are independently selected from the group consisting of hydrogen, Ci-C 6 -alkyl, Ci-C 6 -alkyloxy, C 3 -C 8 -cycloalkyl, and halo.
  • R A is hydrogen. In other of the above embodiments, R B is hydrogen.
  • one of R A and R B is hydrogen, and the other is selected from the group consisting of hydrogen, methyl, methoxy, and halo.
  • R A is hydrogen
  • R B is selected from the group consisting of methyl, methoxy, and halo
  • R B is selected from the group consisting of methyl, methoxy, and fluoro.
  • R B is selected from the group consisting of methyl, methoxy, and chloro.
  • R B is selected from the group consisting of methyl, methoxy, and bromo.
  • R B is selected from the group consisting of methyl, methoxy, and iodo.
  • R B is selected from the group consisting of methyl, methoxy, chloro, and fluoro.
  • R B is hydrogen, and R A is selected from the group consisting of methyl, methoxy, and halo.
  • R A is selected from the group consisting of methyl, methoxy, and fluoro.
  • R A is selected from the group consisting of methyl, methoxy, and chloro.
  • R A is selected from the group consisting of methyl, methoxy, and bromo.
  • R A is selected from the group consisting of methyl, methoxy, and iodo.
  • R A is selected from the group consisting of methyl, methoxy, chloro, and fluoro.
  • R A is hydrogen, and R B is hydrogen.
  • R 6 is selected from the group consisting of C 5 -C 6 -carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl, wherein each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ , wherein R E , R F , R G , R H , R 1 , R J , and R ⁇ are as described below.
  • the C 5 -C 6 -carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are not substituted, hi other such embodiments, the C 5 -C 6 -carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with a substituent selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the C 5 -C 6 -carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with a substituent selected from the group consisting of R E , R F , R 1 , R J , and R ⁇ .
  • the C 5 -C 6 -carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with a substituent selected from the group consisting of R E , R F , and R J .
  • the C 5 -C6-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with a substituent selected from the group consisting of R F and R J .
  • the C 5 -C 6 -carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with R J .
  • the C 5 -C 6 -carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2- ring heterocyclyl are substituted with two substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the C 5 -C 6 -carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with two substituents independently selected from the group consisting of R E , R F , R 1 , R J , and R ⁇ .
  • the C 5 -C 6 -carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2- ring heterocyclyl are substituted with two substituents independently selected from the group consisting of R E , R F , and R J .
  • the C 5 -C 6 -carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with two substituents independently selected from the group consisting of R F and R J .
  • the C 5 -C 6 - carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with three substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the C 5 -C 6 -carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with three substituents independently selected from the group consisting of R E , R F , R 1 , R J , and R ⁇ .
  • the C 5 -C 6 - carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with three substituents independently selected from the group consisting of R E , R F , and R J .
  • the C 5 -C 6 -carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with three substituents independently selected from the group consisting of R F and R J .
  • the C 5 -C 6 -carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with one, two, or three substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the C 5 -C 6 -carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with one, two, or three substituents independently selected from the group consisting of R E , R F , R 1 , R J , and R ⁇ .
  • the C 5 -C 6 - carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with one, two, or three substituents independently selected from the group consisting of R E , R F , and R J .
  • the C 5 -C 6 -carbocyclyl, 5-6-membered heterocyclyl, fused 2- ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with one, two, or three substituents independently selected from the group consisting of R F and R J .
  • R 6 is selected from the group consisting of C 5 -C 6 -carbocyclyl and 5-6- membered heterocyclyl, wherein each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the C 5 -C 6 -carbocyclyl and 5-6-membered heterocyclyl are not substituted.
  • the C 5 -C 6 -carbocyclyl and 5-6-membered heterocyclyl are substituted with a substituent selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the C 5 -C 6 -carbocyclyl and 5-6-membered heterocyclyl are substituted with two substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the C 5 -C 6 -carbocyclyl and 5-6-membered heterocyclyl are substituted with three substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the C 5 -C 6 -carbocyclyl and 5-6-membered heterocyclyl are substituted with one, two, or three substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • R 6 is C 5 -C 6 -carbocyclyl optionally substituted with one or more substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the C 5 -C 6 -carbocyclyl is not substituted.
  • the C 5 -C 6 - carbocyclyl is substituted with a substituent selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the C 5 -C 6 -carbocyclyl is substituted with two substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the C 5 -C 6 -carbocyclyl is substituted with three substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the C 5 -C 6 -carbocyclyl is substituted with one, two, or three substituents independently selected from the group consisting of R E , R r , R G , R H , R 1 , R J , and R ⁇ .
  • R 6 is 5-6-membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the 5-6-membered heterocyclyl is not substituted.
  • the 5-6-membered heterocyclyl is substituted with a substituent selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the 5-6-membered heterocyclyl is substituted with two substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the 5-6-membered heterocyclyl is substituted with three substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the 5-6-membered heterocyclyl is substituted with one, two, or three substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • R 6 is selected from the group consisting of fused 2-ring carbocyclyl and fused 2-ring heterocyclyl, wherein each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the fused 2-ring carbocyclyl and fused 2-ring heterocyclyl are not substituted.
  • the fused 2-ring carbocyclyl and fused 2-ring heterocyclyl are substituted with a substituent selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the fused 2-ring carbocyclyl and fused 2-ring heterocyclyl are substituted with two substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the fused 2-ring carbocyclyl and fused 2-ring heterocyclyl are substituted with three substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the fused 2-ring carbocyclyl and fused 2-ring heterocyclyl are substituted with one, two, or three substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • R 6 is fused 2-ring carbocyclyl optionally substituted with one or more substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the fused 2-ring carbocyclyl is not substituted.
  • the fused 2-ring carbocyclyl is substituted with a substituent selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the fused 2-ring carbocyclyl is substituted with two substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ . In further such embodiments, the fused 2-ring carbocyclyl is substituted with three substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ . In further such embodiments, the fused 2-ring carbocyclyl is substituted with one, two, or three substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • R 6 is fused 2-ring heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the fused 2-ring heterocyclyl is not substituted.
  • the fused 2-ring heterocyclyl is substituted with a substituent selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the fused 2-ring heterocyclyl is substituted with two substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the fused 2-ring heterocyclyl is substituted with three substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the fused 2-ring heterocyclyl is substituted with one, two, or three substituents independently selected from the group consisting of R E , R F , R G , R H , R 1 , R J , and R ⁇ .
  • the optionally substituted Cs-C ⁇ -carbocyclyl is selected from the group consisting of cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl.
  • the optionally substituted C 5 -C 6 -carbocyclyl is phenyl.
  • the optionally substituted C 5 -C 6 -carbocyclyl is C 5 - carbocyclyl.
  • Examples of C 5 -carbocyclyls include cyclopentyl, cyclopentenyl, and cyclopentadienyl.
  • the optionally substituted C 5 -C 6 -carbocyclyl is C 6 - carbocyclyl.
  • Examples of C ⁇ -carbocyclyls include cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl.
  • the optionally substituted 5-6-membered-heterocyclyl is selected from the group consisting of furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl (thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, dihydrooxazolyl, isoxazolyl, dihydroisoxazolyl, oxazolidinyl, isoxazolidinyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxathioly
  • the optionally substituted 5-6-membered-heterocyclyl is 5- membered heterocyclyl.
  • 5-membered heterocyclyl include furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl (thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, dihydrooxazolyl, isoxazolyl, dihydroisoxazolyl, oxazolidinyl, isoxazolidinyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolinyl,
  • the optionally substituted 5-6-membered-heterocyclyl is 6- membered heterocyclyl.
  • 6-membered heterocyclyls include pyranyl, dihydropyranyl, tetrahydropyranyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl, diazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, dihydropyrazinyl, tetrahydropyrazinyl, piperazinyl, triazinyl, dihydrotriazinyl, tetrahydrotriazinyl, triazinanyl, oxazinyl, dihydrooxazinyl, morpholinyl, oxathiazinyl, dihydrooxathiazinyl, oxathiazinanyl, o
  • the optionally substituted fused 2-ring carbocyclyl is selected from the group consisting of naphthalenyl, dihydronaphthalenyl, tetrahydronaphthalenyl, hexahydronaphthalenyl, octahydronaphthalenyl, decahydronaphthalenyl, indenyl, dihydroindenyl, hexahydroindenyl, octahydroindenyl, pentalenyl, octahydropentalenyl, and hexahydropentalenyl.
  • the optionally substituted fused 2-ring carbocyclyl is selected from the group consisting of naphthalenyl and dihydroindenyl. In some such embodiments, the optionally substituted fused 2-ring carbocyclyl is naphthalenyl. In other such embodiments, the optionally substituted fused 2- ring carbocyclyl is dihydroindenyl. In further such embodiments, the optionally substituted fused 2-ring carbocyclyl is indenyl.
  • the optionally substituted fused 2-ring heterocyclyl is selected from the group consisting of
  • X 1 , X 2 , and X 3 are independently selected from the group consisting of N and C(H);
  • X 4 is selected from the group consisting of N(H), O, and S;
  • X 5 , X 6 , and X 7 are independently selected from the group consisting of N and C(H);
  • X 8 is selected from the group consisting of N(H), O, and S;
  • X 9 is selected from the group consisting of N(H), O, and S;
  • X 10 , X 11 , X 12 , and X 13 are independently selected from the group consisting of N and C(H);
  • X 14 is selected from the group consisting of N(H), O, and S;
  • X 15 , X 16 , X 17 , and X 18 are independently selected from the group consisting of N and C(H); one or more of X 19 , X 20 , and X 21 is N, and the remaining one(s) is/are C(H); one or more of X 22 , X 23 , X 24 , and X 25 is N, and the remaining one(s) is/are C(H); one or more of X 26 , X 27 , and X 28 is N, and the remaining one(s) is/are C(H); one or more of X 29 , X 30 , X 31 , and X 32 is N, and the remaining one(s) is/are C(H); one or more of X 33 , X 34 , and X 35 is N, and the remaining one(s) is/are C(H); one or more of X 36 , X 37 , X 38 , and X 39 is N, and the remaining one(s) is/
  • X 40 , X 41 , and X 42 are independently selected from the group consisting of N and C(H); one of X 43 , X 44 , and X 45 is selected from the group consisting of N(H), O, and S, and the remaining two are C(H) 2 ; one of X 46 and X 47 is selected from the group consisting of N(H), O, and S, and the other one is C(H) 2 ;
  • X 48 , X 49 , X 50 , and X 51 are independently selected from the group consisting of N and C(H);
  • X 52 , X 53 , and X 54 are independently selected from the group consisting of N and C(H);
  • X 55 is selected from the group consisting of N(H), O, and S;
  • X 56 , X 57 , and X 58 are independently selected from the group consisting of N and C(H);
  • X 59 is selected from the group consisting of N(H), O, and S;
  • X 60 is selected from the group consisting of N(H), O, and S;
  • X 61 , X 62 , X 63 , and X 64 are independently selected from the group consisting of N and C(H);
  • X 65 is selected from the group consisting of N(H), O, and S;
  • X 66 , X 67 , X 68 , and X 69 are independently selected from the group consisting of N and C(H); one or more of X 70 , X 71 , and X 72 is N, and the remaining one(s) is/are C(H); one or more of X 73 , X 74 , X 75 , and X 76 is N, and the remaining one(s) is/are C(H); and one of X 77 and X 78 is N(H), and the remaining one is C(H) 2 .
  • the optionally substituted fused 2-ring heterocyclyl is selected from the group consisting of
  • the optionally substituted fused 2-ring heterocyclyl is selected from the group consisting of:
  • X 1 , X 2 , and X 3 are C(H).
  • X 5 , X 6 , and X 7 are C(H).
  • X 10 , X 11 , X 12 , and X 13 are C(H).
  • X 15 , X 16 , X 17 , and X 18 are C(H).
  • one of X 19 , X 20 , and X 21 is N.
  • one of X 22 , X 23 , X 24 , and X 25 is N.
  • one of X 26 , X 27 , and X 28 is N, and one of X 29 , X 30 , X 31 , and X 32 is N.
  • X 40 , X 41 , and X 42 are C(H).
  • X 48 , X 49 , X 50 , and X 51 are C(H).
  • X 52 , X 53 , and X 54 are C(H).
  • X 56 , X 57 , and X 58 are C(H).
  • X 61 , X 62 , X 63 , and X 64 are C(H).
  • X 66 , X 67 , X 68 , and X 69 are C(H).
  • one or more of X 70 , X 71 , and X 72 is N, and the remaining one(s) is/are C(H).
  • one or more of X 73 , X 74 , X 75 , and X 76 is N, and the remaining one(s) is/are C(H).
  • Each R E is independently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, cyano, amino, imino, azido, and aldehydo, wherein the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl.
  • each R E is independently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, amino, imino, and aldehydo, wherein the amino optionally is substituted with one or two independently selected alkyl.
  • each R E is independently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, amino, imino, aldehydo, and alkylamino.
  • each R E is independently selected from the group consisting of chloro, fluoro, nitro, hydroxy, oxo, carboxy, amino, imino, aldehydo, and alkylamino.
  • each R E is independently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, cyano, amino, imino, and azido. In some such embodiments, each R E is halo. In other such embodiments, each R E is nitro. In yet other such embodiments, each R E is hydroxy. In yet other such embodiments, each R E is oxo. In yet other such embodiments, each R E is carboxy. In yet other such embodiments, each R E is cyano. In yet other such embodiments, each R E is amino. In further such embodiments, each R E is imino. In yet further such embodiments, each R E is and azido. [00222] In some embodiments, each R E is independently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, cyano, amino, and imino.
  • Each R F is independently selected from the group consisting of alkyl, alkenyl, and alkynyl, wherein: each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, imino, aminosulfonyl, aminocarbonyl, carbocyclyl, and heterocyclyl optionally are substituted with one or two substituents independently selected from the group consisting of alky
  • each R F is independently selected from the group consisting of alkyl, alkenyl, and alkynyl, wherein: each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, imino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkyl, alkenyl
  • each R F is independently selected from the group consisting of the alkyl, alkynyl, and alkynyl, wherein such substituents are not substituted.
  • each R F is independently selected from the group consisting of alkyl, alkenyl, and alkynyl, wherein: each such substituent optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, imino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkylsulf
  • each R F is an independently selected alkyl optionally substituted with a substituent selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, imino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkylsulfonyl, and alkylsulfonylamino, wherein: amino portion of the alkylsulfonylamino optionally is substituted with alkyl.
  • each R F is an independently selected alkyl optionally substituted with a substituent selected from the group consisting of carboxy, halo, amino, imino, and aminosulfonyl, wherein: the amino, imino, and aminosulfonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkylsulfonyl, and alkylsulfonylamino.
  • each R F is an independently selected alkyl optionally substituted with amino, wherein the amino optionally is substituted with alkylsulfonyl.
  • each R F is an independently selected alkyl substituted with amino, wherein the amino is substituted with alkylsulfonyl. In some such embodiments, each R F is methylsulfonylaminomethyl.
  • each R F is independently selected from the group consisting of alkyl, alkenyl, and alkynyl, wherein: each such substituent optionally is substituted with one, two, or three substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl.
  • each R F is independently selected alkyl substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl.
  • Each R G is independently selected from the group consisting of carbocyclyl and heterocyclyl, wherein: each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfon
  • each R G is independently selected from the group consisting of carbocyclyl and heterocyclyl, wherein such substituents are not substituted.
  • each R G is independently selected from the group consisting of carbocyclyl and heterocyclyl, wherein: each such substituent optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl and alkylsulfonyl.
  • the carbocyclyl is C 3 -C 6 -carbocyclyl.
  • the heterocyclyl is 5-6-membered heterocyclyl.
  • Each R H is independently selected from the group consisting of alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, alkenylsulfonyloxy, and alkynylsulfonyloxy, wherein: each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents
  • each R H is independently selected from the group consisting of alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, alkenylsulfonyloxy, and alkynylsulfonyloxy, wherein such substituents are not substituted.
  • each R H is independently selected from the group consisting of alkyloxy and alkylsulfonyloxy, wherein: each such substituent optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl and alkylsulfonyl.
  • each R H is independently selected from the group consisting of alkyloxy and alkylsulfonyloxy, wherein: each such substituent optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, cyano, and aminocarbonyl, wherein: the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl and alkylsulfonyl.
  • each R H is independently selected from the group consisting of alkyloxy and alkylsulfonyloxy, wherein: each such substituent optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, cyano, and aminocarbonyl.
  • each R H is independently selected alkyloxy. [00244] In some embodiments, each R H is independently selected alkylsulfonyloxy.
  • Each R is independently selected from the group consisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aminocarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl, and heterocyclylcarbonyl, wherein:
  • alkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl optionally are substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynylcarbonyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, and
  • the aminocarbonyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxyalkyl, carbocyclyl, heterocyclyl, alkylsulfonyl, and alkylsulfonylamino, wherein: the carbocyclyl and heterocyclyl optionally are substituted with one or two substituents independently selected from the group consisting of halo, alkyl, and oxo.
  • each R 1 is independently selected from the group consisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aminocarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl, and heterocyclylcarbonyl, wherein such substituents are not substituted. [00247] In some embodiments, each R 1 is independently selected from the group consisting of alkylcarbonyl, aminocarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl, and heterocyclylcarbonyl, wherein:
  • the alkylcarbonyl optionally is substituted with a substituent selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, and aminocarbonyl, and
  • the aminocarbonyl optionally is substituted with a substituent selected from the group consisting of alkyl, alkyloxyalkyl, alkylsulfonyl, and alkylsulfonylamino.
  • each R 1 is independently selected from the group consisting of alkylcarbonyl and aminocarbonyl, wherein: the aminocarbonyl optionally is substituted with a substituent selected from the group consisting of alkyl, alkyloxyalkyl, alkylsulfonyl, and alkylsulfonylamino.
  • each R 1 is independently selected from the group consisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, and aminocarbonyl, wherein:
  • alkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl optionally are substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynylcarbonyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, and
  • aminocarbonyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonylamino .
  • each R 1 is independently selected from the group consisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, and aminocarbonyl, wherein such substituents are not substituted.
  • each R 1 is independently selected from the group consisting of alkylcarbonyl and aminocarbonyl, wherein:
  • the alkylcarbonyl optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, and
  • each R 1 is independently selected from the group consisting of alkylcarbonyl and aminocarbonyl, wherein:
  • the alkylcarbonyl optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, cyano, and aminocarbonyl, and
  • aminocarbonyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl and alkylsulfonylamino.
  • each R 1 is independently selected from the group consisting of alkylcarbonyl and aminocarbonyl, wherein: the alkylcarbonyl optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl.
  • each R 1 is independently selected alkylcarbonyl.
  • each R 1 is independently selected aminocarbonyl.
  • Each R J is independently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, alkyloxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, aminocarbonylamino, alkyloxycarbonylaminoimino, alkylsulfonylaminoimino, alkenylsulfonylaminoimino, and alkynylsulfonylaminoimino, wherein:
  • the amino portion of such substituents optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkenyl, alkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
  • the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido, oxo, and amino, and
  • amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl,
  • the alkyl, alkenyl, and alkynyl portion of such substituents optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, and alkynyloxy, wherein: the alkyl optionally is substituted with one or more hydroxy;
  • the carbocyclyl and heterocyclyl portions of such substituents optionally are substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido, and amino, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl.
  • each R J is independently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, alkyloxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, aminocarbonylamino, alkylsulfonylaminoimino, alkenylsulfonylaminoimino, and alkynylsulfonylaminoimino, wherein:
  • the amino portion of such substituents optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkenyl, alkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
  • the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido, oxo, and amino, and
  • amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl,
  • the alkyl, alkenyl, and alkynyl portion of such substituents optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, and alkynyloxy, wherein: the alkyl optionally is substituted with one or more hydroxy;
  • the carbocyclyl and heterocyclyl portions of such substituents optionally are substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido, and amino, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl; and
  • each R J is independently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, alkyloxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, aminocarbonylamino, alkylsulfonylaminoimino, alkenylsulfonylaminoimino, and alkynylsulfonylaminoimino, wherein such substituents are not substituted.
  • each R J is independently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino, alkyloxycarbonylamino, alkylsulfonylamino, aminocarbonylamino, and alkylsulfonylaminoimino, wherein:
  • the amino portion of such substituents optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
  • the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and
  • amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl,
  • the alkyl portion of such substituents optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, wherein: the alkyl optionally is substituted with one or more hydroxy;
  • each R J is independently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylsulfonylamino, and alkylsulfonylaminoimino, wherein:
  • the amino portion of such substituents optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
  • the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and
  • amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl,
  • the alkyl portion of such substituents optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, wherein: the alkyl optionally is substituted with one or more hydroxy; (c) the carbocyclyl and heterocyclyl portions of such substituents optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, and amino, wherein: the amino optionally is substituted with one or two substituents independently selected alkyl.
  • each R J is independently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylsulfonylamino, and alkylsulfonylaminoimino, wherein: the amino portion of such substituents optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
  • the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and
  • amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl.
  • each R J is independently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylsulfonylamino, and alkylsulfonylaminoimino, wherein: the alkyl portion of the alkylsulfonylamino and alkylsulfonylaminoimino optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, wherein: the alkyl optionally is substituted with one or more hydroxy.
  • each R J is independently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylsulfonylamino, and alkylsulfonylaminoimino, wherein: the carbocyclyl and heterocyclyl portions of such substituents optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, and amino.
  • each R J is independently selected from the group consisting of carbocyclylsulfonylamino and heterocyclylsulfonylamino, wherein: the carbocyclyl and heterocyclyl portions of such substituents optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, and amino.
  • each R J is independently selected from the group consisting of alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, and alkylsulfonylaminoimino, wherein:
  • the amino portion of such substituents optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
  • the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and
  • amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl,
  • each R J is an independently selected alkylsulfonylamino, wherein:
  • the amino portion of the alkylsulfonylamino optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
  • the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and
  • amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl,
  • the alkyl portion of the alkylsulfonylamino optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, wherein: the alkyl optionally is substituted with one or more hydroxy.
  • each R J is an independently selected alkylsulfonylamino, wherein: the amino portion of the alkylsulfonylamino optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
  • the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and
  • amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl.
  • each R J is an independently selected alkylsulfonylamino, wherein: the amino portion of the alkylsulfonylamino optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl.
  • each R J is an independently selected alkylsulfonylamino, wherein: the alkyl portion of the alkylsulfonylamino optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, wherein: the alkyl optionally is substituted with one or more hydroxy.
  • each R J is an independently selected alkylsulfonylamino, wherein: the alkyl portion of the alkylsulfonylamino optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano.
  • each R J is an independently selected alkylsulfonylamino. hi some such embodiments, each R J is methylsulfonylamino.
  • each R J is an independently selected alkylsulfonylaminoimino, wherein:
  • the amino portion of the alkylsulfonylaminoimino optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
  • the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and
  • amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl,
  • the alkyl portion of the alkylsulfonylaminoimino optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, wherein: the alkyl optionally is substituted with one or more hydroxy.
  • each R J is an independently selected alkylsulfonylaminoimino, wherein: the amino portion of the alkylsulfonylaminoimino optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein: (1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and
  • amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl.
  • each R J is an independently selected alkylsulfonylaminoimino, wherein: the amino portion of the alkylsulfonylaminoimino optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl.
  • each R J is an independently selected alkylsulfonylaminoimino, wherein: the alkyl portion of the alkylsulfonylaminoimino optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, wherein: the alkyl optionally is substituted with one or more hydroxy.
  • each R J is an independently selected alkylsulfonylaminoimino, wherein: the alkyl portion of the alkylsulfonylaminoimino optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano.
  • each R J is an independently selected alkylsulfonylaminoimino. In some such embodiments, each R J is methylsulfonylaminoimino.
  • each R J is independently selected from the group consisting of alkylcarbonylamino and alkyloxycarbonylamino, wherein: the alkyl portion of such substituents optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano.
  • Each R ⁇ is independently selected from the group consisting of aminosulfonyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl, wherein: (a) the alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl optionally are substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, aminosulfonyl,
  • aminosulfonyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl.
  • each R ⁇ is independently selected from the group consisting of aminosulfonyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl, wherein such substituents are not substituted.
  • each R ⁇ is independently selected from the group consisting of aminosulfonyl and alkylsulfonyl, wherein:
  • the alkylsulfonyl optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl; and
  • aminosulfonyl optionally is substituted with one or two substituents independently selected alkyl.
  • each R ⁇ is independently selected from the group consisting of aminosulfonyl and alkylsulfonyl.
  • R 1 , R J , and R ⁇ have been discussed above. These substituent embodiments can be combined to form various embodiments of compounds of formula I. All embodiments of compounds of formula I formed by combining the substituent embodiments discussed above are within the scope of Applicants' invention, and some illustrative embodiments of the compounds of formula I are provided below. [00284] In some embodiments, in the compounds of formula I: is selected from the group consisting of single carbon-carbon bond and double carbon- carbon bond;
  • R 1 is selected from the group consisting of hydrogen and methyl;
  • R 2 is selected from the group consisting of hydrogen and halo;
  • R 3 is selected from the group consisting of hydrogen and halo;
  • R 4 is selected from the group consisting of d-C 4 -alkyl, C 3 -C 6 -carbocyclyl, and 5-6-membered heterocyclyl, wherein:
  • Ci -C h alky 1 optionally is substituted with up to three substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and
  • the C 3 -C 6 -carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, halo, and alkylsulfonylamino;
  • R 5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy, and halo
  • R 6 is selected from the group consisting of C 5 -C 6 -carbocyclyl and 5-6-membered heterocyclyl, wherein each such substituent is substituted with one, two, or three substituents independently selected from the group consisting of R E , R F , and R J ; each R E is independently selected from the group consisting of chloro, fluoro, nitro, hydroxy, oxo, carboxy, amino, imino, aldehydo, and alkylamino; each R F is an independently selected alkyl optionally substituted with a substituent selected from the group consisting of carboxy, halo, amino, imino, and aminosulfonyl, wherein: the amino, imino, and aminosulfonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkylsulfonyl, and alkylsulfonylamino; each R 1 is independently selected from the group consisting of
  • the amino portion of such substituents optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
  • the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and
  • amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl,
  • the alkyl, alkenyl, and alkynyl portion of such substituents optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, wherein the alkyl optionally is substituted with one or more hydroxy.
  • This invention also is directed, in part, to all isomers of the compounds of formula I (and their salts) ⁇ i.e., structural and stereoisomers).
  • Structural isomers include chain and position isomers.
  • Stereoisomers include E/Z isomers (i.e., isomers with regard to one or more double bonds), enantiomers (i.e., stereo- isomers that have opposite configurations at all stereogenic centers), and diastereoisomers (i.e., stereo- isomers that have the same configuration at one or more stereogenic centers, but differ at other stereogenic centers).
  • This invention also is directed, in part, to all salts of the compounds of formula I.
  • a salt of a compound may be advantageous due to one or more of the salt's properties, such as, for example, enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or other solvents.
  • the salt preferably is pharmaceutically acceptable and/or physiologically compatible.
  • pharmaceutically acceptable is used adjectivally in this patent application to mean that the modified noun is appropriate for use as a pharmaceutical product or as a part of a pharmaceutical product.
  • salts include salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases.
  • these salts typically may be prepared by conventional means by reacting, for example, the appropriate acid or base with a compound of the invention.
  • Pharmaceutically acceptable acid addition salts of the compounds of formula I can be prepared from an inorganic or organic acid.
  • suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid.
  • Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.
  • organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), ethanesulfonate, benzenesulfonate, pantothenate, 2-hydroxyethanesulfonate, sulfanilate, cyclohexylaminosulfonate, algenic acid, beta-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, bisulfate, butyrate, camphorate, camphorsulfonate, cyclopent
  • Pharmaceutically acceptable base addition salts of the compounds of formula I include, for example, metallic salts and organic salts.
  • Preferred metallic salts include alkali metal (group Ia) salts, alkaline earth metal (group Ha) salts, and other physiologically acceptable metal salts. Such salts may be made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.
  • Preferred organic salts can be made from amines, such as tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
  • Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl (C r C 6 ) halides ⁇ e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), and others.
  • C r C 6 lower alkyl
  • halides ⁇ e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides
  • dialkyl sulfates e.g., di
  • the salt is sodium salt of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydro- pyrimidin- 1 (2H)-y l)-2-methoxystyryl)pheny l)methanesulfonamide .
  • the salt is disodium salt of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.
  • the salt is potassium salt of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin- 1 (2H)-y l)-2-methoxystyryl)pheny l)methanesulfonamide .
  • the salt is monopotassium salt of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.
  • compositions containing the compound/salt/isomer contains more than about 85% by weight of the compound/salt/isomer, preferably more than about 90% by weight of the compound/salt/isomer, preferably more than about 95% by weight of the compound/salt/isomer, preferably more than about 97% by weight of the compound/salt/isomer, and preferably more than about 99% by weight of the compound/salt/isomer.
  • This invention also relates, in part, to crystalline forms of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide disodium salt, namely the nonahydrate and tetrahydrate crystalline forms discussed below.
  • This invention relates, in part, to a nonahydrate crystalline disodium salt.
  • the crystallographic unit cell parameters of the nonahydrate crystalline disodium salt have been determined to be as follows: a is 8.9A, b is 9.4A, and c is 20.7A (more precisely, a is 8.926(2)A, b is 9.415(2)A, and c is 20.674(5)A); the cell angles are: ⁇ - 94.8°, ⁇ - 93.3°, and ⁇ - 107.0° (more precisely, ⁇ is 94.796(4)°, ⁇ is 93.345(4)°, and ⁇ is 107.013(4)°); and the cell volume is 1649A 3 (more precisely, 1649.3(7)A 3 ).
  • the salt crystallizes in the P-I space group.
  • the disodium salt nonahydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 4.3 ⁇ 0.2, 10.4 ⁇ 0.2, 10.9 ⁇ 0.2,, 11.6 ⁇ 0.2, 12.9 ⁇ 0.2, 14.7 ⁇ 0.2, 16.4 ⁇ 0.2, 17.8 ⁇ 0.2, 19.4 ⁇ 0.2, 19.8 ⁇ 0.2, 20.8 ⁇ 0.2, 21.9 ⁇ 0.2, and 23.5 ⁇ 0.2 degrees 2 ⁇ .
  • the disodium salt nonahydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 4.3 ⁇ 0.2, 10.4 ⁇ 0.2, 10.9 ⁇ 0.2,, 11.6 ⁇ 0.2, 12.9 ⁇ 0.2, 14.7 ⁇ 0.2, 16.4 ⁇ 0.2, 17.8 ⁇ 0.2, 19.4 ⁇ 0.2, 19.8 ⁇ 0.2, 20.8 ⁇ 0.2, 21.9 ⁇ 0.2, and 23.5 ⁇ 0.2 degrees 2 ⁇ .
  • the disodium salt nonahydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 4.3 ⁇ 0.2, 10.4 ⁇ 0.2, 10.9 ⁇ 0.2,, 11.6 ⁇ 0.2, 12.9 ⁇ 0.2, 14.7 ⁇ 0.2, 16.4 ⁇ 0.2, 17.8 ⁇ 0.2, 19.4 ⁇ 0.2, 19.8 ⁇ 0.2, 20.8 ⁇ 0.2, 21.9 ⁇ 0.2, and 23.5 ⁇ 0.2 degrees 2 ⁇ .
  • the disodium salt nonahydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 4.3 ⁇ 0.2, 10.4 ⁇ 0.2, 10.9 ⁇ 0.2,, 11.6 ⁇ 0.2, 12.9 ⁇ 0.2, 14.7 ⁇ 0.2, 14.9 ⁇ 0.2, 16.4 ⁇ 0.2, 17.8 ⁇ 0.2, 19.4 ⁇ 0.2, 19.7 ⁇ 0.2, 19.8 ⁇ 0.2, 20.8 ⁇ 0.2, 20.9 ⁇ 0.2, 21.9 ⁇ 0.2, 22.1 ⁇ 0.2, and 23.5 ⁇ 0.2 degrees 2 ⁇ .
  • the disodium salt nonahydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 4.3 ⁇ 0.2, 10.4 ⁇ 0.2, 10.9 ⁇ 0.2,, 11.6 ⁇ 0.2, 12.9 ⁇ 0.2, 14.7 ⁇ 0.2, 14.9 ⁇ 0.2, 16.4 ⁇ 0.2, 17.8 ⁇ 0.2, 19.4 ⁇ 0.2, 19.7 ⁇ 0.2, 19.8 ⁇ 0.2, 20.8 ⁇ 0.2, 20.9 ⁇ 0.2, 21.9 ⁇ 0.2, 22.1 ⁇ 0.2, and 23.5 ⁇ 0.2 degrees 2 ⁇ .
  • the disodium salt nonahydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 4.3 ⁇ 0.2, 10.4 ⁇ 0.2, 10.9 ⁇ 0.2,, 11.6 ⁇ 0.2, 12.9 ⁇ 0.2, 14.7 ⁇ 0.2, 14.9 ⁇ 0.2, 16.4 ⁇ 0.2, 17.8 ⁇ 0.2, 19.4 ⁇ 0.2, 19.7 ⁇ 0.2, 19.8 ⁇ 0.2, 20.8 ⁇ 0.2, 20.9 ⁇ 0.2, 21.9 ⁇ 0.2, 22.1 ⁇ 0.2, and 23.5 ⁇ 0.2 degrees 2 ⁇ .
  • the disodium salt nonahydrate has an X-ray powder diffraction pattern substantially as shown in Figure 1.
  • the 2 ⁇ values for the peaks in Figure 1 are as follows: 4.31 (100), 10.36 (12), 10.91 (23), 11.61 (52), 12.93 (24), 14.73 (65), 14.89 (20), 16.44 (41), 17.80 (38), 19.44 (26), 19.67 (37), 19.83 (59), 20.75 (69), 20.89 (21), 21.92 (43), 22.13 (40), and 22.42 (24).
  • This invention also relates, in part, to a process for preparing the disodium salt nonahydrate. It was prepared in aqueous medium. Aqueous NaOH (IM, 1.18ml) was added to (E)-N-(4-(3-tert-butyl-5- (2,4-dioxo-3 ,4-dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide (compound IB-Ll-1.1) (27.82mg) (molar ratio 1:20 acid:base). The resulting suspension was equilibrated at ambient conditions. The disodium salt nonahydrate formed seven days later through a solution-mediated process.
  • the disodium salt nonahydrate was prepared by suspending 278.8mg of compound IB-Ll- 1.1 in 1.25ml THF while heated to about 50°C. Aqueous NaOH (IN, 1.5ml, 2.2molar equivalents) was added. The solid dissolved completely to yield a clear solution, which was naturally cooled to ambient temperatures. The salt crystallized spontaneously. The molecular structure was determined by single crystal diffractometry. [00301] This invention relates, in part, to a tetrahydrate crystalline disodium salt.
  • the disodium salt tetrahydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 4.8 ⁇ 0.2, 12.1 ⁇ 0.2, 14.0 ⁇ 0.2, 17.0 ⁇ 0.2, 17.5 ⁇ 0.2, 20.9 ⁇ 0.2, 21.6 ⁇ 0.2, 25.0 ⁇ 0.2, and 29.5 ⁇ 0.2 degrees 2 ⁇ .
  • the disodium salt tetrahydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 4.8 ⁇ 0.2, 12.1 ⁇ 0.2, 14.0 ⁇ 0.2, 17.0 ⁇ 0.2, 17.5 ⁇ 0.2, 20.9 ⁇ 0.2, 21.6 ⁇ 0.2, 25.0 ⁇ 0.2, and 29.5 ⁇ 0.2 degrees 2 ⁇ .
  • the disodium salt tetrahydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 4.8 ⁇ 0.2, 12.1 ⁇ 0.2, 14.0 ⁇ 0.2, 17.0 ⁇ 0.2, 17.5 ⁇ 0.2, 20.9 ⁇ 0.2, 21.6 ⁇ 0.2, 25.0 ⁇ 0.2, and 29.5 ⁇ 0.2 degrees 2 ⁇ .
  • the disodium salt tetrahydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 4.8 ⁇ 0.2, 12.1 ⁇ 0.2, 14.0 ⁇ 0.2, 14.4 ⁇ 0.2, 17.0 ⁇ 0.2, 17.5 ⁇ 0.2, 20.9 ⁇ 0.2, 21.6 ⁇ 0.2, 25.0 ⁇ 0.2, 29.5 ⁇ 0.2, and 34.2 ⁇ 0.2 degrees 2 ⁇ .
  • the disodium salt tetrahydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 4.8 ⁇ 0.2, 12.1 ⁇ 0.2, 14.0 ⁇ 0.2, 14.4 ⁇ 0.2, 17.0 ⁇ 0.2, 17.5 ⁇ 0.2, 20.9 ⁇ 0.2, 21.6 ⁇ 0.2, 25.0 ⁇ 0.2, 29.5 ⁇ 0.2, and 34.2 ⁇ 0.2 degrees 2 ⁇ .
  • the disodium salt tetrahydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 4.8 ⁇ 0.2, 12.1 ⁇ 0.2, 14.0 ⁇ 0.2, 14.4 ⁇ 0.2, 17.0 ⁇ 0.2, 17.5 ⁇ 0.2, 20.9 ⁇ 0.2, 21.6 ⁇ 0.2, 25.0 ⁇ 0.2, 29.5 ⁇ 0.2, and 34.2 ⁇ 0.2 degrees 2 ⁇ .
  • the disodium salt tetrahydrate has an X-ray powder diffraction pattern substantially as shown in Figure 2.
  • the 2 ⁇ values for the peaks in Figure 2 are as follows: 4.81 (100), 12.07 (7), 14.01 (27), 14.41 (8), 16.96 (18), 17.53 (11), 20.87 (18), 21.58 (22), 24.99 (11), 29.47 (9), and 34.20 (9).
  • This invention also relates, in part, to a process for preparing the disodium salt tetrahydrate by suspending the nonahydrate disodium salt in an organic solvent (e.g., ethanol, 1-propanol, or 2-propanol).
  • an organic solvent e.g., ethanol, 1-propanol, or 2-propanol.
  • This invention also relates, in part, to a crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide dipotassium salt tetrahydrate.
  • the crystallographic unit cell parameters of the dipotassium salt tetrahydrate have been determined to be as follows: a is 14.5A, b is 10.8A, and c is 35.8A (more precisely, a is 14.454(14)A, b is 10.763(14)A, and c is 35.75(4)A); the cell angle is: ⁇ - 98.8° (more precisely, ⁇ is 98.82(3)°); and the cell volume is 5499A 3 (more precisely, 5499(11)A 3 ).
  • the salt crystallizes in the C2/c space group.
  • the dipotassium salt tetrahydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 5.0 ⁇ 0.2, 11.9 ⁇ 0.2, 12.4 ⁇ 0.2, 13.7 ⁇ 0.2, 15.0 ⁇ 0.2, 16.5 ⁇ 0.2, 17.1 ⁇ 0.2, 20.8 ⁇ 0.2, 21.3 ⁇ 0.2, 22.2 ⁇ 0.2, 24.0 ⁇ 0.2, 26.4 ⁇ 0.2, and 29.3 ⁇ 0.2 degrees 2 ⁇ .
  • the dipotassium salt tetrahydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 5.0 ⁇ 0.2, 11.9 ⁇ 0.2, 12.4 ⁇ 0.2, 13.7 ⁇ 0.2, 15.0-fc0.2, 16.5 ⁇ 0.2, 17.1 ⁇ 0.2, 20.8 ⁇ 0.2, 21.3 ⁇ 0.2, 22.2 ⁇ 0.2, 24.0 ⁇ 0.2, 26.4 ⁇ 0.2, and 29.3 ⁇ 0.2 degrees 2 ⁇ .
  • the dipotassium salt tetrahydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 5.0 ⁇ 0.2, 11.9 ⁇ 0.2, 12.4 ⁇ 0.2, 13.7 ⁇ 0.2, 15.0 ⁇ 0.2, 16.5 ⁇ 0.2, 17.1 ⁇ 0.2, 20.8 ⁇ 0.2, 21.3 ⁇ 0.2, 22.2 ⁇ 0.2, 24.0 ⁇ 0.2, 26.4 ⁇ 0.2, and 29.3 ⁇ 0.2 degrees 2 ⁇ .
  • the dipotassium salt tetrahydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 5.0 ⁇ 0.2, 11.9 ⁇ 0.2, 12.4 ⁇ 0.2, 12.6 ⁇ 0.2, 13.7 ⁇ 0.2, 15.0 ⁇ 0.2, 16.5 ⁇ 0.2, 16.7 ⁇ 0.2, 17.1 ⁇ 0.2, 20.7 ⁇ 0.2, 20.8 ⁇ 0.2, 21.3 ⁇ 0.2, 22.2 ⁇ 0.2, 22.4 ⁇ 0.2, 24.0 ⁇ 0.2, 26.4 ⁇ 0.2, and 29.3 ⁇ 0.2 degrees 2 ⁇ .
  • the dipotassium salt tetrahydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 5.0 ⁇ 0.2, 11.9 ⁇ 0.2, 12.4 ⁇ 0.2, 12.6 ⁇ 0.2, 13.7 ⁇ 0.2, 15.0 ⁇ 0.2, 16.5 ⁇ 0.2, 16.7 ⁇ 0.2, 17.1 ⁇ 0.2, 20.7 ⁇ 0.2, 20.8 ⁇ 0.2, 21.3 ⁇ 0.2, 22.2 ⁇ 0.2, 22.4 ⁇ 0.2, 24.0 ⁇ 0.2, 26.4 ⁇ 0.2, and 29.3 ⁇ 0.2 degrees 2 ⁇ .
  • the dipotassium salt tetrahydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 5.0 ⁇ 0.2, 11.9 ⁇ 0.2, 12.4 ⁇ 0.2, 12.6 ⁇ 0.2, 13.7 ⁇ 0.2, 15.0 ⁇ 0.2, 16.5 ⁇ 0.2, 16.7 ⁇ 0.2, 17.1 ⁇ 0.2, 20.7 ⁇ 0.2, 20.8 ⁇ 0.2, 21.3 ⁇ 0.2, 22.2 ⁇ 0.2, 22.4 ⁇ 0.2, 24.0 ⁇ 0.2, 26.4 ⁇ 0.2, and 29.3 ⁇ 0.2 degrees 2 ⁇ .
  • the dipotassium salt tetrahydrate has an X-ray powder diffraction pattern substantially as shown in Figure 4.
  • the 2 ⁇ values for the peaks in Figure 4 are as follows: 5.00 (100), 11.86 (34), 12.39 (32), 12.64 (19), 13.70 (23), 15.03 (21), 16.47 (24), 16.66 (24), 17.12 (28), 20.75 (29), 20.81 (33), 21.34 (22), 22.15 (46), 22.38 (31), 24.02 (24), 26.44 (24), and 29.32 (21).
  • This invention also relates, in part, to a process for preparing the dipotassium salt tetrahydrate by suspending compound IB-Ll-1.1 (261.13mg) in 1.25ml THF while heated to about 50 0 C. Aqueous KOH (IN, 1.3ml, 2.2 molar equivalent) was added. The solid dissolved completely to yield a clear solution, which was naturally cooled to ambient temperatures. Crystallization occurred during the slow evaporation process.
  • This invention also relates, in part, to crystalline forms of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide monopotassium salt, namely the trihydrate and dihydrate crystalline forms discussed below.
  • This invention relates, in part, to a monopotassium salt trihydrate.
  • the crystallographic unit cell parameters of the trihydrate crystalline monopotassium salt have been determined to be as follows: a is 9- ⁇ A, b is 8.3A, and c is 18.6A (more precisely, a is 9.0393(16)A, b is 8.3332(15)A, and c is 18.582(3)A); the cell angles are: ⁇ - 80.5°, ⁇ - 85.1°, and ⁇ - 80.5° (more precisely, ⁇ is 80.511(2)°, ⁇ is 85.134(3)°, and ⁇ is 80.531(2)°); and the cell volume is 1359A 3 (more precisely, 1359.3(4)A 3 ).
  • the salt crystallizes in the P-I space group.
  • the monopotassium salt trihydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 4.8 ⁇ 0.2, 10.8 ⁇ 0.2, 11.3 ⁇ 0.2, 13.4 ⁇ 0.2, 15.3 ⁇ 0.2, 16.9 ⁇ 0.2, 21.2 ⁇ 0.2, 21.7 ⁇ 0.2, 22.1 ⁇ 0.2, 22.5 ⁇ 0.2, and 23.0 ⁇ 0.2 degrees 20.
  • the monopotassium salt trihydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 4.8 ⁇ 0.2, 10.8 ⁇ 0.2, 11.3 ⁇ 0.2, 13.4 ⁇ 0.2, 15.3 ⁇ 0.2, 16.9 ⁇ 0.2, 21.2 ⁇ 0.2, 21.7 ⁇ 0.2, 22.1 ⁇ 0.2, 22.5 ⁇ 0.2, and 23.0 ⁇ 0.2 degrees 20.
  • the monopotassium salt trihydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 4.8 ⁇ 0.2, 10.8 ⁇ 0.2, 11.3 ⁇ 0.2, 13.4 ⁇ 0.2, 15.3 ⁇ 0.2, 16.9 ⁇ 0.2, 21.2 ⁇ 0.2, 21.7 ⁇ 0.2, 22.1 ⁇ 0.2, 22.5 ⁇ 0.2, and 23.0 ⁇ 0.2 degrees 20.
  • the monopotassium salt trihydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 4.8 ⁇ 0.2, 10.8 ⁇ 0.2, 11.3 ⁇ 0.2, 13.4 ⁇ 0.2, 13.6 ⁇ 0.2, 15.3 ⁇ 0.2, 16.9 ⁇ 0.2, 21.2 ⁇ 0.2, 21.7 ⁇ 0.2, 21.7 ⁇ 0.2, 22.1 ⁇ 0.2, 22.5 ⁇ 0.2, 22.6 ⁇ 0.2, and 23.0 ⁇ 0.2 degrees 20.
  • the monopotassium salt trihydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 4.8 ⁇ 0.2, 10.8 ⁇ 0.2, 11.3 ⁇ 0.2, 13.4 ⁇ 0.2, 13.6 ⁇ 0.2, 15.3 ⁇ 0.2, 16.9 ⁇ 0.2, 21.2 ⁇ 0.2, 21.7 ⁇ 0.2, 21.7 ⁇ 0.2, 22.1 ⁇ 0.2, 22.5 ⁇ 0.2, 22.6 ⁇ 0.2, and 23.0 ⁇ 0.2 degrees 20.
  • the monopotassium salt trihydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 4.8 ⁇ 0.2, 10.8 ⁇ 0.2, 11.3 ⁇ 0.2, 13.4 ⁇ 0.2, 13.6 ⁇ 0.2, 15.3 ⁇ 0.2, 16.9 ⁇ 0.2, 21.2 ⁇ 0.2, 21.7 ⁇ 0.2, 21.7 ⁇ 0.2, 22.1 ⁇ 0.2, 22.5 ⁇ 0.2, 22.6 ⁇ 0.2, and 23.0 ⁇ 0.2 degrees 20.
  • the monopotassium salt trihydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 4.8 ⁇ 0.2, 10.8 ⁇ 0.2, 11.3 ⁇ 0.2, 13.4 ⁇ 0.2, 13.6 ⁇ 0.2, 15.3 ⁇ 0.2, 16.9 ⁇ 0.2, 21.2 ⁇ 0.2, 21.7 ⁇ 0.2, 21.7 ⁇ 0.2, 22.1 ⁇ 0.2, 22.5 ⁇ 0.2, 22.6 ⁇ 0.2, and 23.0 ⁇ 0.2 degrees 20.
  • the monopotassium salt trihydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 4.8 ⁇ 0.2, 10.8 ⁇ 0.2, 11.3 ⁇ 0.2, 13.4 ⁇ 0.2, 15.3 ⁇ 0.2, 16.9 ⁇ 0.2, 21.2 ⁇ 0.2, 21.7 ⁇ 0.2, 22.1 ⁇ 0.2, 22.5 ⁇ 0.2, and 23.0 ⁇ 0.2 degrees 20.
  • the monopotassium salt trihydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 4.8 ⁇ 0.2, 10.8 ⁇ 0.2, 11.3 ⁇ 0.2, 13.4 ⁇ 0.2, 15.3 ⁇ 0.2, 16.9 ⁇ 0.2, 21.2 ⁇ 0.2, 21.7 ⁇ 0.2, 22.1 ⁇ 0.2, 22.5 ⁇ 0.2, and 23.0 ⁇ 0.2 degrees 2 ⁇ . [00317] In some embodiments, the monopotassium salt trihydrate has an X-ray powder diffraction pattern substantially as shown in Figure 5.
  • This invention also relates, in part, to a process for preparing the monopotassium salt trihydrate. It was prepared by suspending compound IB-Ll-1.1 (108.81mg) in 0.4ml THF while heated to about 50 0 C. Aqueous KOH solution (IN, 0.278ml, 1.2 molar equivalent) was added. The solid dissolved completely to yield a clear solution. Additional 1.6ml THF was added to the solution, which was then naturally cooled to ambient temperatures and crystallization was observed. Alternatively, the monopotassium salt trihydrate was prepared by suspending compound IB-Ll-1.1 (343.89mg) in 1.0ml THF while heated to 50 0 C.
  • This invention relates, in part, to a monopotassium salt dihydrate.
  • the monopotassium salt dihydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 7.7 ⁇ 0.2, 8.8 ⁇ 0.2, 16.1 ⁇ 0.2, and 19.7 ⁇ 0.2 degrees 2 ⁇ . In some such embodiments, the monopotassium salt dihydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of degrees 20.
  • the monopotassium salt dihydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 7.7 ⁇ 0.2, 8.8 ⁇ 0.2, 12.4 ⁇ 0.2, 14.0 ⁇ 0.2, 16.1 ⁇ 0.2, 17.7 ⁇ 0.2, 19.2 ⁇ 0.2, 19.7 ⁇ 0.2, 23.1 ⁇ 0.2, and 29.2 ⁇ 0.2 degrees 20.
  • the monopotassium salt dihydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 7.7 ⁇ 0.2, 8.8 ⁇ 0.2, 12.4 ⁇ 0.2, 14.0 ⁇ 0.2, 16.1 ⁇ 0.2, 17.7 ⁇ 0.2, 19.2 ⁇ 0.2, 19.7 ⁇ 0.2, 23.1 ⁇ 0.2, and 29.2 ⁇ 0.2 degrees 20.
  • the monopotassium salt dihydrate has an X-ray powder diffraction pattern substantially as shown in Figure 6.
  • the 20 values for the peaks in Figure 6 (and their intensities) are as follows: 7.68 (19), 8.83 (100), 12.40 (7), 13.97 (10), 16.12 (25), 17.75 (9), 19.22 (12), 19.73 (40), 23.05 (9), and 29.21 (7).
  • This invention also relates, in part, to a process for preparing the monopotassium salt dihydrate. It was prepared by suspending the monopotassium salt trihydrate in media of low water activity, such as an ethanol/H 2 O mixture (50/1 v/v).
  • the monopotassium salt dihydrate was prepared by dissolving potassium trihydrate solid (1.8g) in 36mL of IPA and 4ml water at 80°C. The resulting solution was cooled to 55°C over Ih. The solution was then seeded with 7.5mg of dihydrate crystals at 55°C and maintained at 55°C for Ih. Heptane (36ml) was then added over 3h. The reaction mixture was cooled to 0°C, and filtration yielded a material containing both di- and trihydrate crystals. The solid was then reslurried in 2OmL of 10:1 v/v EtOH/H 2 O at 50 0 C for 3h and cooled to 25°C over 5h.
  • the slurry was then mixed at 25°C for additional 3 days and cooled to 0 0 C over 3h and held at this temperature for 2h.
  • the resulting crystals were filtered and air-dried on filter funnel for Ih to give dihydrate.
  • the dihydrate monopotassium salt was also prepared by slurrying a mixture of dihydrate and trihydrate crystals in 10:1 v/v EtOHZH 2 O at 80 0 C for 2 days.
  • the potassium content was confirmed by ion chromatography.
  • This invention also relates, in part, to a crystalline form of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo- 3,4-dihydropyrimidin-l(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide 1/7 potassium salt.
  • the 1/7 potassium salt has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 7.7 ⁇ 0.2, 8.3 ⁇ 0.2, 10.1 ⁇ 0.2, 10.6 ⁇ 0.2, 11.4 ⁇ 0.2, 12.0 ⁇ 0.2, 13.4 ⁇ 0.2, 15.6 ⁇ 0.2, 16.3 ⁇ 0.2, 16.7 ⁇ 0.2, 17.2 ⁇ 0.2, 18.3 ⁇ 0.2, 18.8 ⁇ 0.2, 19.4 ⁇ 0.2, 19.9 ⁇ 0.2, 20.2 ⁇ 0.2, 20.5 ⁇ 0.2, 21.2 ⁇ 0.2, 22.1 ⁇ 0.2, and 22.9 ⁇ 0.2 degrees 2 ⁇ .
  • the 1/7 potassium salt has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 7.7 ⁇ 0.2, 8.3 ⁇ 0.2, 10.1 ⁇ 0.2, 10.6 ⁇ 0.2, 11.4 ⁇ 0.2, 12.0 ⁇ 0.2, 13.4 ⁇ 0.2, 15.6 ⁇ 0.2, 16.3 ⁇ 0.2, 16.7 ⁇ 0.2, 17.2 ⁇ 0.2, 18.3 ⁇ 0.2, 18.8 ⁇ 0.2, 19.4 ⁇ 0.2, 19.9 ⁇ 0.2, 20.2 ⁇ 0.2, 20.5 ⁇ 0.2, 21.2 ⁇ 0.2, 22.1 ⁇ 0.2, and 22.9 ⁇ 0.2 degrees 20.
  • the 1/7 potassium salt has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 7.7 ⁇ 0.2, 8.3 ⁇ 0.2, 10.1 ⁇ 0.2, 10.6 ⁇ 0.2, 11.4 ⁇ 0.2, 12.0 ⁇ 0.2, 13.4 ⁇ 0.2, 15.6 ⁇ 0.2, 16.3 ⁇ 0.2, 16.7 ⁇ 0.2, 17.2 ⁇ 0.2, 18.3 ⁇ 0.2, 18.8 ⁇ 0.2, 19.4 ⁇ 0.2, 19.9 ⁇ 0.2, 20.2 ⁇ 0.2, 20.5 ⁇ 0.2, 21.2 ⁇ 0.2, 22.1 ⁇ 0.2, and 22.9 ⁇ 0.2 degrees 20.
  • the 1/7 potassium salt has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 7.7 ⁇ 0.2, 8.3 ⁇ 0.2, 10.1 ⁇ 0.2, 10.6 ⁇ 0.2, 11.4 ⁇ 0.2, 12.0 ⁇ 0.2, 13.4 ⁇ 0.2, 15.6 ⁇ 0.2, 16.3 ⁇ 0.2, 16.7 ⁇ 0.2, 17.2 ⁇ 0.2, 18.3 ⁇ 0.2, 18.8 ⁇ 0.2, 19.4 ⁇ 0.2, 19.9 ⁇ 0.2, 20.2 ⁇ 0.2, 20.5 ⁇ 0.2, 20.8 ⁇ 0.2, 21.2 ⁇ 0.2, 22.1 ⁇ 0.2, 22.9 ⁇ 0.2, 24.3 ⁇ 0.2, 24.9 ⁇ 0.2, and 25.1 ⁇ 0.2 degrees 2 ⁇ .
  • the 1/7 potassium salt has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 7.7 ⁇ 0.2, 8.3 ⁇ 0.2, 10.1 ⁇ 0.2, 10.6 ⁇ 0.2, 11.4 ⁇ 0.2, 12.0 ⁇ 0.2, 13.4 ⁇ 0.2, 15.6 ⁇ 0.2, 16.3 ⁇ 0.2, 16.7 ⁇ 0.2, 17.2 ⁇ 0.2, 18.3 ⁇ 0.2, 18.8 ⁇ 0.2, 19.4 ⁇ 0.2, 19.9 ⁇ 0.2, 20.2 ⁇ 0.2, 20.5 ⁇ 0.2, 20.8 ⁇ 0.2, 21.2 ⁇ 0.2, 22.1 ⁇ 0.2, 22.9 ⁇ 0.2, 24.3 ⁇ 0.2, 24.9 ⁇ 0.2, and 25.1 ⁇ 0.2 degrees 2 ⁇ .
  • the 1/7 potassium salt has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 7.7 ⁇ 0.2, 8.3 ⁇ 0.2, 10.1 ⁇ 0.2, 10.6 ⁇ 0.2, 11.4 ⁇ 0.2, 12.0 ⁇ 0.2, 13.4 ⁇ 0.2, 15.6 ⁇ 0.2, 16.3 ⁇ 0.2, 16.7 ⁇ 0.2, 17.2 ⁇ 0.2, 18.3 ⁇ 0.2, 18.8 ⁇ 0.2, 19.4 ⁇ 0.2, 19.9 ⁇ 0.2, 20.2 ⁇ 0.2, 20.5 ⁇ 0.2, 20.8 ⁇ 0.2, 21.2 ⁇ 0.2, 22.1 ⁇ 0.2, 22.9 ⁇ 0.2, 24.3 ⁇ 0.2, 24.9 ⁇ 0.2, and 25.1 ⁇ 0.2 degrees 2 ⁇ .
  • the 1/7 potassium salt has an X-ray powder diffraction pattern substantially as shown in Figure 8.
  • the 2 ⁇ values for the peaks in Figure 8 are as follows: 7.71 (19), 8.33 (34), 10.10 (100), 10.66 (29), 11.39 (27), 12.04 (22), 13.39 (39), 15.56 (41), 16.27 (62), 16.69 (70), 17.22 (59), 18.31 (18), 18.78 (47), 19.44 (36), 19.89 (28), 20.19 (33), 20.54 (87), 20.80 (33), 21.15 (47), 22.05 (24), 22.82 (67), 24.32 (22), 24.87 (22), and 25.07 (33).
  • This invention also relates, in part, to a process for preparing the 1/7 potassium salt. It was prepared by suspending compound IB-Ll-1.1 (2g) 6ml THF at 5O 0 C. One molar equivalent of KOH dissolved in 4.3ml water was added, and the reaction mixture was heated to 65°C to dissolve all solids. The solution was then cooled to ambient temperatures over 2h and spontaneous crystallization took place. The slurry was then cooled to 5°C and held at that temperature for 2h. The pale yellow crystals were filtered and air-dried for 24h at ambient conditions. The potassium content was determined by ion chromatography.
  • GJ Crystalline Form of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide Monodiethylamine Salt Tetrahydrate.
  • This invention also relates, in part, to crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide monodiethylamine salt tetrahydrate.
  • the monodiethylamine salt tetrahydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 9.5 ⁇ 0.2, 10.0 ⁇ 0.2, 11.8 ⁇ 0.2, 12.1 ⁇ 0.2, 14.4 ⁇ 0.2, 16.8 ⁇ 0.2, 17.6 ⁇ 0.2, 19.8 ⁇ 0.2, 20.8 ⁇ 0.2, 21.4 ⁇ 0.2, 21.8 ⁇ 0.2, and 29.8 ⁇ 0.2 degrees 20.
  • the monodiethylamine salt tetrahydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 9.5 ⁇ 0.2, 10.0 ⁇ 0.2, 11.8 ⁇ 0.2, 12.1 ⁇ 0.2, 14.4 ⁇ 0.2, 16.8 ⁇ 0.2, 17.6 ⁇ 0.2, 19.8 ⁇ 0.2, 20.8 ⁇ 0.2, 21.4 ⁇ 0.2, 21.8 ⁇ 0.2, and 29.8 ⁇ 0.2 degrees 2 ⁇ .
  • the monodiethylamine salt tetrahydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 9.5 ⁇ 0.2, 10.0 ⁇ 0.2, 11.8 ⁇ 0.2, 12.1 ⁇ 0.2, 14.4 ⁇ 0.2, 16.8 ⁇ 0.2, 17.6 ⁇ 0.2, 19.8 ⁇ 0.2, 20.8 ⁇ 0.2, 21.4 ⁇ 0.2, 21.8 ⁇ 0.2, and 29.8 ⁇ 0.2 degrees 20.
  • the monodiethylamine salt tetrahydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 9.5 ⁇ 0.2, 10.0 ⁇ 0.2, 11.8 ⁇ 0.2, 12.1 ⁇ 0.2, 14.4 ⁇ 0.2, 16.8 ⁇ 0.2, 17.6 ⁇ 0.2, 19.4 ⁇ 0.2, 19.8 ⁇ 0.2, 20.8 ⁇ 0.2, 21.4 ⁇ 0.2, 21.8 ⁇ 0.2, 21.9 ⁇ 0.2, and 29.8 ⁇ 0.2 degrees 2 ⁇ .
  • the monodiethylamine salt tetrahydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 9.5 ⁇ 0.2, 10.0 ⁇ 0.2, 11.8 ⁇ 0.2, 12.1 ⁇ 0.2, 14.4 ⁇ 0.2, 16.8 ⁇ 0.2, 17.6 ⁇ 0.2, 19.4 ⁇ 0.2, 19.8 ⁇ 0.2, 20.8 ⁇ 0.2, 21.4 ⁇ 0.2, 21.8 ⁇ 0.2, 21.9 ⁇ 0.2, and 29.8 ⁇ 0.2 degrees 2 ⁇ .
  • the monodiethylamine salt tetrahydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 9.5 ⁇ 0.2, 10.0 ⁇ 0.2, 11.8 ⁇ 0.2, 12.1 ⁇ 0.2, 14.4 ⁇ 0.2, 16.8 ⁇ 0.2, 17.6 ⁇ 0.2, 19.4 ⁇ 0.2, 19.8 ⁇ 0.2, 20.8 ⁇ 0.2, 21.4 ⁇ 0.2, 21.8 ⁇ 0.2, 21.9 ⁇ 0.2, and 29.8 ⁇ 0.2 degrees 2 ⁇ .
  • the monodiethylamine salt tetrahydrate has an X-ray powder diffraction pattern substantially as shown in Figure 9.
  • the 2 ⁇ values for the peaks in Figure 9 are as follows: 9.45 (100), 9.97 (31), 11.85 (67), 12.09 (16), 14.38 (22), 16.80 (9), 17.59 (10), 19.39 (8), 19.83 (21), 20.85 (25), 21.37 (12), 21.75 (34), 21.87 (8), and 29.78 (7).
  • This invention also relates, in part, to a process for preparing the monodiethylamine salt tetrahydrate. It was prepared in aqueous medium. Compound IB-Ll-1.1 was slowly added to 500ul of IM diethylamine until no more solid can be dissolved into the solution. The solution was then evaporated slowly at ambient temperatures and the salt crystallized 2 days later. Alternatively, the monodiethylamine salt tetrahydrate was prepared by suspending 64.15mg of compound IB-Ll-1.1 in 400ul IM diethylamine while heated to 50 0 C. About 5 drops of THF ( ⁇ 2OuI) was added. The solid dissolved completely upon addition to yield a clear solution. The solution was then evaporated at ambient temperature, and the salt crystallized 4 days later. The stoichiometry of the salt was confirmed by solution 1 H NMR.
  • This invention also relates, in part, to crystalline forms of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide (compound IB-Ll-1.1), namely the true polymorphs (pattern A, pattern B, pattern C, and pattern D) and hydrate (pattern AH, pattern BH, pattern CH, and pattern DH) crystalline forms discussed below.
  • This invention relates, in part, to pattern A crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl)pheny l)methanesulfonamide .
  • the pattern A polymorph has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 5.8 ⁇ 0.2, 9.9 ⁇ 0.2, 11.8 ⁇ 0.2, 12.4 ⁇ 0.2, 14.5 ⁇ 0.2, 18.8 ⁇ 0.2, 22.7 ⁇ 0.2, and 29.2 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern A polymorph has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 5.8 ⁇ 0.2, 9.9 ⁇ 0.2, 11.8 ⁇ 0.2, 12.4 ⁇ 0.2, 14.5 ⁇ 0.2, 18.8 ⁇ 0.2, 22.7 ⁇ 0.2, and 29.2 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern A polymorph has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 5.8 ⁇ 0.2, 9.9 ⁇ 0.2, 11.8 ⁇ 0.2, 12.4 ⁇ 0.2,
  • the pattern A polymorph has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 5.8 ⁇ 0.2, 9.9 ⁇ 0.2, 11.8 ⁇ 0.2, 12.4 ⁇ 0.2,
  • the pattern A polymorph has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 5.8 ⁇ 0.2, 9.9 ⁇ 0.2, 11.8 ⁇ 0.2,
  • the pattern A polymorph has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 5.8 ⁇ 0.2, 9.9 ⁇ 0.2,
  • the pattern A polymorph has an X-ray powder diffraction pattern substantially as shown in Figure 11.
  • the 2 ⁇ values for the peaks in Figure 11 are as follows: 5.85 (28), 9.88 (51), 11.79 (73), 12.38 (56), 14.03 (38), 14.45 (100), 15.27 (29), 18.52 (39),
  • This invention also relates, in part, to a process for preparing pattern A polymorph.
  • Pattern A polymorph was prepared as discussed in Example E below.
  • This invention relates, in part, to pattern B crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide .
  • the pattern B polymorph has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 11.5 ⁇ 0.2, 13.3 ⁇ 0.2, 15.4 ⁇ 0.2,
  • the pattern B polymorph has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 11.5 ⁇ 0.2, 13.3 ⁇ 0.2, 15.4 ⁇ 0.2,
  • the pattern B polymorph has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 11.5 ⁇ 0.2, 13.3 ⁇ 0.2, 15.4 ⁇ 0.2,
  • the pattern B polymorph has an X-ray powder diffraction pattern substantially as shown in Figure 13.
  • the 2 ⁇ values for the peaks in Figure 13 (and their intensities) are as follows: 11.52 (71), 13.30 (87), 15.37 (100), 16.42 (60), 17.13 (69), 18.60 (97), 19.37 (56), 20.40 (62), 21.55 (55), 22.41 (39), 23.99 (33), 26.81 (31), and 28.98 (50).
  • This invention relates, in part, to pattern C crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.
  • the pattern C polymorph has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 7.7 ⁇ 0.2, 10.1 ⁇ 0.2, 10.6 ⁇ 0.2, 12.0
  • the pattern C polymorph has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 7.7 ⁇ 0.2, 10.1 ⁇ 0.2, 10.6 ⁇ 0.2, 12.0
  • the pattern C polymorph has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 7.7 ⁇ 0.2, 10.1 ⁇ 0.2, 10.6 ⁇ 0.2, 12.0
  • the pattern C polymorph has an X-ray powder diffraction pattern substantially as shown in Figure 14.
  • the 2 ⁇ values for the peaks in Figure 14 (and their intensities) are as follows: 7.69 (27), 10.13 (27), 10.64 (49), 12.01 (31), 13.39 (33), 16.25 (91), 19.44 (46), 20.49 (100),
  • This invention relates, in part, to pattern D crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.
  • the pattern D polymorph has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 5.8 ⁇ 0.2, 10.7 ⁇ 0.2, 11.2 ⁇ 0.2,
  • the pattern D polymorph has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 5.8 ⁇ 0.2, 10.7 ⁇ 0.2, 11.2 ⁇ 0.2, 15.2 ⁇ 0.2, 16.1 ⁇ 0.2, 16.9 ⁇ 0.2,
  • the pattern D polymorph has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 5.8 ⁇ 0.2, 10.7 ⁇ 0.2, 11.2 ⁇ 0.2, 15.2 ⁇ 0.2, 16.1 ⁇ 0.2, 16.9 ⁇ 0.2, 19.9 ⁇ 0.2, 22.1 ⁇ 0.2,
  • the pattern D polymorph has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 5.8 ⁇ 0.2, 10.7 ⁇ 0.2, 11.2 ⁇ 0.2,
  • the pattern D polymorph has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 5.8 ⁇ 0.2, 10.7 ⁇ 0.2, 11.2 ⁇ 0.2, 15.2 ⁇ 0.2,
  • the pattern D polymorph has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 5.8 ⁇ 0.2, 10.7 ⁇ 0.2, 11.2 ⁇ 0.2, 15.2 ⁇ 0.2, 16.1 ⁇ 0.2,
  • the pattern D polymorph has an X-ray powder diffraction pattern substantially as shown in Figure 15.
  • the 2 ⁇ values for the peaks in Figure 15 are as follows: 5.81 (24), 10.70 (91), 11.23 (60), 15.17 (28), 16.10 (48), 16.89 (100), 17.10 (42), 19.88 (81),
  • This invention also relates, in part, to a process for preparing pattern B, C, and D polymorphs by heating pattern A polymorph to about 160, about 225, and about 268 0 C, respectively using DSC.
  • This invention also relates, in part, to hydrates of compound IB-Ll-1.1, namely to hydrates A, B, C, D, and E discussed below.
  • This invention relates, in part, to a pattern A (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydro- pyrimidin- 1 (2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide hydrate.
  • the pattern A hydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 5.1 ⁇ 0.2, 7.9 ⁇ 0.2, 9.5 ⁇ 0.2, 10.3 ⁇ 0.2, 13.7 ⁇ 0.2, 16.5 ⁇ 0.2, 17.1 ⁇ 0.2, 17.5 ⁇ 0.2, 18.8 ⁇ 0.2, 19.2 ⁇ 0.2, 20.7 ⁇ 0.2, 21.3 ⁇ 0.2, 21.6 ⁇ 0.2, 25.8 ⁇ 0.2, 26.8 ⁇ 0.2, and 28.4 ⁇ 0.2 degrees 20.
  • the pattern A hydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 5.1 ⁇ 0.2, 7.9 ⁇ 0.2, 9.5 ⁇ 0.2, 10.3 ⁇ 0.2, 13.7 ⁇ 0.2, 16.5 ⁇ 0.2, 17.1 ⁇ 0.2, 17.5 ⁇ 0.2, 18.8 ⁇ 0.2, 19.2 ⁇ 0.2, 20.7 ⁇ 0.2, 21.3 ⁇ 0.2, 21.6 ⁇ 0.2, 25.8 ⁇ 0.2, 26.8 ⁇ 0.2, and 28.4 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern A hydrate has an X- ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 5.1 ⁇ 0.2, 7.9 ⁇ 0.2, 9.5 ⁇ 0.2, 10.3 ⁇ 0.2, 13.7 ⁇ 0.2, 16.5 ⁇ 0.2, 17.1 ⁇ 0.2, 17.5 ⁇ 0.2, 18.8 ⁇ 0.2, 19.2 ⁇ 0.2, 20.7 ⁇ 0.2, 21.3 ⁇ 0.2, 21.6 ⁇ 0.2, 25.8 ⁇ 0.2, 26.8 ⁇ 0.2, and 28.4 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern A hydrate has an X-ray powder diffraction pattern substantially as shown in Figure 16.
  • the 20 values for the peaks in Figure 16 are as follows: 5.13 (13), 7.87 (80), 9.45 (100), 10.29 (60), 13.7 (28), 16.54 (30), 17.07 (17), 17.51 (40), 18.80 (99), 19.18 (74), 20.69 (21), 21.25 (21), 21.63 (23), 25.85 (32), 26.81 (20), and 28.35 (27).
  • This invention also relates, in part, to a process for preparing the pattern A hydrate by suspending pattern A polymorph (discussed above) in ethyl acetate.
  • the recovered pattern A hydrate contains ⁇ 1 water molecules per molecule of compound IB-Ll-1.1.
  • This invention also relates, in part, to a pattern B (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydro- pyrimidin- 1 (2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide hydrate.
  • the pattern B hydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 6.3 ⁇ 0.2, 7.7 ⁇ 0.2, 10.4 ⁇ 0.2, 12.7 ⁇ 0.2, 13.3 ⁇ 0.2, 14.9 ⁇ 0.2, 15.4 ⁇ 0.2, 16.4 ⁇ 0.2, 18.6 ⁇ 0.2, 18.9 ⁇ 0.2, 19.4 ⁇ 0.2, 22.5 ⁇ 0.2, 23.5 ⁇ 0.2, 24.0 ⁇ 0.2, 26.8 ⁇ 0.2, and 29.0 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern B hydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 6.3 ⁇ 0.2, 7.7 ⁇ 0.2, 10.4 ⁇ 0.2, 12.7 ⁇ 0.2, 13.3 ⁇ 0.2, 14.9 ⁇ 0.2, 15.4 ⁇ 0.2, 16.4 ⁇ 0.2, 18.6 ⁇ 0.2, 18.9 ⁇ 0.2, 19.4 ⁇ 0.2, 22.5 ⁇ 0.2, 23.5 ⁇ 0.2, 24.0 ⁇ 0.2, 26.8 ⁇ 0.2, and 29.0 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern B hydrate has an X- ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 6.3 ⁇ 0.2, 7.7 ⁇ 0.2, 10.4 ⁇ 0.2, 12.7 ⁇ 0.2, 13.3 ⁇ 0.2, 14.9 ⁇ 0.2, 15.4 ⁇ 0.2, 16.4 ⁇ 0.2, 18.6 ⁇ 0.2, 18.9 ⁇ 0.2, 19.4 ⁇ 0.2, 22.5 ⁇ 0.2, 23.5 ⁇ 0.2, 24.0 ⁇ 0.2, 26.8 ⁇ 0.2, and 29.0 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern B hydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 6.3 ⁇ 0.2, 7.7 ⁇ 0.2, 10.4 ⁇ 0.2, 12.7 ⁇ 0.2, 13.3 ⁇ 0.2, 13.5 ⁇ 0.2, 14.9 ⁇ 0.2, 15.4 ⁇ 0.2, 16.4 ⁇ 0.2, 18.5 ⁇ 0.2, 18.6 ⁇ 0.2, 18.9 ⁇ 0.2, 19.4 ⁇ 0.2, 22.5 ⁇ 0.2, 23.5 ⁇ 0.2, 24.0 ⁇ 0.2, 26.8 ⁇ 0.2, and 29.0 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern B hydrate has an X- ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 6.3 ⁇ 0.2, 7.7 ⁇ 0.2, 10.4 ⁇ 0.2, 12.7 ⁇ 0.2, 13.3 ⁇ 0.2, 13.5 ⁇ 0.2, 14.9 ⁇ 0.2, 15.4 ⁇ 0.2, 16.4 ⁇ 0.2, 18.5 ⁇ 0.2, 18.6 ⁇ 0.2, 18.9 ⁇ 0.2, 19.4 ⁇ 0.2, 22.5 ⁇ 0.2, 23.5 ⁇ 0.2, 24.0 ⁇ 0.2, 26.8 ⁇ 0.2, and 29.0 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern B hydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 6.3 ⁇ 0.2, 7.7 ⁇ 0.2, 10.4 ⁇ 0.2, 12.7 ⁇ 0.2, 13.3 ⁇ 0.2, 13.5 ⁇ 0.2, 14.9 ⁇ 0.2, 15.4 ⁇ 0.2, 16.4 ⁇ 0.2, 18.5 ⁇ 0.2, 18.6 ⁇ 0.2, 18.9 ⁇ 0.2, 19.4 ⁇ 0.2, 22.5 ⁇ 0.2, 23.5 ⁇ 0.2, 24.0 ⁇ 0.2, 26.8 ⁇ 0.2, and 29.0 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern B hydrate has an X-ray powder diffraction pattern substantially as shown in Figure 18.
  • the 2 ⁇ values for the peaks in Figure 18 are as follows: 6.31 (7), 7.72 (14), 10.45 (24), 12.67 (26), 13.30 (88), 13.50 (44), 14.89 (70), 15.40 (100), 16.43 (43), 18.46 (47), 18.63 (86), 18.91 (26), 19.42 (33), 22.52 (47), 23.52 (44), 24.02 (20), 26.82 (40), and 28.97 (49).
  • This invention also relates, in part, to a process for preparing the pattern B hydrate by suspending pattern A polymorph (discussed above) in acetonitrile/water (9/1 v/v).
  • the recovered pattern B hydrate contains ⁇ 0.7 water molecules per molecule of compound IB-Ll-1.1.
  • This invention also relates, in part, to a pattern C (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide hydrate.
  • the pattern C hydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 10.5 ⁇ 0.2, 13.3 ⁇ 0.2, 14.9 ⁇ 0.2, 15.4 ⁇ 0.2, 16.4 ⁇ 0.2, 18.6 ⁇ 0.2, 19.0 ⁇ 0.2, 19.4 ⁇ 0.2, 22.5 ⁇ 0.2, 23.5 ⁇ 0.2, 26.9 ⁇ 0.2, and 29.0 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern C hydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 10.5 ⁇ 0.2, 13.3 ⁇ 0.2, 14.9 ⁇ 0.2, 15.4 ⁇ 0.2, 16.4 ⁇ 0.2, 18.6 ⁇ 0.2, 19.0 ⁇ 0.2, 19.4 ⁇ 0.2, 22.5 ⁇ 0.2, 23.5 ⁇ 0.2, 26.9 ⁇ 0.2, and 29.0 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern C hydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 10.5 ⁇ 0.2, 13.3 ⁇ 0.2, 14.9 ⁇ 0.2, 15.4 ⁇ 0.2, 16.4 ⁇ 0.2, 18.6 ⁇ 0.2, 19.0 ⁇ 0.2, 19.4 ⁇ 0.2, 22.5 ⁇ 0.2, 23.5 ⁇ 0.2, 26.9 ⁇ 0.2, and 29.0 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern C hydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 10.5 ⁇ 0.2, 13.3 ⁇ 0.2, 13.5 ⁇ 0.2, 14.9 ⁇ 0.2, 15.4 ⁇ 0.2, 16.4 ⁇ 0.2, 18.6 ⁇ 0.2, 19.0 ⁇ 0.2, 19.4 ⁇ 0.2, 22.5 ⁇ 0.2, 23.5 ⁇ 0.2, 26.9 ⁇ 0.2, and 29.0 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern C hydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 10.5 ⁇ 0.2, 13.3 ⁇ 0.2, 13.5 ⁇ 0.2, 14.9 ⁇ 0.2, 15.4 ⁇ 0.2, 16.4 ⁇ 0.2, 18.6 ⁇ 0.2, 19.0 ⁇ 0.2, 19.4 ⁇ 0.2, 22.5 ⁇ 0.2, 23.5 ⁇ 0.2, 26.9 ⁇ 0.2, and 29.0 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern C hydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 10.5 ⁇ 0.2, 13.3 ⁇ 0.2, 13.5 ⁇ 0.2, 14.9 ⁇ 0.2, 15.4 ⁇ 0.2, 16.4 ⁇ 0.2, 18.6 ⁇ 0.2, 19.0 ⁇ 0.2, 19.4 ⁇ 0.2, 22.5 ⁇ 0.2, 23.5 ⁇ 0.2, 26.9 ⁇ 0.2, and 29.0 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern C hydrate has an X-ray powder diffraction pattern substantially as shown in Figure 20.
  • This invention also relates, in part, to a process for preparing the pattern C hydrate by suspending pattern A polymorph (discussed above) in water.
  • the recovered pattern C hydrate contains ⁇ 1 water molecules per molecule of compound IB-Ll-1.1.
  • This invention also relates, in part, to a pattern D (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide hydrate.
  • the crystallographic unit cell parameters of the pattern D hydrate salt have been determined to be as follows: a is 17.8A, b is 9.6A, and c is 27.0A (more precisely, a is 17.783(2)A, b is 9.5651(12)A, and c is 27.014(4)A); the cell angle is: ⁇ - 93.3° (more precisely, ⁇ is 93.256(2)°); and the cell volume is 4588A 3 (more precisely, 4587.5(10)A 3 ).
  • the salt crystallizes in the C2/c space group.
  • the pattern D hydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 6.6 ⁇ 0.2, 10.0 ⁇ 0.2, 10.5 ⁇ 0.2, 1 l.l ⁇ 0.2, 11.6 ⁇ 0.2, 12.2 ⁇ 0.2, 14.2 ⁇ 0.2, 16.6 ⁇ 0.2, 17.1 ⁇ 0.2, 17.7 ⁇ 0.2, 18.5 ⁇ 0.2, 18.8 ⁇ 0.2, 19.3 ⁇ 0.2, 21.4 ⁇ 0.2, 22.7 ⁇ 0.2, 23.1 ⁇ 0.2, 23.6 ⁇ 0.2, 24.6 ⁇ 0.2, 25.2 ⁇ 0.2, 27.2 ⁇ 0.2, 29.1 ⁇ 0.2, and 31.0 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern D hydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 6.6 ⁇ 0.2, 10.0 ⁇ 0.2, 10.5 ⁇ 0.2, l l.l ⁇ 0.2, 11.6 ⁇ 0.2, 12.2 ⁇ 0.2, 14.2 ⁇ 0.2, 16.6 ⁇ 0.2, 17.1 ⁇ 0.2, 17.7 ⁇ 0.2, 18.5 ⁇ 0.2, 18.8 ⁇ 0.2, 19.3 ⁇ 0.2, 21.4 ⁇ 0.2, 22.7 ⁇ 0.2, 23.1 ⁇ 0.2, 23.6 ⁇ 0.2, 24.6 ⁇ 0.2, 25.2 ⁇ 0.2, 27.2 ⁇ 0.2, 29.1 ⁇ 0.2, and 31.0 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern D hydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 6.6 ⁇ 0.2, 10.0 ⁇ 0.2, 10.5 ⁇ 0.2, l l.l ⁇ 0.2, 11.6 ⁇ 0.2, 12.2 ⁇ 0.2, 14.2 ⁇ 0.2, 16.6 ⁇ 0.2, 17.1 ⁇ 0.2, 17.7 ⁇ 0.2, 18.5 ⁇ 0.2, 18.8 ⁇ 0.2, 19.3 ⁇ 0.2, 21.4 ⁇ 0.2, 22.7 ⁇ 0.2, 23.1 ⁇ 0.2, 23.6 ⁇ 0.2, 24.6 ⁇ 0.2, 25.2 ⁇ 0.2, 27.2 ⁇ 0.2, 29.1 ⁇ 0.2, and 31.0 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern D hydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 6.6 ⁇ 0.2, 10.0 ⁇ 0.2, 10.5 ⁇ 0.2, l l.l ⁇ 0.2 5 11.6 ⁇ 0.2, 12.2 ⁇ 0.2, 12.5 ⁇ 0.2, 14.2 ⁇ 0.2, 16.6 ⁇ 0.2, 17.1 ⁇ 0.2, 17.7 ⁇ 0.2, 18.5 ⁇ 0.2, 18.8 ⁇ 0.2, 19.3 ⁇ 0.2, 21.4 ⁇ 0.2, 22.7 ⁇ 0.2, 22.8 ⁇ 0.2, 23.1 ⁇ 0.2, 23.6 ⁇ 0.2, 24.6 ⁇ 0.2, 24.9 ⁇ 0.2, 25.2 ⁇ 0.2, 27.2 ⁇ 0.2, 29.1 ⁇ 0.2, and 31.0 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern D hydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 6.6 ⁇ 0.2, 10.0 ⁇ 0.2, 10.5 ⁇ 0.2, l l.l ⁇ 0.2, 11.6 ⁇ 0.2, 12.2 ⁇ 0.2, 12.5 ⁇ 0.2, 14.2 ⁇ 0.2, 16.6 ⁇ 0.2, 17.1 ⁇ 0.2, 17.7 ⁇ 0.2, 18.5 ⁇ 0.2, 18.8 ⁇ 0.2, 19.3 ⁇ 0.2, 21.4 ⁇ 0.2, 22.7 ⁇ 0.2, 22.8 ⁇ 0.2, 23.1 ⁇ 0.2, 23.6 ⁇ 0.2, 24.6 ⁇ 0.2, 24.9 ⁇ 0.2, 25.2 ⁇ 0.2, 27.2 ⁇ 0.2, 29.1 ⁇ 0.2, and 31.0 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern D hydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 6.6 ⁇ 0.2, 10.0 ⁇ 0.2, 10.5 ⁇ 0.2, l l.l ⁇ 0.2, 11.6 ⁇ 0.2, 12.2 ⁇ 0.2, 12.5 ⁇ 0.2, 14.2 ⁇ 0.2, 16.6 ⁇ 0.2, 17.1 ⁇ 0.2, 17.7 ⁇ 0.2, 18.5 ⁇ 0.2, 18.8 ⁇ 0.2, 19.3 ⁇ 0.2, 21.4 ⁇ 0.2, 22.7 ⁇ 0.2, 22.8 ⁇ 0.2, 23.1 ⁇ 0.2, 23.6 ⁇ 0.2, 24.6 ⁇ 0.2, 24.9 ⁇ 0.2, 25.2 ⁇ 0.2, 27.2 ⁇ 0.2, 29.1 ⁇ 0.2, and 31.0 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern D hydrate has an X-ray powder diffraction pattern substantially as shown in Figure 22.
  • the 2 ⁇ values for the peaks in Figure 22 are as follows: 6.55 (10), 9.96 (12), 10.51 (37), 11.09 (31), 11.62 (100), 12.24 (44), 12.54 (40), 14.22 (15), 16.62 (68), 17.07 (22), 17.77 (21), 18.52 (82), 18.84 (47), 19.30 (63), 21.45 (34), 22.67 (30), 22.80 (34), 23.08 (20), 23.57 (58), 24.63 (73), 24.88 (26), 25.24 (21), 27.23 (36), 29.06 (41), and 31.04 (21).
  • This invention also relates, in part, to a process for preparing the pattern D hydrate. It was prepared by suspending pattern A polymorph (discussed above) in ethanol. Alternatively, it was prepared by suspending compound IB-Ll-1.1 (103.03mg) in 400ul THF while heated to about 55°C. Aqueous NaOH (IM, 264ul, 1.2 molar equivalent) was added. The solid dissolved completely to yield a clear solution. Ethanol (1.6ml) was added to the solution. The solution was allowed to cool naturally to ambient temperatures. Crystals were formed during the slow evaporation process.
  • This invention also relates, in part, to a pattern E (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin- 1 (2H)-yl)-2-methoxystyry l)phenyl)methanesulfonamide hydrate .
  • the crystallographic unit cell parameters of the pattern E hydrate crystalline disodium salt have been determined to be as follows: a is 9.5A, b is 14.5A, and c is 17.3A (more precisely, a is 9.462(2)A, b is 14.462(3)A, and c is 17.281(4)A); the cell angles are: ⁇ - 84.9°, ⁇ - 80.8°, and ⁇ - 81.8° (more precisely, ⁇ is 84.863(4)°, ⁇ is 80.760(4)°, and ⁇ is 81.751(4)°); and the cell volume is 2304A 3 (more precisely, 2304.4(9)A 3 ).
  • the salt crystallizes in the P-I space group.
  • the pattern E hydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 6.2 ⁇ 0.2, 7.8 ⁇ 0.2, 10.2 ⁇ 0.2, 10.7 ⁇ 0.2, 12.1 ⁇ 0.2, 16.3 ⁇ 0.2, 19.7 ⁇ 0.2, 20.9 ⁇ 0.2, 21.8 ⁇ 0.2, 24.5 ⁇ 0.2, and 28.0 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern E hydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 6.2 ⁇ 0.2, 7.8 ⁇ 0.2, 10.2 ⁇ 0.2, 10.7 ⁇ 0.2, 12.1 ⁇ 0.2, 16.3 ⁇ 0.2, 19.7 ⁇ 0.2, 20.9 ⁇ 0.2, 21.8 ⁇ 0.2, 24.5 ⁇ 0.2, and 28.0 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern E hydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 6.2 ⁇ 0.2, 7.8 ⁇ 0.2, 10.2 ⁇ 0.2, 10.7 ⁇ 0.2, 12.1 ⁇ 0.2, 16.3 ⁇ 0.2, 19.7 ⁇ 0.2, 20.9 ⁇ 0.2, 21.8 ⁇ 0.2, 24.5 ⁇ 0.2, and 28.0 ⁇ 0.2 degrees 20.
  • the pattern E hydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 6.2 ⁇ 0.2, 7.8 ⁇ 0.2, 10.2 ⁇ 0.2, 10.4 ⁇ 0.2, 10.7 ⁇ 0.2, 12.1 ⁇ 0.2, 16.3 ⁇ 0.2, 19.7 ⁇ 0.2, 20.9 ⁇ 0.2, 21.8 ⁇ 0.2, 24.5 ⁇ 0.2, and 28.0 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern E hydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 6.2 ⁇ 0.2, 7.8 ⁇ 0.2, 10.2 ⁇ 0.2, 10.4 ⁇ 0.2, 10.7 ⁇ 0.2, 12.1 ⁇ 0.2, 16.3 ⁇ 0.2, 19.7 ⁇ 0.2, 20.9 ⁇ 0.2, 21.8 ⁇ 0.2, 24.5 ⁇ 0.2, and 28.0 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern E hydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 6.2 ⁇ 0.2, 7.8 ⁇ 0.2, 10.2 ⁇ 0.2, 10.4 ⁇ 0.2, 10.7 ⁇ 0.2, 12.1 ⁇ 0.2, 16.3 ⁇ 0.2, 19.7 ⁇ 0.2, 20.9 ⁇ 0.2, 21.8 ⁇ 0.2, 24.5 ⁇ 0.2, and 28.0 ⁇ 0.2 degrees 2 ⁇ .
  • the pattern E hydrate has an X-ray powder diffraction pattern substantially as shown in Figure 23.
  • the 2 ⁇ values for the peaks in Figure 23 are as follows: 6.19 (6), 7.81 (18), 10.17 (13), 10.40 (14), 10.68 (39), 12.06 (20), 16.29 (78), 19.72 (32), 20.88 (100), 21.77 (27), 24.52 (25), and 28.01 (27).
  • This invention also relates, in part, to a process for preparing the pattern E hydrate. It was prepared by suspending compound IB-Ll-1.1 (56.76mg) in 200ul THF while heated. Aqueous NaOH (IM, 146uL, 1.2 molar equivalent) was added, which yielded a clear solution. Ethanol (80OuI) was added to the solution. The solution was allowed to cool naturally to ambient temperatures. Crystals were formed during the slow evaporation process. Although it appears that the lattice can accommodate as much as one water molecule per molecule of compound IB-Ll-1.1, the recovered pattern D hydrate contained -0.25 water molecules per molecule of compound IB-Ll-1.1.
  • compositions comprising one or more compounds and/or salts of the invention (including the crystalline compounds and salts discussed in section G above).
  • the compositions comprise one or more substantially phase pure crystalline forms (compounds/salts/solvates/hydrates) discussed in section G above.
  • the compositions can be pharmaceutical compositions.
  • compositions further comprise one or more additional therapeutic agents.
  • additional therapeutic agents can, but need not be, additional HCV inhibitors.
  • composition depends on the method of administration, and typically comprises one or more conventional pharmaceutically acceptable carriers, adjuvants, and/or vehicles (together referred to as "excipients").
  • excipients are generally discussed in, for example, Hoover, J., Remington's Pharmaceutical Sciences (Mack Publishing Co., 1975) and Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (Lippincott Williams & Wilkins, 2005).
  • Solid dosage forms for oral administration include, for example, capsules, tablets, pills, powders, and granules.
  • the compounds or salts are ordinarily combined with one or more excipients.
  • the compounds or salts can be mixed with, for example, lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
  • Such capsules or tablets can contain a controlled-release formulation, as can be provided in, for example, a dispersion of the compound or salt in hydroxypropylmethyl cellulose.
  • the dosage forms also can comprise buffering agents, such as sodium citrate, or magnesium or calcium carbonate or bicarbonate. Tablets and pills additionally can be prepared with enteric coatings.
  • Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions (including both oil-in-water and water-in-oil emulsions), solutions (including both aqueous and non-aqueous solutions), suspensions (including both aqueous and non-aqueous suspensions), syrups, and elixirs containing inert diluents commonly used in the art (e.g., water).
  • Such compositions also can comprise, for example, wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.
  • Parenteral administration includes subcutaneous injections, intravenous injections, intramuscular injections, intrasternal injections, and infusion.
  • Injectable preparations e.g., sterile injectable aqueous or oleaginous suspensions
  • suitable dispersing, wetting agents, and/or suspending agents can be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents.
  • Acceptable vehicles and solvents include, for example, water, 1,3- butanediol, Ringer's solution, isotonic sodium chloride solution, bland fixed oils (e.g., synthetic mono- or diglycerides), fatty acids (e.g., oleic acid), dimethyl acetamide, surfactants (e.g., ionic and non-ionic detergents), and/or polyethylene glycols.
  • Formulations for parenteral administration may, for example, be prepared from sterile powders or granules having one or more of the excipients mentioned for use in the formulations for oral administration.
  • a compound or salt of the invention can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.
  • the pH may be adjusted, if necessary, with a suitable acid, base, or buffer.
  • Suppositories for rectal administration can be prepared by, for example, mixing a compound or salt of the invention with a suitable nonirritating excipient that is solid at ordinary temperatures, but liquid at the rectal temperature, and will therefore melt in the rectum to release the drug.
  • suitable excipients include, for example, cocoa butter; synthetic mono-, di-, or triglycerides, fatty acids, and/or polyethylene glycols.
  • Topical administration includes the use of transdermal administration, such as transdermal patches or iontophoresis devices.
  • the preferred total daily dose of the compound or salt is typically from about 0.001 to about lOOmg/kg, more preferably from about 0.001 to about 30mg/kg, and even more preferably from about 0.01 to about 10mg/kg (i.e.,mg of the compound or salt per kg body weight).
  • Dosage unit compositions can contain such amounts or submultiples thereof to make up the daily dose.
  • the administration of the compound or salt will be repeated a plurality of times. Multiple doses per day typically may be used to increase the total daily dose, if desired.
  • Factors affecting the preferred dosage regimen include the type, age, weight, sex, diet, and condition of the patient; the severity of the pathological condition; the severity of the pathological condition; the route of administration; pharmacological considerations, such as the activity, efficacy, pharmacokinetic, and toxicology profiles of the particular compound or salt used; whether a drug delivery system is utilized; and whether the compound or salt is administered as part of a drug combination.
  • the dosage regimen actually employed can vary widely, and therefore, can derive from the preferred dosage regimen set forth above.
  • kits This invention also is directed, in part, to a kit comprising one or more compounds and/or salts of the in invention.
  • the kit can optionally contain one or more additional therapeutic agents and/or instructions for, for example, using the kit.
  • This invention also is directed, in part, to a method for inhibiting replication of an RNA virus.
  • the method comprises exposing the virus to one or more compounds and/or salts of this invention.
  • replication of the RNA virus is inhibited in vitro.
  • replication of the RNA virus is inhibited in vivo.
  • the RNA virus whose replication is being inhibited is a single-stranded, positive sense RNA virus.
  • the RNA virus whose replication is being inhibited is a virus from the Flaviviridae family.
  • the RNA virus whose replication is being inhibited is HCV.
  • This invention also is directed, in part, to a method for inhibiting HCV RNA polymerase.
  • the method comprises- exposing the polymerase with one or more compounds and/or salts of this invention.
  • HCV RNA polymerase activity is inhibited in vitro. In other embodiments, HCV RNA polymerase activity is inhibited in vivo.
  • the term "inhibiting” means reducing the level of RNA virus replication/HCV polymerase activity either in vitro or in vivo. For example, if a compound/salt of the invention reduces the level of RNA virus replication by at least about 10% compared to the level of RNA virus replication before the virus was exposed to the compound/salt, then the compound/salt inhibits RNA virus replication. In some embodiments, the compound/salt can inhibit RNA virus replication by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%.
  • This invention also is directed, in part, to a method for treating a disease that can be treated by inhibiting HCV RNA polymerase.
  • this invention also is directed, in part, to a method for treating hepatitis C in an animal in need of such treatment.
  • These methods comprise administering to the animal one or more compounds and/or salts of the invention, and, optionally, one or more additional therapeutic agents.
  • a therapeutically effective amount of the compound(s) and/or salt(s) is administered to the animal.
  • “Treating” means ameliorating, suppressing, eradicating, preventing, reducing the risk of, and/or delaying the onset of the disease being treated.
  • treating encompass administration of the compounds and/or salts of the invention to an HCV-negative patient that is a candidate for an organ transplant.
  • the methods of treatment are particularly suitable for use with humans, but may be used with other animals, particularly mammals.
  • a “therapeutically-effective amount” or “effective amount” is an amount that will achieve the goal of treating the targeted condition.
  • the methods comprise combination therapy, wherein the compound(s) and/or salt(s) of the invention is/are co-administered with a second (or even a third, fourth, etc.) compound, such as, for example, another therapeutic agent used to treat hepatitis C (e.g., interferon or interferon/ribavirin combination, or an HCV inhibitor such as, for example, an HCV polymerase inhibitr or an HCV protease inhibitor).
  • a second (or even a third, fourth, etc.) compound such as, for example, another therapeutic agent used to treat hepatitis C (e.g., interferon or interferon/ribavirin combination, or an HCV inhibitor such as, for example, an HCV polymerase inhibitr or an HCV protease inhibitor).
  • the compound(s) and/or salt(s) of this invention can also be coadministered with therapeutic agents other than therapeutic agents used to treat hepatitis C (e.g., anti-HF
  • the compound(s) and/or salt(s) of the invention and the second, etc. therapeutic agent(s) may be administered in a substantially simultaneous manner (e.g., or within about 5 minutes of each other), in a sequential manner, or both. It is contemplated that such combination therapies may include administering one therapeutic agent multiple times between the administrations of the other. The time period between the administration of each agent may range from a few seconds (or less) to several hours or days, and will depend on, for example, the properties of each composition and active ingredient (e.g., potency, solubility, bioavailability, half-life, and kinetic profile), as well as the condition of the patient.
  • the compound(s) and/or salt(s) of this invention and the second, etc. therapeutic agent may also be administered in a single formulation.
  • This invention also is directed, in part, to a use of one or more compounds and/or salts of the invention, and, optionally one or more additional therapeutic agents to prepare a medicament.
  • the medicament is for co-administration with one or more additional therapeutic agents.
  • the medicament is for inhibiting replication of an RNA virus.
  • the medicament is for treating hepatitis C.
  • This invention also is directed, in part, to one or more compounds and/or salts of the invention, and, optionally one or more additional therapeutic agents, for use as a medicament.
  • the medicament is for inhibiting replication of an RNA virus.
  • the medicament is for treating hepatitis C.
  • This invention also is directed, in part, to intermediates that correspond in structure to formula II that can be used to prepare the compounds of formula I (and their salts)(although some intermediates can also be used, just like the compounds of formula I, as HCV inhibitors, and one skilled in the art can determine such ability of the compounds of formula II by utilizing, for example, the methods discussed below):
  • X 2 is halo
  • X 2 is selected from the group consisting of chloro, bromo, and iodo. In other embodiments, X 2 is selected from the group consisting of chloro and bromo. In yet other embodiments, X 2 is selected from the group consisting of chloro and iodo. In yet other embodiments, X 2 is selected from the group consisting of iodo and bromo. In further embodiments, X 2 is fluoro. In yet further embodiments, X 2 is chloro. In yet further embodiments, X 2 is bromo. And in yet further embodiments, X 2 is iodo.
  • the compounds of formula II correspond in structure to formula HB:
  • R 1 is selected from the group consisting of hydrogen, methyl, and nitrogen-protecting group
  • R 2 is selected from the group consisting of hydrogen and halo
  • R 3 is selected from the group consisting of hydrogen and halo
  • R 4 is selected from the group consisting of Ci-C 4 -alkyl, C 3 -C 6 -carbocyclyl, and 5-6-membered heterocyclyl, wherein:
  • Ci-C 4 -alkyl optionally is substituted with up to three substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and
  • the C 3 -C 6 -carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, halo, and alkylsulfonylamino;
  • R 5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy, and halo; and X 2 is selected from the group consisting of chloro, bromo, and iodo.
  • X 2 is selected from the group consisting of chloro, bromo, and iodo.
  • R 1 is hydrogen
  • R 2 is selected from the group consisting of hydrogen and halo;
  • R 3 is hydrogen;
  • R 4 is tert-butyl;
  • R 5 is selected from the group consisting of hydrogen, hydroxy, and methoxy; and X 2 is selected from the group consisting of bromo and iodo.
  • R 1 is selected from the group consisting of hydrogen and methyl
  • R 2 is selected from the group consisting of hydrogen and methyl
  • R 3 is selected from the group consisting of hydrogen and methyl
  • R 4 is tert-butyl
  • R 5 is selected from the group consisting of hydroxy and methoxy
  • X 2 is selected from the group consisting of chloro, bromo, and iodo.
  • R s is selected from the group consisting of hydroxy and methoxy; and X 2 is selected from the group consisting of chloro, bromo, and iodo.
  • the compound of formula II is selected from the group consisting of
  • This invention also is directed, in part, to starting compounds that correspond in structure to formula III that can be used to prepare the compounds of formulas II and I (and their salts):
  • R 1 is selected from the group consisting of hydrogen, methyl, and nitrogen-protecting group
  • R 2 is selected from the group consisting of hydrogen and halo
  • R 3 is selected from the group consisting of hydrogen and halo.
  • R 1 is selected from the group consisting of hydrogen
  • R 2 is selected from the group consisting of hydrogen and halo
  • R 3 is selected from the group consisting of hydrogen.
  • R 1 is selected from the group consisting of hydrogen and methyl
  • R 2 is selected from the group consisting of hydrogen and methyl
  • R 3 is selected from the group consisting of hydrogen and methyl. [00418] hi some embodiments, the compound of formula III is uracil.
  • This invention also is directed, in part, to starting compounds that correspond in structure to formula IV that can be used to prepare the compounds of formulas II and I (and their salts):
  • R 4 , R 5 , and X 2 are as discussed above for the compounds of formula I and II;
  • X 1 is halo
  • X 1 is selected from the group consisting of chloro, bromo, and iodo. In other embodiments, X 1 is selected from the group consisting of chloro and bromo. In yet other embodiments, X 1 is selected from the group consisting of chloro and iodo. In yet other embodiments, X 1 is selected from the group consisting of iodo and bromo. In further embodiments, X 1 is fluoro. In yet further embodiments, X 1 is chloro.
  • X 1 is bromo. And in yet further embodiments, X 1 is iodo. As to X 1 and X 2 , in some embodiments, X 1 and X 2 are identical. [00422]
  • the various embodiments for R 4 , R 5 , X 1 , and X 2 discussed above can be combined to form various embodiments of compounds of formula IV, and all embodiments of compounds of formula III so formed are within the scope of Applicants' invention. Some exemplary embodiments of the compounds (and salts thereof) of formula IV are discussed below. [00423] In some embodiments of the compounds of formula IV:
  • R 4 is selected from the group consisting of Ci-C 4 -alkyl, C 3 -C 6 -carbocyclyl, and 5-6-membered heterocyclyl, wherein:
  • Ci-C 4 -alkyl optionally is substituted with up to three substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and
  • the C 3 -C 6 -carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, halo, and alkylsulfonylamino;
  • R 5 is selected from the group consisting of hydrogen, hydroxy, and alkyloxy
  • X 1 is selected from the group consisting of chloro, bromo, and iodo
  • X 2 is selected from the group consisting of chloro, bromo, and iodo.
  • R 4 is selected from the group consisting of tert-butyl
  • R 5 is selected from the group consisting of hydrogen, hydroxy, and methoxy
  • X 1 is selected from the group consisting of bromo and iodo
  • X 2 is selected from the group consisting of bromo and iodo.
  • R 4 is selected from the group consisting of tert-butyl
  • R 5 is selected from the group consisting of hydroxy and methoxy
  • X 1 is selected from the group consisting of chloro, bromo, and iodo
  • X 2 is selected from the group consisting of chloro, bromo, and iodo.
  • R 4 is tert-butyl
  • R 5 is selected from the group consisting of hydroxy and methoxy
  • X 1 is selected from the group consisting of chloro, bromo, and iodo
  • X 2 is selected from the group consisting of chloro, bromo, and iodo.
  • the compound of formula IV is selected from the group consisting of
  • This invention also is directed, in part, to a process for preparing compounds of formula II.
  • the process comprises reacting a compound of formula III with a compound of formula IV in the presence of (i) copper (I) salt catalyst and (ii) nitrogenous heteroaryl ligand:
  • R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , and X 2 are as discussed above.
  • compound HI is uracil
  • compound IV corresponds in structure to a compound selected from the group consisting of compound IV-I, IV-Br, and IV-Cl, with compounds IV-
  • Suitable Cu(I) catalysts include, for example, CuI, CuBr, CuCl, Cu 2 O, and CH 3 C(O)OCu.
  • the catalyst is selected from the group consisting of CuI and CuBr.
  • the catalyst is CuI.
  • the catalyst is CuBr.
  • the process is conducted in the presence of a base.
  • the base is an inorganic base.
  • Suitable inorganic bases include, for example, potassium, sodium, and cesium salts ⁇ e.g., K 2 CO 3 , K 3 PO 4 , Cs 2 CO 3 , Na 2 CO 3 ).
  • the base is selected from the group consisting of potassium salt and cesium salt.
  • the salt is selected from the group consisting Of K 3 PO 4 and Cs 2 CO 3 .
  • the base comprises a potassium salt.
  • the potassium salt is K 2 CO 3 .
  • the potassium salt is K 3 PO 4 .
  • the base comprises a cesium salt.
  • the potassium salt is Cs 2 CO 3 .
  • Suitable solvents include, for example, dimethylsulfoxide (DMSO), dimethylformamide (DMF), and acetonitrile (MeCN).
  • DMSO dimethylsulfoxide
  • DMF dimethylformamide
  • MeCN acetonitrile
  • the solvent is DMSO.
  • the process is conducted at a temperature of from about 40 to about 13O 0 C.
  • the nitrogenous heteroaryl ligand comprises 8-hydroxyquinoline.
  • the ligand comprises 2-(2-pyridyl)-benzimidazole.
  • the ligand comprises a picolinamide compound corresponding in structure to formula V:
  • R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are independently selected from the group consisting of hydrogen, Ci -4 -perfluoroalkyl, Ci -4 -alkyloxy, Ci -4 -haloalkyl, chloro, or cyano.
  • R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are independently selected from the group consisting of hydrogen, methyl, methoxy, trifluoromethyl, chloro, and cyano.
  • the ligand of formula V comprises N-(4-cyanophenyl)picolinamide. In other embodiments, the ligand of formula V comprises N-(2-cyanophenyl)picolinamide.
  • the process comprises (a) preparing a compound of formula IV; and (b) reacting a compound of formula III with a compound of formula IV in the presense of (i) copper (I) salt catalyst and (ii) nitrogenous heteroaryl ligand, optionally in the presence of inorganic base.
  • Compound of formula IV-I can be prepared by, for example, converting 2-tert-butylphenol into 2-tert-butyl-4,6-diiodophenol (by, for example, reacting it with NaI and NaOCl), and then converting the 2-tert-butyl-4,6-diiodophenol into l-tert-butyl-3,5-diiodo-2-methoxybenzene (by, for example, treating it with CH 3 I in the presence of a base, such as, for example, NaOH).
  • a base such as, for example, NaOH
  • Compound of formula IV-Br can be prepared by, for example, converting 2-tert-butylphenol into 2,4-dibromo-6-tert-butylphenol (by, for example, reacting it with l,3-dibromo-5,5-dimethylimidazo- lidine-2,4-dione), and then converting the 2,4-dibromo-6-tert-butylphenol into l,5-dibromo-3-tert-butyl- 2-methoxybenzene (by, for example, treating it with CH 3 I in the presence of KOtBu).
  • Compound (1-1) wherein R 7 is, for example, hydrogen or -CO 2 Me, and R 8 is, for example, hydrogen or t-butyl, may be treated with nitric acid in solvents such as, for example, acetic acid or water in a temperature range of about 0 to about 35°C over about 1 to about 5h to provide compound (1-2).
  • solvents such as, for example, acetic acid or water in a temperature range of about 0 to about 35°C over about 1 to about 5h
  • Compound (1-2) may then be reduced using conditions known to those skilled in the art to furnish the corresponding aniline (1-3).
  • Typical conditions for this reduction include using hydrogen at a pressure of about 1 to about 5 atmospheres in the presence of a catalyst such as, for example, palladium or platinum on charcoal in a solvent such as, for example, tetrahydrofuran, ethyl acetate, ethanol, or hexane at or near ambient temperature over a period of about 1 to about 12h.
  • a catalyst such as, for example, palladium or platinum on charcoal
  • a solvent such as, for example, tetrahydrofuran, ethyl acetate, ethanol, or hexane at or near ambient temperature over a period of about 1 to about 12h.
  • an alternative reduction procedure may be more appropriate such as, for example, using iron powder in the presence of a mild acid such as, for example, ammonium chloride or dilute hydrochloric acid at reflux temperatures in a mixture of solvents containing, for example, methanol, water, and/or tetrahydrofuran over about 1 to about 12h
  • Another set of reduction conditions includes the use of sodium borohydride in a solvent mixture such as, for example, water and tetrahydrofuran.
  • Yet another set of reduction conditions includes the use of tin(II) chloride in the presence of hydrochloric acid in such solvents as, for example, water and methanol or mixtures thereof.
  • Compound (1-2) may be modified prior to reduction. For example, treatment of compound (1-2), wherein R 7 is hydrogen, with iodine monochloride in a mixture of methanol and water at or near ambient temperature over a period of about 8 to about 24h supplies compound (1-4), wherein X 1 is iodine.
  • compound (1-2) can be treated with pyridinium hydrobromide perbromide in a solvent such as, for example, acetic acid at or near ambient temperature over a period of about 2 to about 16h to provide compound (1-4), wherein X 1 is bromine. Modifications may be introduced at the phenol moiety in compound (1-4).
  • the phenol may be alkylated with alkyl halides (e.g., methyl iodide), alkyl sulfates (e.g., methyl sulfate), alkenyl halides (e.g., allyl bromide), alkynyl halides (e.g., propargyl bromide) in the presence of a base such as, for example, potassium carbonate in acetone, sodium hydride in dimethylformamide, or potassium t-butoxide in tetrahydrofuran, at temperatures from about 0 to about 35 0 C over a period of about 1 to about 24h to provide compound (1-5), wherein R 9 is, for example, alkyl, alkenyl, or alkynyl.
  • alkyl halides e.g., methyl iodide
  • alkyl sulfates e.g., methyl sulfate
  • alkenyl halides e.g
  • alkylation may be achieved by using a reagent such as (trimethylsilyl) diazomethane in solvents such as, for example, methanol or t-butyl methyl ether, or mixtures thereof in a sealed tube at or near room temperature over about 8 to about 24h.
  • solvents such as, for example, methanol or t-butyl methyl ether, or mixtures thereof in a sealed tube at or near room temperature over about 8 to about 24h.
  • Compound (1-5) may subsequently be reduced to compound (1-6) using the iron powder or tin(II) chloride conditions described above.
  • An alternative reduction procedure employs hydrogenation at approximately 1 atmosphere pressure with a catalyst such as 5% platinum on sulf ⁇ ded carbon in a solvent such as methanol.
  • Protection of the resultant aniline of compound (1-6) with, for example, a t-butyl carbamate can be achieved by treatment with di- tert-butyl dicarbonate in a solvent such as, for example, tetrahydrofuran or dioxane at a temperature of about 50 to about 65 0 C for about 1 to about 8h provides compound (1-7).
  • a solvent such as, for example, tetrahydrofuran or dioxane
  • Modifications may also occur at the phenol moiety in compound (1-2).
  • One skilled in the art may alkylate the phenol of compound (1-2) using, for example, the conditions described above to obtain compound (1-8).
  • Compound (1-8) is transformed into compound (1-9) using, for example, one or more of the appropriate reduction conditions described above.
  • Such a compound may be prepared by exposing compound (1-2) to sulfonyl chlorides such as, for example, methanesulfonyl chloride, cyclohexanesulfonyl chloride, benzenesulfonyl chloride, or 3-chloropropane sulfonyl chloride in the presence of a base such as, for example, triethylamine, diisopropylethylamine, or pyridine in a solvent such as, for example, dichloromethane at or near ambient temperature for a period of about 1 to about 24h.
  • a base such as, for example, triethylamine, diisopropylethylamine, or pyridine
  • a solvent such as, for example, dichloromethane at or near ambient temperature for a period of about 1 to about 24h.
  • One skilled in the art can then transform compound (1-8) into compound (1-9) with an appropriate set of reduction conditions.
  • Aniline (2-4) can be prepared through use of the Curtius rearrangement.
  • compound (2-1) wherein R 4 is not amino
  • compound (2-2) can be treated in refluxing thionyl chloride with a catalytic amount of dimethylformamide for about 1 to about 4h to obtain acid chloride (2-2).
  • Treatment with thionyl chloride at the reflux temperature in solvents such as, for example, chloroform or toluene also furnishes compound (2-2).
  • Compound (2-2) can be reacted with an aqueous solution of sodium azide in a solvent such as, for example, acetone over about 1 to about 8h to provide acyl azide (2-3).
  • Compound (2-3) can then undergo a Curtius rearrangement in refluxing solvents such as dioxane or toluene.
  • the intermediate isocyanate is hydrolyzed with an aqueous acid such as dilute hydrochloric acid in a solvent such as dimethoxyethane to provide compound (2-4).
  • SCHEME 3
  • Compound (3-1), wherein R 10 is, for example, hydrogen, bromine, iodine, or -CO 2 Me, can be treated with an acrylic acid either neat at or near ambient temperature in a solvent such as, for example, toluene and heated to reflux over a period of about 15 to about 48h to supply compound (3-2). When excess of an acrylic acid is used, compound (3-3) is produced.
  • Compound (3-2) or (3-3) can be treated with urea in a solvent such as, for example, acetic acid at about 100 to about 120°C over about 2 to about 48h to supply compound (3-4).
  • Compound (4-2) can be prepared from compound (3-1) dissolved in solvents such as, for example, dimethylformamide or dimethylacetamide by the addition of a benzene solution of (E)-3- methoxyacryloyl isocyanate (prepared as described by Santana, L.; et al. J. Heterocyclic Chem. 1999, 36, 293-295.) at a temperature of about -40 to about -15°C under an inert atmosphere and then warming to ambient temperature for from about 30 min to about 4h.
  • solvents such as, for example, dimethylformamide or dimethylacetamide
  • Compound (4-2) can be treated with an acid such as, for example, sulfuric acid in mixtures of water and ethanol in a temperature range of from about 90 to about 11O 0 C for about 1 to about 8h to supply compound (4-3).
  • an acid such as, for example, sulfuric acid in mixtures of water and ethanol in a temperature range of from about 90 to about 11O 0 C for about 1 to about 8h to supply compound (4-3).
  • compound (4-2) can be cyclized to uracil (4-3) under the basic conditions described by Ueno, Y.; et al. J. Org. Chem. 70:7925-7935 (2005).
  • SCHEME 5 SCHEME 5
  • Compound (9-1) can be treated in refluxing thionyl chloride for about 1 to about 4h to obtain acid chloride (9-2).
  • Treatment with thionyl chloride at the reflux temperature in solvents such as, for example, chloroform or toluene also furnishes compound (9-2).
  • Compound (2) is converted to the corresponding aldehyde (9-3) by reduction with lithium tri-/-butoxyaluminum hydride in a solvent such as, for example, tetrahydrofuran at about -78 °C over from about 1 to about 8h.
  • the reduction can also be achieved by treatment with indium chloride and tributyltin hydride in the presence of triphenylphosphine in a solvent such as tetrahydrofuran or toluene at temperatures from about -40 to about 0 0 C.
  • Compound (9-3) can be treated with compound (9-4) in the presence of a base such as potassium /-butoxide in a solvent such as dichloromethane at or near room temperature over a period of about 1 to about 8h to provide compound (9-5).
  • Compound (10-1), wherein X 1 is halo (e.g., bromine, iodine) can undergo a Suzuki reaction with vinyl boronic acid (10-2) to provide compound (10-3).
  • the reaction typically requires the use of a base and a catalyst.
  • bases include, for example, potassium carbonate, potassium phosphate, potassium f-butoxide, sodium carbonate, cesium carbonate, and cesium fluoride.
  • catalysts include, for example, tris(dibenzylidineacetone)dipalladium (0), palladium acetate, bis(triphenyl phosphine)palladium (II) chloride, tetrakis(triphenylphosphine)palladium, dichloro[l,l'-bis(di-tert- butylphosphino)ferrocene] palladium (II), or dichloro[l,l'-bis(diphenylphosphino)ferrocene] palladium (II) dichloromethane adduct.
  • the reaction may be conducted in a solvent such as, for example, water, dioxane, dimethoxyethane, dimethylformamide, toluene, ethanol, tetrahydrofuran and the like or mixtures thereof.
  • a solvent such as, for example, water, dioxane, dimethoxyethane, dimethylformamide, toluene, ethanol, tetrahydrofuran and the like or mixtures thereof.
  • the reaction may be conducted at ambient or elevated temperatures.
  • Compound (11-1) can be converted to compound (11-2) by treatment with diazomethane in a solvent such as, for example, tetrahydrofuran in the presence of palladium acetate at or near room temperature over a period of about 30 min to about 4h.
  • a solvent such as, for example, tetrahydrofuran
  • Compound (11-1) is reduced to supply compound (14-2).
  • Typical conditions for this reduction include using hydrogen at a pressure of about 1 to about 5 atmospheres in the presence of a catalyst such as, for example, palladium or platinum on charcoal in a solvent such as, for example, tetrahydrofuran, ethyl acetate, ethanol, or hexane at or near ambient temperature over a period of about 1 to about 12h.
  • Compound (15-1) can be converted in a two-step sequence to compound (15-2).
  • the initial step involves reduction of the aromatic nitro moiety with iron powder in the presence of a mild acid such as, for example, ammonium chloride or dilute hydrochloric acid at temperatures from about 60 to about 80 0 C in a mixture of solvents containing, for example, methanol, water, and tetrahydrofuran over about 1 to about 12h.
  • the second step consists of exposure of the aniline, prepared in the first step, to methanesulfonyl chloride in the presence of a base such as pyridine in a solvent such as dichloromethane at or near ambient temperature.
  • Compound (17-1) can be mesylated to provide compound (17-2) by treatment with methanesulfonyl chloride in the presence of a base such as, for example, pyridine in a solvent such as, for example, dichloromethane.
  • a base such as, for example, pyridine
  • a solvent such as, for example, dichloromethane.
  • Compound (17-3) can be exposed to borane dimethyl sulfide complex in a solvent such as, for example, tetrahydrofuran at approximately about 0 to about 1O 0 C to supply compound (17-4).
  • Compounds (17-2) and (17-4) can be combined with acetaldehyde in refluxing tetrahydrofuran. Subsequent treatment with water at room temperature yields compound (17-5).
  • Carboxylic acid (18-1) can be reduced with boron tetrahydrofuran complex with heating to provide alcohol (18-2).
  • Compound (18-2) is converted to the corresponding bromide (18-3) with N- bromosuccinimide and triphenylphosphine in solvents such as, for example, dichloromethane at room temperature in several hours.
  • Compound (18-4) can be used for example to make compound (9-5) as described in Scheme 5.
  • Benzaldehyde (19-1) can be treated with diethyl phosphonate in the presence of a base such as, for example, sodium methoxide in a solvent such as, for example, methanol at room temperature to provide compound (19-2).
  • a base such as, for example, sodium methoxide
  • a solvent such as, for example, methanol at room temperature
  • Compound (19-2) can be treated with N-chlorosuccinimide and triphenylphosphine in dichloromethane at room temperature to yield compound (19-3).
  • Compound (19-2) can also be reacted with (diethylamino)sulfur trifluoride (DAST) to supply compound (19-4).
  • DAST diethylamino)sulfur trifluoride
  • Compound (19-1) can also be treated with p-toluenesulfonic acid and trimethyl orthoformate in methanol at about 50 0 C to provide acetal (19-5).
  • Compound (19-5) can be converted to compound (19-6) by exposure to triethyl phosphite and boron trifluoride diethyl etherate at about -20 0 C to about ambient temperature.
  • Phenol (20-1), wherein R 4 is other than amino, is treated with a source of electrophilic halide, such as, for example, iodine monochloride to provide dihalogenated compound (20-2), wherein X 1 and X 2 are independently bromine or iodine.
  • Compound (20-2) is transformed to compound (20-3) by reaction of an alkylating agent such as, for example, methyl sulfate with a base such as, for example, potassium carbonate in refluxing acetone.
  • methyl iodide in the presence of a base such as, for example, potassium ⁇ -butoxide in a solvent such as, for example, tetrahydrofuran, or dimethylformamide also furnish compound (20-3).
  • compound (20-2) can be methylated with (trimethylsiryl)diazomethane in a solvent such as, for example, t-butyl methyl ether.
  • Compound (20-3) can be reacted with uracil, ligand (20-4), copper (I) iodide, and potassium phosphate in dimethyl sulfoxide at about 40°C to about 100°C to supply compound (20-5).
  • compound (20-3) when in compound (20-3), R 4 is tert-buryl, X 1 is iodo, and X 2 is iodo or bromo, compound (20-3) can be stirred with uracil and compound (20-4) in the presence of CuI and K 2 PCU in DMSO for about 15 to about 24h at about 60 0 C to supply compound (20-5).
  • ligand (20-4) for making (20-5) are 8-hydroxyquinoline and 2-(2-pyridyl)-benzimidazole.
  • Compound (21-1) can be nitrated with nitric acid in acetic acid in a temperature range of about 10 to about 15°C to give compound (21-2).
  • the phenol moiety of compound (21-2) can be protected as a silyl ether, e.g. t-butyldimethylsilyl ether, by treatment with a silyl chloride such as, for example, t-butyl dimethylsilyl chloride and imidazole in a solvent such as, for example, dimethyl formamide at ambient temperature to furnish compound (21-3).
  • Compound (21-3) may then be reduced using conditions known to those skilled in the art to furnish the corresponding aniline (21-4).
  • Typical conditions for this reduction include using hydrogen at a pressure of about 1 to about 5 atmospheres in the presence of a catalyst such as, for example, palladium or platinum on charcoal in a solvent such as, for example, tetrahydrofuran, ethyl acetate, ethanol, methanol, or hexane at or near ambient temperature over a period of about 1 to about 12h.
  • a catalyst such as, for example, palladium or platinum on charcoal
  • a solvent such as, for example, tetrahydrofuran, ethyl acetate, ethanol, methanol, or hexane at or near ambient temperature over a period of about 1 to about 12h.
  • an alternative reduction procedure may be more appropriate such as, for example, using iron powder in the presence of a mild acid such as, for example, ammonium chloride or dilute hydrochloric acid at reflux temperatures in a mixture of solvents containing, for example, methanol, water, and tetrahydrofuran over about 1 to about 12h.
  • a mild acid such as, for example, ammonium chloride or dilute hydrochloric acid at reflux temperatures in a mixture of solvents containing, for example, methanol, water, and tetrahydrofuran over about 1 to about 12h.
  • Aniline (21-4) can then by sulfonylated with methanesulfonyl chloride in the presence of pyridine in a solvent such as, for example, dichloromethane.
  • the starting material and reagents are combined at about 0°C and then allowed to gradually warm to ambient temperature over the course of the reaction to supply compound (21-5).
  • the silyl ether protecting group is removed under conditions familiar to one skilled in the art. For example, tetrabutylammonium fluoride in tetrahydrofuran at room temperature transforms compound (21-5) to compound (21-6).
  • the phenol group of compound (21-6) may be sulfonylated with trifluoromethanesulfonic anhydride in the presence of a base such as, for example, pyridine in a solvent such as, for example, dichloromethane at room temperature to provide compound (21-7).
  • a base such as, for example, pyridine
  • a solvent such as, for example, dichloromethane at room temperature
  • Compound (21-7) can be used as described in Scheme 12 to make compound (12-3).
  • Compound (22-1) is converted to compound (22-2) in a two-step sequence.
  • compound (22- 1) can be hydrolyzed with a base such as, for example, sodium hydroxide, lithium hydroxide, or potassium hydroxide in a solvent such as, for example, methanol, ethanol, or tetrahydrofuran, or mixtures thereof.
  • the resultant reaction mixture can be stirred for a period of about 6 to about 48h at ambient temperature.
  • the intermediate carboxylic acid is treated in refluxing thionyl chloride with or without a catalytic amount of dimethylformamide for about 1 to about 4h to deliver acid chloride (22-2).
  • Treatment with thionyl chloride at reflux temperature in solvents such as, for example, chloroform or toluene also furnishes compound (22-2).
  • solvents such as, for example, chloroform or toluene
  • Treatment of the carboxylic acid with oxalyl chloride in dichloromethane with a catalytic amount of dimethylformamide also furnishes compound (22-2).
  • Compound (22-2) can be treated with an amine or the corresponding salt in a solvent such as, for example, dioxane, dimethylformamide, dimethylacetamide, or dichloromethane optionally in the presence of a base such as, for example, pyridine, triethylamine or diisopropylethylamine at temperatures ranging from at or near ambient to about 100 0 C for between about 1 and about 24h to provide compound (22-4) wherein R 11 and R 12 are independently hydrogen or R F , or taken together with the nitrogen to which they are attached form a 5-6-membered heterocyclyl or a fused 2-ring heterocyclyl.
  • a solvent such as, for example, dioxane, dimethylformamide, dimethylacetamide, or dichloromethane
  • a base such as, for example, pyridine, triethylamine or diisopropylethylamine at temperatures ranging from at or near ambient to about 100 0 C for between about 1 and about 24
  • Compound (22-2) is converted to the corresponding aldehyde (22-3) by reduction with lithium tri-/-butoxyaluminum hydride in a solvent such as, for example, tetrahydrofuran at about -60 0 C to about 78°C.
  • a solvent such as, for example, tetrahydrofuran at about -60 0 C to about 78°C.
  • Compound (22-3) can be converted to compound (23-2) wherein R 11 and R 12 are independently hydrogen or R F , or taken together with the nitrogen to which they are attached form a 5-6-membered heterocyclyl or a fused 2-ring heterocyclyl by treatment with an amine, N(R 1 ')(R 12 ), in the presence of a reductant such as, for example, sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as, for example, methanol, ethanol, dichloromethane, dimethylacetamide, or dimethylformamide over a period of about 1 to about 24h.
  • a reductant such as, for example, sodium triacetoxyborohydride or sodium cyanoborohydride
  • a solvent such as, for example, methanol, ethanol, dichloromethane, dimethylacetamide, or dimethylformamide over a period of about 1 to about 24h.
  • the reaction often proceeds best at an acidic pH that can be maintained by the addition of
  • Compound (22-3) can also be converted to compound (23-3) by reduction with lithium tri-?- butoxyaluminum hydride in a solvent such as tetrahydrofuran at room temperature.
  • Compound (23-3) can be converted to compound of formula (24-2) by treatment with thionyl chloride in dichloromethane at room temperature.
  • Compound (24-2) can be treated with a sodium alkoxide, R 13 ONa, in a heated solution of the corresponding alcohol to provide compound (24-3), wherein R 13 is hydrogen or R F .
  • Compound (25-1) can be brominated by treatment with, for example, pyridinium hydrobromide perbromide in a solvent such as, for example, acetic acid at or near ambient temperature over a period of about 1 to about 8h to give compound (25-2).
  • the amino group of compound (25-2) can be removed by exposure to t-butyl nitrite in a solvent such as, for example, dimethylformamide at a temperature initially at ambient temperature and then increased to the range of about 50 to about 65 0 C to give compound (25- 3). Additional aliquots of t-butyl nitrite can be added at ambient temperature followed by heating until the transformation is complete.
  • Compound (25-3) can be reduced to compound (25-4) by, for example, treatment with iron and ammonium chloride.
  • Example A Preparation of (E)-N-(3-tert-butyl-5-iodo-4-methoxyphenylcarbamoyl)-3-methoxy acrylamide.
  • Part D Preparation of 3-tert-butyl-5-iodo-4-methoxyaniline.
  • a mixture of the product from Part C (5.80g, 17.31mmol), ammonium chloride (1.389g, 26.0mmol), and iron (4.83g, 87mmol) in THF/MeOH/water (20OmL total, 2/2/1) was refluxed for 2h, cooled and filtered through Celite. The filtrate was evaporated and the residue was partitioned between water and EtOAc. The organic layer was washed with saturated brine, dried with sodium sulfate, filtered and evaporated to give a brown oil (5.28g, 100% yield).
  • Example B Preparation of l-(3-tert-butyl-5-iodo-4-methoxyphenyl)dihydropyrimidine- 2,4(lH,3H)-dione.
  • Example C Preparation of l-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(lH,3H)- dione.
  • the precipitate was collected by filtration and washed with >1 liter of water.
  • the salmon-colored solid was sucked as dry as possible, and dried in a vacuum oven at 5O 0 C for 18h. These procedures afforded the product (49.6 Ig, 93%) as a tan solid.
  • Part B Preparation of l-tert-butyl-3,5-diiodo-2-methoxybenzene.
  • a solution of the product from Part A (20.Og, 49.7mmol) in acetone (14OmL) was treated with methyl iodide (3.9mL, 8.83g, 62.2mmol) and 50 % (w/w) sodium hydroxide solution (3.02mL, 4.58g, 57.2mmol) followed by stirring at ambient temperature for 48h.
  • the mixture was concentrated in vacuo to a volume of ca. 50-6OmL, followed by dilution with heptane (8OmL) and water (5OmL). The layers were separated and the organic layer was extracted with saturated sodium chloride solution.
  • a suspension of the product from Part B (12.04g, 28.9mmol), uracil (3.89g, 34.7mmol), N-(2- cyanophenyl)picolinamide (1.29g, 5.79mmol) and tribasic potassium phosphate (12.9g, 60.8mmol) in DMSO (18ImL) was degassed by nitrogen sparge for 1 h.
  • the mixture was then treated with copper (I) iodide (55 lmg, 2.89mmol) and degassing was continued for another lOmin.
  • the mixture was then warmed at 6O 0 C for 18h.
  • the mixture was then poured into water (60OmL) and acidified to pH 3 by addition of 4N hydrochloric acid solution.
  • the mixture was diluted with ethyl acetate, and the organic layer was extracted with water (3x), saturated ammonium chloride solution (Ix) and saturated sodium chloride solution.
  • the solution was dried and treated with (3-mercaptopropyl) silica gel, followed by stirring for 2h.
  • the mixture was filtered and concentrated in vacuo.
  • the solid obtained was triturated with ether-ethyl acetate (>10: 1) and collected by filtration and washed with ether. After drying in a vacuum oven at 5O 0 C for 2h, these procedures afforded the product (2.75 g) as a white solid.
  • the mother liquors were concentrated in vacuo to afford an amber solid.
  • Example D Preparation of l-(3-tert-Butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(lH,3H)- dione.
  • Example E Preparation of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)- 2-methoxystyryl)phenyl)methanesulfonamide.
  • the reaction mixture was diluted with 375mL DCM and 250ml 10% citric acid. The mixture was shaken in a sep funnel and the layers were separated. The DCM layer was washed with a solution of 0.6g L-cysteine in 250ml 5% NaHCO 3 for 30min which changed the DCM layer color from orange to yellow. Repeated the 0.6g L-cysteine in 250ml 5% NaHCO3 for 30min treatment followed by a 250ml 5% NaHCO 3 wash, and a 250ml 10% NaCl wash. The DCM layer was treated with 2gm thiourea silica for 30min.
  • Example 1 Preparation of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide (compound IA-L1-1.9).
  • Part B Preparation of methyl 3-tert-butyl-2-methoxy-5-nitrobenzoate.
  • Part D Preparation of 3-(3-tert-butyl-4-methoxy-5-(methoxycarbonyl)phenylamino) propanoic acid.
  • Part E Preparation of methyl 3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-2- methoxybenzoate.
  • Part F Preparation of 3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)-2-methoxy benzoic acid.
  • Part G Preparation of 3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-2-methoxy- benzaldehyde.
  • Part F The product obtained in Part F (4.07g, 12.71mmol) and thionyl chloride (40.82mL, 559mmol) were combined and the mixture was refluxed for 2h, followed by concentration under vacuum to provide a light yellow colored solid product.
  • the resulting solid was dissolved in ethyl acetate (10OmL), and the solution was washed with water (5OmL) and dried over Na 2 SO ⁇ The drying agent was filtered off and the solvent removed under vacuum to give the aniline adduct as a yellow solid (830mg).
  • the solid (830mg, 2.109mmol) was dissolved in dichloromethane (5OmL), and pyridine (0.512mL, 6.33mmol) and methanesulfonyl chloride (0.18ImL, 2.32mmoi) were added and the resulting solution was stirred at room temperature 16h. Dichloromethane (10OmL) was added followed by extraction with a IN aq.
  • Example 2 Preparation of (Z)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)- 2-methoxyphenyl)-l-chlorovinyl)phenyl)methanesulfonamide (compound IA-L1-1.3).
  • Part C Preparation of (Z)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-2- methoxyphenyl)- 1 -chlorovinyl)phenyl)methanesulfonamide.
  • Example 4 Preparation of (Z)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)- 2-methoxyphenyl)- 1 -fluorovinyl)phenyl)methanesulfonamide (compound IA-L1-1.4).
  • Part B Preparation of (Z)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-2- methoxyphenyl)- 1 -fluorovinyl)phenyl)methanesulfonamide.
  • the product prepared as described in Part A (lOOmg, 0.329mmole) was treated with the product prepared in Example 1, Part G (96mg, 0.329mmole) according to the procedures described in Example 1, Part H and Example 1, Part I to provide 53mg of the title compound as a 1/1 mixture of cis/trans isomers.
  • Example 5 Preparation of (E)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)- 2-methoxyphenyl)- 1 -fluorovinyl)phenyl)methanesulfonamide (compound IA-L1-1.5).
  • Example 7 Preparation of N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-2- methoxyphenyl)cyclopropyl)phenyl)methanesulfonamide (compound IA-L8- 1.1).
  • Part B Preparation of methyl 3-(azidocarbonyl)-5-tert-butylbenzoate.
  • Part D Preparation of methyl 3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-2- methoxybenzoate.
  • Part E Preparation of 3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)benzoic acid.
  • Part F Preparation of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl) styry l)phenyl)methanesulfonamide .
  • Example 10 Preparation of (Z)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)- yl)-2-methoxyphenyl)- 1 -methoxyvinyl)phenyl)methanesulfonamide (compound IA-Ll-1.17).
  • Part B Preparation of diethyl methoxy(4-nitrophenyl)methylphosphonate.
  • Example 11 Preparation of (E)-I -(3-tert-butyl-4-methoxy-5-styrylphenyl)dihydro- pyrimidine- 2,4(1 H,3H)-dione (compound IA-L1-1.18).
  • Part B Preparation of methyl 3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxybenzoate.
  • Part D Preparation of 3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-methoxy benzaldehyde.
  • Part G Preparation of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide.
  • Example 13B Preparation of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)- yl)-2-methoxystyryl)phenyl)methanesulfonamide (compound IB-Ll-1.1).
  • the resulting thick white slurry was cooled to -40 0 C in a dry ice/acetone bath, followed by the addition of the product from Part A (15.0g, 77mmol) dissolved in 6OmL of THF, drop wise over 30min. After the addition was complete, the mixture was stirred for an additional hour at -35°C, then Ih at room temperature. The light yellow solution was then cooled to 0 0 C and acetaldehyde (61.4mL, 1088mmol) added, then the mixture refluxed at 50 0 C for 18h. The solvent was then removed under vacuum to provide an orange syrup, to which water (115mL) was added and the heterogeneous mixture stirred for 3h at room temperature.
  • the light yellow solid generated was collected and washed with water (25OmL) then dried in a vacuum oven overnight.
  • the resultant material was then dissolved in boiling acetone (19OmL), which provided a homogenous yellow solution, followed by removal of the solution from heating and the addition of hexanes (365ml) over 5min time.
  • a white solid formed in the solution and the mixture was stirred until the solution cooled to room temperature, then the white solid was collected and dried in a vacuum oven for lhr to provide the title compound (12. Ig, 85%).
  • Part E Preparation of l-bromo-3-tert-butyl-2-methoxy-5 -nitrobenzene.
  • Part F Preparation of tert-butyl 3-bromo-5-tert-butyl-4-methoxyphenylcarbamate.

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Abstract

This invention relates to: (a) compounds and salts thereof that, inter alia, inhibit HCV; (b) intermediates useful for the preparation of such compounds and salts; (c) compositions comprising such compounds and salts; (d) methods for preparing such intermediates, compounds, salts, and compositions; (e) methods of use of such compounds, salts, and compositions; and (f) kits comprising such compounds, salts, and compositions. The compounds are usefull in the treatment of hepatitis C and are of the following general structure: Formula (I)

Description

N- PHENYL-DIOXO-HYDRO PYRIMIDINES USEFULL AS HEPATITIS C VIRUS (HCV) INHIBITOR
CROSS-REFERENCE TO RELATED PATENT APPLICATIONS
[0001] This patent application claims priority to U.S. Provisional Patent Application No. 60/972,887 (filed September 17, 2007) and U.S. Provisional Patent Application No. 61/096,794 (filed September 13, 2008). The entire text of those applications is incorporated by reference into this application.
FIELD OF THE INVENTION
[0002] This invention is directed to: (a) compounds and salts thereof that, inter alia, are useful as hepatitis C virus (HCV) inhibitors; (b) intermediates useful for the preparation of such compounds and salts; (c) compositions comprising such compounds and salts; (d) methods for preparing such intermediates, compounds, salts, and compositions; (e) methods of use of such compounds, salts, and compositions; and (f) kits comprising such compounds, salts, and compositions.
BACKGROUND OF THE INVENTION
[0003] Hepatitis C is a blood-borne, infectious, viral disease that is caused by a hepatotropic virus called HCV. At least six different HCV genotypes (with several subtypes within each genotype) are known to date. In North America, HCV genotype Ia predominates, followed by HCV genotypes Ib, 2a, 2b, and 3a. hi the United States, HCV genotypes 1, 2, and 3 are the most common, with about 80% of the hepatitis C patients having HCV genotype 1. hi Europe, HCV genotype Ib is predominant, followed by HCV genotypes 2a, 2b, 2c, and 3 a. HCV genotypes 4 and 5 are found almost exclusively in Africa. As discussed below, the patient's HCV genotype is clinically important in determining the patient's potential response to therapy and the required duration of such therapy.
[0004] An HCV infection can cause liver inflammation (hepatitis) that is often asymptomatic, but ensuing chronic hepatitis can result in cirrhosis of the liver (fϊbrotic scarring of the liver), liver cancer, and/or liver failure. The World Health Organization estimates that about 170 million persons worldwide are chronically infected with HCV, and from about three to about four million persons are newly infected globally each year. According to the Centers for Disease Control and Prevention, about four million people in the United States are infected with HCV. Co-infection with the human immunodeficiency virus (HFV) is common, and rates of HCV infection among HIV positive populations are higher. [0005] There is a small chance of clearing the virus spontaneously, but the majority of patients with chronic hepatitis C will not clear it without treatment. Indications for treatment typically include proven HCV infection and persistent abnormal liver function tests. There are two treatment regimens that are primarily used to treat hepatitis C: monotherapy (using an interferon agent - either a "conventional" or longer-acting pegylated interferon) and combination therapy (using an interferon agent and ribavirin). Interferon, which is injected into the bloodstream, works by bolstering the immune response to HCV; and ribavirin, which is taken orally, is believed to work by preventing HCV replication. Taken alone, ribavirin does not effectively suppress HCV levels, but an interferon/ribavirin combination is more effective than interferon alone. Typically, hepatitis C is treated with a combination of pegylated interferon alpha and ribavirin for a period of 24 or 48 weeks, depending on the HCV genotype. [0006] The goal of treatment is sustained viral response — meaning that HCV is not measurable in the blood after therapy is completed. Following treatment with a combination of pegylated interferon alpha and ribavirin, sustained cure rates (sustained viral response) of about 75% or better occur in people with HCV genotypes 2 and 3 in 24 weeks of treatment, about 50% in those with HCV genotype 1 with 48 weeks of treatment, and about 65% in those with HCV genotype 4 in 48 weeks of treatment. [0007] Treatment may be physically demanding, particularly for those with prior history of drug or alcohol abuse, because both interferon and ribavirin have numerous side effects. Common interferon- associated side effects include flu-like symptoms, extreme fatigue, nausea, loss of appetite, thyroid problems, high blood sugar, hair loss, and skin reactions at the injection site. Possible serious interferon- associated side effects include psychoses (e.g., suicidal behavior), heart problems (e.g., heart attack, low blood pressure), other internal organ damage, blood problems (e.g., blood counts falling dangerously low), and new or worsening autoimmune disease (e.g., rheumatoid arthritis). Ribavirin-associated side effects include anemia, fatigue, irritability, skin rash, nasal stuffiness, sinusitis, and cough. Ribavirin can also cause birth defects, so pregnancy in female patients and female partners of male patients must be avoided during treatment and for six months afterward.
[0008] Some patients do not complete treatment because of the serious side effects discussed above; other patients (non-responders) continue to have measurable HCV levels despite treatment; and yet other patients (relapsers) "clear" the virus during therapy, but the virus returns sometime after completion of the treatment regimen. Thus, there continues to be a need for alternative compounds, compositions, and methods of treatment (used either in combination with or in lieu of an interferon agent and/or ribavirin) to alleviate the symptoms of hepatitis C, thereby providing partial or complete relief. This invention provides compounds (including salts thereof), compositions, and methods of treatment that generally address such a need.
SUMMARY OF THE INVENTION
[0009] This invention is directed to compounds that correspond in structure to formula I:
Figure imgf000005_0001
[0010] In formula I:
÷= is selected from the group consisting of single carbon-carbon bond and double carbon- carbon bond;
R1 is selected from the group consisting of hydrogen, methyl, and nitrogen-protecting group;
R2 is selected from the group consisting of hydrogen, halo, hydroxy, methyl, cyclopropyl, and cyclobutyl;
R3 is selected from the group consisting of hydrogen, halo, oxo, and methyl;
R4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein:
(a) the amino, aminocarbonyl, and aminosulfonyl optionally are substituted with:
(1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl, or
(2) two substituents that, together with the amino nitrogen, form a single- ring heterocyclyl, and
(b) the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, and alkylsulfonyl, optionally are substituted with one or more substituents independently selected from the group consisting of halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl, and heterocyclyl, wherein: the amino optionally is substituted with:
(1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl, or
(2) two substituents that, together with the amino nitrogen, form a single- ring heterocyclyl, and
(c) the carbocyclyl and heterocyclyl optionally are substituted with up to three substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl, and heterocyclyl, wherein: the amino optionally is substituted with:
(1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl, or
(2) two substituents that, together with the amino nitrogen, form a single- ring heterocyclyl;
R5 is selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, carbocyclylsulfonyloxy, haloalkylsulfonyloxy, and halo;
L is selected from the group consisting of C(RA)=C(RB), ethylene, and cyclopropyl-l,2-ene;
RA and RB are independently selected from the group consisting of hydrogen, Ci-C6-alkyl, Q-C6- alkyloxy, C3-C8-cycloalkyl, and halo, wherein: the CrC6-alkyl optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, halo, hydroxy, nitro, oxo, amino, cyano, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, and heterocyclyl;
R6 is selected from the group consisting of C5-C6-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl, wherein each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ; each RE is independently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, cyano, amino, imino, azido, and aldehydo, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl; each Rr is independently selected from the group consisting of alkyl, alkenyl, and alkynyl, wherein: each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, imino, aminosulfonyl, aminocarbonyl, carbocyclyl, and heterocyclyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkylsulfonylamino, hydroxy, and alkyloxy, wherein: amino portion of the alkylsulfonylamino optionally is substituted with a substituent selected from the group consisting of alkyl, alkenyl, and alkynyl; each RG is independently selected from the group consisting of carbocyclyl and heterocyclyl, wherein: each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl; each RH is independently selected from the group consisting of alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, alkenylsulfonyloxy, and alkynylsulfonyloxy, wherein: each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl; each R1 is independently selected from the group consisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aminocarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl, and heterocyclylcarbonyl, wherein:
(a) the alkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl optionally are substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, and (b) the aminocarbonyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxyalkyl, carbocyclyl, heterocyclyl, alkylsulfonyl, and alkylsulfonylamino, wherein: the carbocyclyl and heterocyclyl optionally are substituted with one or two substituents independently selected from the group consisting of halo, alkyl, and oxo; each RJ is independently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, alkyloxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, aminocarbonylamino, alkyloxycarbonylaminoimino, alkylsulfonylaminoimino, alkenylsulfonylaminoimino, and alkynylsulfonylaminoimino, wherein:
(a) the amino portion of such substituents optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkenyl, alkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
(1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido, oxo, and amino, and
(2) the amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl,
(b) the alkyl, alkenyl, and alkynyl portion of such substituents optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, and alkynyloxy, wherein: the alkyl optionally is substituted with one or more hydroxy;
(c) the carbocyclyl and heterocyclyl portions of such substituents optionally are substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido, and amino, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl; and each Rκ is independently selected from the group consisting of aminosulfonyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl, wherein:
(a) the alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl optionally are substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl; and
(b) the aminosulfonyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl.
[0011] This invention also is directed to the salts (including pharmaceutically acceptable salts) of the compounds of the invention.
[0012] This invention also is directed to compositions (including pharmaceutical compositions) that comprise one or more compounds and/or salts of the invention, and, optionally, one or more additional therapeutic agents.
[0013] This invention also is directed to kits that comprise one or more compounds and/or salts of the invention, and, optionally, one or more additional therapeutic agents.
[0014] This invention also is directed to methods of use of the compounds, salts, compositions, and/or kits of the invention to, for example, inhibit replication of an RNA virus (including HCV), treat a disease treatable by inhibiting HCV ribonucleic acid (RNA) polymerase (including hepatitis C).
[0015] This invention also is directed to a use of one or more compounds and/or salts of the invention to prepare a medicament. The medicament optionally can comprise one or more additional therapeutic agents. In some embodiments, the medicament is useful for treating hepatitis C.
[0016] Further benefits of Applicants' invention will be apparent to one skilled in the art from reading this patent application.
BRIEF DESCRIPTION OF THE DRAWINGS [0017] Figure 1 shows an illustrative PXRD pattern for the disodium salt nonahydrate of compound IB- Ll-1.1.
[0018] Figure 2 shows an illustrative PXRD pattern for the disodium salt tetrahydrate of compound IB- Ll-1.1.
[0019] Figure 3 shows an illustrative TGA profile of the disodium salt tetrahydrate of compound IB-Ll- 1.1.
[0020] Figure 4 shows an illustrative PXRD pattern for the dipotassium salt tetrahydrate of compound IB-Ll-1.1.
[0021] Figure 5 shows an illustrative PXRD pattern for the monopotassium salt trihydrate of compound IB-Ll-1.1.
[0022] Figure 6 shows an illustrative PXRD pattern for the monopotassium salt dihydrate of compound IB-Ll-1.1.
[0023] Figure 7 shows an illustrative TGA profile of the monopotassium salt dihydrate of compound IB- Ll-1.1.
[0024] Figure 8 shows an illustrative PXRD pattern for the 1/7 potassium salt of compound IB-Ll-1.1. [0025] Figure 9 shows an illustrative PXRD pattern for the monodiethylamine salt tetrahydrate of compound IB-Ll-1.1.
[0026] Figure 10 shows an illustrative TGA profile of the monodiethylamine salt tetrahydrate of compound IB-Ll-1.1.
[0027] Figure 11 shows an illustrative PXRD pattern for the pattern A polymorph of compound IB-Ll- 1.1.
[0028] Figure 12 shows an illustrative DSC profile of the pattern A polymorph of compound EB-Ll-1.1. [0029] Figure 13 shows an illustrative PXRD pattern for the pattern B polymorph of compound IB-Ll- 1.1.
[0030] Figure 14 shows an illustrative PXRD pattern for the pattern C polymorph of compound EB-Ll- 1.1.
[0031] Figure 15 shows an illustrative PXRD pattern for the pattern D polymorph of compound IB-Ll- 1.1.
[0032] Figure 16 shows an illustrative PXRD pattern for the pattern A hydrate of compound IB-Ll-1.1. [0033] Figure 17 shows an illustrative TGA profile of the pattern A hydrate of compound IB-Ll-1.1. [0034] Figure 18 shows an illustrative PXRD pattern for the pattern B hydrate of compound IB-Ll-1.1. [0035] Figure 19 shows an illustrative TGA profile of the pattern B hydrate of compound IB-Ll-1.1. [0036] Figure 20 shows an illustrative PXRD pattern for the pattern C hydrate of compound IB-Ll-1.1. [0037] Figure 21 shows an illustrative TGA profile of the pattern C hydrate of compound IB-Ll-1.1. [0038] Figure 22 shows an illustrative PXRD pattern for the pattern D hydrate of compound EB-Ll-1.1. [0039] Figure 23 shows an illustrative PXRD pattern for the pattern E hydrate of compound IB-Ll-1.1.
DETAILED DESCRIPTION OF THE INVENTION
[0040] This detailed description is intended only to acquaint others skilled in the art with Applicants' invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This description and its specific examples are intended for purposes of illustration only. This invention, therefore, is not limited to the embodiments described in this patent application, and may be variously modified.
A. Definitions.
[0041] The term "alkyl" (alone or in combination with another term(s)) means a straight-or branched- chain saturated hydrocarbyl substituent typically containing from 1 to about 20 carbon atoms, more typically from 1 to about 8 carbon atoms, and even more typically from 1 to about 6 carbon atoms. Examples of such substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, pentyl, iso-amyl, and hexyl. As in this definition, throughout this detailed description Applicants have provided illustrative examples. The provision of such illustrative examples should not be interpreted as if the provided illustrative examples are the only options available to one skilled in the art. [0042] The term "alkenyl" (alone or in combination with another term(s)) means a straight- or branched- chain hydrocarbyl substituent containing one or more double bonds and typically from 2 to about 20 carbon atoms, more typically from about 2 to about 8 carbon atoms, and even more typically from about 2 to about 6 carbon atoms. Examples of such substituents include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1 ,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, and 3-butenyl.
[0043] The term "alkynyl" (alone or in combination with another term(s)) means a straight- or branched- chain hydrocarbyl substituent containing one or more triple bonds and typically from 2 to about 20 carbon atoms, more typically from about 2 to about 8 carbon atoms, and even more typically from about 2 to about 6 carbon atoms. Examples of such substituents include ethynyl, 2-propynyl, 3-propynyl, 2-butynyl, and 3-butynyl.
[0044] The term "carbocyclyl" (alone or in combination with another term(s)) means a saturated cyclic (i.e., "cycloalkyl"), partially saturated cyclic (i.e., "cycloalkenyl"), or completely unsaturated (i.e., "aryl") hydrocarbyl substituent containing from 3 to 14 carbon ring atoms ("ring atoms" are the atoms bound together to form the ring or rings of a cyclic substituent). A carbocyclyl may be a single ring, which typically contains from 3 to 6 ring atoms. Examples of such single-ring carbocyclyls include cyclopropyl (cyclopropanyl), cyclobutyl (cyclobutanyl), cyclopentyl (cyclopentanyl), cyclopentenyl, cyclopentadienyl, cyclohexyl (cyclohexanyl), cyclohexenyl, cyclohexadienyl, and phenyl. A carbocyclyl alternatively may be 2 or 3 rings fused together, such as naphthalenyl, tetrahydronaphthalenyl (tetralinyl), indenyl, indanyl (dihydroindenyl), anthracenyl, phenanthrenyl, and decalinyl.
[0045] The term "cycloalkyl" (alone or in combination with another term(s)) means a saturated cyclic hydrocarbyl substituent containing from 3 to 14 carbon ring atoms. A cycloalkyl may be a single carbon ring, which typically contains from 3 to 6 carbon ring atoms. Examples of single-ring cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A cycloalkyl alternatively may be 2 or 3 carbon rings fused together, such as, decalinyl.
[0046] The term "aryl" (alone or in combination with another term(s)) means an aromatic carbocyclyl containing from 6 to 14 carbon ring atoms. Examples of aryls include phenyl, naphthalenyl, and indenyl.
[0047] In some instances, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkyl, alkenyl, alkynyl, or cycloalkyl) is indicated by the prefix "Cx-Cy-", wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, "Ci-C6-alkyl" refers to an alkyl substituent containing from 1 to 6 carbon atoms. Illustrating further, Cs-Cβ-cycloalkyl means a saturated hydrocarbyl ring containing from 3 to 6 carbon ring atoms.
[0048] The term "hydrogen" (alone or in combination with another term(s)) means a hydrogen radical, and may be depicted as -H.
[0049] The term "hydroxy" (alone or in combination with another term(s)) means -OH.
[0050] The term "nitro" (alone or in combination with another term(s)) means -NO2.
[0051] The term "cyano" (alone or in combination with another term(s)) means -CN, which also may be depicted as -C≡N.
[0052] The term "keto" (alone or in combination with another term(s)) means an oxo radical, and may be depicted as =O.
[0053] The term "carboxy" (alone or in combination with another term(s)) means -C(O)-OH.
[0054] The term "amino" (alone or in combination with another term(s)) means -NH2.
[0055] The term "imino" (alone or in combination with another term(s)) means =NH.
[0056] The term "aminoimino" (alone or in combination with another term(s)) means =NNH2.
[0057] The term "halogen" or "halo" (alone or in combination with another term(s)) means a fluorine radical (which may be depicted as -F), chlorine radical (which may be depicted as -Cl), bromine radical
(which may be depicted as -Br), or iodine radical (which may be depicted as -I).
[0058] A substituent is "substitutable" if it comprises at least one carbon or nitrogen atom that is bonded to one or more hydrogen atoms. Thus, for example, hydrogen, halogen, and cyano do not fall within this definition. In addition, a sulfur atom in a heterocyclyl containing such atom is substitutable with one or two oxo substituents.
[0059] If a substituent is described as being "substituted", a non-hydrogen radical is in the place of hydrogen radical on a carbon or nitrogen of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent in which at least one non-hydrogen radical is in the place of a hydrogen radical on the alkyl substituent. To illustrate, monofluoroalkyl is alkyl substituted with a fluoro radical, and difluoroalkyl is alkyl substituted with two fluoro radicals. It should be recognized that if there are more than one substitution on a substituent, each non-hydrogen radical may be identical or different (unless otherwise stated).
[0060] If a substituent is described as being "optionally substituted", the substituent may be either (1) not substituted or (2) substituted. If a substituent is described as being optionally substituted with up to a particular number of non-hydrogen radicals, that substituent may be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen radicals or by up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for example, if a substituent is described as a heteroaryl optionally substituted with up to 3 non-hydrogen radicals, then any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non- hydrogen radicals as the heteroaryl has substitutable positions. To illustrate, tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non-hydrogen radical. To illustrate further, if an amino nitrogen is described as being optionally substituted with up to 2 non- hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to 2 non- hydrogen radicals, whereas a secondary amino nitrogen will be optionally substituted with up to only 1 non-hydrogen radical.
[0061] This patent application uses the terms "substituent" and "radical" interchangeably. [0062] The prefix "halo" indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen radicals. For example, haloalkyl means an alkyl substituent in which at least one hydrogen radical is replaced with a halogen radical. Examples of haloalkyls include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1,1,1-trifluoroethyl. It should be recognized that if a substituent is substituted by more than one halogen radical, those halogen radicals may be identical or different (unless otherwise stated).
[0063] The prefix "perhalo" indicates that every hydrogen radical on the substituent to which the prefix is attached is replaced with independently selected halogen radicals, i.e., each hydrogen radical on the substituent is replaced with a halogen radical. If all the halogen radicals are identical, the prefix typically will identify the halogen radical. Thus, for example, the term "perfluoro" means that every hydrogen radical on the substituent to which the prefix is attached is substituted with a fluorine radical. To illustrate, the term "perfluoroalkyl" means an alkyl substituent wherein a fluorine radical is in the place of each hydrogen radical.
[0064] The term "carbonyl" (alone or in combination with another term(s)) means -C(O)-. [0065] The term "aminocarbonyl" (alone or in combination with another term(s)) means -C(O)-NH2. [0066] The term "oxy" (alone or in combination with another term(s)) means an ether substituent, and may be depicted as -O- .
[0067] The term "alkoxy" (alone or in combination with another term(s)) means an alkylether substituent, i.e., -O-alkyl. Examples of such a substituent include methoxy (-0-CH3), ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.
[0068] The term "alkylcarbonyl" (alone or in combination with another term(s)) means -C(O)-alkyl.
[0069] The term "aminoalkylcarbonyl" (alone or in combination with another term(s)) means -C(O)- alkyl-NH2.
[0070] The term "alkoxycarbonyl" (alone or in combination with another term(s)) means -C(O)-O-alkyl.
[0071] The term "carbocyclylcarbonyl" (alone or in combination with another term(s)) means -C(O)- carbocyclyl.
[0072] Similarly, the term "heterocyclylcarbonyl" (alone or in combination with another term(s)) means
-C(O)-heterocyclyl.
[0073] The term "carbocyclylalkylcarbonyl" (alone or in combination with another term(s)) means
-C(O)-alkyl-carbocycly 1.
[0074] Similarly, the term "heterocyclylalkylcarbonyl" (alone or in combination with another term(s)) means -C(O)-alkyl-heterocyclyl.
[0075] The term "carbocyclyloxycarbonyl" (alone or in combination with another term(s)) means -C(O)-
O-carbocyclyl.
[0076] The term "carbocyclylalkoxycarbonyl" (alone or in combination with another term(s)) means
-C(O)-O-alkyl-carbocyclyl.
[0077] The term "thio" or "thia" (alone or in combination with another term(s)) means a thiaether substituent, i.e., an ether substituent wherein a divalent sulfur atom is in the place of the ether oxygen atom. Such a substituent may be depicted as -S-. This, for example, "alkyl-thio-alkyl" means alkyl-S- alkyl (alkyl-sulfanyl-alkyl).
[0078] The term "thiol" or "sulfhydryl" (alone or in combination with another term(s)) means a sulfhydryl substituent, and may be depicted as -SH.
[0079] The term "(thiocarbonyl)" (alone or in combination with another term(s)) means a carbonyl wherein the oxygen atom has been replaced with a sulfur. Such a substituent may be depicted as -C(S)-.
[0080] The term "sulfonyl" (alone or in combination with another term(s)) means -S(O)2-.
[0081] The term "aminosulfonyl" (alone or in combination with another term(s)) means -S(O)2-NH2.
[0082] The term "sulfinyl" or "sulfoxido" (alone or in combination with another term(s)) means -S(O)-.
[0083] The term "heterocyclyl" (alone or in combination with another term(s)) means a saturated (i.e.,
"heterocycloalkyl"), partially saturated (i.e., "heterocycloalkenyl"), or completely unsaturated (i.e., "heteroaryl") ring structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
[0084] A heterocyclyl may be a single ring, which typically contains from 3 to 7 ring atoms, more typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms. Examples of single-ring heterocyclyls include furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl (thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, oxazolyl, oxazolidinyl, isoxazolidinyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazo IyI, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5- oxadiazolyl (furazanyl), or 1,3,4-oxadiazolyl), oxatriazolyl (including 1,2,3,4-oxatriazolyl or 1,2,3,5- oxatriazolyl), dioxazolyl (including 1,2,3-dioxazolyl, 1 ,2,4-dioxazolyl, 1,3,2-dioxazolyl, or 1,3,4- dioxazolyl), oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl, dihydropyranyl, thiopyranyl, tetrahydrothiopyranyl, pyridinyl (azinyl), piperidinyl, diazinyl (including pyridazinyl (1,2-diazinyl), pyrimidinyl (1,3-diazinyl), or pyrazinyl (1,4-diazinyl)), piperazinyl, triazinyl (including 1,3,5-triazinyl, 1 ,2,4-triazinyl, and 1,2,3 -triazinyl)), oxazinyl (including 1,2-oxazinyl, 1,3-oxazinyl, or 1,4-oxazinyl)), oxathiazinyl (including 1,2,3-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,5-oxathiazinyl, or 1,2,6-oxathiazinyl)), oxadiazinyl (including 1,2,3-oxadiazinyl, 1,2,4-oxadiazinyl, 1 ,4,2-oxadiazinyl, or 1,3,5-oxadiazinyl)), morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl.
[0085] A heterocyclyl alternatively may be 2 or 3 rings fused together, such as, for example, indolizinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl (including pyrido[3,4-b]- pyridinyl, pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl. Other examples of fused- ring heterocyclyls include benzo-fused heterocyclyls, such as indolyl, isoindolyl (isobenzazolyl, pseudoisoindolyl), indoleninyl (pseudoindolyl), isoindazolyl (benzpyrazolyl), benzazinyl (including quinolinyl (1 -benzazinyl) or isoquinolinyl (2-benzazinyl)), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (1,2-benzodiazinyl) or quinazolinyl (1,3-benzodiazinyl)), benzopyranyl (including chromanyl or isochromanyl), benzoxazinyl (including 1,3,2-benzoxazinyl, 1,4,2- benzoxazinyl, 2,3,1 -benzoxazinyl, or 3,1,4-benzoxazinyl), and benzisoxazinyl (including 1,2- benzisoxazinyl or 1,4-benzisoxazinyl).
[0086] The term "2-fused ring" heterocyclyl (alone or in combination with another term(s)) means a saturated, partially saturated, or aryl heterocyclyl containing 2 fused rings. Examples of 2-fused-ring heterocyclyls include indolizinyl, quinolizinyl, purinyl, naphthyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, and tetrahydroisoquinolinyl.
[0087] The term "heteroaryl" (alone or in combination with another term(s)) means an aromatic heterocyclyl containing from 5 to 14 ring atoms. A heteroaryl may be a single ring or 2 or 3 fused rings.
Examples of heteroaryl substituents include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, pyridazinyl, and 1,3,5-, 1,2,4- or 1,2,3-triazinyl; 5-membered ring substituents such as imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4- oxadiazolyl and isothiazolyl; 6/5-membered fused ring substituents such as benzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-membered fused rings such as benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and benzoxazinyl.
[0088] A prefix attached to a multi-component substituent only applies to the first component. To illustrate, the term "alkylcycloalkyl" contains two components: alkyl and cycloalkyl. Thus, the Q-C6- prefix on Q-Cβ-alkylcycloalkyl means that the alkyl component of the alkylcycloalkyl contains from 1 to
6 carbon atoms; the Ci-C6-prefix does not describe the cycloalkyl component. To illustrate further, the prefix "halo" on haloalkoxyalkyl indicates that only the alkoxy component of the alkoxyalkyl substituent is substituted with one or more halogen radicals. If halogen substitution may alternatively or additionally occur on the alkyl component, the substituent would instead be described as "halogen-substituted alkoxyalkyl" rather than "haloalkoxyalkyl." And finally, if the halogen substitution may only occur on the alkyl component, the substituent would instead be described as "alkoxyhaloalkyl."
[0089] If substituents are described as being "independently selected" from a group, each substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other substituent(s).
[0090] When words are used to describe a substituent, the rightmost-described component of the substituent is the component that has the free valence.
[0091] When a chemical formula is used to describe a substituent, the dash on the left side of the formula indicates the portion of the substituent that has the free valence.
[0092] When a chemical formula is used to describe a linking element between two other elements of a depicted chemical structure, the leftmost dash of the substituent indicates the portion of the substituent that is bound to the left element in the depicted structure. The rightmost dash, on the other hand, indicates the portion of the substituent that is bound to the right element in the depicted structure. To illustrate, if the depicted chemical structure is X-L-Y and L is described as -C(O)-N(H)-, then the chemical would be
X-C(O)-N(H)-Y.
[0093] With reference to the use of the words "comprise" or "comprises" or "comprising" in this patent application (including the claims), Applicants note that unless the context requires otherwise, those words are used on the basis and clear understanding that they are to be interpreted inclusively, rather than exclusively, and that Applicants intend each of those words to be so interpreted in construing this patent application, including the claims below.
[0094] ChemDraw software has been used to generate the compound names in this patent application.
[0095] The term "amorphous" as applied to a compound refers to a solid-state in which the compound molecules are present in a disordered arrangement and do not form a distinguishable crystal lattice or unit cell. When subjected to X-ray powder diffraction, an amorphous compound does not produce any characteristic crystalline peaks.
[0096] The term "crystalline form" as applied to a compound refers to a solid-state in which the compound molecules are arranged to form a distinguishable crystal lattice (i) comprising distinguishable unit cells, and (ii) yielding diffraction pattern peaks when subjected to X-ray radiation.
[0097] The term "purity", unless otherwise qualified, means the chemical purity of a compound according to conventional HPLC assay.
[0098] The term "phase purity" means the solid-state purity of a compound with regard to a particular crystalline or amorphous form of the compound as determined by X-ray powder diffraction analytical methods.
[0099] The term "phase pure" refers to purity with respect to other solid-state forms of the compound, and does not necessarily imply a high degree of chemical purity with respect to other compounds.
[00100] The term "PXRD" means X-ray powder diffraction.
[00101] The term "TGA" means thermogravimetric analysis.
[00102] The term "DSC" means differential scanning calorimetry.
B. Compounds.
[00103] This invention is directed, in part, to compounds that are phenyl-uracil derivatives that correspond in structure to formula I:
Figure imgf000017_0001
[00104] In these compounds, ^=^= is selected from the group consisting of single carbon-carbon bond and double carbon-carbon bond.
[00105] In some embodiments, == is a single carbon-carbon bond. In these embodiments, the compounds of formula I correspond in structure to the following formula (i.e., formula IA):
Figure imgf000018_0001
[00106] In other embodiments, ^=^ is a double carbon-carbon bond. In these embodiments, the compounds of formula I correspond in structure to the following formula (i.e., formula IB):
R1
Figure imgf000018_0002
Bl. Substituent R1.
[0010T]R1 is selected from the group consisting of hydrogen, methyl, and nitrogen-protecting group. [00108] In some embodiments, R1 is hydrogen. [00109] In some embodiments, R1 is methyl.
[00110] In some embodiments, R1 is selected from the group consisting of hydrogen and methyl. [00111] In some embodiments, R1 is a nitrogen-protecting group. In these embodiments, the compounds are useful as intermediates for the preparation of compounds of formula I. Nitrogen-protecting groups suitable for preparing compounds of formula I are known to those skilled in the art.
B2. Substituent R2.
[00112] R2 is selected from the group consisting of hydrogen, halo, hydroxy, methyl, cyclopropyl, and cyclobutyl.
[00113] In some embodiments, R2 is hydrogen.
[00114] In some embodiments, R2 is halo. In some such embodiments, R2 is selected from the group consisting of fluoro and chloro. In other such embodiments, R2 is fluoro. In yet other such embodiments, R2 is chloro. In yet other such embodiments, R2 is bromo. In further such embodiments, R2 is iodo. [00115] In some embodiments, R2 is hydroxy. [00116] In some embodiments, R2 is methyl.
[00117] In some embodiments, R2 is cyclopropyl.
[00118] In some embodiments, R2 is cyclobutyl.
[00119] In some embodiments, R2 is selected from the group consisting of hydrogen, methyl, hydroxy, and halo. In some such embodiments, R2 is selected from the group consisting of hydrogen, methyl, hydroxy, fluoro, and chloro. In other such embodiments, R2 is selected from the group consisting of hydrogen, methyl, hydroxy, and fluoro. In yet other such embodiments, R2 is selected from the group consisting of hydrogen, methyl, hydroxy, and chloro. In yet other such embodiments, R2 is selected from the group consisting of hydrogen, methyl, hydroxy, and bromo. In further such embodiments, R2 is selected from the group consisting of hydrogen, methyl, hydroxy, and iodo.
[0012O]In some embodiments, R2 is selected from the group consisting of hydrogen, methyl, and halo. In some such embodiments, R2 is selected from the group consisting of hydrogen, methyl, fluoro, and chloro. In other such embodiments, R2 is selected from the group consisting of hydrogen, methyl, and fluoro. In yet other such embodiments, R2 is selected from the group consisting of hydrogen, methyl, and chloro. In yet other such embodiments, R2 is selected from the group consisting of hydrogen, methyl, and bromo. In further such embodiments, R2 is selected from the group consisting of hydrogen, methyl, and iodo.
[00121] In some embodiments, R2 is selected from the group consisting of hydrogen and halo. In some such embodiments, R2 is selected from the group consisting of hydrogen, fluoro, and chloro. In other such embodiments, R2 is selected from the group consisting of hydrogen and fluoro. In yet other such embodiments, R2 is selected from the group consisting of hydrogen and chloro. In yet other such embodiments, R2 is selected from the group consisting of hydrogen and bromo. In further such embodiments, R2 is selected from the group consisting of hydrogen and iodo.
B3. Substituent R3.
[00122] R3 is selected from the group consisting of hydrogen, halo, oxo, and methyl. In some such embodiments, R3 is selected from the group consisting of hydrogen, fluoro, oxo, and methyl. In other such embodiments, R3 is selected from the group consisting of hydrogen, chloro, oxo, and methyl. In yet other such embodiments, R3 is selected from the group consisting of hydrogen, bromo, oxo, and methyl. In yet other such embodiments, R3 is selected from the group consisting of hydrogen, iodo, oxo, and methyl.
[00123] In some embodiments, R3 is selected from the group consisting of hydrogen, halo, and oxo. In some such embodiments, R3 is selected from the group consisting of hydrogen, fluoro, and oxo. In other such embodiments, R3 is selected from the group consisting of hydrogen, chloro, and oxo. In yet other such embodiments, R3 is selected from the group consisting of hydrogen, bromo, and oxo. In yet other such embodiments, R3 is selected from the group consisting of hydrogen, iodo, and oxo.
[00124] In some embodiments, R3 is selected from the group consisting of hydrogen and methyl.
[00125] In some embodiments, R3 is hydrogen.
[00126] In some embodiments, R3 is methyl.
[00127] In some embodiments, R3 is oxo.
[00128] In some embodiments, R3 is halo. In some such embodiments, R3 is fluoro. In other such embodiments, R3 is chloro. In yet other such embodiments, R3 is bromo. In further such embodiments,
R3 is iodo.
B4. Substituent R4 '.
[00129] R4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein:
(a) the amino, aminocarbonyl, and aminosulfonyl optionally are substituted with:
(1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl, or
(2) two substituents that, together with the amino nitrogen, form a single- ring heterocyclyl,
(b) the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, and alkylsulfonyl, optionally are substituted with one or more substituents independently selected from the group consisting of halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl, and heterocyclyl, wherein: the amino optionally is substituted with:
(1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl, or
(2) two substituents that, together with the amino nitrogen, form a single- ring heterocyclyl, and
(c) the carbocyclyl and heterocyclyl optionally are substituted with up to three substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl, and heterocyclyl, wherein: the amino optionally is substituted with:
(1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl, or
(2) two substituents that, together with the amino nitrogen, form a single- ring heterocyclyl.
[0013O]In some embodiments, R4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein: the amino, aminocarbonyl, and aminosulfonyl optionally are substituted with:
(1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl, or
(2) two substituents that, together with the amino nitrogen, form a single- ring heterocyclyl.
[0013I] In some embodiments, R4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein: the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, and alkylsulfonyl, optionally are substituted with one or more substituents independently selected from the group consisting of halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl, and heterocyclyl, wherein: the amino optionally is substituted with:
(1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl, or
(2) two substituents that, together with the amino nitrogen, form a single- ring heterocyclyl.
[00132] In some embodiments, R4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein: the carbocyclyl and heterocyclyl optionally are substituted with up to three substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl, and heterocyclyl, wherein: the amino optionally is substituted with: (1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl, or
(2) two substituents that, together with the amino nitrogen, form a single- ring heterocyclyl.
[00133] In some embodiments, R4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein:
(a) the amino, aminocarbonyl, and aminosulfonyl optionally are substituted with:
(1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl, or,
(2) two substituents that, together with the amino nitrogen, form a single-ring heterocyclyl; and
(b) the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyl, carbocyclyl, and heterocyclyl optionally are substituted with up to three substituents independently selected from the group consisting of halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, carbocyclyl, and heterocyclyl, wherein the amino optionally is substituted with:
(1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl, or,
(2) two substituents that, together with the amino nitrogen, form a single-ring heterocyclyl.
[00134] In some embodiments, R4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein: the amino, aminocarbonyl, and aminosulfonyl optionally are substituted with:
(1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl, or,
(2) two substituents that, together with the amino nitrogen, form a single-ring heterocyclyl.
[00135] hi some embodiments, R4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein: the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyl, carbocyclyl, and heterocyclyl optionally are substituted with up to three substituents independently selected from the group consisting of halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, carbocyclyl, and heterocyclyl, wherein the amino optionally is substituted with:
(1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl, or,
(2) two substituents that, together with the amino nitrogen, form a single-ring heterocyclyl.
[00136] In some embodiments, R4 is selected from the group consisting of halo, Ci-Q-alkyl, C2-C4- alkenyl, C2-C4-alkynyl, amino, C]-C4-alkylsulfonyl, C3-C6-carbocyclyl, and 5-6-membered heterocyclyl, wherein:
(a) the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl,
(b) the Ci-C4-alkyl, C2-C4-alkenyl, and C2-C4-alkynyl optionally are substituted with one or more substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and
(c) the C3-C6-carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with up to three substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, and amino, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl.
[00137] In some embodiments, R4 is selected from the group consisting of Ci-C4-alkyl, C2-C4-alkenyl, C2- C4-alkynyl, amino, Q-Gt-alkylsulfonyl, C3-C6-carbocyclyl, and 5-6-membered heterocyclyl, wherein:
(a) the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl,
(b) the Ci-C4-alkyl, C2-C4-alkenyl, and C2-C4-alkynyl optionally are substituted with one or more substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and
(c) the C3-C6-carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with up to three substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, and amino, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl. [00138] In some embodiments, R4 is selected from the group consisting of halo, CrC4-alkyl, C3-C6- carbocyclyl, and 5-6-membered heterocyclyl, wherein:
(a) the CrC4-alkyl optionally is substituted with up to three substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and
(b) the C3-C6-carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, halo, and alkylsulfonylamino.
[00139] In some embodiments, R4 is selected from the group consisting of halo, Ci-C4-alkyl, C3-C6- carbocyclyl, and 5-6-membered heterocyclyl, wherein:
(a) the Ci-C4-alkyl optionally is substituted with one or two substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and
(b) the C3-C6-carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with a substituent selected from the group consisting of alkyl, halo, and alkylsulfonylamino.
[0014O] In some embodiments, R4 is selected from the group consisting of Ci-C4-alkyl, C3-C6- carbocyclyl, and 5-6-membered heterocyclyl, wherein:
(a) the Ci-C4-alkyl optionally is substituted with up to three substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and
(b) the C3-C6-carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, halo, and alkylsulfonylamino .
[0014I]In some embodiments, R4 is selected from the group consisting of halo, tert-butyl, C3-C6- carbocyclyl, and 5-6-membered heterocyclyl, wherein: the C3-C6-carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with a substituent selected from the group consisting of alkyl, halo, and alkylsulfonylamino. [00142] In some embodiments, R4 is selected from the group consisting of tert-butyl, C3-C6-carbocyclyl, and 5-6-membered heterocyclyl, wherein: the C3-C6-carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with a substituent selected from the group consisting of alkyl, halo, and alkylsulfonylamino. [00143] In some embodiments, R4 is selected from the group consisting of halo, alkyl, haloalkyl, carboxyalkyl, hydroxyalkyl, alkyloxyalkyl, trimethylsilylalkynyl, alkylcarbocyclyl, carbocyclyl, alkylheterocyclyl, heterocyclyl, halocarbocyclyl, alkylsulfonylamino, and alkylsulfonyl. [00144] In some embodiments, R4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl. [00145] In some embodiments, R4 is selected from the group consisting of halo, Ci-C4-alkyl, C2-C4- alkenyl, C2-C4-alkynyl, amino, Ci-C4-alkylsulfonyl, C3-C6-carbocyclyl, and 5-6-membered heterocyclyl. In some such embodiment, R4 is selected from the group consisting of halo, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, amino, Q-Q-alkylsulfonyl, C6-carbocyclyl, and 5-6-membered heterocyclyl. In other such embodiment, R4 is selected from the group consisting of halo, CrC4-alkyl, C2-C4-alkenyl, C2-C4- alkynyl, amino, C]-C4-alkylsulfonyl, phenyl, and 5-6-membered heteroaryl.
[00146] In some embodiments, R4 is selected from the group consisting of CpC4-alkyl, C2-C4-alkenyl, C2- C4-alkynyl, amino, CrC4-alkylsulfonyl, C3-C6-carbocyclyl, and 5-6-membered heterocyclyl. In some such embodiment, R4 is selected from the group consisting of C]-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, amino, Q-Q-alkylsulfonyl, C6-carbocyclyl, and 5-6-membered heterocyclyl. In other such embodiment, R4 is selected from the group consisting of CrC4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, amino, Ct-C4- alkylsulfonyl, phenyl, and 5-6-membered heteroaryl.
[00147] In some embodiments, R4 is selected from the group consisting of halo, Ci-C4-alkyl, C3-C6- carbocyclyl, and 5-6-membered heterocyclyl. In some such embodiments, R4 is selected from the group consisting of halo, C]-C4-alkyl, C6-carbocyclyl, and 5-6-membered heterocyclyl. In other such embodiments, R4 is selected from the group consisting of halo, Ci-C4-alkyl, phenyl, and 5-6-membered heteroaryl.
[00148] In some embodiments, R4 is selected from the group consisting of Ci-C4-alkyl, C3-C6- carbocyclyl, and 5-6-membered heterocyclyl. In some such embodiments, R4 is selected from the group consisting of CrC4-alkyl, C6-carbocyclyl, and 5-6-membered heterocyclyl. In other such embodiments, R4 is selected from the group consisting of Q-Q-alkyl, phenyl, and 5-6-membered heteroaryl. [00149] In some embodiments, R4 is selected from the group consisting of halo, tert-butyl, C3-C6- carbocyclyl, and 5-6-membered heterocyclyl. In some such embodiments, R4 is selected from the group consisting of halo, tert-butyl, C6-carbocyclyl, and 5-6-membered heterocyclyl. In other such embodiments, R4 is selected from the group consisting of halo, tert-butyl, phenyl, and 5-6-membered heteroaryl.
[0015O]In some embodiments, R4 is selected from the group consisting of tert-butyl, C3-C6-carbocyclyl, and 5-6-membered heterocyclyl. In some such embodiments, R4 is selected from the group consisting of tert-butyl, C6-carbocyclyl, and 5-6-membered heterocyclyl. In other such embodiments, R4 is selected from the group consisting of tert-butyl, phenyl, and 5-6-membered heteroaryl. [00151] In some embodiments, R4 is selected from the group consisting of C3-C6-carbocyclyl and 5-6- membered heterocyclyl. In some such embodiments, R4 is selected from the group consisting of C6- carbocyclyl, and 5-6-membered heterocyclyl. In other such embodiments, R4 is selected from the group consisting of phenyl and 5-6-membered heteroaryl. [00152] Suitable carbocyclyls for the above embodiments include, for example, cyclopropyl and phenyl.
[00153] Suitable heterocyclyls for the above embodiments include, for example, furanyl, thienyl, and pyridinyl.
[00154] In some embodiments, R4 is selected from the group consisting of halo, alkyl, and alkyloxy.
[00155] In some embodiments, R4 is alkyl.
[00156] In some embodiments, R4 is tert-butyl.
B5. Substituent R5.
[00157] R5 is selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, carbocyclylsulfonyloxy, haloalkylsulfonyloxy, and halo. [00158] In some embodiments, R5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy, and halo. In some such embodiments, R5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy, and fluoro. In other such embodiments, R5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy, and fluoro. hi yet other such embodiments, R5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy, and chloro. hi yet other such embodiments, R5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy, and bromo. hi further such embodiments, R5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy, and iodo.
[00159] In some embodiments, R5 is selected from the group consisting of hydrogen, hydroxy, methoxy, and halo. In some such embodiments, R5 is selected from the group consisting of hydrogen, hydroxy, methoxy, and fluoro. In other such embodiments, R5 is selected from the group consisting of hydrogen, hydroxy, methoxy, and chloro. In yet other such embodiments, R5 is selected from the group consisting of hydrogen, hydroxy, methoxy, and bromo. In further such embodiments, R5 is selected from the group consisting of hydrogen, hydroxy, methoxy, and iodo.
[0016O] In some embodiments, R5 is selected from the group consisting of hydrogen, hydroxy, and alkyloxy. hi some such embodiments, R5 is selected from the group consisting of hydrogen, hydroxy, methoxy, and ethoxy.
[00161] hi some embodiments, R5 is s hydrogen. [00162] In some embodiments, R5 is hydroxy. [00163] In some embodiments, R5 is alkyloxy. [00164] In some embodiments, R5 is methoxy. [00165] hi some embodiments, R5 is ethoxy.
B6. Substituent L.
[00166] L is selected from the group consisting of C(RA)=C(RB), ethylene, and cyclopropyl- 1,2-ene, wherein RA and RB are as discussed below. [00167] In some embodiments, L is C(RA)=C(RB), wherein RA and RB are as discussed below. In these embodiments, the compounds of formula I correspond in structure to formula I-Ll:
Figure imgf000027_0001
[00168] In some such embodiments, the compounds correspond in structure to formula IA-Ll:
Figure imgf000027_0002
[00169] In other such embodiments, the compounds correspond in structure to formula IB-Ll:
Figure imgf000027_0003
[00170] Typically, the compounds of formula I-Ll are more potent if R6 and the phenyl-uracil are on opposite sides of the double bond (i.e., in trans configuration in relation to the double bond). [00171] In some embodiments, L is ethylene. In these embodiments, the compounds of formula I correspond in structure to I-L5-2:
Figure imgf000027_0004
[00172] In some such embodiments, the compounds correspond in structure to formula IA-L5-2:
Figure imgf000028_0001
[00173] In other such embodiments, the compounds correspond in structure to formula IB-L5-2:
Figure imgf000028_0002
[00174] In some embodiments, L is cyclopropyl-l,2-ene. In these embodiments, the compounds of formula I correspond in structure to formula I-L8:
Figure imgf000028_0003
[00175] In some such embodiments, the compounds correspond in structure to formula IA-L8:
Figure imgf000028_0004
[00176] In other such embodiments, the compounds correspond in structure to formula IB-L8:
Figure imgf000029_0001
B 7. Substituents R4 andRB.
[00177] RA and RB are independently selected from the group consisting of hydrogen, Ci-C6-alkyl, Q- C6-alkyloxy, C3-Cg-cycloalkyl, and halo, wherein: the Ci-C6-alkyl optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, halo, hydroxy, nitro, oxo, amino, cyano, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, and heterocyclyl.
[00178] In some embodiments, one of RA and RB is hydrogen, and the other is selected from the group consisting of C]-C6-alkyl, C]-C6-alkyloxy, C3-C8-cycloalkyl, and halo, wherein: the Ci-Cβ-alkyl optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, halo, hydroxy, nitro, oxo, amino, cyano, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, and heterocyclyl. [00179] In some embodiments, RA and RB are independently selected from the group consisting of hydrogen, Ci-C6-alkyl, Ci-C6-alkyloxy, C3-C8-cycloalkyl, and halo.
[0018O]In some of the above embodiments, RA is hydrogen. In other of the above embodiments, RB is hydrogen.
[00181] In some embodiment, one of RA and RB is hydrogen, and the other is selected from the group consisting of hydrogen, methyl, methoxy, and halo.
[00182] In some embodiments, RA is hydrogen, and RB is selected from the group consisting of methyl, methoxy, and halo, hi some such embodiments, RB is selected from the group consisting of methyl, methoxy, and fluoro. In other such embodiments, RB is selected from the group consisting of methyl, methoxy, and chloro. In yet other such embodiments, RB is selected from the group consisting of methyl, methoxy, and bromo. In further such embodiments, RB is selected from the group consisting of methyl, methoxy, and iodo. In yet further such embodiments, RB is selected from the group consisting of methyl, methoxy, chloro, and fluoro.
[00183] In some embodiments, RB is hydrogen, and RA is selected from the group consisting of methyl, methoxy, and halo. In some such embodiments, RA is selected from the group consisting of methyl, methoxy, and fluoro. In other such embodiments, RA is selected from the group consisting of methyl, methoxy, and chloro. In yet other such embodiments, RA is selected from the group consisting of methyl, methoxy, and bromo. In further such embodiments, RA is selected from the group consisting of methyl, methoxy, and iodo. In yet further such embodiments, RA is selected from the group consisting of methyl, methoxy, chloro, and fluoro. [00184] hi some embodiments, RA is hydrogen, and RB is hydrogen.
B8. Substituent R6.
[00185] R6 is selected from the group consisting of C5-C6-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl, wherein each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ, wherein RE, RF, RG, RH, R1, RJ, and Rκ are as described below. In some such embodiments, the C5-C6-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are not substituted, hi other such embodiments, the C5-C6-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with a substituent selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In other such embodiments, the C5-C6-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with a substituent selected from the group consisting of RE, RF, R1, RJ, and Rκ. hi other such embodiments, the C5-C6-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with a substituent selected from the group consisting of RE, RF, and RJ. In other such embodiments, the C5-C6-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with a substituent selected from the group consisting of RF and RJ. In other such embodiments, the C5-C6-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with RJ. In yet other such embodiments, the C5-C6-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2- ring heterocyclyl are substituted with two substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In yet other such embodiments, the C5-C6-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with two substituents independently selected from the group consisting of RE, RF, R1, RJ, and Rκ. In yet other such embodiments, the C5-C6-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2- ring heterocyclyl are substituted with two substituents independently selected from the group consisting of RE, RF, and RJ. In yet other such embodiments, the C5-C6-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with two substituents independently selected from the group consisting of RF and RJ. In further such embodiments, the C5-C6- carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with three substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In further such embodiments, the C5-C6-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with three substituents independently selected from the group consisting of RE, RF, R1, RJ, and Rκ. In further such embodiments, the C5-C6- carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with three substituents independently selected from the group consisting of RE, RF, and RJ. In further such embodiments, the C5-C6-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with three substituents independently selected from the group consisting of RF and RJ. In further such embodiments, the C5-C6-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with one, two, or three substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In further such embodiments, the C5-C6-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with one, two, or three substituents independently selected from the group consisting of RE, RF, R1, RJ, and Rκ. In further such embodiments, the C5-C6- carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with one, two, or three substituents independently selected from the group consisting of RE, RF, and RJ. In further such embodiments, the C5-C6-carbocyclyl, 5-6-membered heterocyclyl, fused 2- ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with one, two, or three substituents independently selected from the group consisting of RF and RJ.
[00186] In some embodiments, R6 is selected from the group consisting of C5-C6-carbocyclyl and 5-6- membered heterocyclyl, wherein each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In some such embodiments, the C5-C6-carbocyclyl and 5-6-membered heterocyclyl are not substituted. In other such embodiments, the C5-C6-carbocyclyl and 5-6-membered heterocyclyl are substituted with a substituent selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In yet other such embodiments, the C5-C6-carbocyclyl and 5-6-membered heterocyclyl are substituted with two substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In further such embodiments, the C5-C6-carbocyclyl and 5-6-membered heterocyclyl are substituted with three substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In further such embodiments, the C5-C6-carbocyclyl and 5-6-membered heterocyclyl are substituted with one, two, or three substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ.
[00187] In some embodiments, R6 is C5-C6-carbocyclyl optionally substituted with one or more substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In some such embodiments, the C5-C6-carbocyclyl is not substituted. In other such embodiments, the C5-C6- carbocyclyl is substituted with a substituent selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In yet other such embodiments, the C5-C6-carbocyclyl is substituted with two substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In further such embodiments, the C5-C6-carbocyclyl is substituted with three substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In further such embodiments, the C5-C6-carbocyclyl is substituted with one, two, or three substituents independently selected from the group consisting of RE, Rr, RG, RH, R1, RJ, and Rκ.
[00188] In some embodiments, R6 is 5-6-membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In some such embodiments, the 5-6-membered heterocyclyl is not substituted. In other such embodiments, the 5-6-membered heterocyclyl is substituted with a substituent selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In yet other such embodiments, the 5-6-membered heterocyclyl is substituted with two substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In further such embodiments, the 5-6-membered heterocyclyl is substituted with three substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In further such embodiments, the 5-6-membered heterocyclyl is substituted with one, two, or three substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. [00189] In some embodiments, R6 is selected from the group consisting of fused 2-ring carbocyclyl and fused 2-ring heterocyclyl, wherein each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In some such embodiments, the fused 2-ring carbocyclyl and fused 2-ring heterocyclyl are not substituted. In other such embodiments, the fused 2-ring carbocyclyl and fused 2-ring heterocyclyl are substituted with a substituent selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In yet other such embodiments, the fused 2-ring carbocyclyl and fused 2-ring heterocyclyl are substituted with two substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In further such embodiments, the fused 2-ring carbocyclyl and fused 2-ring heterocyclyl are substituted with three substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In further such embodiments, the fused 2-ring carbocyclyl and fused 2-ring heterocyclyl are substituted with one, two, or three substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ.
[0019O]In some embodiments, R6 is fused 2-ring carbocyclyl optionally substituted with one or more substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In some such embodiments, the fused 2-ring carbocyclyl is not substituted. In other such embodiments, the fused 2-ring carbocyclyl is substituted with a substituent selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In yet other such embodiments, the fused 2-ring carbocyclyl is substituted with two substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In further such embodiments, the fused 2-ring carbocyclyl is substituted with three substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In further such embodiments, the fused 2-ring carbocyclyl is substituted with one, two, or three substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. [0019I]In some embodiments, R6 is fused 2-ring heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In some such embodiments, the fused 2-ring heterocyclyl is not substituted. In other such embodiments, the fused 2-ring heterocyclyl is substituted with a substituent selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In yet other such embodiments, the fused 2-ring heterocyclyl is substituted with two substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In further such embodiments, the fused 2-ring heterocyclyl is substituted with three substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. In further such embodiments, the fused 2-ring heterocyclyl is substituted with one, two, or three substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ. [00192] In some of the above embodiments, the optionally substituted Cs-Cβ-carbocyclyl is selected from the group consisting of cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl. In some such embodiments, the optionally substituted C5-C6-carbocyclyl is phenyl.
[00193] In some of the above embodiments, the optionally substituted C5-C6-carbocyclyl is C5- carbocyclyl. Examples of C5-carbocyclyls include cyclopentyl, cyclopentenyl, and cyclopentadienyl. [00194] In other of the above embodiments, the optionally substituted C5-C6-carbocyclyl is C6- carbocyclyl. Examples of Cδ-carbocyclyls include cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl.
[00195] In some of the above embodiments, the optionally substituted 5-6-membered-heterocyclyl is selected from the group consisting of furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl (thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, dihydrooxazolyl, isoxazolyl, dihydroisoxazolyl, oxazolidinyl, isoxazolidinyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxathiolyl, oxathiolanyl, triazolyl, oxadiazolyl, furazanyl, tetrazolyl, oxatriazolyl, dioxazolyl, oxathiazolyl, oxathiazolidinyl, dihydrooxadiazolyl, dioxazolidinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl, diazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, dihydropyrazinyl, tetrahydropyrazinyl, piperazinyl, triazinyl, dihydrotriazinyl, tetrahydrotriazinyl, triazinanyl, oxazinyl, dihydrooxazinyl, morpholinyl, oxathiazinyl, dihydrooxathiazinyl, oxathiazinanyl, oxadiazinyl, dihydrooxadiazinyl, oxadiazinanyl, thiopyranyl, dihydrothiopyranyl, and tetrahydrothiopyranyl.
[00196] In some of the above embodiments, the optionally substituted 5-6-membered-heterocyclyl is 5- membered heterocyclyl. Examples of such 5-membered heterocyclyl include furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl (thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, dihydrooxazolyl, isoxazolyl, dihydroisoxazolyl, oxazolidinyl, isoxazolidinyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxathiolyl, oxathiolanyl, triazolyl, oxadiazolyl, furazanyl, tetrazolyl, oxatriazolyl, dioxazolyl, oxathiazolyl, oxathiazolidinyl, dihydrooxadiazolyl, and dioxazolidinyl.
[00197] In other of the above embodiments, the optionally substituted 5-6-membered-heterocyclyl is 6- membered heterocyclyl. Examples of 6-membered heterocyclyls include pyranyl, dihydropyranyl, tetrahydropyranyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl, diazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, dihydropyrazinyl, tetrahydropyrazinyl, piperazinyl, triazinyl, dihydrotriazinyl, tetrahydrotriazinyl, triazinanyl, oxazinyl, dihydrooxazinyl, morpholinyl, oxathiazinyl, dihydrooxathiazinyl, oxathiazinanyl, oxadiazinyl, dihydrooxadiazinyl, oxadiazinanyl, thiopyranyl, dihydrothiopyranyl, and tetrahydrothiopyranyl.
[00198] In some of the above embodiments, the optionally substituted fused 2-ring carbocyclyl is selected from the group consisting of naphthalenyl, dihydronaphthalenyl, tetrahydronaphthalenyl, hexahydronaphthalenyl, octahydronaphthalenyl, decahydronaphthalenyl, indenyl, dihydroindenyl, hexahydroindenyl, octahydroindenyl, pentalenyl, octahydropentalenyl, and hexahydropentalenyl. In some such embodiments, the optionally substituted fused 2-ring carbocyclyl is selected from the group consisting of naphthalenyl and dihydroindenyl. In some such embodiments, the optionally substituted fused 2-ring carbocyclyl is naphthalenyl. In other such embodiments, the optionally substituted fused 2- ring carbocyclyl is dihydroindenyl. In further such embodiments, the optionally substituted fused 2-ring carbocyclyl is indenyl.
[00199] In some of the above embodiments, the optionally substituted fused 2-ring heterocyclyl is selected from the group consisting of
Figure imgf000035_0001
(H22)
X1, X2, and X3 are independently selected from the group consisting of N and C(H); X4 is selected from the group consisting of N(H), O, and S; X5, X6, and X7 are independently selected from the group consisting of N and C(H);
X8 is selected from the group consisting of N(H), O, and S;
X9 is selected from the group consisting of N(H), O, and S;
X10, X11, X12, and X13 are independently selected from the group consisting of N and C(H);
X14 is selected from the group consisting of N(H), O, and S;
X15, X16, X17, and X18 are independently selected from the group consisting of N and C(H); one or more of X19, X20, and X21 is N, and the remaining one(s) is/are C(H); one or more of X22, X23, X24, and X25 is N, and the remaining one(s) is/are C(H); one or more of X26, X27, and X28 is N, and the remaining one(s) is/are C(H); one or more of X29, X30, X31, and X32 is N, and the remaining one(s) is/are C(H); one or more of X33, X34, and X35 is N, and the remaining one(s) is/are C(H); one or more of X36, X37, X38, and X39 is N, and the remaining one(s) is/are C(H);
X40, X41, and X42 are independently selected from the group consisting of N and C(H); one of X43, X44, and X45 is selected from the group consisting of N(H), O, and S, and the remaining two are C(H)2; one of X46 and X47 is selected from the group consisting of N(H), O, and S, and the other one is C(H)2;
X48, X49, X50, and X51 are independently selected from the group consisting of N and C(H);
X52, X53, and X54 are independently selected from the group consisting of N and C(H);
X55 is selected from the group consisting of N(H), O, and S;
X56, X57, and X58 are independently selected from the group consisting of N and C(H);
X59 is selected from the group consisting of N(H), O, and S;
X60 is selected from the group consisting of N(H), O, and S;
X61, X62, X63, and X64 are independently selected from the group consisting of N and C(H);
X65 is selected from the group consisting of N(H), O, and S;
X66, X67, X68, and X69 are independently selected from the group consisting of N and C(H); one or more of X70, X71, and X72 is N, and the remaining one(s) is/are C(H); one or more of X73, X74, X75, and X76 is N, and the remaining one(s) is/are C(H); and one of X77 and X78 is N(H), and the remaining one is C(H)2.
[0020O] In some of the above embodiments, the optionally substituted fused 2-ring heterocyclyl is selected from the group consisting of
Figure imgf000037_0001
[0020I] In some of the above embodiments, the optionally substituted fused 2-ring heterocyclyl is selected from the group consisting of:
Figure imgf000038_0001
(H18) (H20)
(H19)
Figure imgf000038_0002
[00202] In some of the above embodiments, X1, X2, and X3 are C(H). [00203] In some of the above embodiments, X5, X6, and X7 are C(H). [00204] In some of the above embodiments, X10, X11, X12, and X13 are C(H). [00205] In some of the above embodiments, X15, X16, X17, and X18 are C(H). [00206] In some of the above embodiments, one of X19, X20, and X21 is N. [00207] In some of the above embodiments, one of X22, X23, X24, and X25 is N. [00208] In some of the above embodiments, one of X26, X27, and X28 is N, and one of X29, X30, X31, and X32 is N.
[00209] In some of the above embodiments, X40, X41, and X42 are C(H). [0021O] In some of the above embodiments, X48, X49, X50, and X51 are C(H). [0021I] In some of the above embodiments, X52, X53, and X54 are C(H). [00212] In some of the above embodiments, X56, X57, and X58 are C(H). [00213] In some of the above embodiments, X61, X62, X63, and X64 are C(H). [00214] In some of the above embodiments, X66, X67, X68, and X69 are C(H). [00215] In some of the above embodiments, one or more of X70, X71, and X72 is N, and the remaining one(s) is/are C(H). [00216] In some of the above embodiments, one or more of X73, X74, X75, and X76 is N, and the remaining one(s) is/are C(H).
B9. Substituent RE.
[00217] Each RE is independently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, cyano, amino, imino, azido, and aldehydo, wherein the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl. [00218] In some embodiment, each RE is independently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, amino, imino, and aldehydo, wherein the amino optionally is substituted with one or two independently selected alkyl.
[00219] In some embodiment, each RE is independently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, amino, imino, aldehydo, and alkylamino.
[00220] In some embodiment, each RE is independently selected from the group consisting of chloro, fluoro, nitro, hydroxy, oxo, carboxy, amino, imino, aldehydo, and alkylamino.
[0022I] In some embodiment, each RE is independently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, cyano, amino, imino, and azido. In some such embodiments, each RE is halo. In other such embodiments, each RE is nitro. In yet other such embodiments, each RE is hydroxy. In yet other such embodiments, each RE is oxo. In yet other such embodiments, each RE is carboxy. In yet other such embodiments, each RE is cyano. In yet other such embodiments, each RE is amino. In further such embodiments, each RE is imino. In yet further such embodiments, each RE is and azido. [00222] In some embodiments, each RE is independently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, cyano, amino, and imino.
BlO. Substituent RF.
[00223] Each RF is independently selected from the group consisting of alkyl, alkenyl, and alkynyl, wherein: each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, imino, aminosulfonyl, aminocarbonyl, carbocyclyl, and heterocyclyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkylsulfonylamino, hydroxy, and alkyloxy, wherein: amino portion of the alkylsulfonylamino optionally is substituted with a substituent selected from the group consisting of alkyl, alkenyl, and alkynyl. [00224] In some embodiment, each RF is independently selected from the group consisting of alkyl, alkenyl, and alkynyl, wherein: each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, imino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, and alkylsulfonylamino, wherein: amino portion of the alkylsulfonylamino optionally is substituted with a substituent selected from the group consisting of alkyl, alkenyl, and alkynyl.
[00225] In some of the above embodiments, each RF is independently selected from the group consisting of the alkyl, alkynyl, and alkynyl, wherein such substituents are not substituted. [00226] In some embodiments, each RF is independently selected from the group consisting of alkyl, alkenyl, and alkynyl, wherein: each such substituent optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, imino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkylsulfonyl, and alkylsulfonylamino, wherein: amino portion of the alkylsulfonylamino optionally is substituted with alkyl.
[00227] In some embodiments, each RF is an independently selected alkyl optionally substituted with a substituent selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, imino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkylsulfonyl, and alkylsulfonylamino, wherein: amino portion of the alkylsulfonylamino optionally is substituted with alkyl.
[00228] In some embodiments, each RF is an independently selected alkyl optionally substituted with a substituent selected from the group consisting of carboxy, halo, amino, imino, and aminosulfonyl, wherein: the amino, imino, and aminosulfonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkylsulfonyl, and alkylsulfonylamino.
[00229] In some embodiments, each RF is an independently selected alkyl optionally substituted with amino, wherein the amino optionally is substituted with alkylsulfonyl.
[00230] In some embodiments, each RF is an independently selected alkyl substituted with amino, wherein the amino is substituted with alkylsulfonyl. In some such embodiments, each RF is methylsulfonylaminomethyl.
[0023I] In some embodiments, each RF is independently selected from the group consisting of alkyl, alkenyl, and alkynyl, wherein: each such substituent optionally is substituted with one, two, or three substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl. [00232] In some embodiments, each RF is independently selected alkyl substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl.
BIl. Substituent RG.
[00233] Each RG is independently selected from the group consisting of carbocyclyl and heterocyclyl, wherein: each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl.
[00234] In some of the above embodiments, each RG is independently selected from the group consisting of carbocyclyl and heterocyclyl, wherein such substituents are not substituted. [00235] In some embodiments, each RG is independently selected from the group consisting of carbocyclyl and heterocyclyl, wherein: each such substituent optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl and alkylsulfonyl.
[00236] In some of the above embodiments, the carbocyclyl is C3-C6-carbocyclyl. [00237] In some of the above embodiments, the heterocyclyl is 5-6-membered heterocyclyl.
B12. Substituent B?.
[00238] Each RH is independently selected from the group consisting of alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, alkenylsulfonyloxy, and alkynylsulfonyloxy, wherein: each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl.
[00239] In some of the above embodiments, each RH is independently selected from the group consisting of alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, alkenylsulfonyloxy, and alkynylsulfonyloxy, wherein such substituents are not substituted.
[00240] In some embodiments, each RH is independently selected from the group consisting of alkyloxy and alkylsulfonyloxy, wherein: each such substituent optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl and alkylsulfonyl.
[0024I] In some embodiments, each RH is independently selected from the group consisting of alkyloxy and alkylsulfonyloxy, wherein: each such substituent optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, cyano, and aminocarbonyl, wherein: the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl and alkylsulfonyl.
[00242] In some embodiments, each RH is independently selected from the group consisting of alkyloxy and alkylsulfonyloxy, wherein: each such substituent optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, cyano, and aminocarbonyl.
[00243] In some embodiments, each RH is independently selected alkyloxy. [00244] In some embodiments, each RH is independently selected alkylsulfonyloxy.
B13. Substituent R1.
[00245] Each R is independently selected from the group consisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aminocarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl, and heterocyclylcarbonyl, wherein:
(a) the alkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl optionally are substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, and
(b) the aminocarbonyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxyalkyl, carbocyclyl, heterocyclyl, alkylsulfonyl, and alkylsulfonylamino, wherein: the carbocyclyl and heterocyclyl optionally are substituted with one or two substituents independently selected from the group consisting of halo, alkyl, and oxo. [00246] In some embodiments, each R1 is independently selected from the group consisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aminocarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl, and heterocyclylcarbonyl, wherein such substituents are not substituted. [00247] In some embodiments, each R1 is independently selected from the group consisting of alkylcarbonyl, aminocarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl, and heterocyclylcarbonyl, wherein:
(a) the alkylcarbonyl optionally is substituted with a substituent selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, and aminocarbonyl, and
(b) the aminocarbonyl optionally is substituted with a substituent selected from the group consisting of alkyl, alkyloxyalkyl, alkylsulfonyl, and alkylsulfonylamino.
[00248] In some embodiments, each R1 is independently selected from the group consisting of alkylcarbonyl and aminocarbonyl, wherein: the aminocarbonyl optionally is substituted with a substituent selected from the group consisting of alkyl, alkyloxyalkyl, alkylsulfonyl, and alkylsulfonylamino. [00249] In some embodiment, each R1 is independently selected from the group consisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, and aminocarbonyl, wherein:
(a) the alkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl optionally are substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, and
(b) the aminocarbonyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonylamino .
[00250] In some of the above embodiments, each R1 is independently selected from the group consisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, and aminocarbonyl, wherein such substituents are not substituted.
[00251] In some embodiments, each R1 is independently selected from the group consisting of alkylcarbonyl and aminocarbonyl, wherein:
(a) the alkylcarbonyl optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, and
(b) the aminocarbonyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl and alkylsulfonylamino. [00252] In some embodiments, each R1 is independently selected from the group consisting of alkylcarbonyl and aminocarbonyl, wherein:
(a) the alkylcarbonyl optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, cyano, and aminocarbonyl, and
(b) the aminocarbonyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl and alkylsulfonylamino.
[00253] In some embodiments, each R1 is independently selected from the group consisting of alkylcarbonyl and aminocarbonyl, wherein: the alkylcarbonyl optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl.
[00254] In some embodiments, each R1 is independently selected alkylcarbonyl.
[00255] In some embodiments, each R1 is independently selected aminocarbonyl.
B14. SubstituentR1.
[00256] Each RJ is independently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, alkyloxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, aminocarbonylamino, alkyloxycarbonylaminoimino, alkylsulfonylaminoimino, alkenylsulfonylaminoimino, and alkynylsulfonylaminoimino, wherein:
(a) the amino portion of such substituents optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkenyl, alkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
(1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido, oxo, and amino, and
(2) the amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl,
(b) the alkyl, alkenyl, and alkynyl portion of such substituents optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, and alkynyloxy, wherein: the alkyl optionally is substituted with one or more hydroxy;
(c) the carbocyclyl and heterocyclyl portions of such substituents optionally are substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido, and amino, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl.
[00257] In some embodiment, each RJ is independently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, alkyloxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, aminocarbonylamino, alkylsulfonylaminoimino, alkenylsulfonylaminoimino, and alkynylsulfonylaminoimino, wherein:
(a) the amino portion of such substituents optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkenyl, alkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
(1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido, oxo, and amino, and
(2) the amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl,
(b) the alkyl, alkenyl, and alkynyl portion of such substituents optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, and alkynyloxy, wherein: the alkyl optionally is substituted with one or more hydroxy;
(c) the carbocyclyl and heterocyclyl portions of such substituents optionally are substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido, and amino, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl; and
[00258] In some of the above embodiments, each RJ is independently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, alkyloxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, aminocarbonylamino, alkylsulfonylaminoimino, alkenylsulfonylaminoimino, and alkynylsulfonylaminoimino, wherein such substituents are not substituted.
[00259] In some embodiments, each RJ is independently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino, alkyloxycarbonylamino, alkylsulfonylamino, aminocarbonylamino, and alkylsulfonylaminoimino, wherein:
(a) the amino portion of such substituents optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
(1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and
(2) the amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl,
(b) the alkyl portion of such substituents optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, wherein: the alkyl optionally is substituted with one or more hydroxy;
(c) the carbocyclyl and heterocyclyl portions of such substituents optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, and amino, wherein: the amino optionally is substituted with one or two substituents independently selected alkyl.
[00260] In some embodiments, each RJ is independently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylsulfonylamino, and alkylsulfonylaminoimino, wherein:
(a) the amino portion of such substituents optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
(1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and
(2) the amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl,
(b) the alkyl portion of such substituents optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, wherein: the alkyl optionally is substituted with one or more hydroxy; (c) the carbocyclyl and heterocyclyl portions of such substituents optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, and amino, wherein: the amino optionally is substituted with one or two substituents independently selected alkyl.
[0026I]In some embodiments, each RJ is independently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylsulfonylamino, and alkylsulfonylaminoimino, wherein: the amino portion of such substituents optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
(1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and
(2) the amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl.
[00262] In some embodiments, each RJ is independently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylsulfonylamino, and alkylsulfonylaminoimino, wherein: the alkyl portion of the alkylsulfonylamino and alkylsulfonylaminoimino optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, wherein: the alkyl optionally is substituted with one or more hydroxy.
[00263] In some embodiments, each RJ is independently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylsulfonylamino, and alkylsulfonylaminoimino, wherein: the carbocyclyl and heterocyclyl portions of such substituents optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, and amino.
[00264] In some embodiments, each RJ is independently selected from the group consisting of carbocyclylsulfonylamino and heterocyclylsulfonylamino, wherein: the carbocyclyl and heterocyclyl portions of such substituents optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, and amino.
[00265] In some embodiments, each RJ is independently selected from the group consisting of alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, and alkylsulfonylaminoimino, wherein:
(a) the amino portion of such substituents optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
(1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and
(2) the amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl,
(b) the alkyl, alkenyl, and alkynyl portion of such substituents optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, wherein: the alkyl optionally is substituted with one or more hydroxy. [00266] In some embodiments, each RJ is an independently selected alkylsulfonylamino, wherein:
(a) the amino portion of the alkylsulfonylamino optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
(1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and
(2) the amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl,
(b) the alkyl portion of the alkylsulfonylamino optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, wherein: the alkyl optionally is substituted with one or more hydroxy. [00267] In some embodiments, each RJ is an independently selected alkylsulfonylamino, wherein: the amino portion of the alkylsulfonylamino optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
(1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and
(2) the amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl.
[00268] In some embodiments, each RJ is an independently selected alkylsulfonylamino, wherein: the amino portion of the alkylsulfonylamino optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl. [00269] In some embodiments, each RJ is an independently selected alkylsulfonylamino, wherein: the alkyl portion of the alkylsulfonylamino optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, wherein: the alkyl optionally is substituted with one or more hydroxy. [00270] In some embodiments, each RJ is an independently selected alkylsulfonylamino, wherein: the alkyl portion of the alkylsulfonylamino optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano. [00271] hi some embodiments, each RJ is an independently selected alkylsulfonylamino. hi some such embodiments, each RJ is methylsulfonylamino. [00272] In some embodiments, each RJ is an independently selected alkylsulfonylaminoimino, wherein:
(a) the amino portion of the alkylsulfonylaminoimino optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
(1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and
(2) the amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl,
(b) the alkyl portion of the alkylsulfonylaminoimino optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, wherein: the alkyl optionally is substituted with one or more hydroxy. [00273] In some embodiments, each RJ is an independently selected alkylsulfonylaminoimino, wherein: the amino portion of the alkylsulfonylaminoimino optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein: (1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and
(2) the amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl.
[00274] In some embodiments, each RJ is an independently selected alkylsulfonylaminoimino, wherein: the amino portion of the alkylsulfonylaminoimino optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl. [00275] In some embodiments, each RJ is an independently selected alkylsulfonylaminoimino, wherein: the alkyl portion of the alkylsulfonylaminoimino optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, wherein: the alkyl optionally is substituted with one or more hydroxy. [00276] In some embodiments, each RJ is an independently selected alkylsulfonylaminoimino, wherein: the alkyl portion of the alkylsulfonylaminoimino optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano. [00277] In some embodiments, each RJ is an independently selected alkylsulfonylaminoimino. In some such embodiments, each RJ is methylsulfonylaminoimino.
[00278] hi some embodiments, each RJ is independently selected from the group consisting of alkylcarbonylamino and alkyloxycarbonylamino, wherein: the alkyl portion of such substituents optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano.
Bl 5. Substituent Rκ.
[00279] Each Rκ is independently selected from the group consisting of aminosulfonyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl, wherein: (a) the alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl optionally are substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl; and
(b) the aminosulfonyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl.
[0028O]In some of the above embodiments, each Rκ is independently selected from the group consisting of aminosulfonyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl, wherein such substituents are not substituted.
[00281] In some embodiments, each Rκ is independently selected from the group consisting of aminosulfonyl and alkylsulfonyl, wherein:
(a) the alkylsulfonyl optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl; and
(b) the aminosulfonyl optionally is substituted with one or two substituents independently selected alkyl.
[00282] In some embodiments, each Rκ is independently selected from the group consisting of aminosulfonyl and alkylsulfonyl.
C. Embodiments of Compounds of Formula I. [00283] Various embodiments of substituents R1, R2, R3, R4, R5, L, RA, RB, Rc, RD, R6, RE, RF, RG, RH,
R1, RJ, and Rκ have been discussed above. These substituent embodiments can be combined to form various embodiments of compounds of formula I. All embodiments of compounds of formula I formed by combining the substituent embodiments discussed above are within the scope of Applicants' invention, and some illustrative embodiments of the compounds of formula I are provided below. [00284] In some embodiments, in the compounds of formula I: is selected from the group consisting of single carbon-carbon bond and double carbon- carbon bond;
R1 is selected from the group consisting of hydrogen and methyl; R2 is selected from the group consisting of hydrogen and halo; R3 is selected from the group consisting of hydrogen and halo;
R4 is selected from the group consisting of d-C4-alkyl, C3-C6-carbocyclyl, and 5-6-membered heterocyclyl, wherein:
(a) the Ci -Chalky 1 optionally is substituted with up to three substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and
(b) the C3-C6-carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, halo, and alkylsulfonylamino;
R5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy, and halo;
L is selected from the group consisting of C(RA)=C(RB), ethylene, and cyclopropyl-l,2-ene; one of RA and RB is hydrogen, and the other is selected from the group consisting of hydrogen, methyl, methoxy, and halo;
R6 is selected from the group consisting of C5-C6-carbocyclyl and 5-6-membered heterocyclyl, wherein each such substituent is substituted with one, two, or three substituents independently selected from the group consisting of RE, RF, and RJ; each RE is independently selected from the group consisting of chloro, fluoro, nitro, hydroxy, oxo, carboxy, amino, imino, aldehydo, and alkylamino; each RF is an independently selected alkyl optionally substituted with a substituent selected from the group consisting of carboxy, halo, amino, imino, and aminosulfonyl, wherein: the amino, imino, and aminosulfonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkylsulfonyl, and alkylsulfonylamino; each R1 is independently selected from the group consisting of alkylcarbonyl and aminocarbonyl, wherein: the aminocarbonyl optionally is substituted with a substituent selected from the group consisting of alkyl, alkyloxyalkyl, alkylsulfonyl, and alkylsulfonylamino; and each RJ is independently selected from the group consisting of alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, and alkylsulfonylaminoimino, wherein:
(a) the amino portion of such substituents optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
(1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and
(2) the amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl,
(b) the alkyl, alkenyl, and alkynyl portion of such substituents optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, wherein the alkyl optionally is substituted with one or more hydroxy.
[00285] Examples of compounds of formula I (and salts thereof) are shown in Tables 1-7 below. The synthesis examples below provide step-by-step preparation instructions for some of these compounds. The remaining compounds were prepared utilizing the general method-of-preparation discussion, specific synthesis examples below, and/or the discussion throughout this application.
TABLE 1
Figure imgf000056_0001
Figure imgf000056_0002
Figure imgf000057_0002
TABLE 2
substituent(s) as described in the table below
Figure imgf000057_0001
Figure imgf000057_0003
Figure imgf000058_0001
TABLE 3
Figure imgf000059_0001
Figure imgf000059_0003
TABLE 4
Figure imgf000059_0002
Figure imgf000059_0004
TABLE 5
Figure imgf000060_0001
Figure imgf000060_0004
TABLE 6
substituent(s) as described in the table below
Figure imgf000060_0002
Figure imgf000060_0005
TABLE 7
Figure imgf000060_0003
D. homers.
[00286] This invention also is directed, in part, to all isomers of the compounds of formula I (and their salts) {i.e., structural and stereoisomers). Structural isomers include chain and position isomers. Stereoisomers include E/Z isomers (i.e., isomers with regard to one or more double bonds), enantiomers (i.e., stereo- isomers that have opposite configurations at all stereogenic centers), and diastereoisomers (i.e., stereo- isomers that have the same configuration at one or more stereogenic centers, but differ at other stereogenic centers).
E. Salts.
[00287] This invention also is directed, in part, to all salts of the compounds of formula I. A salt of a compound may be advantageous due to one or more of the salt's properties, such as, for example, enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or other solvents. Where a salt is intended to be administered to a patient (as opposed to, for example, being in use in an in vitro context), the salt preferably is pharmaceutically acceptable and/or physiologically compatible. The term "pharmaceutically acceptable" is used adjectivally in this patent application to mean that the modified noun is appropriate for use as a pharmaceutical product or as a part of a pharmaceutical product. Pharmaceutically acceptable salts include salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. In general, these salts typically may be prepared by conventional means by reacting, for example, the appropriate acid or base with a compound of the invention.
[00288] Pharmaceutically acceptable acid addition salts of the compounds of formula I can be prepared from an inorganic or organic acid. Examples of often suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid. Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids. Specific examples of often suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), ethanesulfonate, benzenesulfonate, pantothenate, 2-hydroxyethanesulfonate, sulfanilate, cyclohexylaminosulfonate, algenic acid, beta-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, bisulfate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate, oxalate, palmoate, pectinate, 2- naphthalesulfonate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and undecanoate. [00289] Pharmaceutically acceptable base addition salts of the compounds of formula I include, for example, metallic salts and organic salts. Preferred metallic salts include alkali metal (group Ia) salts, alkaline earth metal (group Ha) salts, and other physiologically acceptable metal salts. Such salts may be made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. Preferred organic salts can be made from amines, such as tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl (CrC6) halides {e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), and others.
[0029O]In some embodiments, the salt is sodium salt of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydro- pyrimidin- 1 (2H)-y l)-2-methoxystyryl)pheny l)methanesulfonamide .
[0029I]In some embodiments, the salt is disodium salt of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.
[00292] In some embodiments, the salt is potassium salt of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin- 1 (2H)-y l)-2-methoxystyryl)pheny l)methanesulfonamide .
[00293] In some embodiments, the salt is monopotassium salt of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.
F. Purity.
[00294] Compounds of formula I (and salts thereof) with any level of purity (including pure and substantially pure) are within the scope of Applicants' invention. The term "substantially pure" in reference to a compound/salt/isomer, means that the preparation/composition containing the compound/salt/isomer contains more than about 85% by weight of the compound/salt/isomer, preferably more than about 90% by weight of the compound/salt/isomer, preferably more than about 95% by weight of the compound/salt/isomer, preferably more than about 97% by weight of the compound/salt/isomer, and preferably more than about 99% by weight of the compound/salt/isomer.
G Crystalline Forms of Some Specific Compounds and Salts of The Invention.
Gl. Crystalline Forms of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide Disodium Salt.
[00295] This invention also relates, in part, to crystalline forms of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide disodium salt, namely the nonahydrate and tetrahydrate crystalline forms discussed below.
[00296] This invention relates, in part, to a nonahydrate crystalline disodium salt. The crystallographic unit cell parameters of the nonahydrate crystalline disodium salt have been determined to be as follows: a is 8.9A, b is 9.4A, and c is 20.7A (more precisely, a is 8.926(2)A, b is 9.415(2)A, and c is 20.674(5)A); the cell angles are: α - 94.8°, β - 93.3°, and γ - 107.0° (more precisely, α is 94.796(4)°, β is 93.345(4)°, and γ is 107.013(4)°); and the cell volume is 1649A3 (more precisely, 1649.3(7)A3). The salt crystallizes in the P-I space group.
[00297] In some embodiments, the disodium salt nonahydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 4.3±0.2, 10.4±0.2, 10.9±0.2,, 11.6±0.2, 12.9±0.2, 14.7±0.2, 16.4±0.2, 17.8±0.2, 19.4±0.2, 19.8±0.2, 20.8±0.2, 21.9±0.2, and 23.5±0.2 degrees 2Θ. In some such embodiments, the disodium salt nonahydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 4.3±0.2, 10.4±0.2, 10.9±0.2,, 11.6±0.2, 12.9±0.2, 14.7±0.2, 16.4±0.2, 17.8±0.2, 19.4±0.2, 19.8±0.2, 20.8±0.2, 21.9±0.2, and 23.5±0.2 degrees 2Θ. In other such embodiments, the disodium salt nonahydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 4.3±0.2, 10.4±0.2, 10.9±0.2,, 11.6±0.2, 12.9±0.2, 14.7±0.2, 16.4±0.2, 17.8±0.2, 19.4±0.2, 19.8±0.2, 20.8±0.2, 21.9±0.2, and 23.5±0.2 degrees 2Θ.
[00298] In some embodiments, the disodium salt nonahydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 4.3±0.2, 10.4±0.2, 10.9±0.2,, 11.6±0.2, 12.9±0.2, 14.7±0.2, 14.9±0.2, 16.4±0.2, 17.8±0.2, 19.4±0.2, 19.7±0.2, 19.8±0.2, 20.8±0.2, 20.9±0.2, 21.9±0.2, 22.1±0.2, and 23.5±0.2 degrees 2Θ. In some such embodiments, the disodium salt nonahydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 4.3±0.2, 10.4±0.2, 10.9±0.2,, 11.6±0.2, 12.9±0.2, 14.7±0.2, 14.9±0.2, 16.4±0.2, 17.8±0.2, 19.4±0.2, 19.7±0.2, 19.8±0.2, 20.8±0.2, 20.9±0.2, 21.9±0.2, 22.1±0.2, and 23.5±0.2 degrees 2Θ. In other such embodiments, the disodium salt nonahydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 4.3±0.2, 10.4±0.2, 10.9±0.2,, 11.6±0.2, 12.9±0.2, 14.7±0.2, 14.9±0.2, 16.4±0.2, 17.8±0.2, 19.4±0.2, 19.7±0.2, 19.8±0.2, 20.8±0.2, 20.9±0.2, 21.9±0.2, 22.1±0.2, and 23.5±0.2 degrees 2Θ.
[00299] In some embodiments, the disodium salt nonahydrate has an X-ray powder diffraction pattern substantially as shown in Figure 1. The 2Θ values for the peaks in Figure 1 (and their intensities) are as follows: 4.31 (100), 10.36 (12), 10.91 (23), 11.61 (52), 12.93 (24), 14.73 (65), 14.89 (20), 16.44 (41), 17.80 (38), 19.44 (26), 19.67 (37), 19.83 (59), 20.75 (69), 20.89 (21), 21.92 (43), 22.13 (40), and 22.42 (24).
[00300] This invention also relates, in part, to a process for preparing the disodium salt nonahydrate. It was prepared in aqueous medium. Aqueous NaOH (IM, 1.18ml) was added to (E)-N-(4-(3-tert-butyl-5- (2,4-dioxo-3 ,4-dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide (compound IB-Ll-1.1) (27.82mg) (molar ratio 1:20 acid:base). The resulting suspension was equilibrated at ambient conditions. The disodium salt nonahydrate formed seven days later through a solution-mediated process. Alternatively, the disodium salt nonahydrate was prepared by suspending 278.8mg of compound IB-Ll- 1.1 in 1.25ml THF while heated to about 50°C. Aqueous NaOH (IN, 1.5ml, 2.2molar equivalents) was added. The solid dissolved completely to yield a clear solution, which was naturally cooled to ambient temperatures. The salt crystallized spontaneously. The molecular structure was determined by single crystal diffractometry. [00301] This invention relates, in part, to a tetrahydrate crystalline disodium salt. [00302] In some embodiments, the disodium salt tetrahydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 4.8±0.2, 12.1±0.2, 14.0±0.2, 17.0±0.2, 17.5±0.2, 20.9±0.2, 21.6±0.2, 25.0±0.2, and 29.5±0.2 degrees 2Θ. In some such embodiments, the disodium salt tetrahydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 4.8±0.2, 12.1±0.2, 14.0±0.2, 17.0±0.2, 17.5±0.2, 20.9±0.2, 21.6±0.2, 25.0±0.2, and 29.5±0.2 degrees 2Θ. In other such embodiments, the disodium salt tetrahydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 4.8±0.2, 12.1±0.2, 14.0±0.2, 17.0±0.2, 17.5±0.2, 20.9±0.2, 21.6±0.2, 25.0±0.2, and 29.5±0.2 degrees 2Θ.
[00303] In some embodiments, the disodium salt tetrahydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 4.8±0.2, 12.1±0.2, 14.0±0.2, 14.4±0.2, 17.0±0.2, 17.5±0.2, 20.9±0.2, 21.6±0.2, 25.0±0.2, 29.5±0.2, and 34.2±0.2 degrees 2Θ. In some such embodiments, the disodium salt tetrahydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 4.8±0.2, 12.1±0.2, 14.0±0.2, 14.4±0.2, 17.0±0.2, 17.5±0.2, 20.9±0.2, 21.6±0.2, 25.0±0.2, 29.5±0.2, and 34.2±0.2 degrees 2Θ. In other such embodiments, the disodium salt tetrahydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 4.8±0.2, 12.1±0.2, 14.0±0.2, 14.4±0.2, 17.0±0.2, 17.5±0.2, 20.9±0.2, 21.6±0.2, 25.0±0.2, 29.5±0.2, and 34.2±0.2 degrees 2Θ.
[00304] In some embodiments, the disodium salt tetrahydrate has an X-ray powder diffraction pattern substantially as shown in Figure 2. The 2Θ values for the peaks in Figure 2 (and their intensities) are as follows: 4.81 (100), 12.07 (7), 14.01 (27), 14.41 (8), 16.96 (18), 17.53 (11), 20.87 (18), 21.58 (22), 24.99 (11), 29.47 (9), and 34.20 (9).
[00305] This invention also relates, in part, to a process for preparing the disodium salt tetrahydrate by suspending the nonahydrate disodium salt in an organic solvent (e.g., ethanol, 1-propanol, or 2-propanol).
G2. Crystalline Form of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3 \4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide Dipotassium Salt.
[00306] This invention also relates, in part, to a crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide dipotassium salt tetrahydrate. [00307] The crystallographic unit cell parameters of the dipotassium salt tetrahydrate have been determined to be as follows: a is 14.5A, b is 10.8A, and c is 35.8A (more precisely, a is 14.454(14)A, b is 10.763(14)A, and c is 35.75(4)A); the cell angle is: β - 98.8° (more precisely, β is 98.82(3)°); and the cell volume is 5499A3 (more precisely, 5499(11)A3). The salt crystallizes in the C2/c space group. [00308] In some embodiments, the dipotassium salt tetrahydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 5.0±0.2, 11.9±0.2, 12.4±0.2, 13.7±0.2, 15.0±0.2, 16.5±0.2, 17.1±0.2, 20.8±0.2, 21.3±0.2, 22.2±0.2, 24.0±0.2, 26.4±0.2, and 29.3±0.2 degrees 2Θ. In some such embodiments, the dipotassium salt tetrahydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 5.0±0.2, 11.9±0.2, 12.4±0.2, 13.7±0.2, 15.0-fc0.2, 16.5±0.2, 17.1±0.2, 20.8±0.2, 21.3±0.2, 22.2±0.2, 24.0±0.2, 26.4±0.2, and 29.3±0.2 degrees 2Θ. In other such embodiments, the dipotassium salt tetrahydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 5.0±0.2, 11.9±0.2, 12.4±0.2, 13.7±0.2, 15.0±0.2, 16.5±0.2, 17.1±0.2, 20.8±0.2, 21.3±0.2, 22.2±0.2, 24.0±0.2, 26.4±0.2, and 29.3±0.2 degrees 2Θ.
[00309] In some embodiments, the dipotassium salt tetrahydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 5.0±0.2, 11.9±0.2, 12.4±0.2, 12.6±0.2, 13.7±0.2, 15.0±0.2, 16.5±0.2, 16.7±0.2, 17.1±0.2, 20.7±0.2, 20.8±0.2, 21.3±0.2, 22.2±0.2, 22.4±0.2, 24.0±0.2, 26.4±0.2, and 29.3±0.2 degrees 2Θ. In some such embodiments, the dipotassium salt tetrahydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 5.0±0.2, 11.9±0.2, 12.4±0.2, 12.6±0.2, 13.7±0.2, 15.0±0.2, 16.5±0.2, 16.7±0.2, 17.1±0.2, 20.7±0.2, 20.8±0.2, 21.3±0.2, 22.2±0.2, 22.4±0.2, 24.0±0.2, 26.4±0.2, and 29.3±0.2 degrees 2Θ. In other such embodiments, the dipotassium salt tetrahydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 5.0±0.2, 11.9±0.2, 12.4±0.2, 12.6±0.2, 13.7±0.2, 15.0±0.2, 16.5±0.2, 16.7±0.2, 17.1±0.2, 20.7±0.2, 20.8±0.2, 21.3±0.2, 22.2±0.2, 22.4±0.2, 24.0±0.2, 26.4±0.2, and 29.3±0.2 degrees 2Θ.
[0031O]In some embodiments, the dipotassium salt tetrahydrate has an X-ray powder diffraction pattern substantially as shown in Figure 4. The 2Θ values for the peaks in Figure 4 (and their intensities) are as follows: 5.00 (100), 11.86 (34), 12.39 (32), 12.64 (19), 13.70 (23), 15.03 (21), 16.47 (24), 16.66 (24), 17.12 (28), 20.75 (29), 20.81 (33), 21.34 (22), 22.15 (46), 22.38 (31), 24.02 (24), 26.44 (24), and 29.32 (21).
[00311] This invention also relates, in part, to a process for preparing the dipotassium salt tetrahydrate by suspending compound IB-Ll-1.1 (261.13mg) in 1.25ml THF while heated to about 500C. Aqueous KOH (IN, 1.3ml, 2.2 molar equivalent) was added. The solid dissolved completely to yield a clear solution, which was naturally cooled to ambient temperatures. Crystallization occurred during the slow evaporation process.
G3. Crystalline Forms of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide Monopotassium Salt.
[00312] This invention also relates, in part, to crystalline forms of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide monopotassium salt, namely the trihydrate and dihydrate crystalline forms discussed below.
[00313] This invention relates, in part, to a monopotassium salt trihydrate. The crystallographic unit cell parameters of the trihydrate crystalline monopotassium salt have been determined to be as follows: a is 9-θA, b is 8.3A, and c is 18.6A (more precisely, a is 9.0393(16)A, b is 8.3332(15)A, and c is 18.582(3)A); the cell angles are: α - 80.5°, β - 85.1°, and γ - 80.5° (more precisely, α is 80.511(2)°, β is 85.134(3)°, and γ is 80.531(2)°); and the cell volume is 1359A3 (more precisely, 1359.3(4)A3). The salt crystallizes in the P-I space group.
[00314] In some embodiments, the monopotassium salt trihydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 4.8±0.2, 10.8±0.2, 11.3±0.2, 13.4±0.2, 15.3±0.2, 16.9±0.2, 21.2±0.2, 21.7±0.2, 22.1±0.2, 22.5±0.2, and 23.0±0.2 degrees 20. In some such embodiments, the monopotassium salt trihydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 4.8±0.2, 10.8±0.2, 11.3±0.2, 13.4±0.2, 15.3±0.2, 16.9±0.2, 21.2±0.2, 21.7±0.2, 22.1±0.2, 22.5±0.2, and 23.0±0.2 degrees 20. In other such embodiments, the monopotassium salt trihydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 4.8±0.2, 10.8±0.2, 11.3±0.2, 13.4±0.2, 15.3±0.2, 16.9±0.2, 21.2±0.2, 21.7±0.2, 22.1±0.2, 22.5±0.2, and 23.0±0.2 degrees 20.
[00315] In some embodiments, the monopotassium salt trihydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 4.8±0.2, 10.8±0.2, 11.3±0.2, 13.4±0.2, 13.6±0.2, 15.3±0.2, 16.9±0.2, 21.2±0.2, 21.7±0.2, 21.7±0.2, 22.1±0.2, 22.5±0.2, 22.6±0.2, and 23.0±0.2 degrees 20. In some such embodiments, the monopotassium salt trihydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 4.8±0.2, 10.8±0.2, 11.3±0.2, 13.4±0.2, 13.6±0.2, 15.3±0.2, 16.9±0.2, 21.2±0.2, 21.7±0.2, 21.7±0.2, 22.1±0.2, 22.5±0.2, 22.6±0.2, and 23.0±0.2 degrees 20. In other such embodiments, the monopotassium salt trihydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 4.8±0.2, 10.8±0.2, 11.3±0.2, 13.4±0.2, 13.6±0.2, 15.3±0.2, 16.9±0.2, 21.2±0.2, 21.7±0.2, 21.7±0.2, 22.1±0.2, 22.5±0.2, 22.6±0.2, and 23.0±0.2 degrees 20.
[00316] In some embodiments, the monopotassium salt trihydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 4.8±0.2, 10.8±0.2, 11.3±0.2, 13.4±0.2, 13.6±0.2, 15.3±0.2, 16.9±0.2, 21.2±0.2, 21.7±0.2, 21.7±0.2, 22.1±0.2, 22.5±0.2, 22.6±0.2, and 23.0±0.2 degrees 20. In some such embodiments, the monopotassium salt trihydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 4.8±0.2, 10.8±0.2, 11.3±0.2, 13.4±0.2, 15.3±0.2, 16.9±0.2, 21.2±0.2, 21.7±0.2, 22.1±0.2, 22.5±0.2, and 23.0±0.2 degrees 20. In other such embodiments, the monopotassium salt trihydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 4.8±0.2, 10.8±0.2, 11.3±0.2, 13.4±0.2, 15.3±0.2, 16.9±0.2, 21.2±0.2, 21.7±0.2, 22.1±0.2, 22.5±0.2, and 23.0±0.2 degrees 2Θ. [00317] In some embodiments, the monopotassium salt trihydrate has an X-ray powder diffraction pattern substantially as shown in Figure 5. The 2Θ values for the peaks in Figure 5 (and their intensities) are as follows: 4.83 (60), 10.79 (100), 11.31 (22), 13.42 (41), 13.59 (18), 15.32 (21), 16.90 (38), 21.24 (22), 21.68 (20), 21.68 (21), 22.15 (22), 22.55 (29), 22.63 (23), and 23.02 (27).
[00318] This invention also relates, in part, to a process for preparing the monopotassium salt trihydrate. It was prepared by suspending compound IB-Ll-1.1 (108.81mg) in 0.4ml THF while heated to about 500C. Aqueous KOH solution (IN, 0.278ml, 1.2 molar equivalent) was added. The solid dissolved completely to yield a clear solution. Additional 1.6ml THF was added to the solution, which was then naturally cooled to ambient temperatures and crystallization was observed. Alternatively, the monopotassium salt trihydrate was prepared by suspending compound IB-Ll-1.1 (343.89mg) in 1.0ml THF while heated to 500C. Aqueous KOH (1 N, 0.878ml, 1.2 molar equivalent) was added. The solid dissolved completely to yield a clear solution. Ethanol was added to the solution dropwise to a total volume of 4.0ml. The solution was then naturally cooled to ambient temperature and crystallization was observed.
[00319] This invention relates, in part, to a monopotassium salt dihydrate.
[00320] In some embodiments, the monopotassium salt dihydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 7.7±0.2, 8.8±0.2, 16.1±0.2, and 19.7±0.2 degrees 2Θ. In some such embodiments, the monopotassium salt dihydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of degrees 20. [00321] In some embodiments, the monopotassium salt dihydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 7.7±0.2, 8.8±0.2, 12.4±0.2, 14.0±0.2, 16.1±0.2, 17.7±0.2, 19.2±0.2, 19.7±0.2, 23.1±0.2, and 29.2±0.2 degrees 20. In some such embodiments, the monopotassium salt dihydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 7.7±0.2, 8.8±0.2, 12.4±0.2, 14.0±0.2, 16.1=1=0.2, 17.7±0.2, 19.2±0.2, 19.7±0.2, 23.1±0.2, and 29.2±0.2 degrees 20. In other such embodiments, the monopotassium salt dihydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 7.7±0.2, 8.8±0.2, 12.4±0.2, 14.0±0.2, 16.1±0.2, 17.7±0.2, 19.2±0.2, 19.7±0.2, 23.1±0.2, and 29.2±0.2 degrees 20.
[00322] In some embodiments, the monopotassium salt dihydrate has an X-ray powder diffraction pattern substantially as shown in Figure 6. The 20 values for the peaks in Figure 6 (and their intensities) are as follows: 7.68 (19), 8.83 (100), 12.40 (7), 13.97 (10), 16.12 (25), 17.75 (9), 19.22 (12), 19.73 (40), 23.05 (9), and 29.21 (7). [00323] This invention also relates, in part, to a process for preparing the monopotassium salt dihydrate. It was prepared by suspending the monopotassium salt trihydrate in media of low water activity, such as an ethanol/H2O mixture (50/1 v/v). Alternatively, the monopotassium salt dihydrate was prepared by dissolving potassium trihydrate solid (1.8g) in 36mL of IPA and 4ml water at 80°C. The resulting solution was cooled to 55°C over Ih. The solution was then seeded with 7.5mg of dihydrate crystals at 55°C and maintained at 55°C for Ih. Heptane (36ml) was then added over 3h. The reaction mixture was cooled to 0°C, and filtration yielded a material containing both di- and trihydrate crystals. The solid was then reslurried in 2OmL of 10:1 v/v EtOH/H2O at 500C for 3h and cooled to 25°C over 5h. The slurry was then mixed at 25°C for additional 3 days and cooled to 00C over 3h and held at this temperature for 2h. The resulting crystals were filtered and air-dried on filter funnel for Ih to give dihydrate. The dihydrate monopotassium salt was also prepared by slurrying a mixture of dihydrate and trihydrate crystals in 10:1 v/v EtOHZH2O at 800C for 2 days. The potassium content was confirmed by ion chromatography.
G4. Crystalline Form of (E)-N-(4-(3-tert-butyl-5-(2, 4-dioxo-3, 4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide 1/7 Potassium Salt.
[00324] This invention also relates, in part, to a crystalline form of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo- 3,4-dihydropyrimidin-l(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide 1/7 potassium salt. [00325] In some embodiments, the 1/7 potassium salt has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 7.7±0.2, 8.3±0.2, 10.1±0.2, 10.6±0.2, 11.4±0.2, 12.0±0.2, 13.4±0.2, 15.6±0.2, 16.3±0.2, 16.7±0.2, 17.2±0.2, 18.3±0.2, 18.8±0.2, 19.4±0.2, 19.9±0.2, 20.2±0.2, 20.5±0.2, 21.2±0.2, 22.1±0.2, and 22.9±0.2 degrees 2Θ. In some such embodiments, the 1/7 potassium salt has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 7.7±0.2, 8.3±0.2, 10.1±0.2, 10.6±0.2, 11.4±0.2, 12.0±0.2, 13.4±0.2, 15.6±0.2, 16.3±0.2, 16.7±0.2, 17.2±0.2, 18.3±0.2, 18.8±0.2, 19.4±0.2, 19.9±0.2, 20.2±0.2, 20.5±0.2, 21.2±0.2, 22.1±0.2, and 22.9±0.2 degrees 20. In other such embodiments, the 1/7 potassium salt has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 7.7±0.2, 8.3±0.2, 10.1±0.2, 10.6±0.2, 11.4±0.2, 12.0±0.2, 13.4±0.2, 15.6±0.2, 16.3±0.2, 16.7±0.2, 17.2±0.2, 18.3±0.2, 18.8±0.2, 19.4±0.2, 19.9±0.2, 20.2±0.2, 20.5±0.2, 21.2±0.2, 22.1±0.2, and 22.9±0.2 degrees 20. [00326] In some embodiments, the 1/7 potassium salt has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 7.7±0.2, 8.3±0.2, 10.1±0.2, 10.6±0.2, 11.4±0.2, 12.0±0.2, 13.4±0.2, 15.6±0.2, 16.3±0.2, 16.7±0.2, 17.2±0.2, 18.3±0.2, 18.8±0.2, 19.4±0.2, 19.9±0.2, 20.2±0.2, 20.5±0.2, 20.8±0.2, 21.2±0.2, 22.1±0.2, 22.9±0.2, 24.3±0.2, 24.9±0.2, and 25.1±0.2 degrees 2Θ. In some such embodiments, the 1/7 potassium salt has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 7.7±0.2, 8.3±0.2, 10.1±0.2, 10.6±0.2, 11.4±0.2, 12.0±0.2, 13.4±0.2, 15.6±0.2, 16.3±0.2, 16.7±0.2, 17.2±0.2, 18.3±0.2, 18.8±0.2, 19.4±0.2, 19.9±0.2, 20.2±0.2, 20.5±0.2, 20.8±0.2, 21.2±0.2, 22.1±0.2, 22.9±0.2, 24.3±0.2, 24.9±0.2, and 25.1±0.2 degrees 2Θ. In other such embodiments, the 1/7 potassium salt has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 7.7±0.2, 8.3±0.2, 10.1±0.2, 10.6±0.2, 11.4±0.2, 12.0±0.2, 13.4±0.2, 15.6±0.2, 16.3±0.2, 16.7±0.2, 17.2±0.2, 18.3±0.2, 18.8±0.2, 19.4±0.2, 19.9±0.2, 20.2±0.2, 20.5±0.2, 20.8±0.2, 21.2±0.2, 22.1±0.2, 22.9±0.2, 24.3±0.2, 24.9±0.2, and 25.1±0.2 degrees 2Θ. [00327] In some embodiments, the 1/7 potassium salt has an X-ray powder diffraction pattern substantially as shown in Figure 8. The 2Θ values for the peaks in Figure 8 (and their intensities) are as follows: 7.71 (19), 8.33 (34), 10.10 (100), 10.66 (29), 11.39 (27), 12.04 (22), 13.39 (39), 15.56 (41), 16.27 (62), 16.69 (70), 17.22 (59), 18.31 (18), 18.78 (47), 19.44 (36), 19.89 (28), 20.19 (33), 20.54 (87), 20.80 (33), 21.15 (47), 22.05 (24), 22.82 (67), 24.32 (22), 24.87 (22), and 25.07 (33). [00328] This invention also relates, in part, to a process for preparing the 1/7 potassium salt. It was prepared by suspending compound IB-Ll-1.1 (2g) 6ml THF at 5O0C. One molar equivalent of KOH dissolved in 4.3ml water was added, and the reaction mixture was heated to 65°C to dissolve all solids. The solution was then cooled to ambient temperatures over 2h and spontaneous crystallization took place. The slurry was then cooled to 5°C and held at that temperature for 2h. The pale yellow crystals were filtered and air-dried for 24h at ambient conditions. The potassium content was determined by ion chromatography.
GJ. Crystalline Form of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide Monodiethylamine Salt Tetrahydrate. [00329] This invention also relates, in part, to crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide monodiethylamine salt tetrahydrate.
[00330] In some embodiments, the monodiethylamine salt tetrahydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 9.5±0.2, 10.0±0.2, 11.8±0.2, 12.1±0.2, 14.4±0.2, 16.8±0.2, 17.6±0.2, 19.8±0.2, 20.8±0.2, 21.4±0.2, 21.8±0.2, and 29.8±0.2 degrees 20. In some such embodiments, the monodiethylamine salt tetrahydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 9.5±0.2, 10.0±0.2, 11.8±0.2, 12.1±0.2, 14.4±0.2, 16.8±0.2, 17.6±0.2, 19.8±0.2, 20.8±0.2, 21.4±0.2, 21.8±0.2, and 29.8±0.2 degrees 2Θ. In other such embodiments, the monodiethylamine salt tetrahydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 9.5±0.2, 10.0±0.2, 11.8±0.2, 12.1±0.2, 14.4±0.2, 16.8±0.2, 17.6±0.2, 19.8±0.2, 20.8±0.2, 21.4±0.2, 21.8±0.2, and 29.8±0.2 degrees 20. [00331] In some embodiments, the monodiethylamine salt tetrahydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 9.5±0.2, 10.0±0.2, 11.8±0.2, 12.1±0.2, 14.4±0.2, 16.8±0.2, 17.6±0.2, 19.4±0.2, 19.8±0.2, 20.8±0.2, 21.4±0.2, 21.8±0.2, 21.9±0.2, and 29.8±0.2 degrees 2Θ. In some such embodiments, the monodiethylamine salt tetrahydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 9.5±0.2, 10.0±0.2, 11.8±0.2, 12.1±0.2, 14.4±0.2, 16.8±0.2, 17.6±0.2, 19.4±0.2, 19.8±0.2, 20.8±0.2, 21.4±0.2, 21.8±0.2, 21.9±0.2, and 29.8±0.2 degrees 2Θ. In other such embodiments, the monodiethylamine salt tetrahydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 9.5±0.2, 10.0±0.2, 11.8±0.2, 12.1±0.2, 14.4±0.2, 16.8±0.2, 17.6±0.2, 19.4±0.2, 19.8±0.2, 20.8±0.2, 21.4±0.2, 21.8±0.2, 21.9±0.2, and 29.8±0.2 degrees 2Θ.
[00332] In some embodiments, the monodiethylamine salt tetrahydrate has an X-ray powder diffraction pattern substantially as shown in Figure 9. The 2Θ values for the peaks in Figure 9 (and their intensities) are as follows: 9.45 (100), 9.97 (31), 11.85 (67), 12.09 (16), 14.38 (22), 16.80 (9), 17.59 (10), 19.39 (8), 19.83 (21), 20.85 (25), 21.37 (12), 21.75 (34), 21.87 (8), and 29.78 (7).
[00333] This invention also relates, in part, to a process for preparing the monodiethylamine salt tetrahydrate. It was prepared in aqueous medium. Compound IB-Ll-1.1 was slowly added to 500ul of IM diethylamine until no more solid can be dissolved into the solution. The solution was then evaporated slowly at ambient temperatures and the salt crystallized 2 days later. Alternatively, the monodiethylamine salt tetrahydrate was prepared by suspending 64.15mg of compound IB-Ll-1.1 in 400ul IM diethylamine while heated to 500C. About 5 drops of THF (~ 2OuI) was added. The solid dissolved completely upon addition to yield a clear solution. The solution was then evaporated at ambient temperature, and the salt crystallized 4 days later. The stoichiometry of the salt was confirmed by solution 1H NMR.
G6. Crystalline Forms of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide (compound IB-Ll-1.1).
[00334] This invention also relates, in part, to crystalline forms of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide (compound IB-Ll-1.1), namely the true polymorphs (pattern A, pattern B, pattern C, and pattern D) and hydrate (pattern AH, pattern BH, pattern CH, and pattern DH) crystalline forms discussed below.
G6A. IB-Ll-Ll True Polymorphs.
[00335] This invention relates, in part, to pattern A crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl)pheny l)methanesulfonamide . [00336] In some embodiments, the pattern A polymorph has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 5.8±0.2, 9.9±0.2, 11.8±0.2, 12.4±0.2, 14.5±0.2, 18.8±0.2, 22.7±0.2, and 29.2±0.2 degrees 2Θ. In some such embodiments, the pattern A polymorph has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 5.8±0.2, 9.9±0.2, 11.8±0.2, 12.4±0.2, 14.5±0.2, 18.8±0.2, 22.7±0.2, and 29.2±0.2 degrees 2Θ. In other such embodiments, the pattern A polymorph has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 5.8±0.2, 9.9±0.2, 11.8±0.2, 12.4±0.2,
14.5±0.2, 18.8±0.2, 22.7±0.2, and 29.2±0.2 degrees 2Θ.
[00337] In some embodiments, the pattern A polymorph has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 5.8±0.2, 9.9±0.2, 11.8±0.2, 12.4±0.2,
14.0±0.2, 14.5±0.2, 15.3±0.2, 18.5±0.2, 18.8±0.2, 22.2±0.2, 22.7±0.2, 23.8±0.2, 26.0±0.2, and 29.2±0.2 degrees 2Θ. In some such embodiments, the pattern A polymorph has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 5.8±0.2, 9.9±0.2, 11.8±0.2,
12.4±0.2, 14.040.2, 14.5±0.2, 15.3±0.2, 18.5±0.2, 18.8±0.2, 22.2±0.2, 22.7±0.2, 23.8±0.2, 26.0±0.2, and
29.2±0.2 degrees 2Θ. In other such embodiments, the pattern A polymorph has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 5.8±0.2, 9.9±0.2,
11.8±0.2, 12.4±0.2, 14.0±0.2, 14.5±0.2, 15.3±0.2, 18.5±0.2, 18.8±0.2, 22.2±0.2, 22.7±0.2, 23.8±0.2,
26.0±0.2, and 29.2±0.2 degrees 2Θ.
[00338] In some embodiments, the pattern A polymorph has an X-ray powder diffraction pattern substantially as shown in Figure 11. The 2Θ values for the peaks in Figure 11 (and their intensities) are as follows: 5.85 (28), 9.88 (51), 11.79 (73), 12.38 (56), 14.03 (38), 14.45 (100), 15.27 (29), 18.52 (39),
18.80 (47), 22.24 (40), 22.72 (77), 23.76 (39), 25.98 (22), and 29.21 (64).
[00339] This invention also relates, in part, to a process for preparing pattern A polymorph. Pattern A polymorph was prepared as discussed in Example E below.
[00340] This invention relates, in part, to pattern B crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide .
[00341] In some embodiments, the pattern B polymorph has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 11.5±0.2, 13.3±0.2, 15.4±0.2,
16.4±0.2, 17.1±0.2, 18.6±0.2, 19.4±0.2, 20.4±0.2, 21.640.2, 22.4±0.2, 24.0±0.2, 26.8±0.2, and 29.0±0.2 degrees 2Θ. In some such embodiments, the pattern B polymorph has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 11.5±0.2, 13.3±0.2, 15.4±0.2,
16.4±0.2, 17.1±0.2, 18.6±0.2, 19.440.2, 20.4±0.2, 21.640.2, 22.4±0.2, 24.0±0.2, 26.8±0.2, and 29.0±0.2 degrees 2Θ. In other such embodiments, the pattern B polymorph has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 11.5±0.2, 13.3±0.2, 15.4±0.2,
16.440.2, 17.140.2, 18.640.2, 19.440.2, 20.4±0.2, 21.640.2, 22.4±0.2, 24.0±0.2, 26.8±0.2, and 29.0±0.2 degrees 2Θ.
[00342] In some embodiments, the pattern B polymorph has an X-ray powder diffraction pattern substantially as shown in Figure 13. The 2Θ values for the peaks in Figure 13 (and their intensities) are as follows: 11.52 (71), 13.30 (87), 15.37 (100), 16.42 (60), 17.13 (69), 18.60 (97), 19.37 (56), 20.40 (62), 21.55 (55), 22.41 (39), 23.99 (33), 26.81 (31), and 28.98 (50).
[00343] This invention relates, in part, to pattern C crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.
[00344] In some embodiments, the pattern C polymorph has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 7.7±0.2, 10.1±0.2, 10.6±0.2, 12.0
±0.2, 13.4±0.2, 16.2±0.2, 19.4±0.2, 20.5±0.2, 21.4±0.2, 22.0±0.2, 22.6±0.2, 24.3±0.2, and 27.6±0.2 degrees 2Θ. In some such embodiments, the pattern C polymorph has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 7.7±0.2, 10.1±0.2, 10.6±0.2, 12.0
±0.2, 13.4±0.2, 16.2±0.2, 19.4±0.2, 20.5±0.2, 21.4±0.2, 22.0±0.2, 22.6±0.2, 24.3±0.2, and 27.6±0.2 degrees 2Θ. In other such embodiments, the pattern C polymorph has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 7.7±0.2, 10.1±0.2, 10.6±0.2, 12.0
±0.2, 13.4±0.2, 16.2±0.2, 19.4±0.2, 20.5±0.2, 21.4±0.2, 22.0±0.2, 22.6±0.2, 24.3±0.2, and 27.6±0.2 degrees 2Θ.
[00345] In some embodiments, the pattern C polymorph has an X-ray powder diffraction pattern substantially as shown in Figure 14. The 2Θ values for the peaks in Figure 14 (and their intensities) are as follows: 7.69 (27), 10.13 (27), 10.64 (49), 12.01 (31), 13.39 (33), 16.25 (91), 19.44 (46), 20.49 (100),
21.40 (35), 22.03 (37), 22.60 (30), 24.32 (23), and 27.55 (27).
[00346] This invention relates, in part, to pattern D crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.
[00347] In some embodiments, the pattern D polymorph has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 5.8±0.2, 10.7±0.2, 11.2±0.2,
15.2±0.2, 16.1±0.2, 16.9±0.2, 19.9±0.2, 22.1±0.2, 24.7±0.2, and 26.0±0.2 degrees 20. In some such embodiments, the pattern D polymorph has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 5.8±0.2, 10.7±0.2, 11.2±0.2, 15.2±0.2, 16.1±0.2, 16.9±0.2,
19.9±0.2, 22.1±0.2, 24.7±0.2, and 26.0±0.2 degrees 20. In other such embodiments, the pattern D polymorph has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 5.8±0.2, 10.7±0.2, 11.2±0.2, 15.2±0.2, 16.1±0.2, 16.9±0.2, 19.9±0.2, 22.1±0.2,
24.7±0.2, and 26.0±0.2 degrees 20.
[00348] hi some embodiments, the pattern D polymorph has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 5.8±0.2, 10.7±0.2, 11.2±0.2,
15.2±0.2, 16.1±0.2, 16.9±0.2, 17.1±0.2, 19.9±0.2, 20.1±0.2, 22.1±0.2, 24.7±0.2, and 26.0±0.2 degrees 20.
In some such embodiments, the pattern D polymorph has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 5.8±0.2, 10.7±0.2, 11.2±0.2, 15.2±0.2,
16.1±0.2, 16.9±0.2, 17.1±0.2, 19.9±0.2, 20.1±0.2, 22.1±0.2, 24.7±0.2, and 26.0±0.2 degrees 20. In other such embodiments, the pattern D polymorph has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 5.8±0.2, 10.7±0.2, 11.2±0.2, 15.2±0.2, 16.1±0.2,
16.9±0.2, 17.1±0.2, 19.9±0.2, 20.1±0.2, 22.1±0.2, 24.7±0.2, and 26.0±0.2 degrees 2Θ.
[00349] In some embodiments, the pattern D polymorph has an X-ray powder diffraction pattern substantially as shown in Figure 15. The 2Θ values for the peaks in Figure 15 (and their intensities) are as follows: 5.81 (24), 10.70 (91), 11.23 (60), 15.17 (28), 16.10 (48), 16.89 (100), 17.10 (42), 19.88 (81),
20.12 (100), 22.12 (59), 24.72 (37), and 25.91 (24).
[00350] This invention also relates, in part, to a process for preparing pattern B, C, and D polymorphs by heating pattern A polymorph to about 160, about 225, and about 2680C, respectively using DSC.
G6B. IB-Ll-L 1 Hydrates.
[00351] This invention also relates, in part, to hydrates of compound IB-Ll-1.1, namely to hydrates A, B, C, D, and E discussed below.
[00352] This invention relates, in part, to a pattern A (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydro- pyrimidin- 1 (2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide hydrate.
[00353] In some embodiments, the pattern A hydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 5.1±0.2, 7.9±0.2, 9.5±0.2, 10.3±0.2, 13.7±0.2, 16.5±0.2, 17.1±0.2, 17.5±0.2, 18.8±0.2, 19.2±0.2, 20.7±0.2, 21.3±0.2, 21.6±0.2, 25.8±0.2, 26.8±0.2, and 28.4±0.2 degrees 20. In some such embodiments, the pattern A hydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 5.1±0.2, 7.9±0.2, 9.5±0.2, 10.3±0.2, 13.7±0.2, 16.5±0.2, 17.1±0.2, 17.5±0.2, 18.8±0.2, 19.2±0.2, 20.7±0.2, 21.3±0.2, 21.6±0.2, 25.8±0.2, 26.8±0.2, and 28.4±0.2 degrees 2Θ. In other such embodiments, the pattern A hydrate has an X- ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 5.1±0.2, 7.9±0.2, 9.5±0.2, 10.3±0.2, 13.7±0.2, 16.5±0.2, 17.1±0.2, 17.5±0.2, 18.8±0.2, 19.2±0.2, 20.7±0.2, 21.3±0.2, 21.6±0.2, 25.8±0.2, 26.8±0.2, and 28.4±0.2 degrees 2Θ.
[00354] In some embodiments, the pattern A hydrate has an X-ray powder diffraction pattern substantially as shown in Figure 16. The 20 values for the peaks in Figure 16 (and their intensities) are as follows: 5.13 (13), 7.87 (80), 9.45 (100), 10.29 (60), 13.7 (28), 16.54 (30), 17.07 (17), 17.51 (40), 18.80 (99), 19.18 (74), 20.69 (21), 21.25 (21), 21.63 (23), 25.85 (32), 26.81 (20), and 28.35 (27). [00355] This invention also relates, in part, to a process for preparing the pattern A hydrate by suspending pattern A polymorph (discussed above) in ethyl acetate. The recovered pattern A hydrate contains ~1 water molecules per molecule of compound IB-Ll-1.1.
[00356] This invention also relates, in part, to a pattern B (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydro- pyrimidin- 1 (2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide hydrate. [00357] In some embodiments, the pattern B hydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 6.3±0.2, 7.7±0.2, 10.4±0.2, 12.7±0.2, 13.3±0.2, 14.9±0.2, 15.4±0.2, 16.4±0.2, 18.6±0.2, 18.9±0.2, 19.4±0.2, 22.5±0.2, 23.5±0.2, 24.0±0.2, 26.8±0.2, and 29.0±0.2 degrees 2Θ. In some such embodiments, the pattern B hydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 6.3±0.2, 7.7±0.2, 10.4±0.2, 12.7±0.2, 13.3±0.2, 14.9±0.2, 15.4±0.2, 16.4±0.2, 18.6±0.2, 18.9±0.2, 19.4±0.2, 22.5±0.2, 23.5±0.2, 24.0±0.2, 26.8±0.2, and 29.0±0.2 degrees 2Θ. In other such embodiments, the pattern B hydrate has an X- ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 6.3±0.2, 7.7±0.2, 10.4±0.2, 12.7±0.2, 13.3±0.2, 14.9±0.2, 15.4±0.2, 16.4±0.2, 18.6±0.2, 18.9±0.2, 19.4±0.2, 22.5±0.2, 23.5±0.2, 24.0±0.2, 26.8±0.2, and 29.0±0.2 degrees 2Θ.
[00358] In some embodiments, the pattern B hydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 6.3±0.2, 7.7±0.2, 10.4±0.2, 12.7±0.2, 13.3±0.2, 13.5±0.2, 14.9±0.2, 15.4±0.2, 16.4±0.2, 18.5±0.2, 18.6±0.2, 18.9±0.2, 19.4±0.2, 22.5±0.2, 23.5±0.2, 24.0±0.2, 26.8±0.2, and 29.0±0.2 degrees 2Θ. In some such embodiments, the pattern B hydrate has an X- ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 6.3±0.2, 7.7±0.2, 10.4±0.2, 12.7±0.2, 13.3±0.2, 13.5±0.2, 14.9±0.2, 15.4±0.2, 16.4±0.2, 18.5±0.2, 18.6±0.2, 18.9±0.2, 19.4±0.2, 22.5±0.2, 23.5±0.2, 24.0±0.2, 26.8±0.2, and 29.0±0.2 degrees 2Θ. In other such embodiments, the pattern B hydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 6.3±0.2, 7.7±0.2, 10.4±0.2, 12.7±0.2, 13.3±0.2, 13.5±0.2, 14.9±0.2, 15.4±0.2, 16.4±0.2, 18.5±0.2, 18.6±0.2, 18.9±0.2, 19.4±0.2, 22.5±0.2, 23.5±0.2, 24.0±0.2, 26.8±0.2, and 29.0±0.2 degrees 2Θ.
[00359] In some embodiments, the pattern B hydrate has an X-ray powder diffraction pattern substantially as shown in Figure 18. The 2Θ values for the peaks in Figure 18 (and their intensities) are as follows: 6.31 (7), 7.72 (14), 10.45 (24), 12.67 (26), 13.30 (88), 13.50 (44), 14.89 (70), 15.40 (100), 16.43 (43), 18.46 (47), 18.63 (86), 18.91 (26), 19.42 (33), 22.52 (47), 23.52 (44), 24.02 (20), 26.82 (40), and 28.97 (49).
[00360] This invention also relates, in part, to a process for preparing the pattern B hydrate by suspending pattern A polymorph (discussed above) in acetonitrile/water (9/1 v/v). The recovered pattern B hydrate contains ~0.7 water molecules per molecule of compound IB-Ll-1.1.
[00361] This invention also relates, in part, to a pattern C (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide hydrate. [00362] In some embodiments, the pattern C hydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 10.5±0.2, 13.3±0.2, 14.9±0.2, 15.4±0.2, 16.4±0.2, 18.6±0.2, 19.0±0.2, 19.4±0.2, 22.5±0.2, 23.5±0.2, 26.9±0.2, and 29.0±0.2 degrees 2Θ. In some such embodiments, the pattern C hydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 10.5±0.2, 13.3±0.2, 14.9±0.2, 15.4±0.2, 16.4±0.2, 18.6±0.2, 19.0±0.2, 19.4±0.2, 22.5±0.2, 23.5±0.2, 26.9±0.2, and 29.0±0.2 degrees 2Θ. In other such embodiments, the pattern C hydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 10.5±0.2, 13.3±0.2, 14.9±0.2, 15.4±0.2, 16.4±0.2, 18.6±0.2, 19.0±0.2, 19.4±0.2, 22.5±0.2, 23.5±0.2, 26.9±0.2, and 29.0±0.2 degrees 2Θ.
[00363] In some embodiments, the pattern C hydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 10.5±0.2, 13.3±0.2, 13.5±0.2, 14.9±0.2, 15.4±0.2, 16.4±0.2, 18.6±0.2, 19.0±0.2, 19.4±0.2, 22.5±0.2, 23.5±0.2, 26.9±0.2, and 29.0±0.2 degrees 2Θ. In some such embodiments, the pattern C hydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 10.5±0.2, 13.3±0.2, 13.5±0.2, 14.9±0.2, 15.4±0.2, 16.4±0.2, 18.6±0.2, 19.0±0.2, 19.4±0.2, 22.5±0.2, 23.5±0.2, 26.9±0.2, and 29.0±0.2 degrees 2Θ. In other such embodiments, the pattern C hydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 10.5±0.2, 13.3±0.2, 13.5±0.2, 14.9±0.2, 15.4±0.2, 16.4±0.2, 18.6±0.2, 19.0±0.2, 19.4±0.2, 22.5±0.2, 23.5±0.2, 26.9±0.2, and 29.0±0.2 degrees 2Θ. [00364] In some embodiments, the pattern C hydrate has an X-ray powder diffraction pattern substantially as shown in Figure 20. The 2Θ values for the peaks in Figure 20 (and their intensities) are as follows: 10.47 (21), 13.31 (56), 13.49 (31), 14.91 (28), 15.40 (86), 16.43 (48), 18.61 (100), 18.96 (20), 19.44 (19), 22.55 (26), 23.54 (39), 26.84 (29), and 28.99 (54).
[00365] This invention also relates, in part, to a process for preparing the pattern C hydrate by suspending pattern A polymorph (discussed above) in water. The recovered pattern C hydrate contains ~1 water molecules per molecule of compound IB-Ll-1.1.
[00366] This invention also relates, in part, to a pattern D (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide hydrate. [00367] The crystallographic unit cell parameters of the pattern D hydrate salt have been determined to be as follows: a is 17.8A, b is 9.6A, and c is 27.0A (more precisely, a is 17.783(2)A, b is 9.5651(12)A, and c is 27.014(4)A); the cell angle is: β - 93.3° (more precisely, β is 93.256(2)°); and the cell volume is 4588A3 (more precisely, 4587.5(10)A3). The salt crystallizes in the C2/c space group.
[00368] In some embodiments, the pattern D hydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 6.6±0.2, 10.0±0.2, 10.5±0.2, 1 l.l±0.2, 11.6±0.2, 12.2±0.2, 14.2±0.2, 16.6±0.2, 17.1±0.2, 17.7±0.2, 18.5±0.2, 18.8±0.2, 19.3±0.2, 21.4±0.2, 22.7±0.2, 23.1±0.2, 23.6±0.2, 24.6±0.2, 25.2±0.2, 27.2±0.2, 29.1±0.2, and 31.0±0.2 degrees 2Θ. In some such embodiments, the pattern D hydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 6.6±0.2, 10.0±0.2, 10.5±0.2, l l.l±0.2, 11.6±0.2, 12.2±0.2, 14.2±0.2, 16.6±0.2, 17.1±0.2, 17.7±0.2, 18.5±0.2, 18.8±0.2, 19.3±0.2, 21.4±0.2, 22.7±0.2, 23.1±0.2, 23.6±0.2, 24.6±0.2, 25.2±0.2, 27.2±0.2, 29.1±0.2, and 31.0±0.2 degrees 2Θ. In other such embodiments, the pattern D hydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 6.6±0.2, 10.0±0.2, 10.5±0.2, l l.l±0.2, 11.6±0.2, 12.2±0.2, 14.2±0.2, 16.6±0.2, 17.1±0.2, 17.7±0.2, 18.5±0.2, 18.8±0.2, 19.3±0.2, 21.4±0.2, 22.7±0.2, 23.1±0.2, 23.6±0.2, 24.6±0.2, 25.2±0.2, 27.2±0.2, 29.1±0.2, and 31.0±0.2 degrees 2Θ.
[00369] In some embodiments, the pattern D hydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 6.6±0.2, 10.0±0.2, 10.5±0.2, l l.l±0.25 11.6±0.2, 12.2±0.2, 12.5±0.2, 14.2±0.2, 16.6±0.2, 17.1±0.2, 17.7±0.2, 18.5±0.2, 18.8±0.2, 19.3±0.2, 21.4±0.2, 22.7±0.2, 22.8±0.2, 23.1±0.2, 23.6±0.2, 24.6±0.2, 24.9±0.2, 25.2±0.2, 27.2±0.2, 29.1±0.2, and 31.0±0.2 degrees 2Θ. In some such embodiments, the pattern D hydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 6.6±0.2, 10.0±0.2, 10.5±0.2, l l.l±0.2, 11.6±0.2, 12.2±0.2, 12.5±0.2, 14.2±0.2, 16.6±0.2, 17.1±0.2, 17.7±0.2, 18.5±0.2, 18.8±0.2, 19.3±0.2, 21.4±0.2, 22.7±0.2, 22.8±0.2, 23.1±0.2, 23.6±0.2, 24.6±0.2, 24.9±0.2, 25.2±0.2, 27.2±0.2, 29.1±0.2, and 31.0±0.2 degrees 2Θ. In other such embodiments, the pattern D hydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 6.6±0.2, 10.0±0.2, 10.5±0.2, l l.l±0.2, 11.6±0.2, 12.2±0.2, 12.5±0.2, 14.2±0.2, 16.6±0.2, 17.1±0.2, 17.7±0.2, 18.5±0.2, 18.8±0.2, 19.3±0.2, 21.4±0.2, 22.7±0.2, 22.8±0.2, 23.1±0.2, 23.6±0.2, 24.6±0.2, 24.9±0.2, 25.2±0.2, 27.2±0.2, 29.1±0.2, and 31.0±0.2 degrees 2Θ.
[00370] In some embodiments, the pattern D hydrate has an X-ray powder diffraction pattern substantially as shown in Figure 22. The 2Θ values for the peaks in Figure 22 (and their intensities) are as follows: 6.55 (10), 9.96 (12), 10.51 (37), 11.09 (31), 11.62 (100), 12.24 (44), 12.54 (40), 14.22 (15), 16.62 (68), 17.07 (22), 17.77 (21), 18.52 (82), 18.84 (47), 19.30 (63), 21.45 (34), 22.67 (30), 22.80 (34), 23.08 (20), 23.57 (58), 24.63 (73), 24.88 (26), 25.24 (21), 27.23 (36), 29.06 (41), and 31.04 (21). [00371] This invention also relates, in part, to a process for preparing the pattern D hydrate. It was prepared by suspending pattern A polymorph (discussed above) in ethanol. Alternatively, it was prepared by suspending compound IB-Ll-1.1 (103.03mg) in 400ul THF while heated to about 55°C. Aqueous NaOH (IM, 264ul, 1.2 molar equivalent) was added. The solid dissolved completely to yield a clear solution. Ethanol (1.6ml) was added to the solution. The solution was allowed to cool naturally to ambient temperatures. Crystals were formed during the slow evaporation process. Although it appears that the lattice can accommodate as much as 0.5 water molecules per molecule of compound IB-Ll-1.1, the recovered pattern D hydrate contained ~0.2 water molecules per molecule of compound IB-Ll-1.1. [00372] This invention also relates, in part, to a pattern E (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin- 1 (2H)-yl)-2-methoxystyry l)phenyl)methanesulfonamide hydrate . [00373] The crystallographic unit cell parameters of the pattern E hydrate crystalline disodium salt have been determined to be as follows: a is 9.5A, b is 14.5A, and c is 17.3A (more precisely, a is 9.462(2)A, b is 14.462(3)A, and c is 17.281(4)A); the cell angles are: α - 84.9°, β - 80.8°, and γ - 81.8° (more precisely, α is 84.863(4)°, β is 80.760(4)°, and γ is 81.751(4)°); and the cell volume is 2304A3 (more precisely, 2304.4(9)A3). The salt crystallizes in the P-I space group.
[00374] In some embodiments, the pattern E hydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 6.2±0.2, 7.8±0.2, 10.2±0.2, 10.7±0.2, 12.1±0.2, 16.3±0.2, 19.7±0.2, 20.9±0.2, 21.8±0.2, 24.5±0.2, and 28.0±0.2 degrees 2Θ. In some such embodiments, the pattern E hydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 6.2±0.2, 7.8±0.2, 10.2±0.2, 10.7±0.2, 12.1±0.2, 16.3±0.2, 19.7±0.2, 20.9±0.2, 21.8±0.2, 24.5±0.2, and 28.0±0.2 degrees 2Θ. In other such embodiments, the pattern E hydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 6.2±0.2, 7.8±0.2, 10.2±0.2, 10.7±0.2, 12.1±0.2, 16.3±0.2, 19.7±0.2, 20.9±0.2, 21.8±0.2, 24.5±0.2, and 28.0±0.2 degrees 20.
[00375] In some embodiments, the pattern E hydrate has an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 6.2±0.2, 7.8±0.2, 10.2±0.2, 10.4±0.2, 10.7±0.2, 12.1±0.2, 16.3±0.2, 19.7±0.2, 20.9±0.2, 21.8±0.2, 24.5±0.2, and 28.0±0.2 degrees 2Θ. In some such embodiments, the pattern E hydrate has an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of 6.2±0.2, 7.8±0.2, 10.2±0.2, 10.4±0.2, 10.7±0.2, 12.1±0.2, 16.3±0.2, 19.7±0.2, 20.9±0.2, 21.8±0.2, 24.5±0.2, and 28.0±0.2 degrees 2Θ. In other such embodiments, the pattern E hydrate has an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 6.2±0.2, 7.8±0.2, 10.2±0.2, 10.4±0.2, 10.7±0.2, 12.1±0.2, 16.3±0.2, 19.7±0.2, 20.9±0.2, 21.8±0.2, 24.5±0.2, and 28.0±0.2 degrees 2Θ.
[00376] In some embodiments, the pattern E hydrate has an X-ray powder diffraction pattern substantially as shown in Figure 23. The 2Θ values for the peaks in Figure 23 (and their intensities) are as follows: 6.19 (6), 7.81 (18), 10.17 (13), 10.40 (14), 10.68 (39), 12.06 (20), 16.29 (78), 19.72 (32), 20.88 (100), 21.77 (27), 24.52 (25), and 28.01 (27).
[00377] This invention also relates, in part, to a process for preparing the pattern E hydrate. It was prepared by suspending compound IB-Ll-1.1 (56.76mg) in 200ul THF while heated. Aqueous NaOH (IM, 146uL, 1.2 molar equivalent) was added, which yielded a clear solution. Ethanol (80OuI) was added to the solution. The solution was allowed to cool naturally to ambient temperatures. Crystals were formed during the slow evaporation process. Although it appears that the lattice can accommodate as much as one water molecule per molecule of compound IB-Ll-1.1, the recovered pattern D hydrate contained -0.25 water molecules per molecule of compound IB-Ll-1.1.
H. Compositions. [00378] This invention also is directed, in part, to compositions comprising one or more compounds and/or salts of the invention (including the crystalline compounds and salts discussed in section G above). In some embodiments, the compositions comprise one or more substantially phase pure crystalline forms (compounds/salts/solvates/hydrates) discussed in section G above. The compositions can be pharmaceutical compositions.
[00379] In some embodiments, the compositions further comprise one or more additional therapeutic agents. Such therapeutic agents can, but need not be, additional HCV inhibitors.
[00380] The preferred composition depends on the method of administration, and typically comprises one or more conventional pharmaceutically acceptable carriers, adjuvants, and/or vehicles (together referred to as "excipients"). Formulation of drugs is generally discussed in, for example, Hoover, J., Remington's Pharmaceutical Sciences (Mack Publishing Co., 1975) and Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (Lippincott Williams & Wilkins, 2005).
[00381] Solid dosage forms for oral administration include, for example, capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds or salts are ordinarily combined with one or more excipients. If administered per os, the compounds or salts can be mixed with, for example, lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets can contain a controlled-release formulation, as can be provided in, for example, a dispersion of the compound or salt in hydroxypropylmethyl cellulose. In the case of capsules, tablets, and pills, the dosage forms also can comprise buffering agents, such as sodium citrate, or magnesium or calcium carbonate or bicarbonate. Tablets and pills additionally can be prepared with enteric coatings.
[00382] Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions (including both oil-in-water and water-in-oil emulsions), solutions (including both aqueous and non-aqueous solutions), suspensions (including both aqueous and non-aqueous suspensions), syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also can comprise, for example, wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.
[00383] Parenteral administration includes subcutaneous injections, intravenous injections, intramuscular injections, intrasternal injections, and infusion. Injectable preparations (e.g., sterile injectable aqueous or oleaginous suspensions) can be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents. Acceptable vehicles and solvents include, for example, water, 1,3- butanediol, Ringer's solution, isotonic sodium chloride solution, bland fixed oils (e.g., synthetic mono- or diglycerides), fatty acids (e.g., oleic acid), dimethyl acetamide, surfactants (e.g., ionic and non-ionic detergents), and/or polyethylene glycols.
[00384] Formulations for parenteral administration may, for example, be prepared from sterile powders or granules having one or more of the excipients mentioned for use in the formulations for oral administration. A compound or salt of the invention can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. The pH may be adjusted, if necessary, with a suitable acid, base, or buffer.
[00385] Suppositories for rectal administration can be prepared by, for example, mixing a compound or salt of the invention with a suitable nonirritating excipient that is solid at ordinary temperatures, but liquid at the rectal temperature, and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter; synthetic mono-, di-, or triglycerides, fatty acids, and/or polyethylene glycols.
[00386] Topical administration includes the use of transdermal administration, such as transdermal patches or iontophoresis devices.
[00387] Other excipients and modes of administration known in the pharmaceutical art also may be used. [00388] Applicants have discovered that some I-Ll compounds in which R6 and the phenyluracil are in trans-position relative to the double bond, when in solution, tend to convert into the corresponding cis- isomer upon exposure to light; thus, it may be desirable to store such solutions under conditions that reduce exposure to light (e.g. , in an amber bottle or in a dark place).
[00389] The preferred total daily dose of the compound or salt (administered in single or divided doses) is typically from about 0.001 to about lOOmg/kg, more preferably from about 0.001 to about 30mg/kg, and even more preferably from about 0.01 to about 10mg/kg (i.e.,mg of the compound or salt per kg body weight). Dosage unit compositions can contain such amounts or submultiples thereof to make up the daily dose. In many instances, the administration of the compound or salt will be repeated a plurality of times. Multiple doses per day typically may be used to increase the total daily dose, if desired. [00390] Factors affecting the preferred dosage regimen include the type, age, weight, sex, diet, and condition of the patient; the severity of the pathological condition; the severity of the pathological condition; the route of administration; pharmacological considerations, such as the activity, efficacy, pharmacokinetic, and toxicology profiles of the particular compound or salt used; whether a drug delivery system is utilized; and whether the compound or salt is administered as part of a drug combination. Thus, the dosage regimen actually employed can vary widely, and therefore, can derive from the preferred dosage regimen set forth above.
/. Kits. [00391] This invention also is directed, in part, to a kit comprising one or more compounds and/or salts of the in invention. The kit can optionally contain one or more additional therapeutic agents and/or instructions for, for example, using the kit.
/. Methods of Use.
[00392] This invention also is directed, in part, to a method for inhibiting replication of an RNA virus. The method comprises exposing the virus to one or more compounds and/or salts of this invention. In some embodiments, replication of the RNA virus is inhibited in vitro. In other embodiments, replication of the RNA virus is inhibited in vivo. In some embodiments, the RNA virus whose replication is being inhibited is a single-stranded, positive sense RNA virus. In some such embodiments, the RNA virus whose replication is being inhibited is a virus from the Flaviviridae family. In some such embodiments, the RNA virus whose replication is being inhibited is HCV.
[00393] This invention also is directed, in part, to a method for inhibiting HCV RNA polymerase. The method comprises- exposing the polymerase with one or more compounds and/or salts of this invention. In some embodiments, HCV RNA polymerase activity is inhibited in vitro. In other embodiments, HCV RNA polymerase activity is inhibited in vivo.
[00394] The term "inhibiting" means reducing the level of RNA virus replication/HCV polymerase activity either in vitro or in vivo. For example, if a compound/salt of the invention reduces the level of RNA virus replication by at least about 10% compared to the level of RNA virus replication before the virus was exposed to the compound/salt, then the compound/salt inhibits RNA virus replication. In some embodiments, the compound/salt can inhibit RNA virus replication by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%.
[00395] This invention also is directed, in part, to a method for treating a disease that can be treated by inhibiting HCV RNA polymerase. Thus, this invention also is directed, in part, to a method for treating hepatitis C in an animal in need of such treatment. These methods comprise administering to the animal one or more compounds and/or salts of the invention, and, optionally, one or more additional therapeutic agents. In some embodiments, a therapeutically effective amount of the compound(s) and/or salt(s) is administered to the animal. "Treating" means ameliorating, suppressing, eradicating, preventing, reducing the risk of, and/or delaying the onset of the disease being treated. Applicants specifically intend that the term "treating" encompass administration of the compounds and/or salts of the invention to an HCV-negative patient that is a candidate for an organ transplant. The methods of treatment are particularly suitable for use with humans, but may be used with other animals, particularly mammals. A "therapeutically-effective amount" or "effective amount" is an amount that will achieve the goal of treating the targeted condition. [00396] In some embodiments, the methods comprise combination therapy, wherein the compound(s) and/or salt(s) of the invention is/are co-administered with a second (or even a third, fourth, etc.) compound, such as, for example, another therapeutic agent used to treat hepatitis C (e.g., interferon or interferon/ribavirin combination, or an HCV inhibitor such as, for example, an HCV polymerase inhibitr or an HCV protease inhibitor). The compound(s) and/or salt(s) of this invention can also be coadministered with therapeutic agents other than therapeutic agents used to treat hepatitis C (e.g., anti-HFV agents). In these co-administration embodiments, the compound(s) and/or salt(s) of the invention and the second, etc. therapeutic agent(s) may be administered in a substantially simultaneous manner (e.g., or within about 5 minutes of each other), in a sequential manner, or both. It is contemplated that such combination therapies may include administering one therapeutic agent multiple times between the administrations of the other. The time period between the administration of each agent may range from a few seconds (or less) to several hours or days, and will depend on, for example, the properties of each composition and active ingredient (e.g., potency, solubility, bioavailability, half-life, and kinetic profile), as well as the condition of the patient. The compound(s) and/or salt(s) of this invention and the second, etc. therapeutic agent may also be administered in a single formulation.
[00397] This invention also is directed, in part, to a use of one or more compounds and/or salts of the invention, and, optionally one or more additional therapeutic agents to prepare a medicament. In some embodiments, the medicament is for co-administration with one or more additional therapeutic agents. [00398] In some embodiments, the medicament is for inhibiting replication of an RNA virus. [00399] In some embodiments, the medicament is for treating hepatitis C.
[00400] This invention also is directed, in part, to one or more compounds and/or salts of the invention, and, optionally one or more additional therapeutic agents, for use as a medicament. In some embodiments, the medicament is for inhibiting replication of an RNA virus. In other embodiments, the medicament is for treating hepatitis C.
K. Intermediate Compounds.
[00401] This invention also is directed, in part, to intermediates that correspond in structure to formula II that can be used to prepare the compounds of formula I (and their salts)(although some intermediates can also be used, just like the compounds of formula I, as HCV inhibitors, and one skilled in the art can determine such ability of the compounds of formula II by utilizing, for example, the methods discussed below):
Figure imgf000082_0001
[00402] In formula II: , R1, R2, R3, R4, and R5 are as discussed above for the compounds of formula I; and
X2 is halo.
[00403] The various embodiments for ^=^, R1, R2, R3, R4, and R5 (as well as their combinations) discussed above apply to the compounds of formula II. As to X2, in some embodiments, X2 is selected from the group consisting of chloro, bromo, and iodo. In other embodiments, X2 is selected from the group consisting of chloro and bromo. In yet other embodiments, X2 is selected from the group consisting of chloro and iodo. In yet other embodiments, X2 is selected from the group consisting of iodo and bromo. In further embodiments, X2 is fluoro. In yet further embodiments, X2 is chloro. In yet further embodiments, X2 is bromo. And in yet further embodiments, X2 is iodo.
[00404] The various embodiments for , R1, R2, R3, R4, R5, and X2 discussed above can be combined to form various embodiments of compounds of formula II, and all embodiments of compounds of formula II so formed are within the scope of Applicants' invention. Some exemplary embodiments of the compounds (and salts thereof) of formula II are discussed below. [00405] In some embodiments, the compounds of formula II correspond in structure to formula IIA:
Figure imgf000082_0002
[00406] In other embodiments, the compounds of formula II correspond in structure to formula HB:
Figure imgf000083_0001
[00407] In some embodiments of the compounds of formula II:
R1 is selected from the group consisting of hydrogen, methyl, and nitrogen-protecting group; R2 is selected from the group consisting of hydrogen and halo; R3 is selected from the group consisting of hydrogen and halo;
R4 is selected from the group consisting of Ci-C4-alkyl, C3-C6-carbocyclyl, and 5-6-membered heterocyclyl, wherein:
(a) the Ci-C4-alkyl optionally is substituted with up to three substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and
(b) the C3-C6-carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, halo, and alkylsulfonylamino;
R5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy, and halo; and X2 is selected from the group consisting of chloro, bromo, and iodo. [00408] In some embodiments of the compounds of formula II: is a double carbon-carbon bond;
R1 is hydrogen;
R2 is selected from the group consisting of hydrogen and halo; R3 is hydrogen; R4 is tert-butyl;
R5 is selected from the group consisting of hydrogen, hydroxy, and methoxy; and X2 is selected from the group consisting of bromo and iodo. [00409] In some embodiments of the compounds of formula II:
R1 is selected from the group consisting of hydrogen and methyl; R2 is selected from the group consisting of hydrogen and methyl; R3 is selected from the group consisting of hydrogen and methyl; R4 is tert-butyl; R5 is selected from the group consisting of hydroxy and methoxy; and X2 is selected from the group consisting of chloro, bromo, and iodo. [0041O] In some embodiments of the compounds of formula II: is a double carbon-carbon bond;
R1 is hydrogen; R2 is hydrogen; R3 is hydrogen; R4 is tert-butyl;
Rs is selected from the group consisting of hydroxy and methoxy; and X2 is selected from the group consisting of chloro, bromo, and iodo. [00411] In some embodiments, the compound of formula II is selected from the group consisting of
Figure imgf000084_0001
[00412] The discussion below provides instructions for the preparation of intermediate compounds of formula II (and salts thereof).
L. Starting Compounds.
[00413] This invention also is directed, in part, to starting compounds that correspond in structure to formula III that can be used to prepare the compounds of formulas II and I (and their salts):
Figure imgf000084_0002
[00414] In formula III, ==, R1, R2, and R3 are as discussed above for the compounds of formula I and II. The various embodiments for ==, R1, R2, and R3 (as well as their combinations) discussed above apply to the compounds of formula III. The various embodiments for =L===, R1, R2, and R3 discussed above can be combined to form various embodiments of compounds of formula III, and all embodiments of compounds of formula III so formed are within the scope of Applicants' invention. Some exemplary embodiments of the compounds (and salts thereof) of formula III are discussed below. [00415] In some embodiments of the compounds of formula III:
R1 is selected from the group consisting of hydrogen, methyl, and nitrogen-protecting group;
R2 is selected from the group consisting of hydrogen and halo; and
R3 is selected from the group consisting of hydrogen and halo. [00416] In some embodiments of the compounds of formula III:
^=^ is a double carbon-carbon bond;
R1 is selected from the group consisting of hydrogen;
R2 is selected from the group consisting of hydrogen and halo; and
R3 is selected from the group consisting of hydrogen. [00417] In some embodiments of the compounds of formula III:
R1 is selected from the group consisting of hydrogen and methyl;
R2 is selected from the group consisting of hydrogen and methyl; and
R3 is selected from the group consisting of hydrogen and methyl. [00418] hi some embodiments, the compound of formula III is uracil.
[00419] This invention also is directed, in part, to starting compounds that correspond in structure to formula IV that can be used to prepare the compounds of formulas II and I (and their salts):
Figure imgf000085_0001
[00420] In formula IV:
R4, R5, and X2 are as discussed above for the compounds of formula I and II; and
X1 is halo.
[00421] The various embodiments for R4, R5, and X2 (as well as their combinations) discussed above apply to the compounds of formula IV. As to X1, in some embodiments, X1 is selected from the group consisting of chloro, bromo, and iodo. In other embodiments, X1 is selected from the group consisting of chloro and bromo. In yet other embodiments, X1 is selected from the group consisting of chloro and iodo. In yet other embodiments, X1 is selected from the group consisting of iodo and bromo. In further embodiments, X1 is fluoro. In yet further embodiments, X1 is chloro. In yet further embodiments, X1 is bromo. And in yet further embodiments, X1 is iodo. As to X1 and X2, in some embodiments, X1 and X2 are identical. [00422] The various embodiments for R4, R5, X1, and X2 discussed above can be combined to form various embodiments of compounds of formula IV, and all embodiments of compounds of formula III so formed are within the scope of Applicants' invention. Some exemplary embodiments of the compounds (and salts thereof) of formula IV are discussed below. [00423] In some embodiments of the compounds of formula IV:
R4 is selected from the group consisting of Ci-C4-alkyl, C3-C6-carbocyclyl, and 5-6-membered heterocyclyl, wherein:
(a) the Ci-C4-alkyl optionally is substituted with up to three substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and
(b) the C3-C6-carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, halo, and alkylsulfonylamino;
R5 is selected from the group consisting of hydrogen, hydroxy, and alkyloxy;
X1 is selected from the group consisting of chloro, bromo, and iodo; and
X2 is selected from the group consisting of chloro, bromo, and iodo. [00424] In some embodiments of the compounds of formula IV:
R4 is selected from the group consisting of tert-butyl;
R5 is selected from the group consisting of hydrogen, hydroxy, and methoxy;
X1 is selected from the group consisting of bromo and iodo; and
X2 is selected from the group consisting of bromo and iodo. [00425] In some embodiments of the compounds of formula IV:
R4 is selected from the group consisting of tert-butyl;
R5 is selected from the group consisting of hydroxy and methoxy;
X1 is selected from the group consisting of chloro, bromo, and iodo; and
X2 is selected from the group consisting of chloro, bromo, and iodo. [00426] In some embodiments of the compounds of formula IV:
R4 is tert-butyl;
R5 is selected from the group consisting of hydroxy and methoxy;
X1 is selected from the group consisting of chloro, bromo, and iodo; and
X2 is selected from the group consisting of chloro, bromo, and iodo. [00427] In some embodiments, the compound of formula IV is selected from the group consisting of
Figure imgf000087_0001
[00428] The discussion below provides instructions for the preparation of starting compounds of formula IV (and salts thereof).
L. Methods for Preparation.
[00429] This invention also is directed, in part, to a process for preparing compounds of formula II. The process comprises reacting a compound of formula III with a compound of formula IV in the presence of (i) copper (I) salt catalyst and (ii) nitrogenous heteroaryl ligand:
Cu(I) catalyst nitrogenous ϊ heteroaryl
Figure imgf000087_0003
ligand
Figure imgf000087_0002
[00430] In the above process, R1, R2, R3, R4, R5, X1, and X2 are as discussed above.
[00431] Applicants have discovered that the process generally results in the substitution of the Nl hydrogen of uracil derivative compound III thus resulting in intermediate compound II. When X2 in intermediate compound II is chloro, bromo, or iodo, then compound II is is suitable for subsequent reaction (e.g. , Suzuki coupling with an appropriate boronic acid or boronate ester) to provide compound of formula I. In other words, when X2 in intermediate compound II is chloro, bromo, or iodo, the above process is suitable for preparing compounds of formula I as well.
[00432] In some embodiments, compound HI is uracil, and compound IV corresponds in structure to a compound selected from the group consisting of compound IV-I, IV-Br, and IV-Cl, with compounds IV-
I and IV-Br typically resulting in better yield than compound IV-Cl.
[00433] Suitable Cu(I) catalysts include, for example, CuI, CuBr, CuCl, Cu2O, and CH3C(O)OCu. In some embodiments, the catalyst is selected from the group consisting of CuI and CuBr. In some such embodiments, the catalyst is CuI. In other such embodiments, the catalyst is CuBr.
[00434] In some embodiments, the process is conducted in the presence of a base. In some such embodiments, the base is an inorganic base. Suitable inorganic bases include, for example, potassium, sodium, and cesium salts {e.g., K2CO3, K3PO4, Cs2CO3, Na2CO3). In some embodiments, the base is selected from the group consisting of potassium salt and cesium salt. In some such embodiments, the salt is selected from the group consisting Of K3PO4 and Cs2CO3. In some embodiments, the base comprises a potassium salt. In some such embodiments, the potassium salt is K2CO3. In other such embodiments, the potassium salt is K3PO4. In some embodiments, the base comprises a cesium salt. In some such embodiments, the potassium salt is Cs2CO3.
[00435] Typically, the process is conducted in the presence of a solvent. Suitable solvents include, for example, dimethylsulfoxide (DMSO), dimethylformamide (DMF), and acetonitrile (MeCN). In some embodiments, the solvent is DMSO.
[00436] Typically, the process is conducted at a temperature of from about 40 to about 13O0C.
[00437] In some embodiments, the nitrogenous heteroaryl ligand comprises 8-hydroxyquinoline. In other embodiments, the ligand comprises 2-(2-pyridyl)-benzimidazole. In yet other embodiments, the ligand comprises a picolinamide compound corresponding in structure to formula V:
Figure imgf000088_0001
[00438] In formula V, R11, R12, R13, R14, R15, R16, and R17 are independently selected from the group consisting of hydrogen, Ci-4-perfluoroalkyl, Ci-4-alkyloxy, Ci-4-haloalkyl, chloro, or cyano. In some embodiments, R11, R12, R13, R14, R15, R16, and R17 are independently selected from the group consisting of hydrogen, methyl, methoxy, trifluoromethyl, chloro, and cyano. In some embodiments, the ligand of formula V comprises N-(4-cyanophenyl)picolinamide. In other embodiments, the ligand of formula V comprises N-(2-cyanophenyl)picolinamide.
[00439] In some embodiments, the process comprises (a) preparing a compound of formula IV; and (b) reacting a compound of formula III with a compound of formula IV in the presense of (i) copper (I) salt catalyst and (ii) nitrogenous heteroaryl ligand, optionally in the presence of inorganic base. [00440] Compound of formula IV-I can be prepared by, for example, converting 2-tert-butylphenol into 2-tert-butyl-4,6-diiodophenol (by, for example, reacting it with NaI and NaOCl), and then converting the 2-tert-butyl-4,6-diiodophenol into l-tert-butyl-3,5-diiodo-2-methoxybenzene (by, for example, treating it with CH3I in the presence of a base, such as, for example, NaOH).
Figure imgf000089_0001
in
[00441] Compound of formula IV-Br can be prepared by, for example, converting 2-tert-butylphenol into 2,4-dibromo-6-tert-butylphenol (by, for example, reacting it with l,3-dibromo-5,5-dimethylimidazo- lidine-2,4-dione), and then converting the 2,4-dibromo-6-tert-butylphenol into l,5-dibromo-3-tert-butyl- 2-methoxybenzene (by, for example, treating it with CH3I in the presence of KOtBu). [00442] Additional information about the preparation of compounds of formulas I and II (and their salts) is provided in the general discussion and/or specific synthesis examples below. In the discussion below, R1, R2, R3, R4, R5, L, RA, RB, Rc, RD, R6, RE, RF, RG, RH, R1, RJ, Rκ, X1, and X2 have the meaning discussed above unless otherwise stated.
SCHEME 1
Figure imgf000089_0002
Figure imgf000089_0003
[00443] Compound (1-1), wherein R7 is, for example, hydrogen or -CO2Me, and R8 is, for example, hydrogen or t-butyl, may be treated with nitric acid in solvents such as, for example, acetic acid or water in a temperature range of about 0 to about 35°C over about 1 to about 5h to provide compound (1-2). Compound (1-2) may then be reduced using conditions known to those skilled in the art to furnish the corresponding aniline (1-3). Typical conditions for this reduction include using hydrogen at a pressure of about 1 to about 5 atmospheres in the presence of a catalyst such as, for example, palladium or platinum on charcoal in a solvent such as, for example, tetrahydrofuran, ethyl acetate, ethanol, or hexane at or near ambient temperature over a period of about 1 to about 12h. Dependent on the functional groups present, an alternative reduction procedure may be more appropriate such as, for example, using iron powder in the presence of a mild acid such as, for example, ammonium chloride or dilute hydrochloric acid at reflux temperatures in a mixture of solvents containing, for example, methanol, water, and/or tetrahydrofuran over about 1 to about 12h. Another set of reduction conditions includes the use of sodium borohydride in a solvent mixture such as, for example, water and tetrahydrofuran. Yet another set of reduction conditions includes the use of tin(II) chloride in the presence of hydrochloric acid in such solvents as, for example, water and methanol or mixtures thereof.
[00444] Compound (1-2) may be modified prior to reduction. For example, treatment of compound (1-2), wherein R7 is hydrogen, with iodine monochloride in a mixture of methanol and water at or near ambient temperature over a period of about 8 to about 24h supplies compound (1-4), wherein X1 is iodine. Alternatively, compound (1-2) can be treated with pyridinium hydrobromide perbromide in a solvent such as, for example, acetic acid at or near ambient temperature over a period of about 2 to about 16h to provide compound (1-4), wherein X1 is bromine. Modifications may be introduced at the phenol moiety in compound (1-4). For example, the phenol may be alkylated with alkyl halides (e.g., methyl iodide), alkyl sulfates (e.g., methyl sulfate), alkenyl halides (e.g., allyl bromide), alkynyl halides (e.g., propargyl bromide) in the presence of a base such as, for example, potassium carbonate in acetone, sodium hydride in dimethylformamide, or potassium t-butoxide in tetrahydrofuran, at temperatures from about 0 to about 350C over a period of about 1 to about 24h to provide compound (1-5), wherein R9 is, for example, alkyl, alkenyl, or alkynyl. Alternatively, alkylation may be achieved by using a reagent such as (trimethylsilyl) diazomethane in solvents such as, for example, methanol or t-butyl methyl ether, or mixtures thereof in a sealed tube at or near room temperature over about 8 to about 24h. Compound (1-5) may subsequently be reduced to compound (1-6) using the iron powder or tin(II) chloride conditions described above. An alternative reduction procedure employs hydrogenation at approximately 1 atmosphere pressure with a catalyst such as 5% platinum on sulfϊded carbon in a solvent such as methanol. Protection of the resultant aniline of compound (1-6) with, for example, a t-butyl carbamate can be achieved by treatment with di- tert-butyl dicarbonate in a solvent such as, for example, tetrahydrofuran or dioxane at a temperature of about 50 to about 650C for about 1 to about 8h provides compound (1-7). [00445] Modifications may also occur at the phenol moiety in compound (1-2). One skilled in the art may alkylate the phenol of compound (1-2) using, for example, the conditions described above to obtain compound (1-8). Compound (1-8) is transformed into compound (1-9) using, for example, one or more of the appropriate reduction conditions described above.
[00446] Another modification of the phenol group in compound (1-2) is sulfonylation to furnish compound (1-8), wherein R9 is alkylsulfonyl, carbocyclylsulfonyl, or haloalkylsulfonyl. Such a compound may be prepared by exposing compound (1-2) to sulfonyl chlorides such as, for example, methanesulfonyl chloride, cyclohexanesulfonyl chloride, benzenesulfonyl chloride, or 3-chloropropane sulfonyl chloride in the presence of a base such as, for example, triethylamine, diisopropylethylamine, or pyridine in a solvent such as, for example, dichloromethane at or near ambient temperature for a period of about 1 to about 24h. One skilled in the art can then transform compound (1-8) into compound (1-9) with an appropriate set of reduction conditions.
SCHEME 2
Figure imgf000091_0001
[00447] Aniline (2-4) can be prepared through use of the Curtius rearrangement. To this end, compound (2-1), wherein R4 is not amino, can be treated in refluxing thionyl chloride with a catalytic amount of dimethylformamide for about 1 to about 4h to obtain acid chloride (2-2). Treatment with thionyl chloride at the reflux temperature in solvents such as, for example, chloroform or toluene also furnishes compound (2-2). Compound (2-2) can be reacted with an aqueous solution of sodium azide in a solvent such as, for example, acetone over about 1 to about 8h to provide acyl azide (2-3). Compound (2-3) can then undergo a Curtius rearrangement in refluxing solvents such as dioxane or toluene. The intermediate isocyanate is hydrolyzed with an aqueous acid such as dilute hydrochloric acid in a solvent such as dimethoxyethane to provide compound (2-4). SCHEME 3
Figure imgf000092_0001
[00448] Compound (3-1), wherein R10 is, for example, hydrogen, bromine, iodine, or -CO2Me, can be treated with an acrylic acid either neat at or near ambient temperature in a solvent such as, for example, toluene and heated to reflux over a period of about 15 to about 48h to supply compound (3-2). When excess of an acrylic acid is used, compound (3-3) is produced. Compound (3-2) or (3-3) can be treated with urea in a solvent such as, for example, acetic acid at about 100 to about 120°C over about 2 to about 48h to supply compound (3-4).
SCHEME 4
Figure imgf000092_0002
[00449] Compound (4-2) can be prepared from compound (3-1) dissolved in solvents such as, for example, dimethylformamide or dimethylacetamide by the addition of a benzene solution of (E)-3- methoxyacryloyl isocyanate (prepared as described by Santana, L.; et al. J. Heterocyclic Chem. 1999, 36, 293-295.) at a temperature of about -40 to about -15°C under an inert atmosphere and then warming to ambient temperature for from about 30 min to about 4h. Compound (4-2) can be treated with an acid such as, for example, sulfuric acid in mixtures of water and ethanol in a temperature range of from about 90 to about 11O0C for about 1 to about 8h to supply compound (4-3). Alternatively, compound (4-2) can be cyclized to uracil (4-3) under the basic conditions described by Ueno, Y.; et al. J. Org. Chem. 70:7925-7935 (2005). SCHEME 5
Figure imgf000093_0001
[00450] Compound (9-1) can be treated in refluxing thionyl chloride for about 1 to about 4h to obtain acid chloride (9-2). Treatment with thionyl chloride at the reflux temperature in solvents such as, for example, chloroform or toluene also furnishes compound (9-2). Compound (2) is converted to the corresponding aldehyde (9-3) by reduction with lithium tri-/-butoxyaluminum hydride in a solvent such as, for example, tetrahydrofuran at about -78 °C over from about 1 to about 8h. The reduction can also be achieved by treatment with indium chloride and tributyltin hydride in the presence of triphenylphosphine in a solvent such as tetrahydrofuran or toluene at temperatures from about -40 to about 00C. Compound (9-3) can be treated with compound (9-4) in the presence of a base such as potassium /-butoxide in a solvent such as dichloromethane at or near room temperature over a period of about 1 to about 8h to provide compound (9-5).
SCHEME 6
Figure imgf000093_0002
[00451] Compound (10-1), wherein X1 is halo (e.g., bromine, iodine) can undergo a Suzuki reaction with vinyl boronic acid (10-2) to provide compound (10-3). The reaction typically requires the use of a base and a catalyst. Examples of bases include, for example, potassium carbonate, potassium phosphate, potassium f-butoxide, sodium carbonate, cesium carbonate, and cesium fluoride. Examples of catalysts include, for example, tris(dibenzylidineacetone)dipalladium (0), palladium acetate, bis(triphenyl phosphine)palladium (II) chloride, tetrakis(triphenylphosphine)palladium, dichloro[l,l'-bis(di-tert- butylphosphino)ferrocene] palladium (II), or dichloro[l,l'-bis(diphenylphosphino)ferrocene] palladium (II) dichloromethane adduct. The reaction may be conducted in a solvent such as, for example, water, dioxane, dimethoxyethane, dimethylformamide, toluene, ethanol, tetrahydrofuran and the like or mixtures thereof. The reaction may be conducted at ambient or elevated temperatures.
SCHEME 7
Figure imgf000094_0001
[00452] Compound (11-1) can be converted to compound (11-2) by treatment with diazomethane in a solvent such as, for example, tetrahydrofuran in the presence of palladium acetate at or near room temperature over a period of about 30 min to about 4h.
SCHEME 8
Figure imgf000094_0002
[00453] Compound (11-1) is reduced to supply compound (14-2). Typical conditions for this reduction include using hydrogen at a pressure of about 1 to about 5 atmospheres in the presence of a catalyst such as, for example, palladium or platinum on charcoal in a solvent such as, for example, tetrahydrofuran, ethyl acetate, ethanol, or hexane at or near ambient temperature over a period of about 1 to about 12h. SCHEME 9
Figure imgf000095_0001
[00454] Compound (15-1) can be converted in a two-step sequence to compound (15-2). The initial step involves reduction of the aromatic nitro moiety with iron powder in the presence of a mild acid such as, for example, ammonium chloride or dilute hydrochloric acid at temperatures from about 60 to about 800C in a mixture of solvents containing, for example, methanol, water, and tetrahydrofuran over about 1 to about 12h. The second step consists of exposure of the aniline, prepared in the first step, to methanesulfonyl chloride in the presence of a base such as pyridine in a solvent such as dichloromethane at or near ambient temperature.
Figure imgf000095_0002
[00455] Compound (17-1) can be mesylated to provide compound (17-2) by treatment with methanesulfonyl chloride in the presence of a base such as, for example, pyridine in a solvent such as, for example, dichloromethane. Compound (17-3) can be exposed to borane dimethyl sulfide complex in a solvent such as, for example, tetrahydrofuran at approximately about 0 to about 1O0C to supply compound (17-4). Compounds (17-2) and (17-4) can be combined with acetaldehyde in refluxing tetrahydrofuran. Subsequent treatment with water at room temperature yields compound (17-5). SCHEME 11
BH3-THF NBS P(OEt)3
R6-CO2H R6-CH2OH R6-CH2Br R6-CH2P(O)(OEt)2
PPh,
(18-1) (18-2) (18-3) (18-4)
[00456] Carboxylic acid (18-1) can be reduced with boron tetrahydrofuran complex with heating to provide alcohol (18-2). Compound (18-2) is converted to the corresponding bromide (18-3) with N- bromosuccinimide and triphenylphosphine in solvents such as, for example, dichloromethane at room temperature in several hours. Treatment of compound (18-3) with triethyl phosphite at about 1200C for about 1 to about 3h supplies compound (18-4). Compound (18-4) can be used for example to make compound (9-5) as described in Scheme 5.
SCHEME 12
Figure imgf000096_0001
[00457] Benzaldehyde (19-1) can be treated with diethyl phosphonate in the presence of a base such as, for example, sodium methoxide in a solvent such as, for example, methanol at room temperature to provide compound (19-2). Compound (19-2) can be treated with N-chlorosuccinimide and triphenylphosphine in dichloromethane at room temperature to yield compound (19-3). Compound (19-2) can also be reacted with (diethylamino)sulfur trifluoride (DAST) to supply compound (19-4).
[00458] Compound (19-1) can also be treated with p-toluenesulfonic acid and trimethyl orthoformate in methanol at about 500C to provide acetal (19-5). Compound (19-5) can be converted to compound (19-6) by exposure to triethyl phosphite and boron trifluoride diethyl etherate at about -200C to about ambient temperature.
[00459] Compounds (19-3), (19-4), and (19-6) can be used for example to make compound (9-5) as described in Scheme 5. SCHEME 13
Figure imgf000097_0001
[00460] Phenol (20-1), wherein R4 is other than amino, is treated with a source of electrophilic halide, such as, for example, iodine monochloride to provide dihalogenated compound (20-2), wherein X1 and X2 are independently bromine or iodine. Compound (20-2) is transformed to compound (20-3) by reaction of an alkylating agent such as, for example, methyl sulfate with a base such as, for example, potassium carbonate in refluxing acetone. Alternatively, methyl iodide in the presence of a base such as, for example, potassium ^-butoxide in a solvent such as, for example, tetrahydrofuran, or dimethylformamide also furnish compound (20-3). In yet another alternative, compound (20-2) can be methylated with (trimethylsiryl)diazomethane in a solvent such as, for example, t-butyl methyl ether. Compound (20-3) can be reacted with uracil, ligand (20-4), copper (I) iodide, and potassium phosphate in dimethyl sulfoxide at about 40°C to about 100°C to supply compound (20-5).
[00461] For example, when in compound (20-3), R4 is tert-buryl, X1 is iodo, and X2 is iodo or bromo, compound (20-3) can be stirred with uracil and compound (20-4) in the presence of CuI and K2PCU in DMSO for about 15 to about 24h at about 600C to supply compound (20-5). Alternatives to ligand (20-4) for making (20-5) are 8-hydroxyquinoline and 2-(2-pyridyl)-benzimidazole.
SCHEME 14
Figure imgf000098_0001
[00462] Compound (21-1) can be nitrated with nitric acid in acetic acid in a temperature range of about 10 to about 15°C to give compound (21-2). The phenol moiety of compound (21-2) can be protected as a silyl ether, e.g. t-butyldimethylsilyl ether, by treatment with a silyl chloride such as, for example, t-butyl dimethylsilyl chloride and imidazole in a solvent such as, for example, dimethyl formamide at ambient temperature to furnish compound (21-3). Compound (21-3) may then be reduced using conditions known to those skilled in the art to furnish the corresponding aniline (21-4).
[00463] Typical conditions for this reduction include using hydrogen at a pressure of about 1 to about 5 atmospheres in the presence of a catalyst such as, for example, palladium or platinum on charcoal in a solvent such as, for example, tetrahydrofuran, ethyl acetate, ethanol, methanol, or hexane at or near ambient temperature over a period of about 1 to about 12h. Dependent on the functional groups present, an alternative reduction procedure may be more appropriate such as, for example, using iron powder in the presence of a mild acid such as, for example, ammonium chloride or dilute hydrochloric acid at reflux temperatures in a mixture of solvents containing, for example, methanol, water, and tetrahydrofuran over about 1 to about 12h.
[00464] Aniline (21-4) can then by sulfonylated with methanesulfonyl chloride in the presence of pyridine in a solvent such as, for example, dichloromethane. The starting material and reagents are combined at about 0°C and then allowed to gradually warm to ambient temperature over the course of the reaction to supply compound (21-5). The silyl ether protecting group is removed under conditions familiar to one skilled in the art. For example, tetrabutylammonium fluoride in tetrahydrofuran at room temperature transforms compound (21-5) to compound (21-6). The phenol group of compound (21-6) may be sulfonylated with trifluoromethanesulfonic anhydride in the presence of a base such as, for example, pyridine in a solvent such as, for example, dichloromethane at room temperature to provide compound (21-7). Compound (21-7) can be used as described in Scheme 12 to make compound (12-3).
SCHEME 15
Figure imgf000099_0001
[00465] Compound (22-1) is converted to compound (22-2) in a two-step sequence. First, compound (22- 1) can be hydrolyzed with a base such as, for example, sodium hydroxide, lithium hydroxide, or potassium hydroxide in a solvent such as, for example, methanol, ethanol, or tetrahydrofuran, or mixtures thereof. The resultant reaction mixture can be stirred for a period of about 6 to about 48h at ambient temperature. Second, the intermediate carboxylic acid is treated in refluxing thionyl chloride with or without a catalytic amount of dimethylformamide for about 1 to about 4h to deliver acid chloride (22-2). Treatment with thionyl chloride at reflux temperature in solvents such as, for example, chloroform or toluene also furnishes compound (22-2). Treatment of the carboxylic acid with oxalyl chloride in dichloromethane with a catalytic amount of dimethylformamide also furnishes compound (22-2). [00466] Compound (22-2) can be treated with an amine or the corresponding salt in a solvent such as, for example, dioxane, dimethylformamide, dimethylacetamide, or dichloromethane optionally in the presence of a base such as, for example, pyridine, triethylamine or diisopropylethylamine at temperatures ranging from at or near ambient to about 1000C for between about 1 and about 24h to provide compound (22-4) wherein R11 and R12 are independently hydrogen or RF, or taken together with the nitrogen to which they are attached form a 5-6-membered heterocyclyl or a fused 2-ring heterocyclyl. [00467] Compound (22-2) is converted to the corresponding aldehyde (22-3) by reduction with lithium tri-/-butoxyaluminum hydride in a solvent such as, for example, tetrahydrofuran at about -600C to about 78°C.
SCHEME 16
Figure imgf000100_0001
Figure imgf000100_0002
Figure imgf000100_0003
[00468] Compound (22-3) can be converted to compound (23-2) wherein R11 and R12 are independently hydrogen or RF, or taken together with the nitrogen to which they are attached form a 5-6-membered heterocyclyl or a fused 2-ring heterocyclyl by treatment with an amine, N(R1 ')(R12), in the presence of a reductant such as, for example, sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as, for example, methanol, ethanol, dichloromethane, dimethylacetamide, or dimethylformamide over a period of about 1 to about 24h. The reaction often proceeds best at an acidic pH that can be maintained by the addition of acetic acid or hydrochloric acid.
[00469] Compound (22-3) can also be converted to compound (23-3) by reduction with lithium tri-?- butoxyaluminum hydride in a solvent such as tetrahydrofuran at room temperature. SCHEME 17
Figure imgf000101_0001
[00470] Compound (23-3) can be converted to compound of formula (24-2) by treatment with thionyl chloride in dichloromethane at room temperature. Compound (24-2) can be treated with a sodium alkoxide, R13ONa, in a heated solution of the corresponding alcohol to provide compound (24-3), wherein R13 is hydrogen or RF.
SCHEME 18
Figure imgf000101_0002
(25-1) (25-2)
Figure imgf000101_0003
(25-3) (25-4)
[00471] Compound (25-1) can be brominated by treatment with, for example, pyridinium hydrobromide perbromide in a solvent such as, for example, acetic acid at or near ambient temperature over a period of about 1 to about 8h to give compound (25-2). The amino group of compound (25-2) can be removed by exposure to t-butyl nitrite in a solvent such as, for example, dimethylformamide at a temperature initially at ambient temperature and then increased to the range of about 50 to about 65 0C to give compound (25- 3). Additional aliquots of t-butyl nitrite can be added at ambient temperature followed by heating until the transformation is complete. Compound (25-3) can be reduced to compound (25-4) by, for example, treatment with iron and ammonium chloride.
EXAMPLES
[00472] The following examples are merely illustrative, and not limiting to this disclosure in any way. [00473] Example A. Preparation of (E)-N-(3-tert-butyl-5-iodo-4-methoxyphenylcarbamoyl)-3-methoxy acrylamide.
Figure imgf000102_0001
[00474] Part A. Preparation of 2-tert-butyl-4-nitrophenol.
[00475] To a vigorously stirred solution of 2-tert-butylphenol (1Og, 66.6mmol) in heptane (67ml) was added at a fast drip a solution of 70% nitric acid (4.25ml, 66.6mmol) diluted with water (4.25ml). The resulting dark red/brown mixture was stirred vigorously for 2h. The suspended solid was collected by filtration washed with hexane (30OmL), water (20OmL) and once again with hexane (20OmL) to give a cocoa colored powder that was dried to constant mass (4.65g, 35.6%).
[00476] Part B. Preparation of 2-tert-butyl-6-iodo-4-nitrophenol.
[00477] To the product from Part A (4.5g, 23.05mmol) dissolved in MeOH (120ml) and water (3OmL) was added iodine monochloride (1.155ml, 23.05mmol) drop wise over a period of lOmin. The mixture was stirred for 2h and diluted into IL of water and allowed to stand overnight. The solid material was collected by filtration and washed 3x50mL with water and dried under vacuum overnight to give a tan solid (7.14g, 96%).
[00478] Part C. Preparation of l-tert-butyl-3-iodo-2-methoxy-5-nitrobenzene.
To an ice bath cooled solution of the product from Part B (5.5g, 17.13mmol) in MTBE (15ml) in a 5OmL pressure vessel was added 2.0M TMS diazomethane (12.85ml, 25.7mmol) followed by drop-wise addition of methanol (1.OmL) resulting in calm bubbling. The vessel was sealed and stirred at room temperature for 16h, cooled and the pressure was released. The solution was partitioned between EtOAc and water. The organic layer was washed with 1.0M HCl, saturated potassium carbonate solution, and saturated NaCl. The organic layer was dried over sodium sulfate, filtered and concentrated to give a red oil that was used without purification (5.4g, 84%).
[00479] Part D. Preparation of 3-tert-butyl-5-iodo-4-methoxyaniline. [00480] A mixture of the product from Part C (5.80g, 17.31mmol), ammonium chloride (1.389g, 26.0mmol), and iron (4.83g, 87mmol) in THF/MeOH/water (20OmL total, 2/2/1) was refluxed for 2h, cooled and filtered through Celite. The filtrate was evaporated and the residue was partitioned between water and EtOAc. The organic layer was washed with saturated brine, dried with sodium sulfate, filtered and evaporated to give a brown oil (5.28g, 100% yield).
[00481] Part E. Preparation of (E)-N-(3-tert-butyl-5-iodo-4-methoxyphenylcarbamoyl)-3-methoxy acrylamide.
[00482] To a solution of the product from Part E (3.05g, lOmmol) in DMF (50ml) at -200C under N2 was added at a fast drip a 0.4M solution in benzene of (E)-3-methoxyacryloyl isocyanate (50.0ml, 20.00mmol, prepared by the method of Santana et al., J. Heterocyclic Chem. 36:293 (1999). The solution was stirred for 15min at -200C, warmed to room temperature for 45min and diluted into EtOAc. The EtOAc layer was washed 4 x 30OmL with water, 2 x 10OmL with brine, dried (Na2SO4) and concentrated to a brown solid. The residue was triturated in Et2O/hexane to give a fine powder that was collected by filtration and dried to give a tan powder (2.46g, 57%).
[00483] Example B. Preparation of l-(3-tert-butyl-5-iodo-4-methoxyphenyl)dihydropyrimidine- 2,4(lH,3H)-dione.
Figure imgf000103_0001
[00484] To a suspension of the product from Example A (2.46g, 5.69mmol) in ethanol (50ml) was added a solution of 5.5mL OfH2SO4 in 5OmL water and the mixture was heated at 110°C for 2.5h to give a clear solution. The solution was cooled and diluted with 5OmL of water while stirring to give an off-white solid that was collected by filtration, washed with water and dried (2.06g, 90%).
[00485] Example C. Preparation of l-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(lH,3H)- dione.
Figure imgf000103_0002
[00486] Part A. Preparation of 2-tert-butyl-4,6-diiodophenol.
[00487] A solution of 2-tert-butylphenol (20.Og, 133mmol) in methanol (266mL) was treated with sodium hydroxide pellets (6.39g, 160mmol). The mixture was stirred until all the sodium hydroxide had dissolved and was then cooled in an ice-salt bath to -20C. Sodium iodide (15.0g, lOOmmol) was added and then 10 % sodium hypochlorite solution (45mL, 73.3mmol) was added drop wise at a rate such that the solution temperature rose no higher than 1.3°C. This sequence of events was repeated (3x) until a total of 6Og (400mmol) of sodium iodide had been added and the sodium hypochlorite solution was added until the solution color changed from a light green-yellow color to the color of weak iced tea. This required all but 16mL of the 18OmL total sodium hypochlorite solution measured out. With continued cooling at ca. 2°C, a solution of sodium thiosulfate pentahydrate (2Og) in water (10OmL) was added drop wise over 20min. After addition, the solution was acidified to pH 3 by drop wise addition of concentrated hydrochloric acid (ca. 35mL required of 4OmL placed in the addition funnel). The precipitate was collected by filtration and washed with >1 liter of water. The salmon-colored solid was sucked as dry as possible, and dried in a vacuum oven at 5O0C for 18h. These procedures afforded the product (49.6 Ig, 93%) as a tan solid.
[00488]Part B. Preparation of l-tert-butyl-3,5-diiodo-2-methoxybenzene.
[00489] A solution of the product from Part A (20.Og, 49.7mmol) in acetone (14OmL) was treated with methyl iodide (3.9mL, 8.83g, 62.2mmol) and 50 % (w/w) sodium hydroxide solution (3.02mL, 4.58g, 57.2mmol) followed by stirring at ambient temperature for 48h. The mixture was concentrated in vacuo to a volume of ca. 50-6OmL, followed by dilution with heptane (8OmL) and water (5OmL). The layers were separated and the organic layer was extracted with saturated sodium chloride solution. Drying (Na2SC^) and concentration in vacuo afforded the product (20.59g, 99%) as a light yellow oil. [00490] Part C. Preparation of l-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(lH,3H)-dione. [00491] A suspension of the product from Part B (12.04g, 28.9mmol), uracil (3.89g, 34.7mmol), N-(2- cyanophenyl)picolinamide (1.29g, 5.79mmol) and tribasic potassium phosphate (12.9g, 60.8mmol) in DMSO (18ImL) was degassed by nitrogen sparge for 1 h. The mixture was then treated with copper (I) iodide (55 lmg, 2.89mmol) and degassing was continued for another lOmin. The mixture was then warmed at 6O0C for 18h. The mixture was then poured into water (60OmL) and acidified to pH 3 by addition of 4N hydrochloric acid solution. The mixture was diluted with ethyl acetate, and the organic layer was extracted with water (3x), saturated ammonium chloride solution (Ix) and saturated sodium chloride solution. The solution was dried and treated with (3-mercaptopropyl) silica gel, followed by stirring for 2h. The mixture was filtered and concentrated in vacuo. The solid obtained was triturated with ether-ethyl acetate (>10: 1) and collected by filtration and washed with ether. After drying in a vacuum oven at 5O0C for 2h, these procedures afforded the product (2.75 g) as a white solid. The mother liquors were concentrated in vacuo to afford an amber solid. This material was chromatographed over a Flash 65 silica gel cartridge, eluting with 20-100 % ethyl acetate in hexanes. These procedures afforded a nearly white solid, which was triturated with ether-hexanes and collected by filtration. After drying in a vacuum oven for 3h, these procedures afforded another 4.3 Ig of the product as a white solid. Total yield: 7.06g (61 %).
[00492] Example D. Preparation of l-(3-tert-Butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(lH,3H)- dione.
Figure imgf000105_0001
[00493] Part A. Preparation of 2-tert-butyl-4,6-diiodophenol.
[00494] 2-ført-Butylphenol (99.95g, 665.36mmol) was dissolved in 125OmL methanol and converted to the corresponding phenoxide with 31.96g (799.0mmol, 1.2equiv.) of sodium hydroxide by stirring the sodium hydroxide pellets at room temperature, and then cooling the reaction mixture in an ice/salt bath. Sodium iodide (299.34g, 1997.07mmol, 3.0equiv.) and 8.3% bleach (1265.83g, 1411.39mmol, 2.1equiv.) were added to the cold reaction solution in four equal portions, the bleach being added while keeping the reaction mixture at <0°C. 50OmL of 20% (w/w) sodium thiosulfate solution was added over an 18- minute period, with the temperature rising from -0.60C to 2.5°C. The pH of the reaction mixture was adjusted to approximately 3 by adding 197.5mL of cone. HCl over a period of 97min with the reaction temperature going from 1.20C to 4.1°C. The resulting slurry was filtered, and the wet cake washed with ~ 2L of water. The wet cake was left on the Buchner funnel under vacuum overnight (approximately 15h) to yield 289.33g (potency adjusted yield = 254.6Ig) of the title product. [00495] Part B. Preparation of l-ter7-butyl-3,5-diiodo-2-methoxybenzene. [00496] The product from Part A (93%assay, 21.6g, 50mmol) was dissolved in 14OmL of acetone. Methyl iodide (4.2mL, 67.5mmol, 1.35equiv.) was added, followed by 50% aqueous sodium hydroxide (5.0g, 62.5mmol, 1.25equiv.). The reaction was stirred overnight, then concentrated to approximately 50- 6OmL. 8OmL of heptanes was added followed by 5OmL of water, and the layers were shaken and separated, and the aqueous layer was back extracted with 2OmL of heptanes. The organic layers were combined and washed twice with 5OmL each of 10% aqueous NaCl to afford 91.1 grams of a heptane solution, which assayed to 19. Ig of the title compound. [00497] Part C. Preparation of l-(3-tert-Butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(lH,3H)-dione. [00498] Uracil (33.3g, 297mmol, 1.2equiv.), K3PO4 (106g, 500mmol, 2.1equiv.), CuI (4.6g, 24.2mmol, O.lequiv.), and N-(2-cyanophenyl)picolinamide (6.4g , 28.7mmol, 0.12equiv.) were charged to a flask and inerted with argon. The l-terr-butyl-3,5-diiodo-2-methoxybenzene was solvent switched into MeCN, dissolved in IL DMSO and sparged with argon and added to the solids. The reaction was heated to 6O0C for 16h. After cooling, the reaction was diluted with 2L EtOAc and washed with 2.6L water (back extracted with 3 x IL EtOAc). The combined organic layers were washed with 2 x IL of 0.25M (CuOAc)2 then 2 x 83OmL 15% NH4Cl then 80OmL brine. The organic layer was then concentrated and chased with IL heptane, then triturated with refluxing 85:15 (v/v) heptane :iPrO Ac for 4h. After cooling, the product was collected by filtration and washed with an additional 33OmL of 85: 15 v/v heptanes:EtOAc to yield after drying 66.9g (70% yield) of the product as a white solid. [00499] Example E. Preparation of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)- 2-methoxystyryl)phenyl)methanesulfonamide.
Figure imgf000106_0001
[00500] The boronic acid (96% potency) (3.75g, 15.6mmol, 1.2eq), product from Example D (5.Og, 12.5mmol), Cytec ligand (175mg, 5mol%), Pd2(dba)3 (46mg, 0.4mol%) and potassium phosphate (5.25g, 25.0mmol, 2eq.) were charged to a 3 neck RB flask. The solids were purged with nitrogen for lOmin. 75mL 4:1 THF:water was sparged lOmin and charged to the flask. The mixture was stirred to dissolve the solids followed by heating the mixture at 5O0C in darkness overnight. HPLC showed the reaction was not complete after stirring overnight (~ 2% iodouracil remained). The reaction mixture was diluted with 375mL DCM and 250ml 10% citric acid. The mixture was shaken in a sep funnel and the layers were separated. The DCM layer was washed with a solution of 0.6g L-cysteine in 250ml 5% NaHCO3 for 30min which changed the DCM layer color from orange to yellow. Repeated the 0.6g L-cysteine in 250ml 5% NaHCO3 for 30min treatment followed by a 250ml 5% NaHCO3 wash, and a 250ml 10% NaCl wash. The DCM layer was treated with 2gm thiourea silica for 30min. Added lgm carbon to decolorize mixed 5min and filtered through hy-flo. The wet cake was washed with DCM. The DCM solution was then stripped to give 6.74g of a light yellow solid. The solids were -92% pure. The solids were heated in a mixture of 192ml DCM and 9mlL MeOH. They never completely dissolved. Cooled to room temp with mixing. 80ml heptane was added and more product began to crystallize. The slurry stirred over the weekend. Added 50ml heptane in portions until a total of 230ml heptane was added. The product was filtered. Filtrate was measured at 1.21mg/mL at 210nm and 1.35 at 220nm, which equals a 522-582mg loss in the liquors or 9-10% loss vs. theoretical. The wet cake was washed with 50ml of a 27ml Heptane:22ml DCM: ImI MeOH mixture. The wash contained 0.5mg/mL product or 25mg (0.4% vs. theoretical). Product yield 5.22gm (88.9%), purity 99.2%PA. Iodouracil was removed in the crystallization. Samples were submitted to solid state for analysis and analytical for Pd determination. NMR did not show any residual solvent.
[00501] Example 1. Preparation of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide (compound IA-L1-1.9).
Figure imgf000107_0001
[00502] Part A. Preparation of methyl 3-tert-butyl-2-hydroxy-5-nitrobenzoate.
[00503] Methyl 3,5-di-tert-butyl-2-hydroxybenzoate (28.66g, 108.4mmol) was dissolved with stirring in
43OmL glacial acetic acid and the resulting mixture was treated drop wise with fuming nitric acid (90%,
179.26mL). When the addition was complete, the resulting mixture was stirred for 2.5h. The reaction mixture was poured into a 2.0L of crushed ice and allowed to stand 30min. Afterwards, 1.0L of water was added and the ice water mixture was allowed to melt. The mixture was then filtered, washed with water and dried to provide the title compound (24.57g, 89%).
[00504] Part B. Preparation of methyl 3-tert-butyl-2-methoxy-5-nitrobenzoate.
[00505] Methyl 3-tert-butyl-2-hydroxy-5-nitrobenzoate (11.41g, 45.0mmol), potassium carbonate (9.34g,
67.6mmol), acetone (20OmL), and dimethyl sulfate (6.46g, 67.6mmol) were added together. The resultant mixture was then heated to reflux for 16h. The mixture was then filtered and the solid was washed with ethyl acetate. The resulting organic liquid was then concentrated under vacuum to an oil and redissolved in ethyl acetate (60OmL). The organic solution was then washed with water, dried, filtered and concentrated under vacuum to an oil that was then subjected to purification via column chromatography
(gradient of 5% to 40% EtOAc/Hexanes) to yield the title compound as an oil (10.42, 87%).
[00506] Part C. Preparation of methyl 5-amino-3-tert-butyl-2-methoxybenzoate. [00507] Methyl 3-tert-butyl-2-methoxy-5-nitrobenzoate (10.42g, 39.0mmol), iron powder (325mesh,
10.89g, 195mmol), ammonium chloride (3.13g, 58.5mmol), water (3OmL), and methanol (15OmL) were added together. The resultant mixture was then refluxed for Ih. The mixture was then cooled to room temperature, filtered through celite, and the celite washed with methanol. The filtrate was then concentrated under vacuum and dissolved in ethyl acetate (60OmL). The resultant solution was then washed with water and brine. The organic extract was then dried, filtered and concentrated under vacuum to yield the title compound as an oil (9.25g, 100%).
[00508] Part D. Preparation of 3-(3-tert-butyl-4-methoxy-5-(methoxycarbonyl)phenylamino) propanoic acid.
[00509] The product from Part C (16.44g, 69.3mmol) was dissolved in toluene (20OmL). This mixture was heated to reflux and acrylic acid added over time (ImL of acrylic acid added every 3h, 5.23mL total,
76.2mmol). The mixture was then refluxed for 24h. The mixture was then cooled and concentrated under vacuum to dryness to yield an oil as the crude title compound that was used directly in the next reaction.
[00510]Part E. Preparation of methyl 3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-2- methoxybenzoate.
[00511] The product from Part D (21.43g, 69.3mmol), urea (10.4g, 173mmol) and acetic acid (glacial,
20OmL) were added together. The mixture was then heated to 12O0C for 18.5h followed by concentration under vacuum to give an oil. To this oil was added methanol (13mL), and ethyl acetate (35OmL). The resultant mixture was allowed to stand for 24-48h whereby a precipitate formed. The resulting solid was filtered off and washed with a small amount of methanol (1OmL) and then air dried to yield the title compound as a solid (15.26g, 66%).
[00512] Part F. Preparation of 3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)-2-methoxy benzoic acid.
[00513] The product from Part D (4.52g, 13.52mmol), methanol (7OmL), and tetrahydrofuran (7OmL) were added together. The mixture was then stirred vigorously until a homogenous solution resulted.
Once homogenous, a solution of aqueous sodium hydroxide (1.0M, 68mL) was added. The mixture was then stirred for 12h, the mixture was then concentrated under vacuum to remove the organic solvent, followed by the addition of aqueous hydrochloric acid (1.0M, 8OmL) that resulted in solid formation. The mixture was then concentrated under vacuum. To this material was added hydrochloric acid (12M,
10OmL) and the resultant material heated to 1000C for 1.5h. The reaction was then cooled and water added. The resulting solid was filtered, washed with water, and dried to yield the title compound as a solid (3.55g, 82%).
[00514]Part G. Preparation of 3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-2-methoxy- benzaldehyde. [00515] The product obtained in Part F (4.07g, 12.71mmol) and thionyl chloride (40.82mL, 559mmol) were combined and the mixture was refluxed for 2h, followed by concentration under vacuum to provide a light yellow colored solid product. The solid was dissolved in tetrahydrofuran (125mL), the solution cooled to -780C and LiAlH(O^Bu)3 (IM, 14mL) was added slowly over lOmin while maintaining the temperature at -780C. The mixture was stirred at -780C for 2h, and the reaction was quenched with hydrochloric acid (aq., IM, 25mL) at -780C. The mixture was warmed to room temperature and ethyl acetate was added. The layers were separated and the aqueous layer was washed with ethyl acetate. The organic extracts were combined and washed with half saturated sodium bicarbonate solution. The organic layer was dried, filtered and concentrated under vacuum to yield the title compound as a solid (3.73g, 96%).
[00516] Part H. Preparation of l-(3-tert-butyl-4-methoxy-5-(4-nitrostyryl)phenyl)dihydro- pyrimidine- 2,4(lH,3H)-dione.
[00517] The product prepared in Part G (1.0Og, 3.29mmol) and diethyl 4-nitrobenzyl- phosphonate (0.853g, 3.12mmol) were dissolved in dichloromethane (5OmL). Solid potassium tert-butoxide (0.737g, 6.57mmol) was added portion wise at room temperature. The resultant dark red solution was stirred for 1.5h at room temperature. IN aqueous HCl (5OmL) solution was added and the mixture was stirred 30min, and then diluted with dichloromethane (5OmL). The resultant organic layer was separated and dried. The material was purified by column chromatography on silica gel using 99/1 dichloromethane/methanol as eluent to obtain the title compound as a solid (1.12g, 80%). [00518] Part I. Preparation of Preparation of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin- l(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.
[00519]The product obtained in Part H (l.lg, 2.60mmol), iron (0.725g, 12.99mmol), and ammonium chloride (0.208g , 3.90mmol) was added to a mixture of tetrahydrofuran (4OmL), ethanol (4OmL) and water (12mL). The slurry was heated to 9O0C for 45min, and then cooled to ambient temperature. The solution was filtered through a pad of celite (1Og), washed with ethanol (2OmL), and the filtrate concentrated under vacuum to a solid. The resulting solid was dissolved in ethyl acetate (10OmL), and the solution was washed with water (5OmL) and dried over Na2SO^ The drying agent was filtered off and the solvent removed under vacuum to give the aniline adduct as a yellow solid (830mg). [00520] The solid (830mg, 2.109mmol) was dissolved in dichloromethane (5OmL), and pyridine (0.512mL, 6.33mmol) and methanesulfonyl chloride (0.18ImL, 2.32mmoi) were added and the resulting solution was stirred at room temperature 16h. Dichloromethane (10OmL) was added followed by extraction with a IN aq. HCl solution (2 x 5OmL). The organic layer was dried, concentrated under vacuum and purified by column chromatography on silica gel using 98/2 CH2Cl2ZMeOH to provide the title compound as a solid (480mg, 39%, two steps), m.p. = 260-2610C (trans-isomer) 1H NMR (500 MHz, DMSOd6): δ ppm 1.37 (s, 9H), 2.71 (t, J=6.7Hz, 2H), 3.01 (s, 3H), 3.75 (s, 3H), 3.79 (t, J=6.6Hz, 2H), 7.13 (d, J=16.5Hz, IH), 7.15 (d, J=2.4Hz, 2H), 7.23 (d, J=8.5Hz, 2H), 7.25 (d, J=16.5 Hz, IH), 7.51 (d, J=2.4Hz, IH), 7.61 (d, J=8.6Hz, 2H), 9.80(bs, IH), 10.30 (s, IH). (trans-isomer).
[00521] Example 2. Preparation of (Z)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)- 2-methoxyphenyl)-l-chlorovinyl)phenyl)methanesulfonamide (compound IA-L1-1.3).
Figure imgf000110_0001
[00522] Part A. Preparation of diethyl hydroxy(4-nitrophenyl)methylphosphonate.
[00523] The title compound was prepared as described in Taylor, WP, et. Al, Bioorg. Med. Chem.
4: 1515-1520 (1996). 4-Nitrobenzaldehyde (3.0g, 19.85mmol) and diethyl phosphonate (2.74g,
19.85mmol) were combined and treated with a 0.5N solution of sodium methoxide in methanol
(0.993mL, 0.496mmol). The resulting red-orange solution was stirred 12h at room temperature. The reaction mixture was extracted with dichloromethane (2OmL) followed by half saturated ammonium chloride (2OmL). The organic layer was separated, dried and concentrated under vacuum to provide the title compound as a semi-solid (5.1g, 89%).
[00524] Part B. Preparation of diethyl chloro(4-nitrophenyl)methylphosphonate.
[00525] The product prepared in Part A (500mg, 1.729mmol) was dissolved in dichloromethane (1OmL) and treated with triphenylphosphine (998mg, 3.80mmol), followed by N-chlorosuccinimide (462mg,
3.46mmol). The mixture was stirred at room temperature for 18h. The solution was concentrated under vacuum and the residue was purified by column chromatography using silica gel eluting with a 1/1 mixture of hexanes/ethyl acetate to provide the title compound as an oil (262mg, 49%).
[00526]Part C. Preparation of (Z)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-2- methoxyphenyl)- 1 -chlorovinyl)phenyl)methanesulfonamide.
[00527] The product prepared in Example 1, Part G (lOOmg, 0.329mmole) was treated with the product obtained from Part B using the procedures described in Example 1, Part H and Example 1, Part I to provide 39mg of the title compound. 1H NMR (300 MHz, DMSO-d6): δ ppm 1.36 (s, 9H), 2.71 (t,
J=6.8Hz, 2H), 3.06 (s, 3H), 3.71 (s, 3H), 3.78 (t, J=6.8Hz, 2H), 7.23 (d, J=2.6 Hz, IH), 7.27 (s, IH), 7.28
(d, J=8.6Hz, 2H), 7.48 (d, J=2.6 Hz, IH), 7.78 d, J=8.8 Hz, IH), 10.05(s, IH), 10.34 (s, IH). [00528] Example 3. Preparation of (E)-l-(3-tert-butyl-5-(4-fluorostyryl)-4-methoxyphenyl) dihydropyrimidine-2,4(lH,3H)-dione (compound IA-Ll-1.12).
Figure imgf000111_0001
[00529] The title compound was prepared according the procedures described in Example 1, Part H and Example 1, Part I using the product obtained in Example 1, Part G (50mg, 0.164mmol) and diethyl 4- fluorobenzylphosphonate (40.5mg, 0.164mmol). The title compound was obtained as a solid (30mg, 46%). 1H NMR (300 MHz, DMSOd6): δ ppm 1.37 (s, 9H), 2.72 (t, J=6.6Hz, 2H), 3.76 (s, 3H), 3.79 (t, =6.6Hz, 2H), 7.21 (m, 4H), 7.30 (d, J=16.3Hz, IH), 7.53 (d, J=2.6Hz, IH), 7.73 (m, 2H), 10.35 (s, IH).
[00530] Example 4. Preparation of (Z)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)- 2-methoxyphenyl)- 1 -fluorovinyl)phenyl)methanesulfonamide (compound IA-L1-1.4).
Figure imgf000111_0002
[00531] Part A. Preparation of diethyl fluoro(4-nitrophenyl)methylphosphonate.
[00532] The title compound was prepared as described in Taylor, WP, et. Al, Bioorg. Med. Chem.
4:1515-1520 (1996). The product from Example 2, Part A (500mg, 1.729mmol) was dissolved in dichloromethane (1OmL) and treated by drop wise addition of (diethylamino)sulfur trifluoride (DAST)
(2.5mL, 18.9mmol). The mixture was stirred at room temperature for 18h. A solution of half saturated sodium phosphate monobasic (2OmL) was added followed by dichloromethane (2OmL) addition and separation of the resulting organic phase. The organic solution was dried and concentrated under vacuum, and then subjected to column chromatography using silica gel eluting with a 1/1 mixture of hexanes/ethyl acetate to provide the title compound as an oil (215mg, 43%).
[00533] Part B. Preparation of (Z)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-2- methoxyphenyl)- 1 -fluorovinyl)phenyl)methanesulfonamide. [00534] The product prepared as described in Part A (lOOmg, 0.329mmole) was treated with the product prepared in Example 1, Part G (96mg, 0.329mmole) according to the procedures described in Example 1, Part H and Example 1, Part I to provide 53mg of the title compound as a 1/1 mixture of cis/trans isomers. Reverse phase HPLC chromatographic separation using a 40-100% gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid provided the title compound as a solid (20mg). 1H NMR (300 MHz, DMSOd6): δ ppm 1.37 (s, 9H), 2.71 (t, J=6.8Hz, 2H), 3.06 (s, 3H), 3.77 (s, 3H), 3.78 (m, 2H), 6.62 (d, J=40.4Hz, IH), 7.18 (d, J=2.6Hz, IH), 7.30 (d, J=8.4Hz, 2H), 7.55 (d, J=2.6Hz, IH), 7.75 (d, J=8.8Hz, 2H), 10.08 (s, lH), 10.33 (s, IH).
[00535] Example 5. Preparation of (E)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)- 2-methoxyphenyl)- 1 -fluorovinyl)phenyl)methanesulfonamide (compound IA-L1-1.5).
Figure imgf000112_0001
[00536] Reverse phase HPLC chromatographic separation of the 1/1 mixture of cis/trans isomeric material (53mg) from Example 4, Part A using a 40-100% gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid provided the title compound as a solid (16.5mg). 1H NMR (300 MHz, DMSOd6): δ ppm 1.33 (s, 9H), 2.60 (t, J=6.6Hz, 2H), 3.01 (s, 3H), 3.57 (t, J=6.6Hz, 2H) 3.79 (s, 3H), 6.46 (d, J=21.3Hz, IH), 6.87 (d, J=2.2Hz, IH), 7.14 (m, 3H), 7.36 (d, J=8.8Hz, 2H), 10.02 (s, IH), 10.24 (s, IH).
[00537] Example 6. Preparation of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-2- methoxystyryl)-2-fluorophenyl)methanesulfonamide (compound IA-L1-1.26)
Figure imgf000112_0002
[00538] Part A. Preparation of 4-(bromomethyl)-2-fluoro- 1 -nitrobenzene.
[00539] (3-Fluoro-4-nitrophenol)methanol (1.24g, 7.25mmol) was dissolved in dichloromethane (25mL) and treated with triphenylphosphine (2.281g, 8.70mmol) followed by N-bromosuccinimide (1.548g, 8.70mmol). The mixture was stirred at room temperature for 2h. Water (5OmL) and dichloromethane (4OmL) were added, and the organic layer was separated and dried. The solution was concentrated under vacuum and purified by column chromatography using silica gel eluting with a 5/1 mixture of hexanes/ethyl acetate to provide the title compound as a solid (1.21%, 75%). [00540] Part B. Preparation of diethyl 3-fluoro-4-nitrobenzylphosphonate. [00541] The product prepared in Part A (1.27g, 5.43mmol) was added to triethyl phosphite (8mL, 54.3mmol) and the solution heated to 1200C for lhr. After cooling, the excess triethyl phosphite was removed by heating under vacuum and the residue subjected to column chromatography on silica gel using 99/1 dichloromethane/methanol as eluent to obtain the crude title compound as an oil (800mg). [00542]Part C. Preparation of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-2- methoxystyryl)-2-fluorophenyl)methanesulfonamide.
[00543] The product described in Example 1, Part G (533mg, 1.751mmole) was treated with the product described in Part B (510mg, 1.751mmole) according to the procedures described in Example 1, Part H and Example 1, Part I to provide 80mg of the title compound. 1H NMR (300 MHz, DMSOd6): δ ppm 1.37 (s, 9H), 2.71 (t, J=6.5Hz, 2H), 3.05 (s, 3H), 3.76 (s, 3H), 3.79 (t, J=6.6Hz, 2H), 7.18 (m, 2H), 7.36 (d, J=16.5Hz, IH), 7.39 (m, IH), 7.44 (m, IH), 7.52 (d, J=2.6Hz, IH), 7.63 (m, IH), 9.65 (s, IH), 10.35 (s, IH).
[00544] Example 7. Preparation of N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-2- methoxyphenyl)cyclopropyl)phenyl)methanesulfonamide (compound IA-L8- 1.1).
Figure imgf000113_0001
[00545] The product obtained as described in Example 1, Part I (30mg, 0.064mmol) was dissolved in tetrahydrofuran (2mL) and treated with 0.95mL of a 0.67M ether solution of diazomethane (0.636mmol) followed by palladium acetate (0.7mg, 0.003 lmmol). The mixture was stirred for30 min at room temperature followed by removal of the solid by filtration and concentration of the filtrate. The filtrate was purified by column chromatography on silica gel using 98/2 dichloromethane/methanol as eluent to obtain the title compound as a solid (21.6mg, 70%). m.p. 265-2660C. 1H NMR (300 MHz, DMSO-d6): δ ppm 1.33 (s, 9H) 1.50 (m, 2H), 2.13 (m, IH), 2.27 (m, IH), 2.69 (t, J=6.6Hz, 2H), 2.94 (s, 3H), 3.63 (s, 3H), 3.74 (t, J=6.6Hz, 2H),6.84 (d, J=2.6Hz, IH), 7.04 (d, J=2.6Hz, IH), 7.14 (d, J=8.8Hz, 2H), 7.20 (d, J=8.8Hz, 2H), 9.60 (s, 1H),1O.29 (s, IH).
[00546] Example 8. Preparation of N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-2- methoxyphenethyl)phenyl)methanesulfonamide (compound IA-L5-2-1.1).
Figure imgf000114_0001
[00547] The product obtained as described in Example 1, Part I (415mg, 0.88mmol) was dissolved in methanol (3OmL) and treated with 50mg of 10% palladium on carbon. The slurry was stirred for 48h at room temperature under latm of hydrogen. The reaction mixture was filtered through celite and concentrated in vacuo to provide the title compound as a solid (230mg, 55%). m.p. 233-2340C. 1H NMR (300 MHz, DMSO-d6): δ ppm 1.34 (s, 9H), 2.68 (t, J=6.8Hz, 2H), 2.86 (s, 4H), 2.93 (s, 3H), 3.70 (m, 2H), 3.74 (s, 3H), 7.11 (m, 4H), 7.23 (m, 2H), 9.59 (s, IH), 10.29 (s, ).
[00548] Example 9. Preparation of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)- yl)styryl)phenyl)methanesulfonamide (compound IA-Ll-1.16)
Figure imgf000114_0002
[00549] Part A. Preparation of methyl 3-tert-butyl-5-(chlorocarbonyl)benzoate.
[00550] A mixture of 3-tert-butyl-5-(methoxycarbonyl)benzoic acid (9.18g, 38.9mmol, prepared by the method of Carter et. al., WO2005021500A1), thionyl chloride (75mL) and 1 drop of DMF in toluene
(20OmL) was heated at reflux for 2h, cooled and concentrated. The residue was azeotroped with toluene
(3 x 5OmL )and dried under high vacuum to give the title compound as an off-white waxy solid (9.9g, quantitative yield).
[00551] Part B. Preparation of methyl 3-(azidocarbonyl)-5-tert-butylbenzoate.
[00552] To the product of Part A (9.9g, 38.9mmol) in acetone (200ml) was added at a fast drip a solution of sodium azide (10.12g, 156mmol) dissolved in water (2OmL). The mixture was stirred for 2h and diluted with EtOAc. The organic layer was washed with H2O, saturated brine, dried (Na2SO4), filtered and concentrated to give the title compound as a white solid (9.9g, 97%).
[00553] Part C. Preparation of methyl 3-amino-5-tert-butylbenzoate.
[00554] The product from Part B (9.9g, 37.9mmol) in toluene (10OmL) was heated at reflux for Ih and concentrated to give the intermediate isocyanate which was dissolved in DME (6OmL) treated with 8%
HCl (15OmL) and stirred for 16h. The mixture was concentrated and the residue was dissolved in water, neutralized with solid sodium bicarbonate and extracted 3 x 10OmL with EtOAc. The organics were combined, washed with saturated NaCl, dried (Na2SO4), filtered and concentrated. The crude product was chromatographed on silica eluting with 2: 1 hexane/EtOAc to give the title compound as an oil (2.7g,
35%).
[00555] Part D. Preparation of methyl 3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-2- methoxybenzoate.
[00556] A mixture of the product of Part C (2.34g, 11.29mmol) and acrylic acid (2.32ml, 33.9mmol) in toluene (60ml) was heated at reflux under nitrogen for 24h, cooled and concentrated. The resulting residue was then treated with urea (2.03g, 33.9mmol) in acetic acid (35ml) and heated at 1200C for 24h, cooled and concentrated. The residue was azeotroped 3 x 5OmL with toluene and dissolved in 10OmL of
EtOAc. The organic layer was washed with dilute aqueous NaHCO3, H2O, saturated brine, dried
(Na2SO4), filtered and concentrated to give the title compound as a white solid (2.1g, 61%).
[00557]Part E. Preparation of 3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)benzoic acid.
[00558] A mixture of the product from Part D (1.8g, 5.91mmol) and IM NaOH (29.6ml, 29.6mmol) in
MeOH (15ml) and THF (15mL) was stirred for 24h and concentrated. The residue was treated with
5OmL of IM HCl and extracted into EtOAc. The EtOAc layer was washed with H2O, saturated brine, dried (Na2SO4), filtered and concentrated to give a white solid. This intermediate urea was combined with 2OmL of concentrated HCl and heated at 1000C for Ih, cooled and diluted with 75mL of ice water to give a white powder which was collected by filtration and dried to constant mass to give the title compound (1.6g, 93%).
[00559]Part F. Preparation of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl) styry l)phenyl)methanesulfonamide .
[00560] The product described in Part E was treated with thionyl chloride and lithium tri-tert- butoxyaluminum hydride according to procedures described in Example 1, Part G to produce 3-tert- butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)benzaldehyde. The aldehyde was treated with diethyl 4- nitrobenzylphosphonate according the procedures described in Example 1, Part H and Example 1, Part
I to provide the title compound (85mg). 1H NMR (300 MHz, DMSO-d6): δ ppm 1.32 (s, 9 H) 2.72 (t, J=6.43 Hz, 2 H) 3.01 (s, 3 H) 3.82 (t, J=6.62 Hz, 2 H) 7.18 - 7.25 (m, 5 H) 7.39 (s, 1 H) 7.46 (s, 1 H) 7.58 (d, J=8.46 Hz, 2 H) 9.84 (s, 1 H) 10.37 (s, 1 H).
[00561] Example 10. Preparation of (Z)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)- yl)-2-methoxyphenyl)- 1 -methoxyvinyl)phenyl)methanesulfonamide (compound IA-Ll-1.17).
Figure imgf000116_0001
[00562] Part A. Preparation of l-(dimethoxymethyl)-4-nitrobenzene.
[00563] A flask equipped with a magnetic stir bar and vigreux column was charged with 4-nitro- benzaldehyde (5.Og, 33.1mmol), pyridinium/?-toluenesulfonate (1.66g, 6.62mmol), trimethoxymethane
(3.51g, 33.1mmol) and methanol (10OmL). The mixture was heated at 5O0C for 12h and was concentrated in vacuo. The residue was redissolved in EtOAc and washed with aq. NaOH (IM), H2O and brine. The mixture was dried (Na2SO4), filtered and concentrated in vacuo to yield the title compound as a clear, light yellow oily product (6.36g , 97%).
[00564] Part B. Preparation of diethyl methoxy(4-nitrophenyl)methylphosphonate.
[00565] The product from Part A (3.Og, 15.2mmol) and triethyl phosphite (2.53g, 15.2mmol) were dissolved in dichloromethane (3OmL) under a nitrogen atmosphere, cooled to -200C and treated with drop wise addition of boron trifluoride etherate (2.27g, lδmmol). The mixture was allowed to slowly warm to room temperature overnight with stirring. Water was added and the resulting mixture was stirred 5min, separated and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo to a solid residue.
The residue was purified on silica gel (100% EtOAc to 3% CH3OH/EtOAc) to yield the title compound as a light yellow oily product (3.78 g , 82%).
[00566] Part C. Preparation of (Z)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)-2- methoxyphenyl)- 1 -methoxyvinyl)phenyl)methanesulfonamide.
[00567] The product obtained according to the procedure described in Example 1, Part G (400mg,
1.314mmole) was treated with the product obtained in Part B (399mg, 1.314mmole) according to the procedures described in Example 1, Part H and Example 1, Part I to provide the title compound (17mg
, 6%). 1H NMR (300 MHz, DMSO-d6): δ ppm 1.36 (s, 9 H) 2.71 (t, J=6.62 Hz, 2 H) 3.05 (s, 3 H) 3.58 (s,
3 H) 3.75 (s, 3 H) 3.76 - 3.81 (m, 2 H) 6.25 (s, 1 H) 7.11 (d, J=2.57 Hz, 1 H) 7.27 (d, J=8.46 Hz, 2 H) 7.60 (d, J=8.82 Hz, 2 H) 7.67 (d, J=2.57 Hz, 1 H) 9.96 (s, 1 H) 10.32 (s, 1 H).
[00568] Example 11. Preparation of (E)-I -(3-tert-butyl-4-methoxy-5-styrylphenyl)dihydro- pyrimidine- 2,4(1 H,3H)-dione (compound IA-L1-1.18).
Figure imgf000117_0001
[00569] The product obtained according to procedure described in Example 1, Part G (50mg, 0.164mmole) was treated with diethyl benzylphosphonate (0.034ml, 0.164mmole) according to the procedure described in Example 1, Part H to provide the title compound (13mg , 19%). 1H NMR (300 MHz, DMSOd6): δ ppm 1.37 (s, 9 H) 2.72 (t, J=6.62 Hz, 2 H) 3.76 (s, 3 H) 3.80 (t, J=6.80 Hz, 2 H) 7.16 - 7.18 (m, 1 H) 7.21 - 7.23 (m, 1 H) 7.29 - 7.33 (m, 2 H) 7.36 - 7.43 (m, 2 H) 7.54 (d, J=2.57 Hz, 1 H) 7.64 (d, J=7.35 Hz, 2 H) 10.35 (s, 1 H).
[00570] Example 12. Preparation of (E)-l-(3-tert-butyl-4-methoxy-5-(4-methoxystyryl)phenyl)dihydro pyrimidine-2,4(lH,3H)-dione (compound IA-Ll-1.14).
Figure imgf000117_0002
[00571] The product obtained according to procedure described in Example 1, Part G (50mg, 0.164mmole) was treated with diethyl 4-methoxybenzylphosphonate (0.028ml, 0.164mmole) according to the procedure described in Example 1, Part H to provide the title compound (4mg , 4%). 1H NMR (300 MHz, DMSOd6): δ ppm 1.37 (s, 9 H) 2.71 (t, J=6.62 Hz, 2 H) 3.70 - 3.81 (m, 8 H) 6.96 (d, J=8.82 Hz, 2 H) 7.13 (d, J=2.21 Hz, 1 H) 7.15 (d, J=2.57 Hz, 2 H) 7.50 (d, J=2.57 Hz, 1 H) 7.58 (d, J=8.46 Hz, 2 H) 10.34 (s, 1 H). [00572] Example 13A. Preparation of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)- yl)-2-methoxystyryl)phenyl)methanesulfonamide (compound IB-Ll-1.1).
Figure imgf000118_0001
[00573] Part A. Preparation of (E)-methyl 3-tert-butyl-2-methoxy-5-(3-(3-methoxyacryloyl)ureido) benzoate.
[00574] The product obtained as described in Example 1, Part C (2.Og, 8.43mmol) was dissolved in
3OmL of N,N-dimethylacetamide and cooled to -250C. A 0.5Molar solution of E-3-methoxyacryloyl isocyanate in benzene (21.9mL, 10.96mmol) was added drop wise and the resulting solution was stirred at ambient temperature for 4h, and then poured into water. The product was extracted into dichloromethane, washed with brine, dried over sodium sulfate, filtered and evaporated under vacuum to give the title compound.
[00575]Part B. Preparation of methyl 3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxybenzoate.
[00576] The product from Part A (3.1g, 8.51mmol) was dissolved in ethanol (6OmL). To this solution was added a mixture of concentrated sulfuric acid (6mL) and water (6OmL). The heterogeneous mixture was heated at 1000C for 3h. The ethanol was removed under vacuum, and then the aqueous solution was extracted with dichloromethane and evaporated to dryness. This residue was purified by column chromatography on silica gel, eluting with 1% methanol/dichloromethane to yield the title compound
(1.23g, 44%).
[00577]Part C. Preparation of 3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-methoxy benzoic acid.
[00578] The product from Part B (1.23g, 3.7mmol) was taken up in ethanol (5mL) and IM sodium hydroxide solution (1OmL) and stirred at ambient temperature for 18h. The solution was acidified with
IM HCl and the resulting solid was filtered and dried to give the title compound (0.945 g,80%).
[00579]Part D. Preparation of 3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-methoxy benzaldehyde.
[00580] The product from Part C (0.945g, 2.97mmol) was taken up in thionyl chloride (4.5mL) and the mixture was heated at 8O0C for 40min. After evaporation to dryness, the acid chloride was dissolved in dry THF (8mL) and cooled to -780C. A 1 M solution of lithium tri-tert-butoxyaluminum hydride in THF (3.OmL, 3.0mmol) was added drop wise. After 45min the cold reaction was quenched with IM HCl
(5mL), extracted into ethyl acetate, and purified by column chromatography on silica gel, eluting with dichloromethane followed by 1% methanol/dichloromethane to give the title compound (0.635 g , 71%).
[00581]Part E. Preparation of (E)-l-(3-tert-butyl-4-methoxy-5-(4-nitrostyryl)phenyl)pyrimidine-
2,4(lH,3H)-dione.
[00582] The product of Part D (0.634g, 2.1mmol) and diethyl 4-nitrobenzylphosphonate (0.573g,
2.1mmol) were combined in dichloromethane (25mL) at ambient temperature. Potassium tert- butoxide
(0.494g, 4.4mmol) was added portion wise and the resulting red/brown heterogeneous mixture was stirred for 1.5h. This mixture was quenched with IM HCl (15mL), poured into water and extracted into ethyl acetate, and the crude product was purified by column chromatography on silica gel, eluting with 1% methanol/dichloromethane to give the title compound (0.735g , 83%).
[00583]Part F. Preparation of (E)-l-(3-(4-aminosryryl)-5-tert-butyl-4-methoxyphenyl)pyrimidine-
2,4(lH,3H)-dione.
[00584] The product from Part E (0.735g, 1.74mmol), ammonium chloride (0.14g, 2.62mmol), and iron
(0.487g, 8.72mmol) were combined in a solution of ethanol (1OmL), water (5mL), and THF (1OmL) and heated at 750C for Ih. The mixture was filtered through diatomaceous earth, rinsing well with THF and concentrated to give the title compound.
[00585]Part G. Preparation of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide.
[00586] The product from Part F (0.683g, 1.75mmol) and pyridine (0.564mL, 6,98mmol) were combined in dichloromethane (15mL) at ambient temperature. Methane sulfonylchloride (0.163mL, 2.1mmol) was added drop wise and the solution was stirred for 18h. The mixture was poured into IM HCl and extracted into dichloromethane, concentrated, and purified by column chromatography on silica gel, eluting with
1%, 2% methanol/dichloromethane. Trituration from dichloromethane provided a solid that was filtered and dried to give the title compound as a colorless powder (0.465g , 57%). 1H NMR (300 MHz, DMSO-
D6) δ ppm 1.38 (s, 9 H), 3.01 (s, 3 H), 3.79 (s, 3 H) 5.65 (d, J=7.72 Hz, 1 H), 7.17 - 7.28 (m, 5 H), 7.58 -
7.70 (m, 3 H), 7.75 (d, J=7.72 Hz, 1 H), 9.86 (s, 1 H), 11.42 (s, 1 H).
[00587] Example 13B. Preparation of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)- yl)-2-methoxystyryl)phenyl)methanesulfonamide (compound IB-Ll-1.1).
Figure imgf000120_0001
[00588] Part A. Preparation of N-(4-ethynylphenyl)methanesulfonamide.
[00589] In a 2L, 3 -neck round-bottom flask equipped with an overhead stirrer was added 4-ethynylaniline (3Og, 256mmol) and pyridine (42.5ml, 525mmol) in dichloromethane (512ml) to give an orange solution. The mixture was cooled to 5°C and methanesulfonyl chloride (19.96ml, 256mmol) was added drop wise over 15min. The reaction solution was stirred at 5°C for 2h and washed with IM aqueous HCl (3x250mL). The dichloromethane layer was then washed sequentially with saturated aqueous NaHCO3, water, and saturated aqueous NaCl. The dichloromethane layer was dried over sodium sulfate and treated simultaneously with decolorizing charcoal for 30min, the solution then filtered through Celite and the filtrate was concentrated. The pink/orange solid was dissolved in a minimal amount of hot ethyl acetate (50-75mL) and slowly diluted with hexanes (500-60OmI) to give orange crystals that were collected by filtration and dried to provide the title compound (40.Og, 80%). [00590] Part B. Preparation of (E)-4-(methylsulfonamido)styrylboronic acid.
[00591] (Reference: Org. Prep. Proc. Int., 2004, 36, 573-579) To a flask was added borane-methyl sulfide complex (8.03mL, 85mmol) followed by tetrahydrofuran (16mL) and the mixture then cooled to O0C. (lR)-(+)-alpha-pinene (26.2mL, 169mmol) was then added drop wise (over lOmin) to the ice-cooled solution. The mixture was then stirred at O0C for Ih followed by stirring 2h at room temperature. The resulting thick white slurry was cooled to -400C in a dry ice/acetone bath, followed by the addition of the product from Part A (15.0g, 77mmol) dissolved in 6OmL of THF, drop wise over 30min. After the addition was complete, the mixture was stirred for an additional hour at -35°C, then Ih at room temperature. The light yellow solution was then cooled to 00C and acetaldehyde (61.4mL, 1088mmol) added, then the mixture refluxed at 500C for 18h. The solvent was then removed under vacuum to provide an orange syrup, to which water (115mL) was added and the heterogeneous mixture stirred for 3h at room temperature. The light yellow solid generated was collected and washed with water (25OmL) then dried in a vacuum oven overnight. The resultant material was then dissolved in boiling acetone (19OmL), which provided a homogenous yellow solution, followed by removal of the solution from heating and the addition of hexanes (365ml) over 5min time. A white solid formed in the solution and the mixture was stirred until the solution cooled to room temperature, then the white solid was collected and dried in a vacuum oven for lhr to provide the title compound (12. Ig, 85%).
[00592] Part C. Preparation of 2-tert-butyl-4-nitrophenol.
[00593] To a vigorously stirred solution of 2-tert-butylphenol (1Og, 66.6mmol) in heptane (67ml) was added at a fast drip a solution of 70% nitric acid (4.25ml, 66.6mmol) diluted with water (4.25ml). The resulting dark red/brown mixture was stirred vigorously for 2h. The suspended solid was collected by filtration washed with hexane (30OmL), water (20OmL) and once again with hexane (20OmL) to give a cocoa colored powder that was dried to constant mass (4.65g, 35.6%).
[00594] Part D. Preparation of 2-bromo-6-tert-butyl-4-nitrophenol.
[00595] A solution of the product from Part C (l.Og, 5.12mmol) in glacial acetic acid (10.25mL) was treated portion wise with pyridine hydrobromide perbromide (1.8Og, 5.63mmol) followed by stirring at room temperature for 2h. Additional pyridinium hydrobromide perbromide (3.6g) was added in two portions and after another 3h of stirring, the reaction was complete. The mixture was poured into ice water, and the mixture treated with a small amount of sodium sulfite. The resulting solid was filtered and dried under vacuum to give the title compound as a brown solid (1.4Og, 100 %).
[00596] Part E. Preparation of l-bromo-3-tert-butyl-2-methoxy-5 -nitrobenzene.
[00597] A solution of the product from Part D (1.4Og, 5.1 lmmol) in 10:1 t-butylmethylether-methanol
(25.5mL) was treated with 2.0M trimethylsilyldiazomethane in ether (5.ImL, 10.21mmol), followed by stirring at room temperature for 18h. The mixture was concentrated under vacuum to afford a yellow oil, which was purified by silica gel column chromatography eluting with EtOAc/hexanes to give the title compound as a yellow oil (1.36g, 92 %).
[00598] Part F. Preparation of tert-butyl 3-bromo-5-tert-butyl-4-methoxyphenylcarbamate.
[00599] A solution of the product from Part E (960mg, 3.33mmol) in methanol (17mL) was treated with
5 % platinum on sulfided carbon (lOOmg), followed by hydrogenation under balloon pressure for 3h, and then filtered through celite and concentrated under vacuum to afford the 3-bromo-5-tert-butyl-4- methoxyaniline as a yellow oil (860mg, 3.33mmol, 100%). A solution of this material in THF (17mL) was treated with di-tert-butyl dicarbonate (800mg, 3.66mmol) followed by warming at reflux for 2h.
Concentration under vacuum afforded a beige solid, which was purified by silica gel column chromatography eluting with EtOAc/hexanes. Solid was triturated with hexanes, collected by filtration, and dried under vacuum to give the title compound as a nearly white solid (890mg, 75 %).
[00600] Part G. Preparation of (E)-N-(3-bromo-5-tert-butyl-4-methoxyphenylcarbamoyl)-3-methoxy acrylamide.
[00601] The product from Part F (2.Og, 5.58mmol) was dissolved in dichloromethane (1OmL) and trifluoroacetic acid (5mL) added. The solution was stirred at room temperature for Ih followed by concentration under vacuum and the addition of 10% aqueous sodium bicarbonate (5OmL), followed by extraction with ethyl acetate (3 x 5OmL). The combined organic extracts were dried and concentrated to provide a residue that was dissolved in 1OmL of N,N-dimethylacetamide and cooled to -250C. A 0.5 molar solution of E-3-methoxyacryloyl isocyanate in benzene (20.3mL, 1 l.lόmmol) was added drop wise and the resulting solution was stirred at ambient temperature for 4h, and then poured into water. The product was extracted into dichloromethane, washed with brine, dried over sodium sulfate, filtered and evaporated under vacuum to give the title compound.
[00602] Part H. Preparation of l-(3-bromo-5-tert-butyl-4-methoxyphenyl)pyrimidine-2,4(lH,3H)-dione. [00603] The product from Part G (2.15g, 5.58mmol) was dissolved in ethanol (1OmL). To this solution was added a mixture of concentrated sulfuric acid (ImL) and water (1OmL). The heterogeneous mixture was heated at 1000C for 2h. The ethanol was removed under vacuum, and then the aqueous solution was extracted with dichloromethane and evaporated to dryness. This residue was purified by column chromatography on silica gel, eluting with 1% methanol/dichloromethane to yield the title compound (1.35g, 69%).
[00604]Part I. Preparation of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide.
[00605] The product from Part H (8.0g, 22.65mmol), the product from Part B (5.9Og, 24.46mmol), 1,1'- bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.738g, 1.132mmol), and potassium phosphate (9.62g, 45.3mmol) were dissolved in a mixture of tetrahydrofuran (128mL) and water (32mL). Nitrogen gas was bubbled through the resultant mixture for 10 min followed by heating the solution at 500C for 5h in darkness. The reaction was allowed to cool to room temperature followed by the addition of saturated aqueous ammonium chloride (5OmL), water (20OmL), and the solution extracted with dichloromethane (60OmL). To the organic extract was added magnesium sulfate, and 3-mercaptopropyl-functionalized silica gel (20 g) and the resultant solution stirred in darkness for 18h. The solids were then removed by filtration and the filtrate concentrated under vacuum and subjected to silica gel column chromatography using a 99/1 to 99/2 dichloromethane/methanol gradient to provide the title compound (7.4 g, 70%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.38 (s, 9 H), 3.01 (s, 3 H), 3.79 (s, 3 H) 5.65 (d, J=7.72 Hz, 1 H), 7.17 - 7.28 (m, 5 H), 7.58 - 7.70 (m, 3 H), 7.75 (d, J=7.72 Hz, 1 H), 9.86 (s, 1 H), 11.42 (s, 1 H). [00606] Example 14. Preparation of (E)-N-(4-(3-tert-butyl-5-(5-fluoro-2,4-dioxo-3,4-dihydro- pyrimidin- 1 (2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide (compound IB-Ll-1.2).
Figure imgf000123_0001
[00607] Part A. Preparation of methyl 3-tert-butyl-5-(5-fluoro-6-methoxy-2,4-dioxotetrahydro- pyrimidin- 1 (2H)-yl)-2-methoxybenzoate.
[00608] The fluorination procedure was performed as described in LaI, GS, et al. J. Org Chem., 60:7340- 7342 (1995). The product from Example 13A, Part B (0.42g, 1.26mmol) and Selectfluor™ (0.672g, 1.9mmol) were combined in a mixture of acetonitrile (8mL) and methanol (ImL) and heated at 9O0C under N2 for 5h. The solution was diluted with water, extracted into ethyl acetate, washed with sodium bicarbonate solution, concentrated and purified by column chromatography on silica gel to give the title compound (0.138g, 29%).
[00609]Part B. Preparation of methyl 3-tert-butyl-5-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)- y l)-2-methoxybenzoate .
[00610] The product from Part A (0.134g, 0.35mmol) and triethylamine (ImL) were combined in methanol (4mL) and stirred at ambient temperature for 18h. The solution was quenched with IM HCl, extracted into dichloromethane and concentrated to give the title compound (0.113g , 92%). [00611]Part C. Preparation of 3-tert-butyl-5-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxybenzoic acid.
[00612]The product from Part B (0.113g, 0.32mmol) was treated as described in Example 13A, Part C to give the title compound (0.088g, 81%).
[00613]Part D. Preparation of 3-tert-butyl-5-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxybenzaldehyde.
[00614] The product from Part C (0.088g, 0.26mmol) was treated as described in Example 13A, Part D to give the title compound (0.075g, 90%).
[00615] Part E. Preparation of (E)-l-(3-tert-butyl-4-methoxy-5-(4-nitrostyryl)phenyl)-5- fluoropyrimidine-2,4( 1 H,3 H)-dione . [00616] The product of Part D (0.075g, 0.23mmol) was treated as described in Example 13A, Part E to give 0.077g (75%).
[00617]Part F. Preparation of (E)-l-(3-(4-aminostyryl)-5-tert-butyl-4-methoxyphenyl)-5-fluoro pyrimidine-2,4(lH,3H)-dione.
[00618] The product of Part E (0.077g, O.lδmmol) was treated as described in Example 13A, Part F to give the title compound (0.07 Ig, 94%).
[00619]Part G. Preparation of (E)-N-(4-(3-tert-butyl-5-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin- l(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.
[00620]The product of Part F (0.071g, 0.17mmol) was treated as described in Example 13A, Part G to give the title compound (0.048g, 57%). 1H NMR (300 MHz5 DMSO-D6): δ ppm 1.38 (s, 9 H), 3.01 (s, 3
H), 3.79 (s, 3 H) 7.19 - 7.27 (m, 5 H), 7.62 (d, J=8.82 Hz, 2 H), 7.66 (d, J=2.57 Hz, 1 H), 8.25 (d, J=6.99
Hz, IH).
[00621] Example 15. Preparation of (E)-N-(4-(3-bromo-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide (compound IB-L1-1.52).
Figure imgf000124_0001
[00622] Part A. Preparation of 2-bromo-4,6-diiodophenol.
[00623] A IL round-bottom flask was charged with 2-bromophenol (8.65g, 50mmol) and methanol (100ml) to give a colorless solution. Sodium hydroxide (2.4Og, 60.0mmol) was added and stirred until the hydroxide pellets had dissolved. The solution was cooled in an ice water bath and sodium iodide (5.6g, 37.4mmol) was added followed by drop-wise addition of sodium hypochlorite (17mL, 27.5mmol) to give a transparent brown/red solution and gradual precipitation of a thick, white solid. The addition of sodium iodide and bleach was repeated 3 times to give an orange mixture that was stirred for 2h, treated with a solution of sodium thiosulfate in water (2Og in 10OmL), stirred for 15min and treated drop-wise with concentrated HCl to a constant pH of 1. The mixture was stirred for 15min and filtered to collect a white solid that was washed repeatedly with water and dried to constant mass (14.7g, 69%). [00624] Part B . Preparation of 1 -bromo-3 , 5 -diiodo-2-methoxybenzene .
[00625] A 50OmL round-bottom flask was charged with the product from Part A (14.7g, 34.6mmol), iodomethane (2.70ml, 43.3mmol), and sodium hydroxide (2.101ml, 39.8mmol) in acetone (96ml) to give a tan solution. The mixture was stirred for 24h and concentrated. The residue was dissolved in ethyl acetate, washed with water and saturated sodium chloride, dried over sodium sulfate, filtered and concentrated to give a white solid. The solid was recrystallized from hot hexane to give a white solid that was collected by filtration (12.3g, 81%).
[00626] Part C. Preparation of l-(3-bromo-5-iodo-4-methoxyphenyl)pyrimidine-2,4(lH,3H)-dione. [00627] A 25OmL round-bottom flask was charged with the product from Part B (8.09g, 18.44mmol), pyrimidine-2,4(lH,3H)-dione (2.273g, 20.28mmol), N-(2-cyanophenyl)picolinamide (0.823g, 3.69mmol), copper (I) iodide (0.351g, 1.844mmol) and potassium phosphate (8.22g, 38.7mmol) in DMSO (70ml). The mixture was sealed, sparged with nitrogen for 15min and heated at 600C for 16h. The mixture was partitioned with ethyl acetate and water. The organic layer was washed with IM HCl, water, brine, dried with sodium sulfate, and filtered. The filtrate was treated with 3-mercaptopropyl functionalized silica gel (Aldrich catalog #538086), filtered through celite and evaporated to give an off-white solid (3.92g, 50%). [00628]Part D. Preparation of (E)-N-(4-(3-bromo-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide.
[00629] To a 100ml round-bottom flask was added the product from Part C (846mg, 2.0mmol), the product from Example 13B, Part B (482mg, 2.000mmol), potassium phosphate (892mg, 4.20mmol), l,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (PA-Ph) (CAS 97739-46-3) (17.54mg, 0.060mmol) and tris(dibenzylideneacetone)dipalladium(0) (18.3 lmg, 0.020mmol) in THF (12.0ml) and water (4.0ml). The flask was sealed and the mixture was sparged with nitrogen for 5min and stirred at ambient temperature for 72h. The mixture was partitioned with ethyl acetate and IM HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried with sodium sulfate and filtered. The filtrate was treated with 3-mercaptopropyl functionalized silica gel, filtered and evaporated. The residue was triturated with a minimal amount of methanol/ CH2Cl2 to give the title compound as a white solid (595mg, 60%). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.03 (s, 3 H) 3.82 (s, 3 H) 5.69 (dd, J=7.72, 1.50 Hz, 1 H) 7.24 (d, J=8.46 Hz, 2 H) 7.35 (m, 2 H) 7.61 (d, J=8.46 Hz, 2 H) 7.69 (d, J=2.21 Hz, 1 H) 7.78 (d, J=8.09 Hz, 1 H) 7.87 (d, J=2.21 Hz, 1 H) 9.90 (s, 1 H) 11.50 (s, 1 H). MS (ESI-) m/z 490,492 (M-H)+.
[00630] Example 16. Preparation of (E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-methoxy- 3-(thiophen-2-yl)styryl)phenyl)methanesulfonamide (compound IB-L1-1.48).
Figure imgf000126_0001
[00631] To a 5ml microwave tube was added the product from Example 15, Part D (40mg, 0.081mmol), thiophen-2-ylboronic acid (10.40mg, O.Oδlmmol), l,l'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (2.65mg, 4.06μmol) and potassium phosphate (34.5mg, 0.162mmol) in THF (3.0ml) and water (1.0ml). The vessel was sealed and the mixture was sparged by nitrogen for 5min and heated at 500C for 3h. The mixture was partitioned with ethyl acetate and IM HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried with sodium sulfate and filtered. The filtrate was treated with 3-mercaptopropyl functionalized silica gel, filtered through celite and evaporated. The residue was purified by reverse phase chromatography to give the title compound as a white solid (20mg, 50%). 1H NMR (300 MHz, DMSOd6) δ ppm 3.03 (s, 3 H) 3.70 (s, 3 H) 5.70 (dd, J=7.72, 2.21 Hz, 1 H) 7.18 (dd, J=5.43, 4.05 Hz, 1 H) 7.25 (d, J=8.82 Hz, 2 H) 7.35 (s, 2 H) 7.63 (d, J=8.82 Hz, 2 H) 7.68 (m, 2 H) 7.77 (m, 2 H) 7.83 (d, J=7.72 Hz, 1 H) 9.89 (s, 1 H) 11.49 (d, J=2.21 Hz, 1 H). MS (ESI+) m/z 496 (M+H)+.
[00632] Example 17. Preparation of (E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-3-(furan-2- yl)-2-methoxystyryl)phenyl)methanesulfonamide (compound IB-L1-1.46).
Figure imgf000126_0002
[00633] The title compound was prepared according to the procedure of Example 16 substituting furan-2- ylboronic acid for thiophen-2-ylboronic acid to give a white solid (22mg, 56%). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.03 (s, 3 H) 3.76 (s, 3 H) 5.69 (d, J=7.72 Hz, 1 H) 6.69 (dd, J=3.31, 1.84 Hz, 1 H) 7.08 (d, J=2.57 Hz, 1 H) 7.25 (d, J=8.46 Hz, 2 H) 7.36 (m, 2 H) 7.63 (d, J=8.82 Hz, 2 H) 7.67 (d, J=2.57 Hz, 1 H) 7.77 (d, J=2.57 Hz, 1 H) 7.82 (m, J=7.72 Hz, 2 H) 9.88 (s, 1 H) 11.48 (s, 1 H). MS (ESI+) m/z 497 (M+NH4)+.
[00634] Example 18. Preparation of (E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin- 1 (2H)-yl)-2-methoxy- 3-(pyridin-4-yl)styryl)phenyl)methanesulfonamide (compound IB-L1-1.55).
Figure imgf000127_0001
[00635] The title compound was prepared according to the procedure of Example 16 substituting 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine for thiophen-2-ylboronic acid to give a white solid (15mg, 38%). 1H NMR (300 MHz, DMSOd6) δ ppm 3.03 (s, 3 H) 3.49 (s, 3 H) 5.72 (dd, J=7.72, 2.21 Hz, 1 H) 7.25 (d, J=8.46 Hz, 2 H) 7.38 (d, J=4.41 Hz, 2 H) 7.51 (d, J=2.57 Hz, 1 H) 7.63 (d, J=8.82 Hz, 2 H) 7.80 (d, J=5.88 Hz, 2 H) 7.85 (d, J=7.72 Hz, 1 H) 7.97 (d, J=2.57 Hz, 1 H) 8.77 (d, J=6.25 Hz, 2 H) 9.90 (s, 1 H) 11.51 (d, J=2.21 Hz, 1 H). MS (ESI+) m/z 491 (M+H)+.
[00636] Example 19. Preparation of (E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-methoxy- 3-(pyridin-3- yl)styryl)phenyl)methanesulfonamide (compound IB-L1-1.53).
Figure imgf000127_0002
[00637] The title compound was prepared according to the procedure of Example 16 substituting 3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine for thiophen-2-ylboronic acid to give a white solid (19mg, 48%). 1H NMR (300 MHz, DMSOd6) δ ppm 3.02 (s, 3 H) 3.45 (s, 3 H) 5.71 (dd, J=8.09, 2.21 Hz, 1 H) 7.24 (d, J=8.46 Hz, 2 H) 7.37 (d, J=2.94 Hz, 2 H) 7.47 (d, J=2.57 Hz, 1 H) 7.63 (m, 3 H) 7.85 (d, J=7.72 Hz, 1 H) 7.93 (d, J=2.57 Hz, 1 H) 8.15 (m, 1 H) 8.68 (dd, J=4.80 Hz, 1.47 Hz, 1 H) 8.86 (d, J=1.84 Hz, 1 H) 9.89 (s, 1 H) 11.50 (d, J=2.21 Hz, 1 H). MS (ESI+) m/z 491 (M+H)+. [00638] Example 20. Preparation of (E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin- 1 (2H)-yl)-2-methoxy- 3 -(thiophen-3 -yl)styryl)phenyl)methanesulfonamide (compound IB-Ll-1.47).
Figure imgf000128_0001
[00639] The title compound was prepared according to the procedure of Example 16 substituting thiophen-3 -ylboronic acid for thiophen-2-ylboronic acid to give a white solid (19mg, 38%). 1H NMR (300 MHz, DMSO-dδ) δ ppm 3.02 (s, 3 H) 3.55 (s, 3 H) 5.69 (d, J=8.09 Hz, 1 H) 7.24 (d, J=8.46 Hz, 2 H) 7.36 (s, 2 H) 7.55 (m, 2 H) 7.61 (d, J=8.46 Hz, 2 H) 7.67 (dd, J=5.15, 2.94 Hz, 1 H) 7.78 (d, J=2.57 Hz, 1 H) 7.83 (d, J=7.72 Hz, 1 H) 7.93 (dd, J=2.57, 0.96 Hz, 1 H) 9.88 (s, 1 H) 11.48 (s, 1 H). MS (ESI-) m/z 494 (M-H)+.
[00640] Example 21. Preparation of (E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-3-(furan-3- yl)-2-methoxystyryl)phenyl)methanesulfonamide (compound IB-L1-1.50).
Figure imgf000128_0002
[00641] The title compound was prepared according to the procedure of Example 16 substituting furan-3- ylboronic acid acid for thiophen-2-ylboronic acid to give a white solid (14mg, 29%). 1H NMR (300 MHz, DMSOd6) δ ppm 3.02 (s, 3 H) 3.69 (s, 3 H) 5.69 (d, J=8.09 Hz, 1 H) 7.05 (dd, J=2.57, 0.90 Hz, 1 H) 7.24 (d, J=8.82 Hz, 2 H) 7.34 (s, 2 H) 7.61 (m, 3 H) 7.74 (d, J=2.57 Hz, 1 H) 7.80 (m, 2 H) 8.25 (s, 1 H) 9.88 (s, 1 H) 11.49 (s, 1 H). MS (ESI-) m/z 478 (M-H)+. [00642] Example 22. Preparation of (E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-3-(l- hydroxy-2-methylpropan-2-yl)-2-methoxystyryl)phenyl)methanesulfonamide (compound IB-L1-1.45).
Figure imgf000129_0001
[00643] Part A. Preparation of 2-(2-hydroxy-3,5-diiodophenyl)acetic acid.
[00644] To a 25OmL round-bottom flask was added 2-(2-hydroxyphenyl)acetic acid (Aldrich, 3.04g, 20mmol) in acetonitrile (50ml) to give a colorless solution. N-iodosuccimide (9.0Og, 40.0mmol) was added portionwise over 15min to give a red/brown transparent solution that was stirred for 16h. The mixture was concentrated and the resulting solid was triturated in 75mL of water and filtered to collect an orange solid that was dried under vacuum. The crude solid was recrystallized from toluene to give a light orange powder (6.Og, 74%).
[00645] Part B. Preparation of methyl 2-(3,5-diiodo-2-methoxyphenyl)acetate.
[00646] To a 25OmL round-bottom flask was added the product from Part A (6g, 14.85mmol), potassium carbonate (6.16g, 44.6mmol), and dimethyl sulfate (4.12g, 32.7mmol) in acetone (49.5ml) to give a brown suspension. The suspension was heated at reflux for 16h, cooled, concentrated and the residue was partitioned between EtOAc and water. The EtOAc layer was washed with brine, dried (Na2SO4) and concentrated to a brown oil that was chromatographed on a 4Og silica cartridge eluting with 3 : 1 hexane/EtOAc to give a yellow oil (6.Og, 94%).
[00647] Part C. Preparation of methyl 2-(3,5-diiodo-2-methoxyphenyl)-2-methylpropanoate. [00648] To a 10OmL round-bottom flask under nitrogen was added the product from Part B (1.728g, 4mmol) in anhydrous THF (20ml) and HMPA (2ml) to give a colorless solution. Methyl iodide (1.251ml, 20.00mmol) was added and the solution was cooled to -400C. Potassium t-butoxide( 12.00ml, 12.00mmol) was added drop-wise and the mixture was stirred at -40 to -200C for 30min and quenched with IM HCl to a pH of 1. The mixture was extracted 3 X 40ml with EtOAc. The extracts were combined, washed with brine, dried (Na2SO4) and concentrated. The crude product was flash chromatographed on a 4Og ISCO silica cartridge eluting with 9:1 hexane/EtOAc to give the bis- methylated product as a yellow oil (1.63g, 89%).
[00649] Part D. Preparation of 2-(3,5-diiodo-2-methoxyphenyl)-2-methylpropanoic acid. [00650] A suspension of the product from Part C (2.63g, 5.72mmol) in MeOH (40ml) and THF (40ml) was treated with 4.0M sodium hydroxide (28ml, 112mmol) and heated at 80°C for 48h. The organic solvent was evaporated and the remaining aqueous solution was acidified with IM HCl producing a solid that was collected by filtration, washed with water and dried to give the desired carboxylic acid (2.46g,
96%).
[00651]Part E. Preparation of 2-(3,5-diiodo-2-methoxyphenyl)-2-methylpropan-l-ol.
[00652] A solution of the product from Part D (1.0Og, 2.242mmol) in THF (40ml) was treated drop-wise with borane THF complex 1.0M (20ml, 20mmol) and then heated at 50°C for 24h. The mixture was treated with methanol (2OmL), refluxed for 30min and concentrated. The resulting residue was washed with water, brine, dried with sodium sulfate, filtered and evaporated. The residue was chromatographed on silica gel eluting with hexane/EtOAc (4:1) to give the desired product (810mg, 84%).
[00653] Part F. Preparation of tert-butyl(2-(3,5-diiodo-2-methoxyphenyl)-2-methylpropoxy)- dimethylsilane.
[00654] A solution of the product from Part E (432mg, l.OOOmmol) in DMF (5ml) was treated with tert- butyldimethylchlorosilane (301mg, 2.000mmol), and imidazole (204mg, 3.00mmol) and stirred for 2h.
The mixture was partitioned between IM HCl and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, brine, dried with sodium sulfate, filtered and evaporated. The residue was chromatographed on silica gel eluting with hexane/EtOAc (9: 1) to give the desired product (522mg,
96%).
[00655] Part G. Preparation of l-(3-(l-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-5-iodo-4- methoxyphenyl)pyrimidine-2,4( 1 H,3H)-dione.
[00656] To a 5OmL round-bottom flask was added the product from Part F (520mg, 0.952mmol), pyrimidine-2,4(lH,3H)-dione (117mg, 1.047mmol), N-(2-cyanophenyl)picolinamide (42.5mg,
0.190mmol), copper(I) iodide (18.13mg, 0.095mmol) and potassium phosphate (424mg, 1.999mmol) in
DMSO (5ml). The vessel was sealed, sparged with nitrogen and then heated at 600C for 24h. The mixture was partitioned between IM HCl and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, brine, dried with sodium sulfate, and filtered. The filtrate was treated with
3-mercaptopropyl functionalized silica gel, filtered and evaporated. The residue was chromatographed on silica gel eluting with hexane/EtOAc (3:2) to give the product as a solid (285mg, 65%).
[00657]Part H. Preparation of (E)-N-(4-(3-(l-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-5-(2,4- dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.
[00658] To a 5ml microwave tube was added the product from Part G (53mg, 0. lmmol), the product from Example 13B, Part B (24mg, 0. lmmol), potassium phosphate (44.0mg, 0.2mmol), PA-Ph (CAS
97739-46-3) (0.87mg, 3.0μmol) and tris(dibenzylideneacetone)palladium(0) (0.9mg, lμmol) in THF
(3.0ml) and water (1.0ml). The vessel was sealed and the mixture was sparged with nitrogen for 5min and then heated at 5O0C for 2h. The mixture was partitioned between IM HCl and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, brine, dried with sodium sulfate and filtered. The filtrate was treated with 3-mercaptopropyl functionalized silica gel, filtered and evaporated.
The residue was chromatographed on silica gel eluting with hexane/EtOAc (1:1) to give a solid (50mg, 83
%).
[00659] Part I. Preparation of (E)-N-(4-(5-(2,4-dioxo-3 ,4-dihydropyrimidin- 1 (2H)-yl)-3 -( 1 -hydroxy-2- methylpropan-2-yl)-2-methoxystyryl)phenyl)methanesulfonamide.
[00660] A solution of the product from Part H (120mg, 0.20mmol) in THF (5.0ml) was treated with 1 M
TBAF (0.800ml, 0.800mmol) in THF and stirred for 16h. The mixture was partitioned with water and ethyl acetate. The organic layer was washed (3 X brine), dried with sodium sulfate, filtered and evaporated. The residue was chromatographed on silica gel eluting with 4% methanol in CH2Cl2 to give a solid (85mg, 88 %). 1H NMR (300 MHz, DMSOd6) δ ppm 1.30 (s, 6 H) 3.01 (s, 3 H) 3.62 (d, J=5.52 Hz,
2 H) 3.77 (s, 3 H) 4.67 (t, J=5.33 Hz, 1 H) 5.66 (d, J=8.09 Hz, 1 H) 7.21 (m, 5 H) 7.62 (m, 3 H) 7.72 (d,
J=8.09 Hz, 1 H) 9.85 (s, 1 H) 11.42 (s, 1 H). MS (ESI+) m/z 503 (M+NH4)+.
[00661] Example 23. Preparation of (E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-3-iodo-2- methoxystyryl)phenyl)methanesulfonamide (compound IB-L1-1.51).
Figure imgf000131_0001
[00662] Part A. Preparation of l,3,5-triiodo-2-methoxybenzene.
[00663] In a 25OmL pressure vessel was added 2,4,6-triiodophenol (5g, 10.60mmol) in MTBE (60ml) to give a yellow solution. The solution was cooled in an ice bath and 2.0M trimethylsilyldiazomethane
(7.95ml, 15.90mmol) was added at a fast drip followed by dropwise addition of methanol (6mL) resulting in calm bubbling. The vessel was sealed and stirred at room temperature for 4h. The reaction solution was partitioned between EtOAc and water and the organic layer was washed with IM HCl, saturated
NaHCO3, and saturated NaCl. The EtOAc was dried (MgSO4), filtered and concentrated to give a tan solid that was used without purification (4.8g, 94 %).
[00664]Part B. Preparation of l-(3,5-diiodo-4-methoxyphenyl)pyrimidine-2,4(lH,3H)-dione.
[00665] To a 10OmL round-bottom flask under N2 was added the product from Part A (3.5g, 7.2mmol), lH-pyrimidine-2,4-dione (0.97g, 8.64mmol), and potassium phosphate tribasic (3.2g, 15.0mmol) in DMSO (50ml) to give a colorless suspension. N-(2-cyanophenyl)picolinamide (320mg, 1.44mmol) was added and the mix was sparged with N2 for 5min. Copper(I) iodide (137mg, 0.72mmol) was added and the mix was sparged once again for lOmin, placed under N2 and heated at 600C for 18h. The mixture was cooled and partitioned between EtOAc and water adjusting the pH to 1 with HCl. The aqueous layer was extracted 2X with EtOAc. The organics were combined, washed with water, saturated NaHCO3, and saturated NaCl, dried (Na2SO4), treated with 3-mercaptopropyl functionalized silica, filtered and concentrated. The resulting solid was triturated in 2: 1 hexane/EtOAc to give an off white powder (2.2g, 62 %).
[00666] Part C. Preparation of (E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-3-iodo-2- methoxystyryl)phenyl)methanesulfonamide.
[00667] In a 5ml microwave tube was mixed the product from Part B (141mg, 0.30mmol), the product from Example 13B, Part B (72.3mg, 0.300mmol), l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride CH2Cl2 complex (12.25mg, 0.015mmol) and potassium phosphate (70.0mg, 0.330mmol) in THF (3.0ml) and water (1.0ml). The mixture was sparged with nitrogen for 5min and heated at 500C for 2h. The mixture was partitioned with ethyl acetate and IM HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried with sodium sulfate and filtered. The filtrate was treated with 3-mercaptopropyl functionalized silica gel, filtered and evaporated. The residue was chromatographed on silica eluting with 5% methanol in CH2Cl2 to give a solid (47mg, 29%). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.02 (s, 3 H) 3.77 (s, 3 H) 5.67 (d, J=7.72 Hz, 1 H) 7.28 (m, 4 H) 7.60 (d, J=8.82 Hz, 2 H) 7.76 (d, J=8.09 Hz, 1 H) 7.81 (d, J=2.57 Hz, 1 H) 7.86 (d, J=2.21 Hz, 1 H) 9.90 (s, 1 H) 11.48 (s, 1 H). MS (ESI-) m/z 538 (M-H)+.
[00668] Example 24. Preparation of (E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-methoxy- 3-(methylsulfonyl)styryl)phenyl)methanesulfonamide (compound IB-L1-1.49).
Figure imgf000132_0001
[00669] Part A. Preparation of 4-nitrobenzene-2-diazo- 1 -oxide.
[0067O] To a 25OmL round-bottom flask was added 2-amino-4-nitrophenol (6.165g, 40.0mmol) in 48% tetrafluoroboric acid (15ml). Sodium nitrite (2.76g, 40.0mmol) in water (6ml) was added dropwise at 00C and the mixture was stirred at room temperature for 30min. The solid was collected by filtration, washed with tetrafluoroboric acid and water. The solid was suspended in acetone (50ml), filtered and dried to give a solid (3.3 Ig, 50%).
[00671] Part B. Preparation of 2-(methylthio)-4-nitrophenol.
[00672]To a IL beaker was added the product from Part A (2.7Og, 16.35mmol) in ice water (25Og) to give a brown suspension. Copper (0.52Og, 8.18mmol) was added, followed by addition of sodium thiomethoxide (2.292g, 32.7mmol) in water (50ml) slowly. The mixture was stirred at room temperature for 24h. The mixture was filtered and the filtrate was acidified with IM HCl producing a solid that was collected by filtration and dried (2.53g, 84%).
[00673] Part C. Preparation of 2-(methylsulfonyl)-4-nitrophenol.
[00674] To a 25OmL round-bottom flask was added the product from Part B (LI l Ig, ό.OOmmol) in
MeOH (20ml) to give a brown suspension. Oxone (7.746g, 12.60mmol) in water (20ml) was added slowly at O0C. The mixture was warmed to room temperature, stirred for Ih and partitioned with ethyl acetate and IM HCl. The organic layer was washed with brine, dried with sodium sulfate, filtered and evaporated. The residue was chromatographed on silica gel eluting with 1% to 5% methanol in CH2CI2 to give a solid (0.472g, 36%).
[00675] Part D. Preparation of 2-iodo-6-(methylsulfonyl)-4-nitrophenol.
[00676]To a 5OmL round-bottom flask was added the product from Part C (470mg, 2.164mmol) in
MeOH (10ml) and water (2.5ml). Iodine monochloride (0.130ml, 2.60mmol) in CH2Cl2 (2.OmL) was added drop-wise and the mixture was stirred at room temperature, poured into water (20OmL) and stirred for lOmin. The resulting solid was collected by filtration and dried (636mg, 86%).
[00677] Part E. Preparation of l-iodo-2-methoxy-3-(methylsulfonyl)-5-nitrobenzene.
[00678] To a 5OmL pressure vessel was added the product from Part D (630mg, 1.836mmol) in MTBE
(6ml) to give a yellow solution. The mixture was cooled in an ice bath and 2M trimethylsilyl- diazomethane (1.377ml, 2.75mmol) was added at a fast drip followed by drop-wise addition of MeOH
(0.4ml) resulting in calm bubbling. The vessel was sealed and stirred at room temperature for Ih. The mixture was partitioned with ethyl acetate and IM HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried with sodium sulfate, filtered and evaporated to give an off-white solid
(655mg, 100%).
[00679] Part F. Preparation of 3-iodo-4-methoxy-5-(methylsulfonyl)aniline.
[00680] To a 25OmL round-bottom flask was added the product from Part E (0.65Og, 1.820mmol), ammonium chloride (0.146g, 2.73mmol), and iron (0.508g, 9.10mmol) in THF/MeOH/water (50ml,
2/2/1). The mixture was refluxed for 2h, cooled and filtered. The filtrate was evaporated and the residue was partitioned with ethyl acetate and water. The organic layer was washed with brine, dried with sodium sulfate, filtered and evaporated to give a solid (590mg, 99%). [00681] Part G. Preparation of (E)-N-(3-iodo-4-methoxy-5-(methylsulfonyl)phenylcarbamoyl)-3- methoxyacrylamide.
[00682] To a 10OmL round-bottom flask was added the product from Part F (500mg, 1.528mmol) in
DMF (15.0ml). The solution was cooled under nitrogen to -200C and (E)-3-methoxyacryloyl isocyanate
(15.28ml, 6.1 lmmol; prepared as described by Santana, L.; et al. J. Heterocyclic Chem. 1999, 36, 293-
295) was added dropwise. The mixture was stirred at this temperature for 15min, then warmed to room temperature and stirred for 45min. The mixture was diluted with ethyl acetate and washed by water (3 x
50ml), brine (3 x 50ml), dried with sodium sulfate, filtered and evaporated. The residue was triturated with ethyl acetate/hexane to give a solid (425mg, 61%).
[00683] Part H. Preparation of l-(3-iodo-4-methoxy-5-(methylsulfonyl)phenyl)pyrimidine-2,4(lH,3H)- dione.
[00684] To a 10OmL round-bottom flask was added the product from Part G (420mg, 0.925mmol) in ethanol (10ml) to give a suspension. Concentrated sulfuric acid (ImL, 18.76mmol) in water (10ml) was added and the mixture was heated at 1100C for 2h. The reaction mix was cooled, diluted with water
(50ml) and stirred for lOmin. The solid material was collected by filtration, washed with water and dried to give a white solid (325mg, 83%).
[00685]Part I. Preparation of (E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-methoxy-3-
(methylsulfonyl)styryl)phenyl)methanesulfonamide.
[00686] In a 5ml microwave tube was added the product from Part H (63.3mg, 0.15mmol), the product from Example 13B, Part B (36.2mg, 0.150mmol), potassium phosphate (66.9mg, 0.315mmol), PA-Ph
(CAS 97739-46-3) (1.315mg, 4.50μmol) and tris(dibenzylideneacetone)dipalladium(0) (1.374mg,
1.500μmol) in THF (3.0ml) and water (1.0ml). The vessel was sealed and the mixture was sparged with nitrogen for 5min and heated at 5O0C for 2h. The mixture was partitioned with ethyl acetate and IM HCl.
The organic layer was washed with saturated sodium bicarbonate, brine, dried with sodium sulfate and filtered. The filtrate was treated with 3-mercaprpropyl functionalized silica gel, filtered and evaporated.
The residue was triturated with methanol/ CH2Cl2 to give a solid (62mg, 84%). 1H NMR (300 MHz,
DMSOd6) δ ppm 3.03 (s, 3 H) 3.37 (s, 3 H) 3.94 (s, 3 H) 5.72 (d, J=7.72 Hz, 1 H) 7.26 (m, 3 H) 7.45 (m,
1 H) 7.65 (d, J=8.46 Hz, 2 H) 7.77 (d, J=2.57 Hz, 1 H) 7.81 (d, J=8.09 Hz, 1 H) 8.21 (d, J=2.57 Hz, 1 H)
9.93 (s, 1 H) 11.52 (s, 1 H). MS (ESI+) m/z 509 (M+NH4)+. [00687] Example 25. Preparation of (£)-methyl 2-(3-tørt-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl)-5-(methylsulfonamido)benzoate (compound IB-L1-1.7).
Figure imgf000135_0001
[00688] Part A. Preparation of methyl 2-((diethoxyphosphoryl)methyl)-5-nitrobenzoate.
[00689] To a solution of methyl 2-methyl-5-nitrobenzoate (0.40 g, 2.05mmol) in CCl4 (20ml) was added
N-bromosuccinimide (365mg, 2.05mmol) and 2,2'-azobisisobutyronitrile (34mg, 0.21mmol). The resulting mixture was stirred at reflux for 18h, cooled to room temperature and partitioned between
EtOAc (50ml) and H2O (50ml). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 1:3 EtOAc:hexanes as the eluent to give the bromide as an oil (345mg, 61%). The oil was placed in triethylphosphite (5ml) and heated with stirring at 12O0C for 3h. The mixture was allowed to cool to room temperature, and the crude product was purified by column chromatography on silica gel using 5% MeOH in CH2Cl2 as the eluent. The title compound was obtained as an oil (313mg, 75%).
[00690] Part B. Preparation of (£)-methyl 2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-
2-methoxystyryl)-5 -nitrobenzoate .
[0069I]To a solution of the product from Part A (360mg, 1.09mmol) and the product from Example
13A, Part D (329mg, 1.09mmol) in anhydrous CH2Cl2 (10ml) was added potassium tøt-butoxide
(305mg, 2.72mmol). The resulting dark red solution was stirred at room temperature for Ih, and then poured into 1 N aq. HCl (10ml). The resulting mixture was extracted with CH2Cl2 (10ml), dried over
Na2SO4, filtered and concentrated in vacuo to give a solid. A solution of the solid in thionyl chloride
(2.3ml) was heated at 85°C for 30min, and the thionyl chloride was removed in vacuo. The residue was stirred in a 2: 1 mixture of CH2Cl2 and MeOH (3ml) for 30min, and evaporated to dryness in vacuo. The crude product was purified by column chromatography on silica gel using 3% MeOH in CH2Cl2 as the eluent to give the title compound (350mg, 69%).
[00692] Part C. Preparation of (^-methyl 2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-
2-methoxystyryl)-5 -(methy lsulfonamido)benzoate .
[00693] To a solution of the product from Part B (465mg, 0.97mmol) in a 2:2:1 mixture of
TΗF:MeOΗ:Η2O (10ml) was added iron powder (271mg, 4.85mmol), and ammonium chloride (78mg, 1.46mmol). The mixture was heated at 8O0C for 45min, filtered through celite, and concentrated to dryness in vacuo. The residue was combined with methanesulfonyl chloride (0.16ml, 2.0mmol) and triethylamine (0.392ml, 4.85mmol) in anhydrous CH2Cl2 (10ml) and the resulting mixture was stirred at room temperature for 3h. The mixture was partitioned between 1 N HCl (20ml) and CH2Cl2 (20ml), and the organic layer was dried over Na2Sθ4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 3% MeOH in CH2Cl2 as the eluent to give the title compound (270mg, 53%). 1H NMR (300 MHz, DMSOd6) δ 11.42 (s, 1 H) 10.07 (s, 1 H) 7.90 (d, J=8.82 Hz, 1 H) 7.66 - 7.79 (m, 3 H) 7.52 (d, J=2.57 Hz, 1 H) 7.44 (dd, J=8.64, 2.39 Hz, 1 H) 7.14 - 7.26 (m, 2 H) 5.65 (dd, J=7.72, 1.84 Hz, 1 H) 3.86 (s, 3 H) 3.79 (s, 3 H) 3.04 (s, 3 H) 1.38 (s, 9 H).
[00694] Example 26. Preparation of (£)-2-(3-fe^-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)-5-(methylsulfonamido)benzoic acid (compound IB-L1-1.4).
Figure imgf000136_0001
[00695] A solution of the product from Example 25 (55mg, 0.104mmol) in THF (ImI) and IN aq. NaOH (ImI) was stirred in the dark at room temperature for 1.5h. IN aqueous HCl was added until pH 3, and the resulting mixture was extracted with EtOAc (2 x 2ml). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the title compound (53mg, 99%). 1H NMR (300 MHz, DMSO- d6) δ 13.22 (br s, 1 H) 11.40 (d, J=2.21 Hz, 1 H) 10.02 (s, 1 H) 7.72 - 7.91 (m, 3 H) 7.68 (d, J=2.57 Hz, 1 H) 7.49 (d, J=2.57 Hz, 1 H) 7.42 (dd, J=8.64, 2.39 Hz, 1 H) 7.21 (d, J=2.57 Hz, 1 H) 7.16 (d, J=16.18 Hz, 1 H) 5.64 (dd, J=7.72, 2.21 Hz, 1 H) 3.79 (s, 3 H) 3.04 (s, 3 H) 1.38 (s, 9 H).
[00696] Example 27. Preparation of (£)-N-(4-(3-^^-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)- 2-methoxystyryl)-3-(morpholine-4-carbonyl)phenyl)methanesulfonamide (compound IB-L1-1.23).
Figure imgf000136_0002
[00697] Part A. Preparation of (£)-2-(3-rerr-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)-5-(methylsulfonamido)benzoyl chloride.
[00698] A solution of the product from Example 26 (257mg, 0.50mmol) in thionyl chloride (1.5ml) was heated at 850C for 40min and then concentrated and dried in vacuo to give the title compound as a solid
(0.27 g).
[00699]Part B. Preparation of (£)-N-(4<3-te^butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)-3-(morpholine-4-carbonyl)phenyl)methanesulfonamide.
[00700] To a solution of the product from Part A (24mg, 0.045mmol) in anhydrous CH2Cl2 (ImI) was added morpholine (0.02ml, 0.226mmol). The mixture was stirred at room temperature for 2h, and then partitioned between 1 Ν aq. HCl (5ml) and EtOAc (2 x 5ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 4% MeOH in CH2Cl2 as the eluent to give the title compound (19mg,
71%). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.41 (d, J=I.84 Hz, 1 H) 10.04 (s, 1 H) 7.85 (d, J=8.46
Hz, 1 H) 7.75 (d, J=8.09 Hz, 1 H) 7.52 (d, J=2.57 Hz, 1 H) 6.99 - 7.34 (m, 5 H) 5.65 (dd, J=7.72, 1.84
Hz, 1 H) 3.76 (s, 3 H) 3.56 - 3.71 (m, 4 H) 3.40 - 3.51 (m, 2 H) 3.11 - 3.22 (m, 2 H) 3.06 (s, 3 H) 1.38 (s,
9 H).
[00701] Example 28. Preparation of (£)-N-(4-(3-fø^-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)- 2-methoxystyryl)-3-(hydroxymethyl)phenyl)methanesulfonamide (compound IB-Ll-1.10).
Figure imgf000137_0001
[00702] To a solution of the product from Example 27, Part A (375mg, 0.705mmol) in anhydrous THF (5ml) at O0C under N2 gas was added a 1.0 M solution of lithium terf-butoxyaluminiumhydride (1.8ml, 1.8mmol) dropwise. The resulting mixture was stirred at 00C for 30min, and then allowed to warm to room temperature and was stirred for Ih. The mixture was partitioned between 1 N aq. HCl (10ml) and EtOAc (2 x 10ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 3% MeOH in CH2Cl2 as the eluent to give the title compound (220mg, 63%). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.41 (s, 1 H) 9.82 (s, 1 H) 7.73 (t, J=8.27 Hz, 2 H) 7.66 (d, J=2.57 Hz, 1 H) 7.31 - 7.39 (m, 2 H) 7.20 (d, J=2.57 Hz, 1 H) 7.12 - 7.19 (m, 2 H) 5.65 (d, J=8.09 Hz, 1 H) 5.28 (t, J=5.52 Hz, 1 H) 4.65 (d, J=5.52 Hz, 2 H) 3.79 (s, 3 H) 3.00 (s, 3 H) 1.38 (s, 9 H).
[00703] Example 29. Preparation of (^-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)- 2-methoxystyryl)-3 -(methoxymethyl)phenyl)methanesulfonamide (compound IB-Ll-1.13).
Figure imgf000138_0001
[00704] To a solution of the product from Example 28 (32mg, 0.064mmol) in anhydrous CH2Cl2 (ImI) was added thionyl chloride (23 μL, 0.32mmol), and the resulting mixture was stirred at room temperature for 30min. The mixture was partitioned between saturated aq. NaHCO3 (5ml) and CH2Cl2 (5ml) and the organic layer was dried over Na2SO4, filtered and concentrated. The residue was dissolved in MeOH (ImI), and a solution of 25% NaOMe in MeOH (58μL, 0.254mmol) was added. The resulting mixture was stirred at 5O0C for 2h. The mixture was partitioned between 1 N aq. HCl (10ml) and EtOAc (2 x 10ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 3% MeOH in CH2Cl2 as the eluent to give the title compound (15mg, 46%). 1H NMR (300 MHz, DMSO-d6) δ 11.43 (s, 1 H) 9.86 (s, 1 H) 7.62 - 7.87 (m, 3 H) 7.12 - 7.39 (m, 5 H) 5.66 (d, J=7.72 Hz, 1 H) 4.58 (s, 2 H) 3.78 (s, 3 H) 3.35 (s, 3 H) 3.00 (s, 3 H) 1.38 (s, 9 H).
[00705] Example 30. Preparation of (J£)-N-(4-(3-fø^-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)- 2-methoxystyryl)-3 -((isopentylamino)methyl)phenyl)methanesulfonamide (compound EB-Ll-1.31).
Figure imgf000138_0002
[00706]Part A. Preparation of (£)-N-(4-(3-førf-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)-3-formylphenyl)methanesulfonamide.
[00707] To a solution of the product from Example 28 (0.60 g, 1.20mmol) in anhydrous DMA (15ml) was added 2-iodoxybenzoic acid (336mg, 1.20mmol). The mixture was stirred at room temperature for Ih, and then partitioned between EtOAc (20ml) and H2O (2x 20ml). The organic layer was dried over Na2SOzI, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 2% MeOH in CH2Cl2 as the eluent to give the title compound as a colorless solid (395mg, 66%). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.43 (d, J=2.21 Hz, 1 H) 10.45 (s, 1 H) 10.15 (s, 1 H) 8.06 (d, J=16.18 Hz, 1 H) 7.97 (d, J=8.82 Hz, 1 H) 7.73 - 7.78 (m, 2 H) 7.69 (d, J=2.57 Hz, 1 H) 7.51 (dd, J=8.64, 2.39 Hz, 1 H) 7.30 (d, J=16.18 Hz, 1 H) 7.26 (d, J=2.57 Hz, 1 H) 5.66 (dd, J=7.72, 2.21 Hz, 1 H) 3.81 (s, 3 H) 3.07 (s, 3 H) 1.39 (s, 9 H).
[00708] Part B. Preparation of (JE)-N-(4-(3-førf-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)-3-((isopentylamino)methyl)phenyl)methanesulfonamide.
[00709] To a solution of the product from Part A (50mg, O.lOmmol) and 3-methylbutan-l -amine (12μL, O.lOmmol) in anhydrous TΗF (3ml) was added sodium triacetoxyborohydride (32mg, 0.15mmol) and AcOH (9μL, 0.15mmol). The resulting mixture was stirred at room temperature for 4 h, and then partitioned between H2O (10ml) and EtOAc (2 x 10ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 3% MeOH in CH2Cl2 as the eluent to give the title compound (37mg, 65%). 1H NMR (300 MHz, DMSO-d6) δ 11.45 (d, J=I.84 Hz, 1 H) 10.04 (s, 1 H) 8.80 - 8.87 (m, 1 H) 7.88 (d, J=8.46 Hz, 1 H) 7.71 - 7.77 (m, 2 H) 7.41 - 7.48 (m, 1 H) 7.37 (d, J=2.21 Hz, 1 H) 7.21 - 7.29 (m, 3 H) 5.67 (dd, J=7.91, 2.02 Hz, 1 H) 4.30 - 4.38 (m, 2 H) 3.80 (s, 3 H) 3.10 (s, 3 H) 2.95 - 3.04 (m, 2 H) 1.49 - 1.67 (m, 3 H) 1.38 (s, 9 H) 0.86 (d, J=6.25 Hz, 6 H).
[00710] Example 31. Preparation of N-(4-(3-te^butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)-3-((£)-(methoxyimino)methyl)phenyl)methanesulfonamide (compound IB-Ll-1.19).
Figure imgf000139_0001
[0071I]To a solution of the product from Example 30, Part A (35mg, 0.070mmol) in EtOH (2ml) was added O-methoxylamine hydrochloride (29mg, 0.35mmol) and sodium bicarbonate (30mg, 0.35mmol). The resulting mixture was stirred at 7O0C for 2h. To the mixture was added 1 N aq. HCl (ImI) to give a colorless precipitate that was filtered and dried to give the title compound as a colorless solid (24mg, 64%). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.43 (d, J=2.21 Hz, 1 H) 9.94 (s, 1 H) 8.74 (s, 1 H) 7.79 7.85 (m, 2 H) 7.76 (d, J=7.72 Hz, 1 H) 7.57 - 7.65 (m, 2 H) 7.32 (dd, J=8.64, 2.39 Hz, 1 H) 7.23 (d, J=2.57 Hz, 1 H) 7.18 (d, J=16.18 Hz, 1 H) 5.66 (dd, J=7.72, 2.21 Hz, 1 H) 3.93 (s, 3 H) 3.79 (s, 3 H) 3.03 (s, 3 H) 1.38 (s, 9 H).
[00712] Example 32. Preparation of (£)-N-(4-(3-rert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)- 2-methoxystyryl)-3 -(oxazol-2-yl)phenyl)methanesulfonamide (compound EB-Ll-1.26).
Figure imgf000140_0001
[00713] To a solution of the product from Example 27, Part A (80mg, 0.15mmol) in tetramethylene sulfone (1.5ml) was added IH-1, 2,3 -triazole (lOμL, 0.17mmol) and potassium carbonate (73mg, 0.53mmol). The mixture was heated for 35min at 13O0C in a microwave reactor. After cooling to room temperature, the mixture was partitioned between 1 N aqueous HCl (10ml) and EtOAc (2 x 10ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 3% MeOH in CH2Cl2 as the eluent to give the title compound (37mg, 46%). 1H NMR (300 MHz, DMSOd6) δ 11.41 (d, J=I .84 Hz, 1 H) 10.10 (s, 1 H) 8.29 (d, J=LlO Hz, 1 H) 8.05 (d, J=16.18 Hz, 1 H) 7.95 (d, J=8.82 Hz, 1 H) 7.82 (d, J=2.21 Hz, 1 H) 7.74 (d, J=8.09 Hz, 1 H) 7.51 (d, J=2.57 Hz, 1 H) 7.46 (d, J=0.74 Hz, 1 H) 7.39 (dd, J=8.64, 2.39 Hz, 1 H) 7.20 - 7.30 (m, 2 H) 5.65 (dd, J=7.91, 2.02 Hz, 1 H) 3.80 (s, 3 H) 3.07 (s, 3 H) 1.38 (s, 9 H).
[00714] Example 33. Preparation of (£)-N<4-(3-før^butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)- 2-methoxystyryl)-3-(lH-imidazol-2-yl)phenyl)methanesulfonamide (compound IB-Ll-1.16).
Figure imgf000140_0002
[00715] To a solution of the product from Example 30, Part A (50mg, O.lOmmol) in EtOH (2ml) was added glyoxal (57uL, 0.50mmol) and concentrated aqueous NH4OH (7OuL, 0.50mmol). The resulting mixture was stirred at room temperature for 16h. To the mixture was added 1 N aq. HCl until pH = 7, and the mixture was partitioned between H2O (10ml) and EtOAc (2 x 10ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 5% MeOH in CH2Cl2 as the eluent to give the title compound (27mg, 50%). 1H NMR (300 MHz, DMSO-d6) δ 12.39 (s, 1 H) 11.40 (d, J=I.84 Hz, 1 H) 9.98 (s, 1 H) 7.89 (d, J=8.82 Hz, 1 H) 7.66 - 7.76 (m, 2 H) 7.38 (t, J=2.21 Hz, 2 H) 7.23 - 7.31 (m, 2 H) 7.06 - 7.21 (m, 3 H) 5.63 (dd, J=8.09, 1.84 Hz, 1 H) 3.78 (s, 3 H) 3.07 (s, 3 H) 1.37 (s, 9 H).
[00716] Example 34. Preparation of (E)-tert-buty\ 2-(3-fert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin- l(2H)-yl)-2-methoxystyryl)-5-(methylsulfonamido)phenylcarbamate (compound IB-L1-1.32).
Figure imgf000141_0001
[00717] To a solution of the product from Example 26 (75mg, 0.146mmol) in ter/-butanol (4ml) was added diphenylphosphoryl azide (47μL 0.219mmol) and triethylamine (31μL, 0.219mmol). The resulting mixture was stirred at 8O0C for 18h. The cooled mixture was partitioned between H2O (10ml) and EtOAc (2 x 10ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 3% MeOH in CH2Cl2 as the eluent to give the title compound (16mg, 19%). 1H NMR (300 MHz, DMSO-d6) δ 11.45 (d, J=I .84 Hz, 1 H) 9.86 (s, 1 H) 9.03 (s, 1 H) 7.75 (d, J=7.72 Hz, 2 H) 7.55 (d, J=2.57 Hz, 1 H) 7.10 - 7.33 (m, 4 H) 7.04 (dd, J=8.64, 2.39 Hz, 1 H) 5.66 (dd, J=7.91, 2.02 Hz, 1 H) 3.78 (s, 3 H) 3.02 (s, 3 H) 1.45 (s, 9 H) 1.38 (s, 9 H).
[00718] Example 35. Preparation of (£)-N-(3-amino-4-(3-fø^-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide (compound EB-L1-1.28).
Figure imgf000141_0002
[00719] The procedure described for the preparation of Example 34 provided the title compound, which was purified by column chromatography on silica gel using 5% methanol in CH2Cl2 as the eluent (6mg, 9%). 1H NMR (300 MHz, DMSOd6) δ 11.44 (d, J=2.21 Hz, 1 H) 9.55 (s, 1 H) 7.77 (d, J=2.57 Hz, 1 H) 7.75 (d, J=8.09 Hz, 1 H) 7.45 (d, J=8.46 Hz, 1 H) 7.33 (d, ./=15.81 Hz, 1 H) 7.15 (d, J=2.57 Hz, 1 H) 7.00 (d, J=16.18 Hz, 1 H) 6.56 (d, J=2.21 Hz, 1 H) 6.44 (dd, J=8.46, 2.21 Hz, 1 H) 5.66 (dd, J=T.91, 2.02 Hz, 1 H) 5.56 (s, 2 H) 3.78 (s, 3 H) 2.97 (s, 3 H) 1.37 (s, 9 H).
[00720] Example 36. Preparation of (^-N-(4-(3-tørt-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)- 2-methoxystyryl)-2-fluorophenyl)methanesulfonamide (compound IB-L1-1.5).
Figure imgf000142_0001
[00721] Part A. Preparation of (3-fluoro-4-nitrophenyl)methanol.
[00722]To a solution of 3-fluoro-4-nitrobenzoic acid (2.0 g, 10.8mmol) in TΗF (50ml) at O0C was added
BH3-Me2S complex (2.215ml, 22.15mmol) drop-wise. The mixture was stirred at O0C for 3h, and was then stirred at 650C for 18h. To the cooled mixture was added ice (5Og), followed by 1 Ν aq. HCl
(100ml), and the resulting mixture was extracted with EtOAc (200ml). The organic layer was dried over
Νa2Sθ4, filtered and concentrated in vacuo to provide the title compound as a white solid (1.79g, 97%).
[00723] Part B. Preparation of 4-(bromomethyl)-2-fluoro-l -nitrobenzene.
[00724] A solution of the product from Part A (1.79 g, 10.46mmol), N-bromosuccinimide (2.234 g,
12.55mmol) and triphenylphosphine (3.29 g, 12.55mmol) in CH2Cl2 (100ml) and THF (50ml) was stirred at room temperature for 3h. The mixture was partitioned between H2O (200ml) and EtOAc (400ml), and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 1 : 1 EtOAc:hexanes as the eluent to give the title compound (1.14 g, 47%).
[00725] Part C. Preparation of diethyl 3-fluoro-4-nitrobenzylphosphonate.
[00726] The product from Part B (1.25 g, 5.34mmol) was subjected to the conditions described for
Example 6, Part B to provide the title product (0.75 g, 48%).
[00727]Part D. Preparation of (£)-N-(4-(3-^rt-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)-2-fluorophenyl)methanesulfonamide.
[00728] The product from Part C (0.193 g, 0.662mmol) was subjected to the conditions described for
Example 13A, Part E, Part F, and Part G to provide the title product as a colorless solid (15mg, 5%).
1H NMR (300 MHz, DMSO-d6) δ 11.43(s,lH), 9.67(s,lH), 7.76(d,J=8.1Hz,lH), 7.62(m,2H), 7.41(m,2H),
7.38(m,lH), 7.23(m,2H), 5.66(dd,J=8.0,2.0Hz,lH), 3.80(s,3H), 3.05(s,3H), 1.38(s,9H). [00729] Example 37. Preparation of (£)-N-(4-(3-fert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)- 2-methoxystyryl)-2-fluoro-5-methylphenyl)methanesulfonamide (compound IB-Ll-1.15).
Figure imgf000143_0001
[00730] Part A. Preparation of N-(4-bromo-2-fluoro-5-methylphenyl)methanesulfonamide.
[0073I]To a solution of 4-bromo-2-fluoro-5-methylaniline (2.04 g, lO.Ommol) in anhydrous CH2Cl2
(20ml) and pyridine (3.23ml, 40.0mmol) was added methanesulfonyl chloride (0.86ml, 1 l.Ommol) and the resulting mixture was stirred at room temperature for 2h. Solvent was removed in vacuo, and the residue was partitioned between EtOAc and IM aq. HCl. The organic layer was washed with saturated aqueous NaHCO3, brine and then dried over Na2SO4. The drying agent was filtered off, and the filtrate was concentrated to give the title compound as a solid (2.80 g, 99%).
[00732] Part B. Preparation of N-(4-ethynyl-2-fluoro-5-methylphenyl)methanesulfonamide.
[00733] A mixture of the product from Part A (3.0 g, 10.63mmol), triphenylphosphine (0.279 g, l.Oόmmol), trimethylsilylacetate (6.0ml, 42.5mmol) and palladium(II) acetate (0.12 g, 0.53mmol) in triethylamine (30ml) and toluene (15ml) under N2 was heated at 8O0C for 5h. The mixture was allowed to cool to room temperature, and was partitioned between EtOAc and IM aq. HCl. The organic layer was washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 10% to
35% EtOAc in hexanes to give an oil (3.0 g, 94%). To a solution of the oil (3.0 g, lO.Ommol) in MeOH
(50ml) was added IM aq. NaOH (21ml, 21.0mmol), and the resulting mixture was stirred at room temperature for 45min. The mixture was partitioned between EtOAc and IM aq. HCl, and the organic layer was washed with brine and dried over Na2SO4. The drying agent was filtered off, and the filtrate was concentrated in vacuo to give the title compound as a solid (2.3 g, quant.).
[00734] Part C. Preparation of (£)-5-fluoro-2-methyl-4-(methylsulfonamido)styrylboronic acid.
[00735] The product from Part B (0.20 g, 0.88mmol) was subjected to the conditions described for the preparation of Example 13B, Part B to give the title compound (42mg, 17%).
[00736]Part D. Preparation of (^-N-(4-(3-te^butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)-2-fluoro-5-methylphenyl)methanesulfonamide.
[00737] The product from Part C (40mg, 0.15mmol) was subjected to the conditions described for the preparation of Example 13B, Part I to give the title compound (51 mg, 83%). 1H NMR (300 MHz, DMSOd6) δ 11.42 (d, J=2.21 Hz, 1 H) 9.59 (s, 1 H) 7.70 - 7.78 (m, 2 H) 7.66 (d, J=I 1.77 Hz, 1 H) 7.20 7.32 (m, 3 H) 5.65 (dd, J=7.72, 2.21 Hz, 1 H) 3.79 (s, 3 H) 3.05 (s, 3 H) 2.38 (s, 3 H) 1.38 (s, 9 H).
[00738] Example 38. Preparation of methyl 2-(3-tørt-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)- yl)-2-methoxyphenethyl)-5-(methylsulfonamido)benzoate (compound IB-L5-2-1.1).
Figure imgf000144_0001
[00739] To a solution of the product from Example 25 (40mg, 0.076mmol) in MeOH (2ml) and TΗF (2ml) was added 10% Pd/C (20mg) and the resulting mixture was stirred at room temperature under 1 atm H2 for 16h. The mixture was filtered through celite and concentrated in vacuo to give a solid (27.5mg, 68%). 1H NMR (300 MHz, DMSOd6) δ 11.39 (s, 1 H) 9.88 (s, 1 H) 7.61 - 7.71 (m, 2 H) 7.28 - 7.36 (m, 2 H) 7.20 (d, J=2.57 Hz, 1 H) 7.13 (d, J-2.94 Hz, 1 H) 5.64 (d, J=7.72 Hz, 1 H) 3.83 (s, 3 H) 3.75 (s, 3 H) 3.14 (dd, J=10.30, 5.88 Hz, 2 H) 2.96 (s, 3 H) 2.83 - 2.92 (m, 2 H) 1.34 (s, 9 H).
[00740] Example 39. Preparation of N-(4-(3-re^-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxyphenethyl)phenyl)methanesulfonamide (compound B8-L5-2-1.2).
Figure imgf000144_0002
[00741] The product from Example 13B, Part M (200mg, 0.426mmol) was dissolved in MeOH (10ml) followed by the addition of 10% Palladium on activated Carbon (50mg). The resultant mixture was evacuated and a hydrogen balloon attached then stirred at room temperature for 48h. The mixture was then filtered through celite and the filtrate concentrated under vacuum to an oil which was dissolved in ethanol (4ml) then a IN solution of aqueous sodium hydroxide (3.8ml, 3.8mmol) was added and the solution stirred at room temperature for 18h. The ethanol was then removed under vacuum and a IN solution of aqueous hydrochloric acid (4ml) was added to acidify the mixture followed by extraction with EtOAc (2 x 1OmL). The organic extracts were combined, dried and purified by column chromatography on silica gel using 5% MeOH in CH2CI2 as the eluent to provide the title compound as a colorless solid (82mg, 41%). 1H NMR (300MHz, DMSOd6) δ 11.39 (s, IH), 9.60 (s, IH), 7.65 (d, J=8.1Hz, IH), 7.23 (m, 3H), 7.17 (m, 3H), 5.64 (d, J=7.7Hz, IH), 3.77 (s, 3H), 2.93 (s, 3H), 2.88 (br s, 4H), 1.35 (s, 9H).
[00742] Example 40. Preparation of (JE)-N-(4-(3-fø^-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)- 2-ethoxystyryl)phenyl)methanesulfbnamide (compound IB-L1-1.30).
Figure imgf000145_0001
[00743] Part A. Preparation of 2-tert-butyl-4-iodophenol.
[00744] To a 25OmL round-bottom flask was added 2-tert-butylphenol (3.76g, 25mmol) in MeOH
(50.0ml) to give a colorless solution. Sodium hydroxide (1.20Og, 30.0mmol) was added and the mix was stirred until the hydroxide was completely dissolved. The solution was cooled to 00C and treated with sodium iodide (1.75g, 11.6mmol) followed by drop-wise addition of 10% sodium hypochlorite solution
(7.2ml, 11.6mmol). The addition of sodium iodide followed by sodium hypochlorite was repeated twice and the mixture was stirred at O0C for 30min. The mixture was treated with 10% w/w solution of sodium thiosulfate, stirred for 30min and treated with concentrated HCl dropwise to a constant pΗ of 1. The mixture was extracted 3X with EtOAc. The extracts were combined, washed with brine, dried (MgS04), filtered and concentrated. The crude oil was flash chromatographed on an Isco 8Og silica cartridge eluting with hexane to > 4:1 hexane/EtOAc to give a yellow oil (5.2g, 75%).
[00745] Part B. Preparation of 2-bromo-6-tert-butyl-4-iodophenol.
[00746]To a 25OmL round-bottom flask was added the product from Part A (4.8g, 17.38mmol) and 1,3- dibromo-5,5-dimethylhydantoin (2.6 Ig, 9.13mmol) in chloroform (87ml) to give an orange solution. The reaction mixture was stirred for 2h resulting in a black solution that was washed with water, brine, dried
(Na2SO4) and concentrated. The black oil was flash chromatographed on a 12Og Isco silica cartridge eluting with hexane to give a pinkish solid (4.84g, 78%).
[00747] Part C. Preparation of l-bromo-3-tert-butyl-2-ethoxy-5-iodobenzene.
[00748] To a 5OmL round-bottom flask was added the product from Part B (888mg, 2.5mmol), ethyl iodide (409mg, 2.63mmol), and potassium carbonate (415mg, 3.00mmol) in acetone (12ml) to give a green suspension. The mixture was heated at reflux for 16h, cooled and concentrated. The residue was partitioned between water and EtOAc. The organic layer was washed twice with brine, dried over Na2SO4, filtered and concentrated to a red oil. The oil was flash chromatographed on an Isco 4Og silica cartridge eluting with hexane to give a clear oil (820mg, 86%).
[00749] Part D. Preparation of l-(3-bromo-5-tert-butyl-4-ethoxyphenyl)pyrimidine-2,4(lH,3H)-dione. [00750] In a 2OmL microwave tube under nitrogen flush was added the product from Part C (0.4g, 1.044mmol), lH-Pyrimidine-2,4-dione (0.14Og, 1.253mmol), and potassium phosphate tribasic (0.465g, 2.193mmol) in DMSO (5ml) to give a colorless suspension. N-(2-cyanophenyl)picolinamide (0.047g, 0.209mmol) was added and the mix was sparged with nitrogen for lOmin. Copper(I) iodide (0.02Og, 0.104mmol) was added and the mix was sparged once again for lOmin, placed under nitrogen and heated at 600C for 18h. The mixture was cooled and partitioned between EtOAc and water adjusting the pH to 1 with HCl. The aqueous layer was extracted 2X with EtOAc. The organics were combined, washed with water, saturated NaHCθ3, and saturated NaCl. The organic layer was dried (Na2SO4), stirred with 3- mercaptopropyl functionalized silica for Ih, filtered and concentrated. The crude product was purified by chromatography on an Isco 12g silica cartridge eluting with 2% MeOH in CH2Cl2 to give a white powder (266mg, 69%).
[00751]Part E. Preparation of (£)-N-(4-(3-fcr/-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- ethoxystyryl)phenyl)methanesulfonamide.
[00752] A mixture of the product from Part D (55.1mg, 0.15mmol), the product from Example 13B, Part B (36.2mg, 0.150mmol), potassium phosphate tribasic (63.7mg, 0.300mmol) and l,l'-bis(di-tert- butylphosphino)ferrocene palladium dichloride (4.89mg, 7.50μmol) in TΗF (3ml) water (ImI) was sparged for lOmin with nitrogen, and then sealed and heated at 50 0C for 4h. The mixture was cooled to room temperature and diluted into EtOAc. The EtOAc layer was washed with IM HCl, saturated ΝaΗCO3, saturated NaCl, dried (Na2SO4) and treated simultaneously with mercaptopropyl silica gel, filtered and concentrated. The crude product was purified by column chromatography on silica gel using 2% MeOH in CH2Cl2 as the eluent to give the title compound as a solid (40mg, 55%) m.p. 265-266 0C. 1H NMR (300 MHz, DMSO-d6) δ 11.42 (s, 1 H) 9.87 (s, 1 H) 7.76 (d, J=8.09 Hz, 1 H) 7.55 - 7.66 (m, 3 H) 7.17 - 7.27 (m, 5 H) 5.65 (dd, J=7.72, 1.47 Hz, 1 H) 3.89 (q, J=6.74 Hz, 2 H) 3.02 (s, 3 H) 1.45 (t, J=6.99 Hz, 3 H) 1.39 (s, 9 H).
[00753] The following compounds were prepared utilizing the above discussion:
[00754] (E)-N-(4-( 1 -(3 -tert-butyl-5-(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)-2-methoxyphenyl) prop- 1 - en-2-yl)phenyl)methanesulfonamide (compound IA-L1-1.6). 1H NMR (300 MHz, DMSO-d6) δ 2.14 (s, 3
H) 2.70 (t, J=6.62 Hz, 2 H) 3.01 (s, 3 H) 3.68 (s, 3 H) 3.78 (t, J=6.62 Hz, 2 H) 6.82 (s, 1 H) 7.10 - 7.17
(m, 2 H) 7.23 (d, J=8.46 Hz, 2 H) 7.59 (d, J=8.46 Hz, 2 H) 9.78 (s, 1 H) 10.32 (s, 1 H).
[00755] (Z)-N-(4-(3 -tert-butyl-5 -(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)-2-methoxystyryl)phenyl) methanesulfonamide (compound IA-Ll-1.10). 1H NMR (SOO MHz, DMSO-d6) δ 10.23 (s, 1 H) 9.74 (s, 1 H) 7.23 (d, J=8.46 Hz, 2 H) 7.13 (d, J=2.57 Hz, 1 H) 7.06 (d, J=8.82 Hz, 2 H) 6.92 (d, J=2.57 Hz, 1 H)
6.54 - 6.67 (m, 2 H) 3.78 (s, 3 H) 3.57 (t, J=6.62 Hz, 2 H) 2.96 (s, 3 H) 2.60 (t, J=6.80 Hz, 2 H) 1.34 (s, 9
H).
[00756] (E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-2-methoxystyryl) phenyl)-N-
(methylsulfonyl)acetamide (compound IA-Ll-1.11). 1H NMR (300 MHz, DMSOd6) δ 10.36 (s, 1 H)
7.77 (d, J=8.46 Hz, 2 H) 7.56 (d, J=2.21 Hz, 1 H) 7.39 - 7.50 (m, 3 H) 7.25 (d, J=16.55 Hz, 1 H) 7.19 (d,
J=2.57 Hz, 1 H) 3.74 - 3.85 (m, 5 H) 3.54 (s, 3 H) 2.72 (t, J=6.62 Hz, 2 H) 1.94 (s, 3 H) 1.38 (s, 9 H).
[00757] (E)-l-(3-(4-aminostyryl)-5-tert-butyl-4-methoxyphenyl)dihydropyrimidine-2,4(lH,3H)-dione
(compound IA-L1-1.13). 1H NMR (300 MHz, DMSOd6) δ 1.36 (s, 9 H) 2.70 (t, J=6.62 Hz, 2 H) 3.74 (s,
3 H) 3.77 (t, J=6.62 Hz, 2 H) 5.34 (s, 1 H) 6.57 (d, J=8.46 Hz, 2 H) 6.98 (s, 1 H) 7.07 (d, J=2.21 Hz, 1 H)
7.17 (s, 2 H) 7.30 (d, J=8.09 Hz, 2 H) 7.45 (d, J=2.21 Hz, 1 H) 10.32 (s, 1 H).
[00758] (Z)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-2-methoxystyryl)phenyl) methanesulfonamide (compound IA-L1-1.20). 1H NMR (500 MHz, DMSOd6): δ ppm 1.37 (s, 9H), 2.71
(t, J=6.7Hz, 2H), 3.01 (s, 3H), 3.75 (s, 3H), 3.79 (t, J=6.6Hz, 2H), 7.13 (d, J=16.5Hz, IH), 7.15 (d,
J=2.4Hz, 2H), 7.23 (d, J=8.5Hz, 2H), 7.25 (d, J=16.5 Hz, IH), 7.51 (d, J=2.4Hz, IH), 7.61 (d, J=8.6Hz,
2H), 9.80(bs, IH), 10.30 (s, IH).
[00759]N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-2-methoxyphenyl)-l- fluorovinyl)phenyl)methanesulfonamide (compound IA-L1-1.21). (racemic mixture (1:1) of compounds
IA-L1-1.4 and IA-L1-1.5).
[00760] (E)- 1 -(3-tert-butyl-4-methoxy-5-(4-nitrostyryl)phenyl)dihydropyrimidine-2,4( 1 H,3H)-dione
(compound IA-L1-1.22).
[00761] l-{3-tert-butyl-5-[(Z)-2-chloro-2-(4-nitro-phenyl)-vinyl]-4-methoxy-phenyl}-dihydro- pyrimidine-2,4-dione (compound IA-L1-1.23).
[00762] l-{3-tert-butyl-4-methoxy-5-[(E)-2-(4-nitro-phenyl)-propenyl]-phenyl}-dihydro-pyrimidine-2,4- dione (compound IA-L1-1.24).
[00763] l-{3-tert-Butyl-5-[(E)-2-(4-nitro-phenyl)-vinyl]-phenyl}-dihydro-pyrimidine-2,4-dione
(compound IA-L1-1.25). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.33 (s, 9 H) 2.70 - 2.77 (m, 2 H) 3.84
(t, J=6.80 Hz, 2 H) 7.33 (s, 1 H) 7.49 (d, J=4.04 Hz, 2 H) 7.56 (d, J=5.88 Hz, 2 H) 7.89 (d, J=8.82 Hz, 2
H) 8.25 (d, J=8.82 Hz, 2 H) 10.40 (s, 1 H)
[00764]N-(4-{(E)-2-[3-tert-Butyl-5-(dioxo-tetrahydro-pyrimidin-l-yl)-2-methoxy-phenyl]-vinyl}-3- methoxy-phenyl)-methanesulfonamide (compound IA-L1-1.27). 1H NMR (300 MHz, DMSO-D6) δ ppm
10.33 (s, 1 H) 9.86 (s, 1 H) 7.64 (d, J=8.46 Hz, 1 H) 7.45 (d, J=2.21 Hz, 1 H) 7.26 (s, 2 H) 7.12 (d,
.7=2.21 Hz, 1 H) 6.89 (s, 1 H) 6.85 (dd, J=8.46, 1.84 Hz, 1 H) 3.84 (s, 3 H) 3.78 (t, J=6.80 Hz, 2 H) 3.74
(s, 3 H) 3.04 (s, 3 H) 2.71 (t, J=6.62 Hz, 2 H) 1.37 (s, 9 H) [00765]N-(4-{(E)-2-[3-tert-Butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-2-methoxy-phenyl]- vinyl}-3-formyl-phenyl)-methanesulfonamide (compound IB-L1-1.6). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.39 (s, 9 H) 3.07 (s, 3 H) 3.81 (s, 3 H) 5.66 (dd, J=7.72, 2.21 Hz, 1 H) 7.26 (d, J=2.57 Hz, 1 H) 7.30 (d, J=I 6.18 Hz, 1 H) 7.51 (dd, J=8.64, 2.39 Hz, 1 H) 7.69 (d, J=2.57 Hz, 1 H) 7.73 - 7.78 (m, 2 H) 7.97 (d, J=8.82 Hz, 1 H) 8.06 (d, J=16.18 Hz, 1 H) 10.15 (s, 1 H) 10.45 (s, 1 H) 11.43 (d, J=2.21 Hz, 1 H) [00766]N-[4-{(E)-2-[3-tert-Butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-2-methoxy-phenyl]- vinyl}-3-(hydroxyimino-methyl)-phenyl]-methanesulfonamide (compound IB-L1-1.8). 1H NMR (300 MHz, DMSOd6) δ 1.38 (s, 9 H) 3.03 (s, 3 H) 3.79 (s, 3 H) 5.66 (dd, J=7.91, 2.02 Hz, 1 H) 7.16 (d, J=15.81 Hz, 1 H) 7.22 (d, J=2.57 Hz, 1 H) 7.26 (dd, J=8.64, 2.39 Hz, 1 H) 7.59 (d, J=16.18 Hz, 1 H) 7.63 (d, 3=2.21 Hz, 1 H) 7.73 - 7.83 (m, 3 H) 8.64 (s, 1 H) 9.96 (s, 1 H) 11.42 (d, J=2.21 Hz, 1 H) 11.50 (s, 1 H).
[00767] 2-{(E)-2-[3-tert-Butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-2-methoxy-phenyl]-vinyl}- 5-methanesulfonylamino-N-(2-methoxy-ethyl)-benzamide (compound IB-L1-1.9). 1H NMR (300 MHz, DMSO-D6) δ 1.38 (s, 9 H) 3.05 (s, 3 H) 3.20 (s, 3 H) 3.37 - 3.49 (m, 4 H) 3.78 (s, 3 H) 5.64 (d, J=7.72 Hz, 1 H) 7.15 (d, J=2.57 Hz, 1 H) 7.20 (d, J=2.57 Hz, 1 H) 7.24 (s, 2 H) 7.28 (dd, J=8.46, 2.21 Hz, 1 H) 7.42 (d, J=2.57 Hz, 1 H) 7.73 (d, J=7.72 Hz, 1 H) 7.87 (d, J=8.82 Hz, 1 H) 8.49 (t, J=5.15 Hz, 1 H) 9.99 (s, I H) 11.42 (s, I H).
[00768]2-{(E)-2-[3-tert-Butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-2-methoxy-phenyl]-vinyl}- 5-methanesulfonylamino-benzoic acid ethyl ester (compound IB-Ll-1.11). 1H NMR (300 MHz, DMSOd6) δ 1.31 (t, J=7.17 Hz, 3 H) 1.38 (s, 9 H) 3.05 (s, 3 H) 3.79 (s, 3 H) 4.33 (q, J=7.23 Hz, 2 H) 5.65 (dd, J=7.72, 2.21 Hz, 1 H) 7.15 - 7.25 (m, 2 H) 7.46 (dd, J=8.64, 2.39 Hz, 1 H) 7.52 (d, J=2.57 Hz, 1 H) 7.68 (d, J=2.57 Hz, 1 H) 7.71 - 7.81 (m, 2 H) 7.90 (d, J=8.46 Hz, 1 H) 10.06 (s, 1 H) 11.42 (d, J=1.84 Hz, 1 H).
[00769]N-(4-{(E)-2-[3-tert-Butyl-2-chloro-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-phenyl]-vinyl}- phenyl)-methanesulfonamide (compound IB-L1-1.12). 1H NMR (300 MHz, DMSOd6) δ ppm 1.49 (s, 9 H) 3.02 (s, 3 H) 5.69 (d, J=7.72 Hz, 1 H) 7.22 (m, 3 H) 7.41 (d, J=2.21 Hz, 1 H) 7.51 (d, J=16.18 Hz, 1 H) 7.59 (d, J=8.82 Hz, 2 H) 7.78 (d, J=2.21 Hz, 1 H) 7.80 (d, J=8.09 Hz, 1 H) 9.90 (s, 1 H) 11.47 (s, 1 H). [00770] 2-{(E)-2-[3-tert-Butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-2-methoxy-phenyl]-vinyl}- 5-methanesulfonylamino-N,N-dimethyl-benzamide (compound IB-Ll-1.14). 1H NMR (300 MHz, DMSOd6) δ 1.37 (s, 9 H) 2.76 (s, 3 H) 3.03 (s, 3 H) 3.05 (s, 3 H) 3.76 (s, 3 H) 5.64 (dd, J=7.91, 1.65 Hz, 1 H) 6.95 (d, J=16.55 Hz, 1 H) 7.02 (d, J=2.21 Hz, 1 H) 7.17 - 7.25 (m, 2 H) 7.27 (dd, J=8.64, 2.39 Hz, 1 H) 7.48 (d, J=2.57 Hz, 1 H) 7.74 (d, J=8.09 Hz, 1 H) 7.82 (d, J=8.82 Hz, 1 H) 10.03 (s, 1 H) 11.39 - 11.43 (m, 1 H). [00771]2-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-2-methoxy-phenyl]-vinyl}-5- methanesulfonylamino-N-methyl-benzamide (compound IB-L1-1.17). 1H NMR (300 MHz, DMSOd6) δ
1.38 (s, 9 H) 2.77 (d, J=4.41 Hz, 3 H) 3.06 (s, 3 H) 3.77 (s, 3 H) 5.64 (dd, J=7.72, 1.84 Hz, 1 H) 7.16 - 7.33 (m, 5 H) 7.43 (d, J=2.21 Hz, 1 H) 7.73 (d, J=7.72 Hz, 1 H) 7.84 (d, J=8.46 Hz, 1 H) 8.37 (q, J=4.41 Hz, 1 H) 10.00 (s, 1 H) 11.40 (d, J=I.84 Hz, 1 H).
[00772]2-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-2-methoxy-phenyl]-vinyl}- N-( 1 , 1 -dioxo-tetrahydro- 1 lambda* 6 *-thiophen-3 -yl)-5 -methanesulfonylamino-N-methyl-benzamide (compound IB-L1-1.18). 1H NMR (300 MHz, DMSO-d6) δ 1.37 (s, 9 H) 2.17 - 2.47 (m, 2 H) 2.70 (s, 3 H) 3.06 (s, 3 H) 3.15 - 3.31 (m, 2 H) 3.36 - 3.51 (m, 2 H) 3.77 (s, 3 H) 5.37 (dt, J=17.74, 8.96 Hz, 1 H) 5.65 (dd, J=7.91, 2.02 Hz, 1 H) 6.93 (d, J=16.18 Hz, 1 H) 7.05 (d, J=2.21 Hz, 1 H) 7.19 - 7.35 (m, 3 H) 7.50 (d, J=2.57 Hz, 1 H) 7.76 (d, J=8.09 Hz, 1 H) 7.87 (d, J=8.82 Hz, 1 H) 10.04 (s, 1 H) 11.38 (d, J=2.21 Hz, 1 H).
[00773]N-(4-{(E)-2-[3-tert-butyl-5-(5-chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-2-methoxy- phenyl]-vinyl}-phenyl)-methanesulfonamide (Compound IB-L1-1.20). 1H NMR (300 MHz, DMSO-D6) δ ppm 11.31 (s, 1 H) 9.77 (s, 1 H) 7.53 (d, J=8.09 Hz, 1 H) 7.23 (d, J=8.46 Hz, 2 H) 7.17 (d, J=2.57 Hz, 1 H) 7.06 (d, J=8.82 Hz, 2 H) 7.01 (d, J=2.57 Hz, 1 H) 6.53 - 6.71 (m, 2 H) 5.56 (d, J=7.72 Hz, 1 H) 3.81 (s, 3 H) 2.96 (s, 3 H) 1.35 (s, 9 H)
[00774] 2-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-2-methoxy-phenyl]-vinyl}-5- methanesulfonylamino-benzamide (compound IB-L1-1.21). 1H NMR (300 MHz, DMSOd6) δ 1.38 (s, 9 H) 3.07 (s, 3 H) 3.78 (s, 3 H) 5.64 (d, J=7.72 Hz, 1 H) 7.18 - 7.34 (m, 5 H) 7.43 (d, J=2.21 Hz, 1 H) 7.54 (s, 1 H) 7.73 (d, J=7.72 Hz, 1 H) 7.84 (d, J=8.46 Hz, 1 H) 7.93 (s, 1 H).
[00775] N-(3-(azetidine- 1 -carbonyl)-4- {(E)-2-[3-tert-butyl-5-(2,4-dioxo-3 ,4-dihydro-2H-pyrimidin- 1 -yl)- 2-methoxy-phenyl] -vinyl }-phenyl)-methanesulfonamide (compound (compound IB-L1-1.22). 1H NMR (300 MHz, DMSOd6) δ 1.38 (s, 9 H) 3.07 (s, 3 H) 3.78 (s, 3 H) 5.64 (d, J=7.72 Hz, 1 H) 7.18 - 7.34 (m, 5 H) 7.43 (d, j=2.21 Hz, 1 H) 7.54 (s, 1 H) 7.73 (d, J=7.72 Hz, 1 H) 7.84 (d, J=8.46 Hz, 1 H) 7.93 (s, 1 H). [00776] 2-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-2-methoxy-phenyl]-vinyl}-5- methanesulfonylamino-N-(2-methoxy-ethyl)-N-methyl-benzamide (compound IB-L1-1.24). 1H NMR (300 MHz, DMSOd6) δ 1.40 (s, 9 H) 2.81 (s, 3 H) 3.07 (s, 3 H) 3.23 (s, 3 H) 3.29 (t, J=5.33 Hz, 1 H)
3.39 (t, j=4.96 Hz, 1 H) 3.62 (t, J=4.78 Hz, 2 H) 3.82 (s, 3 H) 5.68 (d, J=8.09 Hz, 1 H) 6.96 - 7.07 (m, 1 H) 7.09 - 7.17 (m, 1 H) 7.23 - 7.38 (m, 3 H) 7.49 (dd, J=16.55, 2.57 Hz, 1 H) 7.71 - 7.76 (m, 1 H) 7.83 - 7.94 (m, 1 H).
[00777]N-(4-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-2-methoxy-phenyl]- vinyl}-3-isopropoxymethyl-phenyl)-methanesulfonamide (compound IB-L1-1.25). 1H NMR (300 MHz, DMSOd6) δ 1.16 (d, J=5.88 Hz, 6 H) 1.38 (s, 9 H) 3.01 (s, 3 H) 3.69 (dt, J=12.13, 6.07 Hz, 1 H) 3.79 (s, 3 H) 4.59 (s, 2 H) 5.65 (dd, J=7.91, 2.02 Hz, 1 H) 7.13 - 7.29 (m, 4 H) 7.32 - 7.40 (m, 1 H) 7.59 (d, J=2.57 Hz, 1 H) 7.75 (d, J=8.09 Hz, 2 H) 9.86 (s, 1 H) 11.43 (d, J=I.84 Hz, 1 H). [00778]N-[4-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-2-methoxy-phenyl]- vinyl}-3-(pyrrolidine-l-carbonyl)-phenyl]-methanesulfonamide (compound IB-L1-1.27). 1H NMR (300 MHz, DMSOd6) δ 1.37 (s, 9 H) 1.73 - 1.89 (m, 4 H) 3.03 - 3.12 (m, 5 H) 3.51 (t, J=6.80 Hz, 2 H) 3.76 (s, 3 H) 5.64 (dd, J=7.91, 2.02 Hz, 1 H) 6.99 - 7.06 (m, 1 H) 7.08 (d, J=2.21 Hz, 1 H) 7.19 - 7.31 (m, 3 H) 7.46 (d, J=2.57 Hz, 1 H) 7.75 (d, J=8.09 Hz, 1 H) 7.82 (d, J=8.82 Hz, 1 H) 10.01 (s, 1 H) 11.41 (d, J=2.21 Hz, 1 H).
[00779]N-[4-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-2-methoxy-phenyl]- vinyl}-3-(3-hydroxy-azetidin-l-ylmethyl)-phenyl]-methanesulfonamide (compound IB-L1-1.29). 1H NMR (300 MHz, DMSOd6) δ 1.38 (s, 9 H) 2.78 - 2.85 (m, 2 H) 2.99 (s, 3 H) 3.50 - 3.58 (m, 2 H) 3.71 (s, 2 H) 3.79 (s, 3 H) 4.19 (td, J=12.41, 6.07 Hz, 1 H) 5.29 (d, J=6.25 Hz, 1 H) 5.66 (d, J=8.09 Hz, 1 H) 7.10
- 7.18 (m, 2 H) 7.20 (t, J=2.21 Hz, 2 H) 7.35 - 7.42 (m, 1 H) 7.63 (d, J=2.57 Hz, 1 H) 7.69 (d, J=8.46 Hz,
1 H) 7.76 (d, J=7.72 Hz, 1 H) 9.78 (s, 1 H) 11.42 (s, 1 H).
[00780]N-(4-{(E)-2-[3-tert-Butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-2-methoxy-phenyl]- vinyl}-3-pyrrolidin-l-ylmethyl-phenyl)-methanesulfonamide (compound IB-L1-1.33). 1H NMR (500 MHz, DMSOd6) δ 1.40 (s, 9 H) 1.72 - 1.95 (m, 4 H) 2.84 (s, 2 H) 2.88 - 2.98 (m, 2 H) 3.01 (s, 3 H) 3.81 (s, 3 H) 3.86 - 4.23 (m, 2 H) 5.63 (d, J=7.81 Hz, 1 H) 7.17 (d, J=15.63 Hz, 1 H) 7.21 - 7.28 (m, 2 H) 7.32
- 7.38 (m, 1 H) 7.47 (d, J=16.11 Hz, 1 H) 7.53 - 7.59 (m, 1 H) 7.61 (d, J=7.81 Hz, 1 H) 7.70 (d, J=6.35 Hz, 1 H) 9.42 (s, 1 H) 10.88 (s, 1 H).
[00781]N-(4-{(Z)-2-[3-tert-Butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-yl)-2-methoxy-phenyl]- vinyl}-phenyl)-methanesulfonamide (compound IB-L1-1.34 1H NMR (300 MHz, DMSO-D6) δ ppm 11.31 (s, I H) 9.77 (s, 1 H) 7.53 (d, J=8.09 Hz, 1 H) 7.23 (d, J=8.46 Hz, 2 H) 7.17 (d, J=2.57 Hz, I H) 7.06 (d, J=8.82 Hz, 2 H) 7.01 (d, J=2.57 Hz, 1 H) 6.53 - 6.71 (m, 2 H) 5.56 (d, J=7.72 Hz, 1 H) 3.81 (s, 3 H) 2.96 (s, 3 H) 1.35 (s, 9 H)
[00782] N-(4-(3 -tert-butyl-5 -(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)phenethyl)phenyl)methane sulfonamide (compound IA-L5-2-1.2). 1H NMR (300 MHz, DMSOd6) δ 1.25 (s, 9 H) 2.69 (t, J=6.62 Hz,
2 H) 2.83 (s, 4 H) 2.91 (s, 3 H) 3.75 (t, J=6.62 Hz, 2 H) 6.99 - 7.21 (m, 7 H) 9.60 (s, 1 H) 10.31 (s, 1 H). [00783] methyl 2-(3 -tert-butyl-5 -(2,4-dioxo-3 ,4-dihydropyrimidin- 1 (2H)-yl)-2-methoxyphen ethyl)-5- (methylsulfonamido)benzoate (compound IB-L5-2-1.1). 1H NMR (300 MHz, DMSO-d6) δ 1.34 (s, 9 H) 2.83 - 2.92 (m, 2 H) 2.96 (s, 3 H) 3.14 (dd, J=10.30, 5.88 Hz, 2 H) 3.75 (s, 3 H) 3.83 (s, 3 H) 5.64 (d, J=7.72 Hz, 1 H) 7.13 (d, J=2.94 Hz, 1 H) 7.20 (d, J=2.57 Hz, 1 H) 7.28 - 7.36 (m, 2 H) 7.61 - 7.71 (m, 2 H) 9.88 (s, I H) 11.39 (s, I H)
[00784]N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-methoxyphenethyl)phenyl) methanesulfonamide (compound IB-L5-2-1.2). 1H NMR (300 MHz, DMSO-d6): δ 11.39 (s,lH), 9.60 (s,lH), 7.65 (d, J=8.1Hz,lH), 7.23(m,3H), 7.17(m,3H), 5.64(d,J=7.7Hz,lH), 3.77(s,3H), 2.93(s,3H),
2.88(bs,4H), 1.35(s,9H)
[00785] The following compounds can be prepared utilizing the above discussion:
TABLE A
Figure imgf000151_0001
IA-L1-1.15
[00786] HCV Polymerase Inhibition Assay
[00787] Either two-fold serial dilutions (fractional inhibition assay) or a narrower range of dilutions spanning the IC50 of the inhibitor (tight binding assay) of the inhibitors were incubated with 2OmM Tris- Cl pH 7.4, 2mM MnCl2, ImM dithiothreitol, ImM ethylene diamine tetraacetic acid (EDTA), 60 to 125μM GTP and 20 to 5OnM Δ21 NS5B (HCV Strain IB (BK, Genbank accession number M58335, or H77, Genbank accession number AFOl 1751)) for 15min at room temperature. The reaction was initiated by the addition of 20μM CTP, 20μM ATP, lμM 3H-UTP (lOmCi/umol), 5nM template RNA and 0.1 U/μl RNase inhibitor (RNasin, Promega), and allowed to proceed for 2 to 4h at room temperature. Reaction volume was 50μl. The reaction was terminated by the addition of 1 volume of 4mM spermine in 1OmM Tris-Cl pH 8.0, ImM EDTA. After incubation for at least 15 min at room temperature, the precipitated RNA was captured by filtering through a GF/B filter (Millipore) in a 96 well format. The filter plate was washed three times with 200μl each of 2mM spermine, 1OmM Tris-Cl pH 8.0, ImM EDTA, and 2 times with ethanol. After air-drying, 30μl of Microscint 20 scintillation cocktail (Packard) was added to each well, and the retained cpm were determined by scintillation counting. IC50 values were calculated by a two-variable nonlinear regression equation using an uninhibited control and a fully inhibited control sample to determine the minimum and maximum for the curve. Tight-binding assays were performed on those compounds exhibiting IC50 values less than 0.005μM in the fractional inhibition assay in order to more precisely measure the IC50 values. Retained cpm were plotted vs. inhibitor concentration and fit to equation 1 using non-linear regression (ref. 1) to obtain the IC5O values:
Retained cpm=A[sqrt{(IC5o+IrEt)Λ2+4*IC5o*Et} -(IC5o+It-Et)] (eqn 1 ) where A=Vmax[S]/2(Km+[S]); It=total inhibitor concentration and Et=total active concentration of enzyme.
[00788] Ref. Morrison, J. F. and S. R. Stone. 1985. Approaches to the study and analysis of the inhibition of enzymes by slow- and tight-binding inhibitors. Comments MoI. Cell. Biophys. 2: 347-368. [00789] The sequence of the template RNA used was: 5'-GGGCGAAUUG GGCCCUCUAG AUGCAUGCUC GAGCGGCCGC CAGUGUGAUG GAUAUCUGCA GAAUUCGCCC UUGGUGGCUC CAUCUUAGCC CUAGUCACGG CUAGCUGUGA AAGGUCCGUG AGCCGCUUGA CUGCAGAGAG UGCUGAUACU GGCCUCUCUG CAGAUC AAGUC-3' [00790] When tested by the above method, the compounds of this invention inhibit HCV polymerase IA and/or IB. The legend in the table below is as follows: A - IC50 < 0.0IuM; B - 0.IuM > IC50 > 0.0IuM; C - IuM > IC50 > 0.IuM; and D - IC50 > IuM; ND - not determined.
Figure imgf000152_0001
Figure imgf000152_0002
Figure imgf000153_0001
[00791] HCV Polymerase Replicon Assay
[00792] Two stable subgenomic replicon cell lines were used for compound characterization in cell culture: one derived from genotype la-H77 and one derived from genotype lb-Conl (obtained from Apath, LLC, St. Louis, MO). All replicon constructs were bicistronic subgenomic replicons similar to those described by Bartenschlager and coworkers (Lohmann et al., Replication of Subgenomic Hepatitis C Virus RNAs in a Hepatoma Cell Line, SCIENCE 285: 110-3(1999)). The genotype Ia replicon construct contains NS3-NS5B coding region derived from the H77 strain of HCV (la-H77) (Blight et al., Efficient Replication of Hepatitis C Virus Genotype Ia RNAs in Cell Culture, J. VlROL. 77:3181-90 (2003)). The replicon also has a firefly luciferase reporter and a neomycin phosphotransferase (Neo) selectable marker. These two coding regions, separated by the FMDV 2a protease, comprise the first cistron of the bicistronic replicon construct, with the second cistron containing the NS3-NS5B coding region with addition of adaptive mutations E1202G, K1691R, K2040R and S2204I. The lb-Conl replicon construct is identical to the la-H77 replicon, except that the NS3-NS5B coding region was derived from the lb-Conl strain, and the adaptive mutations are E1202G, T 12801 and S2204I. Replicon cell lines were maintained in Dulbecco's modified Eagles medium (DMEM) containing 10% (v/v) fetal bovine serum (FBS), 100 IU/ml penicillin, lOOmg/ml streptomycin (Invitrogen), and 200mg/ml G418 (Invitrogen). [00793] The inhibitory effects of compounds on HCV replication were determined by measuring activity of the luciferase reporter gene. Briefly, replicon-containing cells were seeded into 96 well plates at a density of 5000 cells per well in lOOul DMEM containing 5% FBS. 16-24h later, the compounds were diluted in dimethyl sulfoxide (DMSO) to generate a 20Ox stock in a series of eight half-log dilutions. The dilution series was then further diluted 100-fold in the medium containing 5% FBS. Medium with the inhibitor was added to the overnight cell culture plates already containing lOOul of DMEM with 5% FBS. In assays measuring inhibitory activity in the presence of human plasma, the medium from the overnight cell culture plates was replaced with DMEM containing 40% human plasma and 5% FBS. The cells were incubated for three days in the tissue culture incubators and were then lysed for RNA extraction. For the luciferase assay, 30ul of Passive Lysis buffer (Promega) was added to each well, and then the plates were incubated for 15min with rocking to lyse the cells. Luciferin solution (50 to 10OuI, Promega) was added to each well, and luciferase activity was measured with a Victor II luminometer (Perkin-Elmer). The percent inhibition of HCV RNA replication was calculated for each compound concentration and the EC5O value was calculated using nonlinear regression curve fitting to the 4-parameter logistic equation and GraphPad Prism 4 software.
[00794] When tested by the above method, the compounds of this invention inhibit HCV polymerase IA and/or IB. The legend in the table below is as follows: A - EC50 < 0.0IuM; B - O.luM > EC50 > 0.0IuM; C - IuM > EC50 > O.luM; and D - EC50 > IuM; ND - not determined.
Figure imgf000154_0001
Figure imgf000155_0001
*********** [00795] All references (patent and non-patent) cited above are incorporated by reference into this patent application. The discussion of those references is intended merely to summarize the assertions made by their authors. No admission is made that any reference (or a portion of ay reference) is relevant prior art (or prior art at all). Applicants reserve the right to challenge the accuracy and pertinence of the cited references.

Claims

WE CLAIM:
1. A compound or salt thereof, wherein: the compound corresponds in structure to formula I:
Figure imgf000157_0001
~-= is selected from the group consisting of single carbon-carbon bond and double carbon- carbon bond;
R1 is selected from the group consisting of hydrogen, methyl, and nitrogen-protecting group;
R2 is selected from the group consisting of hydrogen, halo, hydroxy, methyl, cyclopropyl, and cyclobutyl;
R3 is selected from the group consisting of hydrogen, halo, oxo, and methyl;
R4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein:
(a) the amino, aminocarbonyl, and aminosulfonyl optionally are substituted with:
(1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl, or
(2) two substituents that, together with the amino nitrogen, form a single- ring heterocyclyl, and
(b) the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, and alkylsulfonyl, optionally are substituted with one or more substituents independently selected from the group consisting of halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl, and heterocyclyl, wherein: the amino optionally is substituted with:
(1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl, or
(2) two substituents that, together with the amino nitrogen, form a single- ring heterocyclyl, and
(c) the carbocyclyl and heterocyclyl optionally are substituted with up to three substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl, and heterocyclyl, wherein: the amino optionally is substituted with:
(1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl, or
(2) two substituents that, together with the amino nitrogen, form a single- ring heterocyclyl;
R5 is selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, carbocyclylsulfonyloxy, haloalkylsulfonyloxy, and halo;
L is selected from the group consisting of C(RA)=C(RB), ethylene, and cyclopropyl-l,2-ene;
RA and RB are independently selected from the group consisting of hydrogen, Ci-C6-alkyl, C1-C6- alkyloxy, C3-Cg-cycloalkyl, and halo, wherein: the Ci-Cβ-alkyl optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, halo, hydroxy, nitro, oxo, amino, cyano, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, and heterocyclyl;
R6 is selected from the group consisting of C5-C6-carbocyclyl and 5-6-membered heterocyclyl, wherein each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ; each RE is independently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, cyano, amino, imino, azido, and aldehydo, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl; each RF is independently selected from the group consisting of alkyl, alkenyl, and alkynyl, wherein: each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, imino, aminosulfonyl, aminocarbonyl, carbocyclyl, and heterocyclyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkylsulfonylamino, hydroxy, and alkyloxy, wherein: amino portion of the alkylsulfonylamino optionally is substituted with a substituent selected from the group consisting of alkyl, alkenyl, and alkynyl; each RG is independently selected from the group consisting of carbocyclyl and heterocyclyl, wherein: each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl; each RH is independently selected from the group consisting of alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, alkenylsulfonyloxy, and alkynylsulfonyloxy, wherein: each such substituent optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl; each R1 is independently selected from the group consisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aminocarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl, and heterocyclylcarbonyl, wherein:
(a) the alkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl optionally are substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, and (b) the aminocarbonyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxyalkyl, carbocyclyl, heterocyclyl, alkylsulfonyl, and alkylsulfonylamino, wherein: the carbocyclyl and heterocyclyl optionally are substituted with one or two substituents independently selected from the group consisting of halo, alkyl, and oxo; each RJ is independently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, alkyloxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, aminocarbonylamino, alkyloxycarbonylaminoimino, alkylsulfonylaminoimino, alkenylsulfonylaminoimino, and alkynylsulfonylaminoimino, wherein:
(a) the amino portion of such substituents optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkenyl, alkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
(1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido, oxo, and amino, and
(2) the amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl,
(b) the alkyl, alkenyl, and alkynyl portion of such substituents optionally is substituted with one or more substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, and alkynyloxy, wherein: the alkyl optionally is substituted with one or more hydroxy; (c) the carbocyclyl and heterocyclyl portions of such substituents optionally are substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido, and amino, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl; and each Rκ is independently selected from the group consisting of aminosulfonyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl, wherein:
(a) the alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl optionally are substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl; and
(b) the aminosulfonyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl.
2. The compound or salt of claim 1, wherein: R1 is selected from the group consisting of hydrogen and methyl; R2 is selected from the group consisting of hydrogen and halo; R3 is selected from the group consisting of hydrogen and halo;
R4 is selected from the group consisting of Ci-C4-alkyl, C3-C6-carbocyclyl, and 5-6-membered heterocyclyl, wherein:
(a) the Ci-C4-alkyl optionally is substituted with up to three substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and
(b) the C3-C6-carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, halo, and alkylsulfonylamino;
R5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy, and halo; one of RA and RB is hydrogen, and the other is selected from the group consisting of hydrogen, methyl, methoxy, and halo;
R6 is selected from the group consisting of C5-C6-carbocyclyl and 5-6-membered heterocyclyl, wherein each such substituent is substituted with one, two, three substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ, and Rκ; each RE is independently selected from the group consisting of chloro, fluoro, nitro, hydroxy, oxo, carboxy, amino, imino, aldehydo, and alkylamino; each RF is an independently selected alkyl optionally substituted with a substituent selected from the group consisting of carboxy, halo, amino, imino, and aminosulfonyl, wherein: the amino, imino, and aminosulfonyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, alkylsulfonyl, and alkylsulfonylamino; each R1 is independently selected from the group consisting of alkylcarbonyl and aminocarbonyl, wherein: the aminocarbonyl optionally is substituted with a substituent selected from the group consisting of alkyl, alkyloxyalkyl, alkylsulfonyl, and alkylsulfonylamino; each RJ is independently selected from the group consisting of alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, and alkylsulfonylaminoimino, wherein:
(a) the amino portion of such substituents optionally is substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
(1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl optionally are substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and
(2) the amino portion of the aminocarbonylalkyl optionally is substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, and alkynyl,
(b) the alkyl, alkenyl, and alkynyl portion of such substituents optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein: the amino optionally is substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, wherein: the alkyl optionally is substituted with one or more hydroxy; and each Rκ is independently selected from the group consisting of aminosulfonyl and alkylsulfonyl, wherein:
(a) the alkylsulfonyl optionally is substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl; and
(b) the aminosulfonyl optionally is substituted with one or two substituents independently selected alkyl.
3. The compound or salt of any one of claims land 2, wherein R6 is selected from the group consisting of C5-C6-carbocyclyl and 5-6-membered heterocyclyl, wherein each such substituent is substituted with one, two, or three substituents independently selected from the group consisting of RE, RF, R1, RJ, and Rκ.
4. The compound or salt of any one of claims 1-3, wherein: R1 is hydrogen;
R2 is selected from the group consisting of hydrogen and halo;
R3 is hydrogen;
R4 is tert-butyl;
R5 is selected from the group consisting of hydroxy and methoxy;
RA is hydrogen; and
RB is hydrogen.
5. The compound or salt of any one of claims 1-4, wherein:
R6 is selected from the group consisting of C5-C6-carbocyclyl and 5-6-membered heterocyclyl, wherein each such substituent is substituted with one, two, or three substituents independently selected from the group consisting of RE, RF, and RJ.
6. The compound or salt of any one of claims 1-5, wherein:
R6 is selected from the group consisting of C5-C6-carbocyclyl and 5-6-membered heterocyclyl, wherein each such substituent is substituted with a substituent selected from the group consisting of RF and RJ;
RF is alkylsulfonylaminoalkyl; and
RJ is alkylsulfonylamino.
7. The compound or salt of any one of claims 1-6, wherein:
R6 is phenyl substituted with a substituent selected from the group consisting of RF and RJ; RF is alkylsulfonylaminoalkyl; and RJ is alkylsulfonylamino.
8. The compound or salt of any one of claims 1-7, wherein L is C(RA)=C(RB).
*
9. The compound or salt of any one of claims 1-8, wherein ÷^= is a double carbon-carbon bond.
10. A compound or salt thereof, wherein the compound is selected from the group of compounds shown in Tables 1-7.
11. (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3 ,4-dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl) phenyl)methanesulfonamide crystalline form selected from the group consisting of: crystalline (E)-N-(4-(3 -tert-butyl-5 -(2,4-dioxo-3 ,4-dihydropyrimidin- 1 (2H)-yl)-2-methoxystyry 1) phenyl)methanesulfonamide disodium salt nonahydrate having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 4.3±0.2, 10.4±0.2, 10.9±0.2, 11.6±0.2, 12.9±0.2, 14.7±0.2, 16.4±0.2, 17.8±0.2, 19.4±0.2, 19.8±0.2, 20.8±0.2, 21.9±0.2, and 23.5±0.2 degrees 2Θ; crystalline (E)-N-(4-(3 -tert-butyl-5 -(2,4-dioxo-3 ,4-dihydropyrimidin- 1 (2H)-yl)-2-methoxystyry 1) phenyl)methanesulfonamide disodium salt nonahydrate having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 4.3±0.2, 10.4±0.2, 10.9±0.2, 11.6±0.2, 12.9±0.2, 14.7±0.2, 14.9±0.2, 16.4±0.2, 17.8±0.2, 19.4±0.2, 19.7±0.2, 19.8±0.2, 20.8±0.2, 20.9±0.2, 21.9±0.2, 22.1±0.2, and 23.5±0.2 degrees 2Θ; crystalline (E)-N-(4-(3 -tert-butyl-5 -(2,4-dioxo-3 ,4-dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl) phenyl)methanesulfonamide disodium salt nonahydrate having an X-ray powder diffraction pattern substantially as shown in Figure 1; crystalline (E)-N-(4-(3 -tert-butyl-5 -(2,4-dioxo-3 ,4-dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl) phenyl)methanesulfonamide nonahydrate disodium salt having cell unit parameters, wherein a is 8.9A, b is 9.4A, and c is 20.7A; crystalline (E)-N-(4-(3 -tert-butyl-5 -(2,4-dioxo-3 ,4-dihydropyrimidin- l(2H)-yl)-2-methoxystyryl) phenyl)methanesulfonamide disodium salt tetrahydrate having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 4.8±0.2, 12.1±0.2, 14.0±0.2, 17.0±0.2, 17.5±0.2, 20.9±0.2, 21.6±0.2, 25.0±0.2, and 29.5±0.2 degrees 2Θ; crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyriraidin-l(2H)-yl)-2-methoxystyryl) phenyl)methanesulfonamide disodium salt tetrahydrate having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 4.8±0.2, 12.1±0.2, 14.0±0.2, 14.4±0.2, 17.0±0.2, 17.5±0.2, 20.9±0.2, 21.6±0.2, 25.0±0.2, 29.5±0.2, and 34.2±0.2 degrees 2Θ; crystalline (E)-N-(4-(3 -tert-butyl-5 -(2,4-dioxo-3 ,4-dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl) phenyl)methanesulfonamide disodium salt tetrahydrate having an X-ray powder diffraction pattern substantially as shown in Figure 2; crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-methoxystyryl) phenyl)methanesulfonamide dipotassium salt tetrahydrate having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 5.0±0.2, 1 1.9±0.2, 12.4±0.2, 13.7±0.2, 15.0±0.2, 16.5±0.2, 17.1±0.2, 20.8±0.2, 21.3±0.2, 22.2±0.2, 24.0±0.2, 26.4±0.2, and 29.3±0.2 degrees 2Θ; crystalline (E)-N-(4-(3 -tert-butyl-5 -(2,4-dioxo-3 ,4-dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl) phenyl)methanesulfonamide dipotassium salt tetrahydrate having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 5.0±0.2, 1 1.9±0.2, 12.4±0.2, 12.6±0.2, 13.7±0.2, 15.0±0.2, 16.5±0.2, 16.7±0.2, 17.1±0.2, 20.7±0.2, 20.8±0.2, 21.3±0.2, 22.2±0.2, 22.4±0.2, 24.0±0.2, 26.4±0.2, and 29.3±0.2 degrees 2Θ; crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3 ,4-dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl) phenyl)methanesulfonamide dipotassium salt tetrahydrate having an X-ray powder diffraction pattern substantially as shown in Figure 4; crystalline (E)-N-(4-(3 -tert-butyl-5-(2,4-dioxo-3 ,4-dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl) phenyl)methanesulfonamide dipotassium salt tetrahydrate having unit cell parameters, wherein a is 14.5A, b is 10.8A, and c is 35.8A; crystalline (E)-N-(4-(3 -tert-butyl-5-(2,4-dioxo-3 ,4-dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl) phenyl)methanesulfonamide monopotassium salt trihydrate having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 4.8±0.2, 10.8±0.2, 11.3±0.2, 13.4±0.2, 15.3±0.2, 16.9±0.2, 21.2±0.2, 21.7±0.2, 22.1±0.2, 22.5±0.2, and 23.0±0.2 degrees 2Θ; crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-methoxystyryl) phenyl)methanesulfonamide monopotassium salt trihydrate having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 4.8±0.2, 10.8±0.2, 11.3±0.2, 13.4±0.2, 13.6±0.2, 15.3±0.2, 16.9±0.2, 21.2±0.2, 21.7±0.2, 21.7±0.2, 22.1±0.2, 22.5±0.2, 22.6±0.2, and 23.0±0.2 degrees 2Θ; crystalline (E)-N-(4-(3 -tert-butyl-5 -(2,4-dioxo-3 ,4-dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl) phenyl)methanesulfonamide monopotassium salt trihydrate having an X-ray powder diffraction pattern comprising five or more peaks selected from the group consisting of 4.8±0.2, 10.8±0.2, 11.3±0.2, 13.4±0.2, 15.3±0.2, 16.9±0.2, 21.2±0.2, 21.7±0.2, 22.1±0.2, 22.5±0.2, and 23.0±0.2 degrees 2Θ; crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-methoxystyryl) phenyl)methanesulfonamide monopotassium salt trihydrate having unit cell parameters, wherein a is 9.0A, b is 8.3 A, and c is 18.6A; crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-methoxystyryl) phenyl)methanesulfonamide monopotassium salt dihydrate having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 7.7±0.2, 8.8±0.2, 16.1±0.2, and 19.7±0.2 degrees 2Θ; crystalline (E)-N-(4-(3 -tert-butyl-5 -(2,4-dioxo-3 ,4-dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl) phenyl)methanesulfonamide monopotassium salt dihydrate having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 7.7±0.2, 8.8±0.2, 12.4±0.2, 14.0±0.2, 16.1±0.2, 17.7±0.2, 19.2±0.2, 19.7±0.2, 23. l±0.2, and 29.2±0.2 degrees 2Θ; crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-methoxystyryl) phenyl)methanesulfonamide monopotassium salt dihydrate having an X-ray powder diffraction pattern substantially as shown in Figure 6; crystalline (E)-N-(4-(3 -tert-butyl-5-(2,4-dioxo-3 ,4-dihydropyrimidin- 1 (2H)-yl)-2-methoxysryryl) phenyl)methanesulfonamide 1/7 potassium salt having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 7.7±0.2, 8.3±0.2, 10.1±0.2, 10.6±0.2, 11.4±0.2, 12.0±0.2, 13.4±0.2, 15.6±0.2, 16.3±0.2, 16.7±0.2, 17.2±0.2, 18.3±0.2, 18.8±0.2, 19.4±0.2, 19.9±0.2, 20.2±0.2, 20.5±0.2, 21.2±0.2, 22.1±0.2, and 22.9±0.2 degrees 2Θ; crystalline (E)-N-(4-(3 -tert-butyl-5 -(2,4-dioxo-3 ,4-dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl) phenyl)methanesulfonamide 1/7 potassium salt having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 7.7±0.2, 8.3±0.2, 10.1±0.2, 10.6±0.2, 1 1.4±0.2, 12.0±0.2, 13.4±0.2, 15.6±0.2, 16.3±0.2, 16.7±0.2, 17.2±0.2, 18.3±0.2, 18.8±0.2, 19.4±0.2, 19.9±0.2, 20.2±0.2, 20.5±0.2, 20.8±0.2, 21.2±0.2, 22.1±0.2, 22.9±0.2, 24.3±0.2, 24.9±0.2, and 25.1±0.2 degrees 2Θ; crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-methoxystyryl) phenyl)methanesulfonamide 1/7 potassium salt having an X-ray powder diffraction pattern substantially as shown in Figure 8; crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin- 1 (2H)-yl)-2-methoxystyryl) phenyl)methanesulfonamide monodiethylamine salt tetrahydrate having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 9.5±0.2, 10.0±0.2, 11.8±0.2, 12.1±0.2, 14.4±0.2, 16.8±0.2, 17.6±0.2, 19.8±0.2, 20.8±0.2, 21.4±0.2, 21.8±0.2, and 29.8±0.2 degrees 2Θ; crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-methoxystyryl) phenyl)methanesulfonamide monodiethylamine salt tetrahydrate having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 9.5±0.2, 10.0±0.2, 11.8±0.2, 12.1±0.2, 14.4±0.2, 16.8±0.2, 17.6±0.2, 19.4±0.2, 19.8±0.2, 20.8±0.2, 21.4±0.2, 21.8±0.2, 21.9±0.2, and 29.8±0.2 degrees 2Θ; crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-methoxystyryl) phenyl)methanesulfonamide monodiethylamine salt tetrahydrate having an X-ray powder diffraction pattern substantially as shown in Figure 9; crystalline pattern A (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 5.8±0.2, 9.9±0.2, 11.8±0.2, 12.4±0.2, 14.5±0.2, 18.8±0.2, 22.7±0.2, and 29.2±0.2 degrees 2Θ; crystalline pattern A (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 5.8±0.2, 9.9±0.2, 11.8±0.2, 12.4±0.2, 14.0±0.2, 14.5±0.2, 15.3±0.2, 18.5±0.2, 18.8±0.2, 22.2±0.2, 22.7±0.2, 23.8±0.2, 26.0±0.2, and 29.2±0.2 degrees 2Θ; crystalline pattern A (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide having an X-ray powder diffraction pattern substantially as shown in Figure 11; crystalline pattern B (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 11.5±0.2, 13.3±0.2, 15.4±0.2, 16.4±0.2, 17.1±0.2, 18.6±0.2, 19.4±0.2, 20.4±0.2, 21.6±0.2, 22.4±0.2, 24.0±0.2, 26.8±0.2, and 29.0±0.2 degrees 2Θ; crystalline pattern B (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide having an X-ray powder diffraction pattern substantially as shown in Figure 13; crystalline pattern C (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 7.7±0.2, 10.1±0.2, 10.6±0.2, 12.0 ±0.2, 13.4±0.2, 16.2±0.2, 19.4±0.2, 20.5±0.2, 21.4±0.2, 22.0±0.2, 22.6±0.2, 24.3±0.2, and 27.6±0.2 degrees 2Θ; crystalline pattern C (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide having an X-ray powder diffraction pattern substantially as shown in Figure 14; crystalline pattern D (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 5.8±0.2, 10.7±0.2, 1 1.2±0.2, 15.2±0.2, 16.1±0.2, 16.9±0.2, 19.9±0.2, 22.1±0.2, 24.7±0.2, and 26.0±0.2 degrees 2Θ; crystalline pattern D (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 5.8±0.2, 10.7±0.2, 11.2±0.2, 15.2±0.2, 16.1±0.2, 16.9±0.2, 17.1±0.2, 19.9±0.2, 20.1±0.2, 22.1±0.2, 24.7±0.2, and 26.0±0.2 degrees 2Θ; crystalline pattern D (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide having an X-ray powder diffraction pattern substantially as shown in Figure 15; crystalline pattern A (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide hydrate having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 5.1±0.2, 7.9±0.2, 9.5±0.2, 10.3±0.2, 13.7±0.2, 16.5±0.2, 17.1±0.2, 17.5±0.2, 18.8±0.2, 19.2±0.2, 20.7±0.2, 21.3±0.2, 21.6±0.2, 25.8±0.2, 26.8±0.2, and 28.4±0.2 degrees 2Θ; crystalline pattern A (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide hydrate having an X-ray powder diffraction pattern substantially as shown in Figure 16; crystalline pattern A (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide hydrate having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 6.3±0.2, 7.7±0.2, 10.4±0.2, 12.7±0.2, 13.3±0.2, 14.9±0.2, 15.4±0.2, 16.4±0.2, 18.6±0.2, 18.9±0.2, 19.4±0.2, 22.5±0.2, 23.5±0.2, 24.0±0.2, 26.8±0.2, and 29.0±0.2 degrees 2Θ; crystalline pattern B (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide hydrate having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 6.3±0.2, 7.7±0.2, 10.4±0.2, 12.7±0.2, 13.3±0.2, 13.5±0.2, 14.9±0.2, 15.4±0.2, 16.4±0.2, 18.5±0.2, 18.6±0.2, 18.9±0.2, 19.4±0.2, 22.5±0.2, 23.5±0.2, 24.0±0.2, 26.8±0.2, and 29.0±0.2 degrees 2Θ; crystalline pattern B (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide hydrate having an X-ray powder diffraction pattern substantially as shown in Figure 18; crystalline pattern C (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide hydrate having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 10.5±0.2, 13.3±0.2, 14.9±0.2, 15.4±0.2, 16.4±0.2, 18.6±0.2, 19.0±0.2, 19.4±0.2, 22.5±0.2, 23.5±0.2, 26.9±0.2, and 29.0±0.2 degrees 2Θ; crystalline pattern C (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide hydrate having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 10.5±0.2, 13.3±0.2, 13.5±0.2, 14.9±0.2, 15.4±0.2, 16.4±0.2, 18.6±0.2, 19.0±0.2, 19.4±0.2, 22.5±0.2, 23.5±0.2, 26.9±0.2, and 29.0±0.2 degrees 2Θ; crystalline pattern C (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide hydrate having an X-ray powder diffraction pattern substantially as shown in Figure 20; crystalline pattern D (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide hydrate having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 6.6±0.2, 10.0±0.2, 10.5±0.2, H .l±O.2, 11.6=1=0.2, 12.2±0.2, 14.2±0.2, 16.6±0.2, 17.1±0.2, 17.7±0.2, 18.5±0.2, 18.8±0.2, 19.3±0.2, 21.4±0.2, 22.7±0.2, 23.1±0.2, 23.6±0.2, 24.6±0.2, 25.2±0.2, 27.2±0.2, 29.1±0.2, and 31.0±0.2 degrees 2Θ; crystalline pattern D (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide hydrate having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 6.6±0.2, 10.0±0.2, 10.5±0.2, l l .l±0.2, 11.6±0.2, 12.2±0.2, 12.5±0.2, 14.2±0.2, 16.6±0.2, 17.1±0.2, 17.7±0.2, 18.5±0.2, 18.8±0.2, 19.3±0.2, 21.4±0.2, 22.7±0.2, 22.8±0.2, 23.1±0.2, 23.6±0.2, 24.6±0.2, 24.9±0.2, 25.2±0.2, 27.2±0.2, 29.1±0.2, and 31.0±0.2 degrees 2Θ; crystalline pattern D (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide hydrate having an X-ray powder diffraction pattern substantially as shown in Figure 22; crystalline pattern D (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide hydrate having unit cell parameters, wherein a is 17.8 A, b is 9.6A, and c is 27.0A; crystalline pattern E (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide hydrate having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 6.2±0.2, 7.8±0.2, 10.2±0.2, 10.7±0.2, 12.1±0.2, 16.3±0.2, 19.7±0.2, 20.9±0.2, 21.8±0.2, 24.5±0.2, and 28.0±0.2 degrees 2Θ; crystalline pattern E (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide hydrate having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 6.2±0.2, 7.8±0.2, 10.2±0.2, 10.4±0.2, 10.7±0.2, 12.1±0.2, 16.3±0.2, 19.7±0.2, 20.9±0.2, 21.8±0.2, 24.5±0.2, and 28.0±0.2 degrees 2Θ; crystalline pattern E (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide hydrate having an X-ray powder diffraction pattern substantially as shown in Figure 23; and crystalline pattern E (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxystyryl)phenyl)methanesulfonamide hydrate having unit cell parameters, wherein a is 9.5A, b is 14.5A, and c is l7.3A.
12. A composition comprising (a) one or more compounds and/or salts recited in any one of claims 1-10 or one or more crystalline forms recited in claim 11; (b) one or more excipients; and, optionally, (c) one or more additional therapeutic agents.
13. A method for inhibiting replication of a ribonucleic acid (RNA) virus, wherein the method comprises exposing the virus to one or more compounds and/or salts recited in any one of claims 1-10 or one or more crystalline forms recited in claim 11.
14. A method for treating hepatitis C in a mammal in need of such treatment, wherein the method comprises administering to the mammal one or more compounds and/or salts recited in any one of claims 1-10 or one or more crystalline forms recited in claim 11, and, optionally, one or more additional therapeutic agents.
15. A process for preparing the compound or salt of claim 1, wherein the process comprises reacting a compound of formula III (wherein R1, R2, and R3 are as defined in claim 1) with a compound of formula IV (wherein R4 and R5 are as defined in claim 1; X1 is halo; and X2 is selected from the group consisting of chloro, bromo, and iodo) in the presence of (i) copper (I) salt catalyst and (ii) nitrogenous heteroaryl ligand
Figure imgf000170_0001
16. The process of any one of claims 20 and 21, wherein the process is conducted in the presence of a base.
17. The process of claim 16, wherein the base is selected from the group consisting of potassium salt, sodium salt, and cesium salt.
18. The process of any one of claims 15-17, wherein the nitrogenous heteroaryl ligand comprises a picolinamide compound corresponding in structure to formula V:
Figure imgf000171_0001
R11, R12, R13, R14, R15, R16, and R17 are independently selected from the group consisting of hydrogen, Ci-4-perfluoroalkyl, C].4-alkyloxy, Ci-4-haloalkyl, chloro, and cyano.
19. The process of any one of claims 15-17, wherein the nitrogenous heteroaryl ligand is selected from the group consisting of 8-hydroxyquinoline, 2-(2-pyridyl)-benzimidazole, N-(4-cyano- phenyl)picolinamide, and N-(2-cyanophenyl)picolinamide.
20. The process of any one of claims 15-19, wherein the copper catalyst is selected from the group consisting of CuI, CuBr, CuCl, Cu2O, and CH3C(O)OCu.
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