WO2005105777A1 - Substituted thiophene amide compounds for the treatment of inflammation - Google Patents

Substituted thiophene amide compounds for the treatment of inflammation Download PDF

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WO2005105777A1
WO2005105777A1 PCT/IB2005/001123 IB2005001123W WO2005105777A1 WO 2005105777 A1 WO2005105777 A1 WO 2005105777A1 IB 2005001123 W IB2005001123 W IB 2005001123W WO 2005105777 A1 WO2005105777 A1 WO 2005105777A1
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alkyl
group
membered
amino
aryl
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PCT/IB2005/001123
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French (fr)
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Dominique Bonafoux
Michael Clare
Theresa Reher Fletcher
Bruce Cameron Hamper
Patrick James Lennon
William D. Mcghee
David Scott Oburn
Matthew Todd Reding
Michael Brent Tollefson
Serge G. Wolfson
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Pharmacia & Upjohn Company Llc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07D409/12—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 chain containing hetero atoms as chain links

Definitions

  • This invention generally relates to anti-inflammatory pharmaceutical agents and specifically relates to thiophene compounds as inhibitors of IKK-2, an kB kinase.
  • the invention is further related to compositions comprising such compounds, and methods for treating cancer, inflammation, and inflammation-associated disorders such as arthritis.
  • Rheumatoid arthritis is a common inflammatory disease affecting approximately 1 % of the population. The disease is characterized by multiple painful swollen joints that severely limit the patient's daily function, and can progress to the destruction of the affected joints.
  • a common treatment for rheumatoid arthritis is anti-inflammatory steroids. Steroids are clinically very effective, but are limited in their use because of multiple severe side-effects. Thus, a need exists for an anti- rheumatoid arthritis treatment that offers the potency of steroids without the associated toxicity.
  • One of the mechanisms by which steroids exert their broad spectrum anti-inflammatory action is by inhibiting the activation of the transcription factor NF-/ B.
  • NF- ⁇ B plays a prominent role in immune and inflammatory responses by regulating the transcription of many early, inducible genes in a variety of cells including inflammatory enzymes such as COX-2 and iNOS.
  • NF- ⁇ B is sequestered in an inactive form in the cytoplasm by a member of the kB family of inhibitory proteins, and this prevents gene transcription of these responsive genes in the nucleus. Stimulation of cells leads to the phosphorylation, ubiquination and degradation of kB thereby releasing NF- B to the nucleus for activation of gene transcription.
  • Chronic activation of NF-/ B has been demonstrated in vascular endothelium and synovial lining cells from patients with RA.
  • IKK-1 and IKK-2 which phosphorylate kB and thereby initiate its degradation, have been cloned and initially characterized; these kinases appear to represent the critical, common denominator in the activation of NF-/cB since antisense or dominant-negative IKK constructs block NF- B nuclear translocation and inhibit NF- ⁇ B linked reported genes. Therefore, IKK-1 and/or IKK-2 represent novel and powerful targets for drug development. [0003] It has been reported that selective IKK-2 inhibitors could be useful for the treatment of inflammatory diseases. See, e.g., Karin et al.. Nat. Revs. 3. 17-26, 2004. [0004] PCT Publication No.
  • WO 01/58890 describes thiophenecarboxamides as inhibitors of IKK-2.
  • PCT Publication No. WO 02/30353 describes 2-aminothiophene-3-carboxamides as NF- ⁇ B inhibitors.
  • PCT Publication No. WO 03/10163 describes ureido-carboxamido thiophene compounds as inhibitors of IKK-2 kinase.
  • PCT Publication No. WO 03/29242 describes ureido-thiophenecarboxamide derivatives as NF- ⁇ B inhibitors.
  • This invention provides for, in part, IKK-2-inhibiting compounds of Formula I: [0010] wherein R is selected from the group consisting of: [0012] wherein X is selected from the group consisting of a bond, alkyl, cycloalkyl, alkenyl, and heterocycloalkyl; [0013] wherein Y is O or S; [0014] wherein Z is selected from the group consisting of hydrido, halo, alkyl, cyano, and haloalkyl; [0015] wherein R 1 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, or where R 1 and R 2 together with the atoms to which they are attached form a heterocyclic moiety, or where R 1 and
  • the instant invention is also directed to pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically-acceptable salt thereof, as defined above, and a pharmaceutically acceptable carrier, diluent, or adjuvant.
  • the instant invention is also directed to a method of treating or preventing inflammation or an inflammation-associated disorder, the method comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need of such treatment or susceptible to such inflammation or inflammation-associated disorder.
  • Other objects of the invention will be in part apparent and in part pointed out hereinafter.
  • Compounds of Formula I may be useful for treating, among other things, inflammation in a subject, such as, as an analgesic in the treatment of pain and headaches, or as an antipyretic for the treatment of fever.
  • compounds of the present invention may be useful to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, psoriatic arthritis, and pyogenic arthritis.
  • Compounds of the invention may be further useful in the treatment of frailty, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, menstrual cramps (e.g., dysmenorrhea), premature labor, tendinitis, bursitis, dermatological conditions such as psoriasis, eczema, bums, sunburn, dermatitis, pancreatitis, hepatitis, and from post-operative inflammation including from ophthalmic surgery such as cataract surgery and refractive surgery.
  • Compounds of the invention also would be useful to treat , gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis.
  • Compounds of the invention would be useful for the prevention or treatment of cancer, such as colorectal cancer, and cancer of the breast, lung, prostate, bladder, cervix and skin, as well as treatment of cancer stem cells.
  • Compounds of the invention would be useful in treating inflammation and tissue damage in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular junction disease including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, nephritis, hypersensitivity, swelling occurring after injury, myocardial ischemia, and the like.
  • the compounds would also be useful in the treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis.
  • the compounds would also be useful for the treatment of certain central nervous system disorders, such as cortical dementias including Alzheimer's disease, and central nervous system damage resulting from stroke, ischemia and trauma.
  • the compounds of the invention are useful as anti-inflammatory agents, such as for the treatment of arthritis, with the additional benefit of having significantly less harmful side effects.
  • These compounds would also be useful in the treatment of allergic rhinitis, respiratory distress syndrome, and atherosclerosis.
  • the compounds would also be useful in the treatment of pain, but not limited to postoperative pain, dental pain, muscular pain, and pain resulting from cancer.
  • the compounds would be useful for the prevention of dementias, such as Alzheimer's disease.
  • these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
  • the present compounds may also be used in co-therapies, partially or completely, in place of other conventional antiinflammatory therapies, such as together with steroids, NSAIDs, COX-2 selective inhibitors, 5-lipoxygenase inhibitors, LTB antagonists and LTA 4 hydrolase inhibitors.
  • cardiovascular ischemia examples include cardiovascular ischemia, diabetes (type I or type II), congestive heart failure, myocarditis, atherosclerosis, migraine, glaucoma, aortic aneurysm, reflux esophagitis, diarrhea, irritable bowel syndrome, cystic fibrosis, emphysema, asthma, bronchiectasis, hyperalgesia (allodynia), and cerebral ischemia (both focal ischemia, thrombotic stroke and global ischemia (for example, secondary to cardiac arrest).
  • diabetes type I or type II
  • congestive heart failure myocarditis
  • atherosclerosis migraine
  • glaucoma glaucoma
  • aortic aneurysm aortic aneurysm
  • reflux esophagitis diarrhea
  • cystic fibrosis emphysema
  • asthma bronchiectasis
  • hyperalgesia allodynia
  • the compounds of the present invention may also be useful in the treatment of pain including somatogenic (either nociceptive or neuropathic), both acute and chronic.
  • a compound of the present invention could be used in any situation including neuropathic pain that a common NSAID or opioid analgesic would traditionally be administered.
  • Conjunctive treatment of a compound of the present invention with an antineoplastic agent may produce a beneficial effect or alternatively reduce the toxic side effects associated with chemotherapy by reducing the therapeutic dose of the side effect-causing agent needed for therapeutic efficacy or by directly reducing symptoms of toxic side effects caused by the side effect-causing agent.
  • a compound of the present invention may further be useful as an adjunct to radiation therapy to reduce side effects or enhance efficacy.
  • another agent which can be combined therapeutically with a compound of the present invention includes any therapeutic agent which is capable of inhibiting the enzyme cyclooxygenase-2 ("COX-2").
  • COX-2 inhibiting agents inhibit COX-2 selectively relative to the enzyme cyclooxygenase-1 ("COX-1").
  • COX-1 cyclooxygenase-1
  • COX-2 selective inhibitor Such a COX-2 inhibitor is known as a "COX-2 selective inhibitor”.
  • a compound of the present invention can be therapeutically combined with a COX-2 selective inhibitor wherein the COX-2 selective inhibitor selectively inhibits COX-2 at a ratio of at least 10:1 relative to inhibition of COX-1 , more preferably at least 30:1 , and still more preferably at least 50:1 in an In vitro test.
  • COX-2 selective inhibitors useful in therapeutic combination with the compounds of the present invention include celecoxib, valdecoxib, deracoxib, etoricoxib, rofecoxib, ABT- 963 (2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl-3(2H)- pyridazinone; described in PCT Publication No. WO 00/24719), or meloxicam.
  • a compound of the present invention can also be advantageously used in therapeutic combination with a prodrug of a COX-2 selective inhibitor, for example parecoxib.
  • DFMO Alpha-difluoromethylomithine
  • 5-FU-fibrinogen 5-FU-fibrinogen
  • acanthifolic acid amino
  • EX-015 benzrabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N-(2'-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropyl pyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim, methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661 , NCI NSC-612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, Taiho UFT, ur
  • radioprotective agents which may be used in a combination therapy with the compounds of this invention include AD-5, adchnon, amifostine analogues, detox, dimesna, 1-102, MM- 159, N-acylated-dehydroalanines, TGF-Genentech, tiprotimod, amifostine, WR-151327, FUT-187, ketoprofen transdermal, nabumetone, superoxide dismutase (Chiron) and superoxide dismutase Enzon.
  • the compounds of the present invention may also be useful in treatment or prevention of angiogenesis-related disorders or conditions, for example, tumor growth, metastasis, macular degeneration, and atherosclerosis.
  • the present invention also provides therapeutic combinations for the treatment or prevention of ophthalmic disorders or conditions such as glaucoma.
  • the present inventive compounds advantageously may be used in therapeutic combination with a drug which reduces the intraocular pressure of patients afflicted with glaucoma.
  • intraocular pressure-reducing drugs include without limitation latanoprost, travoprost, bimatoprost, or unoprostol.
  • the therapeutic combination of a compound of the present invention plus an intraocular pressure-reducing drug may be useful because each is believed to achieve its effects by affecting a different mechanism.
  • the present inventive compounds can be used in therapeutic combination with an antihyperlipidemic or cholesterol-lowering drug such as a benzothiepine or a benzothiazepine antihyperlipidemic drug.
  • an antihyperlipidemic or cholesterol-lowering drug such as a benzothiepine or a benzothiazepine antihyperlipidemic drug.
  • benzothiepine antihyperlipidemic drugs useful in the present inventive therapeutic combination can be found in U.S. Patent No. 5,994,391, herein incorporated by reference.
  • Some benzothiazepine antihyperlipidemic drugs are described in PCT Publication No. WO 93/16055.
  • the antihyperlipidemic or cholesterol-lowering drug useful in combination with a compound of the present invention can be an HMG Co-A reductase inhibitor.
  • HMG Co-A reductase inhibitors useful in the present therapeutic combination include, individually, benfluorex, fluvastatin, lovastatin, pravastatin, simvastatin, atorvastatin, cerivastatin, bervastatin, ZD-9720 (described in PCT Publication No. WO 97/06802), ZD-4522 (CAS No. 147098-20-2 for the calcium salt; CAS No. 147098-18-8 for the sodium salt; described in European Patent No. EP 521471), BMS 180431 (CAS No. 129829-03-4), or NK-104 (CAS No. 141750-63-2).
  • the therapeutic combination of a compound of the present invention plus an antihyperlipidemic or cholesterol-lowering drug may be useful, for example, in reducing the risk of formation of atherosclerotic lesions in blood vessels.
  • atherosclerotic lesions often initiate at inflamed sites in blood vessels.
  • antihyperlipidemic or cholesterol-lowering drug reduce risk of formation of atherosclerotic lesions by lowering lipid levels in blood.
  • the compounds of the present combination may work in concert to provide improved control of atherosclerotic lesions by, for example, reducing inflammation of the blood vessels in concert with lowering blood lipid levels.
  • the present compounds can be used in combination with other compounds or therapies for the treatment of central nervous conditions or disorders such as migraine.
  • the present compounds can be used in therapeutic combination with caffeine, a 5-HT-1 B/1 D agonist (for example, a triptan such as sumatriptan, naratriptan, zolmitriptan, rizatriptan, almotriptan, or frovatriptan), a dopamine D4 antagonist (e.g., sonepiprazole), aspirin, acetaminophen, ibuprofen, indomethacin, naproxen sodium, isometheptene, dichloralphenazone, butalbital, an ergot alkaloid (e.g., ergotamine, dihydroergotamine, bromocriptine, ergonovine, or methyl ergonovine), a tricyclic antidepressant (e.g., amitriptyline or nortrip
  • the present invention includes compounds that selectively inhibit IKK-2 over other kinases.
  • Such other kinases include, but are not limited to, Abl(h), Abl(T315l), Abl(T315l), AMPK, Aurora- A, BTK, CaMKII, CaMKIV, CDK1/cyclinB, CDK2, CDK2/cyclin A, CDK2/cyclinE, CHK1 , CHK2, CK1 , CK1(y), CK , CK2, c-RAF(h), CSK, cSRC(h), DYRKIa, ERK2, Fyn, GSK3 ⁇ , IGF-1 R, IKK1 , IKKi, IKK2(h), JNK SAPK1C, JNK1, JNK1 ⁇ 1(h), JNK2, JNK2 ⁇ 2(h), JNK3, Lck, MAPK1(h), MAPK2(h), MAPK2/ERK2, MAPKAP-K1 a, MAPKAP-K2, MEK
  • MRSK2/APKAPk1b MSK, MSK1 , NEK2a, NEK6, p38 alpha, p38 beta, p38 delta, p38 gamma, p70 S6K, PAK2, PDGFR ⁇ , PDK1, PHK, PKA, PKB ⁇ ph, PKCf, PKC ⁇ , PKCy, PKC£, PKCe, PRAK, ROCK-II, Rsk1, Rsk2, RSKB, SAPK2a/p38, SAPK2b, SAPK2b/p38 ⁇ 2, SAPK3, SAPK3/p38g, SAPK4, SAPK4/p38d, SGK, TBK-1 , and ZAP-70.
  • the compounds may have an IKK-2 IC 50 of less than about 10 ⁇ M, preferably less than about 1 ⁇ M, and have a selectivity ratio of IKK-2 inhibition over IKK-1 inhibition of at least 50, or at least 100.
  • the compounds may have an IKK-1 IC 50 of greater than 10 ⁇ M, or greater than 100 ⁇ M.
  • the compound of Formula I is a compound of Formula IA: [0044] IA [0045] wherein R is selected from the group consisting of: [0047] wherein X is selected from the group consisting of a bond, alkyl, cycloalkyl, alkenyl, and heterocycloalkyl; [0048] wherein Z is selected from the group consisting of hydrido, halo, alkyl, cyano, and haloalkyl; [0049] wherein R 1 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, or where R 1 and R 2 together with the atoms to which they are attached form a heterocyclic moiety, or where R 1 and R 1a together with the nitrogen to which they are attached form a heterocycl
  • the compound of Formula IA is a compound wherein X is selected from the group consisting of a bond, C ⁇ alkyl, C 3-12 cycloalkyl, C 2 - ⁇ alkenyl, and 3- to 12- membered heterocycloalkyl; [0057] wherein Z is selected from the group consisting of hydrido, halo, C ⁇ . 6 alkyl, cyano, and C 1-6 haloalkyl; [0058] wherein R ,1 is selected from the group consisting of C ⁇ alkyl, C -12 cycloalkyl, C 2 - 6 alkenyl, C 3 .
  • R is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-(C 1-6 alkyl)amino, N,N-di(C 1 _ 6 alkyl)amino, N-(C 3-12 aryl)amino, N- (C- ⁇ - 6 alkyl)-N-(C 3-12 aryl)amino, N-hydroxyamino, N
  • cycloalkyl C ⁇ e alkoxy, C 2 . 6 alkenyl, C 2 . 6 alkenyloxy, C ⁇ aryl, C 3- ⁇ 2 aryloxy, C 4 _ 20 aralkyl, C 4-2 o aralkylcarbonyl, C 4-20 aralkylcarbonylamino, 3- to 14-membered heteroarylcarbonyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 3- to 12-membered heteroaryl, C 2 .
  • R 1a is selected from the group consisting of hydrido, hydroxyl, C,_ 6 alkoxy, C-i_ 6 alkyl, C 1-8 haloalkyl, C 3-12 aryl, and 3- to 12-membered heteroaryl, or where R 1a and R 1 together with the nitrogen to which they are attached form a 3- to 12-membered heterocyclic moiety; [0061] wherein R 2 is selected from the group consisting of hydrido, hydroxyl, C,_ 6 alkoxy, C-i_ 6 alkyl, C 1-8 haloalkyl, C 3-12 aryl, and 3- to 12-membered heteroaryl, or where R 1a and R 1 together with the nitrogen to which they are attached form a 3- to 12-membered heterocyclic moiety; [0061] wherein R 2 is selected from the group consisting of hydrido, hydroxyl, C,_ 6 alkoxy, C-i_ 6 alkyl, C 1-8 haloalkyl,
  • R 3 is selected from the group consisting of C ⁇ -s alkyl, C-,. 6 haloalkyl, and -NR 7 R 8 ; and [0063] wherein R 4 , R 5 , R 6 , R 7 , and R 8 are independently selected from the group consisting of hydrido, hydroxyl, C 1-6 alkoxy, C 1-6 alkyl, C-
  • the compound of Formula IA is a compound wherein X is selected from the group consisting of a bond, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, propenyl, butenyl, pentenyl, and heterocycloalkyl; [0065] wherein Z is selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyano, and haloalkyl; [0066] wherein R 1 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyano, and haloalkyl; [0066] wherein R
  • Z is selected from the group consisting of hydrido, halo, alkyl, cyano, and haloalkyl;
  • R 9 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, or where R 9 and R 10 together with the atoms to which they are attached form a heterocyclic moiety;
  • R 9 is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-alkylamino, N,N-dialkylamino, N-arylamino, N-alkyl-N-arylamino, N- hydroxyamino, N-alkyl-N-hydroxyamino, N-aryl-N-hydroxyamino, halo, cyano, keto,
  • the compound of Formula IIA is a compound wherein Z is selected from the group consisting of hydrido, halo, C 1-6 alkyl, cyano, and C 1-s haloalkyl; [0081] wherein R 9 is selected from the group consisting of C 1-6 alkyl, C 3- 2 cycloalkyl, C 2 . 6 alkenyl, C 3-12 cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, C 3 .
  • R 9 is optionally substituted by one or more substituents independently selected from the group consisting of amino, N ⁇ C ⁇ s alkyl)amino, N,N-di(C 1- ⁇ alkyl)amino, N-(C 3 .
  • R 10 is selected from the group consisting of hydrido, hydroxyl, C 1-8 alkoxy, C 1-6 alkyl, C ⁇ -S haloalkyl, C 3 .
  • R 11 and R 12 are independently selected from the group consisting of hydrido, hydroxyl, C 1-6 alkoxy, C 1- ⁇ alkyl, C ⁇ haloalkyl, C 3-12 aryl, and 3- to 12-membered heteroaryl.
  • the compound of Formula IIA is a compound wherein Z is selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyano, and haloalkyl; [0086] wherein R 9 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, propenyl, butenyl, pentenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazo
  • the compound of Formula I is a compound of Formula IIC: [0095] wherein Z is selected from the group consisting of hydrido, halo, alkyl, cyano, and haloalkyl; [0096] wherein R 9 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, or where R 9 and R 9a together with the nitrogen to which they are attached form a heterocyclic moiety; [0097] wherein R 9 is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-alkylamino, N,N-dialkylamin
  • the compound of Formula IIC is a compound wherein Z is selected from the group consisting of hydrido, halo, C-
  • R 9 is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-(C ⁇ . 6 alkyl)amino, N,N-di(C 1 . 6 alkyl)amino, N-(C 3 .
  • R 9a is selected from the group consisting of hydrido, hydroxyl, C-,. 6 alkoxy, C ⁇ _s alkyl, C ⁇ .
  • R 11 and R 12 are independently selected from the group consisting of hydrido, hydroxyl, C 1-s alkoxy, C 1-s alkyl, C -6 haloalkyl, C 3- ⁇ 2 aryl, and 3- to 12-membered heteroaryl.
  • the compound of Formula IIC is a compound wherein Z is selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyano, and haloalkyl; [00107] wherein R 9 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, propenyl, butenyl, pentenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazo
  • the compound of Formula I is a compound of Formula IID: [00113] wherein Z, R 9 , R 9a , R 1 , and R 12 are as defined above for Formula IIC; or a pharmaceutically acceptable salt thereof.
  • the compound of Formula I is a compound of Formula HE:
  • Z is selected from the group consisting of hydrido, halo, alkyl, cyano, and haloalkyl;
  • R is selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
  • R is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-alkylamino, N,N-dialkylamino, N-arylamino, N-alkyl-N-arylamino, N- ⁇ hydroxyamino, N-alkyl-N-hydroxyamino, N-aryl-N-hydroxyamino, halo, cyano, keto, hydroxyl, alkyl, haloalkyl, cycloalkyl, alkoxy, al
  • the compound of Formula HE is a compound wherein Z is selected from the group consisting of hydrido, halo, C 1-6 alkyl, cyano, and C ⁇ haloalkyl; [00122] wherein R is selected from the group consisting of C ⁇ s alkyl, C 3-12 cycloalkyl, C 2-6 alkenyl, C 3-12 cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, C 3 .
  • R 1 is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-(C 1 . 6 alkyl)amino, N,N-di(C ⁇ . s alkyl)amino, N-(C 3-12 aryl)amino, N- (C ⁇ e alkyl)-N-(C 3-12 aryl)amino, N-hydroxyamino, N-(C 1- ⁇ alkyl)-N-hydroxyamino, N-(C 3 .
  • R 1 and R 2 are independently selected from the group consisting of hydrido, hydroxyl, C 1-6 alkoxy, C -6 alkyl, C ⁇ haloalkyl, C 3 .
  • the compound of Formula HE is a compound wherein Z is selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyano, and haloalkyl; [00126] wherein R 1 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, propenyl, butenyl, pentenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, piperidinyl, pyrrolidinyl, pyrazolid
  • the compound of Formula I is a compound of Formula III:
  • R a is selected from the group consisting of halo, cyano, alkyl, cycloalkyl, haloalkyl, alkoxy, aryl, aryloxy, aralkoxy, alkoxycarbonyl, carboxyl, heterocycloalkylalkyl, and alkylsulfonyl, or wherein R a and R 10 together with the atoms to which they are attached form a heterocyclic moiety; [00136] wherein R b , R c , R d , and R e are independently selected from the group consisting of halo, cyano, alkyl, cycloalkyl, haloalkyl, alkoxy, aryl, aryloxy, aralkoxy, alkoxycarbonyl, carboxyl, heterocycloalkylalkyl, and alkylsulfonyl;
  • the compound of Formula III is a compound wherein X is a bond or C 1- ⁇ alkyl; [00142] wherein R a is selected from the group consisting of halo, cyano, C 1-6 alkyl, cycloalkyl, C-,. 15 haloalkyl, C ⁇ -6 alkoxy, C 3-12 aryl, C 3 . 12 aryloxy, C 3-12 aralkoxy, C 2 . 6 alkoxycarbonyl, carboxyl, 3- to 18- membered heterocycloalkylalkyl, and C- ⁇ .
  • R b , R°, R d , and R e are independently selected from the group consisting of halo, cyano, C ⁇ . ⁇ alkyl, cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3 . 12 aryl, C 3-12 aryloxy, C 3 . 12 aralkoxy, C 2-B alkoxycarbonyl, carboxyl, 3- to 18-membered heterocycloalkylalkyl, and C ⁇ .
  • R 10 is selected from the group consisting of hydrido and C ⁇ . ⁇ alkyl, or R 10 and R a together with the atoms to which they are attached form a 3- to 12-membered heterocyclic moiety; and [00145] wherein R 11 and R 2 are independently selected from the group consisting of hydrido and C ⁇ -6 alkyl; [00146] wherein R a and R b , or R and R c , or R c and R d , or R d and R e may form a ring moiety fused to the phenyl ring to which they are both attached, said ring moiety selected from the group consisting of C 3-12 cycloalkyl, C 3 ⁇ 2 cycloalkenyl, C 3-12 aryl, 3- to 12-membered heterocycloalkyl, 3- to 12- membered heterocycloalkenyl, and 3- to 12-membered heteroaryl
  • the compound of Formula III is a compound wherein X is selected from the group consisting of a bond, methyl, ethyl, and propyl; [00148] wherein R a is selected from the group consisting of chloro, fluoro, bromo, cyano, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, chloromethyl, trifluoromethyl, methoxy, phenyl, phenoxy, benzyloxy, methoxycarbonyl, carboxyl, piperidinylmethyl, methylsulfonyl, benzyloxyphenyl, and methylpiperazinylmethyl, or wherein R a and R 10 together with the atoms to which they are attached form an isoindoledionyl group;
  • X is alkyl
  • R a , R b , R c , R d , and R e are independently selected from the group consisting of halo, cyano, alkyl, haloalkyl, alkoxy, aryl, and aralkoxy; and [00157] wherein R 11 and R 12 are independently selected from the group consisting of hydrido and alkyl; [00158] wherein R a and R , or R b and R°, or R c and R d , or R d and R e may form an aryl moiety fused to the phenyl ring to which they are both attached, wherein said aryl moiety may be substituted by one or more substituents selected from the group consisting of halo, alkyl, and alkoxy; [00159] or a pharmaceutically acceptable salt thereof.
  • the compound of Formula IV is a compound
  • R a , R b , R c , R d , and R e are independently selected from the group consisting of halo, cyano, C -3 alkyl, C -6 haloalkyl, C ⁇ -S alkoxy, C 3 . 12 aryl, and C 4 . 14 aralkoxy; and [00162] wherein R 11 and R 12 are independently selected from the group consisting of hydrido and d. 6 alkyl; [00163] wherein R a and R b , or R b and R c , or R c and R d , or R d and R e may form an C 3 .
  • the compound of Formula IV is a compound wherein X is selected from the group consisting of methyl, ethyl, and propyl; [00165] wherein R a , R b , R c , R d , and R e are independently selected from the group consisting of chloro, bromo, fluoro, cyano, methyl, trifluoromethyl, methoxy, phenyl, and benzyloxy; and [[0000166] wherein R 11 and R 12 are independently selected from the group consisting of hydrido and methyl [00167] wherein R a and R b , or R b and R c , or R c and R d , or R d and R e , together with the phenyl ring to which they are attached, may form a naphthyl ring, wherein said naphthyl ring may be optionally substituted by one or more substituents selected from the group consisting
  • X is a bond or alkyl; [00171] wherein R is a 5- to 12-membered heterocyclic moiety; [00172] wherein R is optionally substituted by one or more substituents independently selected from the group consisting of halo, alkyl, alkoxycarbonyl, carboxyl, and heteroarylalkyl; [00173] wherein R 10 , R 1 , and R 12 are independently selected from the group consisting of hydrido and alkyl; [00174] or a pharmaceutically acceptable salt thereof.
  • the compound of Formula V is a compound wherein X is a bond or C ⁇ _ ⁇ alkyl; [00176] wherein R is optionally substituted by one or more substituents independently selected from the group consisting of halo, C 1-s alkyl, C ⁇ _ 7 alkoxycarbonyl, carboxyl, and 3- to 12-membered heteroarylalkyl; [00177] wherein R 0 , R 11 , and R 12 are independently selected from the group consisting of hydrido and C 1-6 alkyl.
  • the compound of Formula V is a compound wherein X is selected from the group consisting of a bond, methyl, ethyl, and propyl; [00179] wherein R is a heterocyclic moiety selected from the group consisting of pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, 7-azabicyclo[2.2.1]heptane, isoindolinyl, piperidinyl, and pyrrolidinyl; [00180] wherein R is optionally substituted by one or more substituents independently selected from the group consisting of bromo, chloro, fluoro, methyl, methoxycarbonyl, propoxycarbonyl, carboxyl, and pyridinyl methyl; [00181] wherein R 10 , R 11 , and R 12 are independently selected from the group consisting of hydrido
  • X is alkyl; [00185] wherein R is selected from the group consisting of alkyl, alkenyl, C 3 . 12 cycloalkyl, and C 3- ⁇ 2 cycloalkenyl; [00186] wherein R is optionally substituted by one or more substituents independently selected from the group consisting of cyano, keto, alkyl, alkoxy, haloalkyl, alkylcarbonyl, aryl, cycloalkyl, aralkylcarbonyl, aralkylcarbonylamino, heteroarylcarbonyl, alkoxycarbonyl, carboxyl, and alkoxyalkoxycarbonyl; and [00187] wherein R 11 and R 12 are independently selected from the group consisting of hydrido and alkyl; [00188] or a pharmaceutically acceptable salt thereof.
  • the compound of Formula VII is a compound wherein X is C 1 - 3 alkyl; [00190] wherein R is selected from the group consisting of C ⁇ -6 alkyl, C 2-6 alkenyl, C 3- ⁇ 2 cycloalkyl, and C 3-12 cycloalkenyl; [00191] wherein R is optionally substituted by one or more substituents independently selected from the group consisting of cyano, keto, C ⁇ _ 6 alkyl, C -6 alkoxy, d. 6 haloalkyl, C 2 . 7 alkylcarbonyl, C 3 . 12 aryl, C 3-12 cycloalkyl, C 4 .
  • R 11 and R 12 are independently selected from the group consisting of hydrido and C ⁇ s alkyl.
  • the compound of Formula VII is a compound wherein X is selected from the group consisting of methyl, ethyl, and propyl; [00194] wherein R is selected from the group consisting of methyl, ethyl, propyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthyl, octahydroindyl, octahydropentalene, bicyclo[2 2.1]heptyl, tricyclo[2.2.1.0 ⁇ 2,6 ⁇ ]heptyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, decahydronaphthenyl, hexahydroindenyl, hexahydropentalen
  • hydro denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals may be attached to a carbon atom to form a methylene (-CH 2 -) radical.
  • halo denotes halogen atoms such as fluorine, chlorine, bromine, or iodine.
  • amido when used by itself or with other terms such as “amidoalkyl”, “N- monoalkylamido”, “N-monoarylamido”, “N,N-dialkylamido”, “N-alkyl-N-arylamido", “N-alkyl-N- hydroxyamido” and “N-alkyl-N-hydroxyamidoalkyl”, embraces a carbonyl radical substituted with an amino radical.
  • N-alkylamido and “N,N-dialkylamido” denote amido groups which have been substituted with one alkyl radical and with two alkyl radicals, respectively.
  • N-monoarylamido and N-alkyl-N-arylamido denote amido radicals substituted, respectively, with one aryl radical, and one alkyl and one aryl radical.
  • N-alkyl-N-hydroxyamido embraces amido radicals substituted with a hydroxyl radical and with an alkyl radical.
  • sulfamyl or “sulfonamidyl” denotes a sulfonyl radical substituted with an amino radical, forming a sulfonamide (-S0 2 NH 2 ).
  • the amino radical may be substituted with alkyl and/or aryl moieties to form, e.g., "N-alkylsulfamyl", “N-arylsulfamyl", “N,N-dialkylsulfamyI,” and "N-alkyl-N- arylsulfamyl” radicals.
  • alkyl used alone or within other terms such as "haloalkyl" and
  • alkylsulfonyl embraces linear or branched radicals having one to about twenty carbon atoms. More preferred are “lower alkyl” radicals having one to about eight carbon atoms. Examples of alkyl radicals include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, and t-butyl), pentyl (including n-pentyl and isoamyl), hexyl, octyl and the like.
  • cycloalkyl embraces radicals having three to ten carbon atoms, and includes monocyclic, bicyclic, and tricyclic radicals.
  • cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decahydronaphthyl, octahydroindyl, octahydropentalene, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, and bicyclo[4.2.2]decyI.
  • alkylcarbonyl embraces radicals having a carbonyl radical substituted with an alkyl radical.
  • An example of an alkylcarbonyl radical is acetyl.
  • alkylthio embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom.
  • An example of an alkylthio radical is methylthio (CH 3 S-).
  • alkylsulfonyl embraces alkyl radicals as defined above attached to a divalent sulfonyl radical, -S0 2 -.
  • amidoalkyl embraces alkyl radicals substituted with amido radicals.
  • N-alkyl-N-hydroxyamidoalkyl embraces alkyl radicals substituted with an N- alkyl-N-hydroxyamido radical.
  • aminoalkyl embraces alkyl radicals substituted with amino radicals.
  • carboxyalkyl embraces radicals having a carboxyl moiety attached to an alkyl radical.
  • haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl, and polyhaloalkyl radicals.
  • a monohaloalkyl radical for one example, may have a bromo, chloro, or a fluoro atom within the radical.
  • Dihaloalkyl radicals may have two of the same halo atoms or a combination of different halo radicals; polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals.
  • hydroxyalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms, any of which may be substituted with one or more hydroxyl radicals.
  • N-alkylamino and N, N-dialkylamino denote amino groups which have been substituted with one alkyl radical and with two alkyl radicals, respectively.
  • alkoxy embraces linear or branched oxy-containing alkyl radicals having one to about ten carbon atoms. Examples of “alkoxy” radicals include methoxy and butoxy.
  • alkoxyalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms substituted by one or more alkoxy radicals each having one to about ten carbon atoms.
  • "Alkoxy” or “alkoxyalkyl” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro, or bromo, to provide "haloalkoxy" or "haloalkoxyalkyl” radicals.
  • alkoxycarbonyl means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical. Examples of such alkoxycarbonyl radicals include methoxycarbonyl and t-butoxycarbonyl.
  • alkylaminoalkyl embraces aminoalkyl radicals wherein the nitrogen atom is substituted with an alkyl radical.
  • alkylcarbonylalkyl denotes an alkyl radical substituted with an “alkylcarbonyl” radical.
  • alkenyl used alone or within other terms such as “haloalkenyl,” embraces unsaturated linear or branched radicals having two to about twenty carbon atoms and containing at least one carbon-carbon double bond. Examples of alkenyl radicals include ethenyl, propenyl butenyl, pentenyl, and the like.
  • cycloalkenyl embraces unsaturated radicals having three to ten carbon atoms and containing at least one carbon-carbon double bond, and includes monocyclic, bicyclic, and tricyclic radicals.
  • cycloalkenyl radicals include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, decahydronaphthenyl, hexahydroindenyl, hexahydropentalenyl, bicyclo[2.1.0]pentenyl, bicyclo[1.1.1]pentenyl, bicyclo[2.1.1]hexenyl, bicyclo[2.2.1]heptenyl, bicyclo[3.1.1]heptenyl, bicyclo[3.2.1]octenyl, bicyclo[2.2.2]octenyl, and bicyclo[4.2.2]decenyl.
  • alkynyl used alone or within other terms such as “haloalkynyl,” embraces unsaturated linear or branched radicals having two to about twenty carbon atoms and containing at least one carbon-carbon triple bond. Examples of alkynyl radicals include ethynyl, propynyl butynyl, pentynyl, and the like.
  • aryl alone or in combination, means a carbocyclic aromatic system containing one, two, or three rings wherein at least one of the rings is aromatic, and wherein such rings may be attached together in a pendant manner or may be fused.
  • aryl radicals include phenyl, naphthyl, tetrahydronapthyl, indyl, and biphenyl.
  • Aryl moieties, alone or in combination, may be optionally substituted by one or more substituents selected from the group consisting of amino, halo, cyano, hydroxyl, alkyl, alkoxy, and carboxyl.
  • aralkyl embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenethyl, and diphenethyl.
  • arylsulfonyl embraces aryl radicals as defined above attached to a sulfonyl radical.
  • acyl whether used alone or within a term such as “acylamino,” denotes a radical provided by the residue after removal of hydroxyl from an organic acid.
  • acylamino embraces an amino radical substituted with an acyl group.
  • heterocyclic or “heterocycle” means a saturated or unsaturated mono- or multi-ring carbocyclic system wherein one or more carbon atoms in the system are replaced by nitrogen, sulfur, phosphorous, and/or oxygen.
  • heterocyclic embraces "heteroaryl” groups, which means a carbocyclic aromatic system containing one, two, or three rings wherein at least one of the rings is aromatic, wherein such rings may be attached together in a pendant manner or may be fused, and wherein one or more carbon atoms in the system are replaced by nitrogen, sulfur, phosphorous, and/or oxygen.
  • Heterocyclic includes, for example, the following structures: [00240] wherein Z, ⁇ Z 2 , and Z 3 are independently carbon, sulfur, phosphorous, oxygen, or nitrogen, with the proviso that one of Z, Z 1 , Z 2 , or Z 3 is other than carbon, but is not oxygen or sulfur when attached to another Z atom by a double bond or when attached to another oxygen or sulfur atom.
  • heterocyclyl embraces each of the following groups, although this listing is not meant to limit the definition to these groups only: furanyl; thienyl; pyrrolyl; 2-isopyrrolyl; 3-isopyrrolyl; pyrazolyl; 2-isoimidazolyl; 1,2,3-triazolyl; 1 ,2,4-triazolyl; 1,2-dithiolyl; 1,3-dithiolyl; 1 ,2,3-oxathiolyl; isoxazolyl; oxazolyl; thiazolyl; isothiazolyl; 1 ,2,3-oxadiazolyl; 1 ,2,4-oxadiazolyl; 1 ,2,5-oxadiazolyl; 1,3,4- oxadiazolyl; 1,2,3,4-oxatri
  • 1,3,4-dioxazolyl 1,2,5-oxathiazolyl; 1 ,3-oxathiolyl; 1 ,2-pyranyl; 1 ,4-pyranyl; 1 ,2-pyranonyl; 1,4-pyranonyl;
  • heterocyclic moieties may be optionally substituted by one or more substituents selected from the group consisting of amino, halo, cyano, hydroxyl, alkyl, alkoxy, and carboxyl.
  • substituents selected from the group consisting of amino, halo, cyano, hydroxyl, alkyl, alkoxy, and carboxyl.
  • fused bicyclic radicals examples include benzofuran, benzothiophene, and the like.
  • heterocycloalkyl embraces heterocyclic-substituted alkyl radicals such as pyridylmethyl and thienylmethyl.
  • benzyl and phenylmethyl are interchangeable.
  • phrases "combination therapy”, “co-administration”, “administration with”, or “co- therapy”, in defining the use of a selective IKK-2 inhibitory agent in combination with another therapeutic agent such as another analgesic agent, is intended to embrace administration of each agent in a sequential manner in a regimen that may provide beneficial effects of the drug combination, and is ' intended as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single capsule or dosage device having a fixed ratio of these active agents or in multiple, separate capsules or dosage devices for each agent, where the separate capsules or dosage devices can be taken together contemporaneously, or taken within a period of time sufficient to receive a beneficial effect from both of the constituent agents of the combination.
  • the term "subject" for purposes of treatment includes any human or animal subject who is in need of the prevention of, or who has pain, inflammation and/or any one of the known inflammation- associated disorders.
  • the subject is typically a human subject.
  • therapeutic combination refers to the combination of two or more therapeutic compounds and, optionally, one or more pharmaceutically acceptable carrier used to provide dosage forms that produce a beneficial effect of each therapeutic compound in the subject at the desired time, .whether the therapeutic compounds are administered substantially simultaneously, or sequentially.
  • therapeutically effective refers to an amount of a therapeutic compound, or amounts of combined therapeutic compounds in combination therapy.
  • the amount or combined amounts achieve one or more of the goals of preventing, inhibiting, reducing or eliminating the inflammation or inflammation-related disease or condition.
  • a "therapeutically-effective" amount of each agent in a combination therapy is expected to be less than an amount used in treatment using agent by itself, thus while avoiding adverse side effects typically associated with alternative therapies, namely higher dose monotherapy of each agent by itself.
  • the terms “treating” or “to treat” means to alleviate symptoms, eliminate the causation either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms in a subject.
  • treatment includes alleviation, elimination of causation of or prevention of pain and/or inflammation associated with, but not limited to, any of the diseases or disorders described above.
  • Pharmaceutically acceptable salts of the compounds of Formula I include the acid addition and base salts thereof.
  • Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicoti ⁇ ate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • compositions of Formula I may be prepared by one or more of three methods: (i) by reacting the compound of Formula I with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of Formula I or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by converting one salt of the compound of Formula I to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column. All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionization in the resulting salt may vary from completely ionized to almost non-ionized.
  • the compounds of the invention may exist in both unsolvated and solvated forms.
  • solvate is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • hydrate is employed when said solvent is water.
  • complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
  • complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts.
  • the resulting complexes may be ionized, partially ionized; or non-ionized.
  • references to compounds of Formula I include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
  • the compounds of the invention include compounds of Formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of Formula I.
  • prodrugs of the compounds of Formula I are also within the scope of the invention.
  • prodrug refers to a compound that is a drug precursor which, following . administration to a subject and subsequent absorption, is converted to an active species in vivo via some process, such as a metabolic process. Other products from the conversion process are easily disposed of by the body.
  • prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of Formula I with certain moieties known to those skilled in the art as "pro-moieties.”
  • prodrugs in accordance with the invention include: (i) where the compound of Formula I contains a carboxylic acid functionality (-C0 2 H), an ester thereof, for example, a compound wherein the hydrogen of the carboxylic acid functionality of the compound of Formula I is replaced by C ⁇ Ca alkyl; (ii) where the compound of Formula I contains an alcohol functionality (-OH), an ether thereof, for example, a compound wherein the hydrogen of the alcohol functionality of the compound of Formula I is replaced by C r C 6 alkanoyloxymethyl; and (iii) where the compound of Formula I contains a primary or secondary amino functionality (-NH 2 or -NHR where R ⁇ H), an amide
  • Some examples of metabolites in accordance with the invention include: (i) where the compound of Formula I contains a methyl group, an hydroxymethyl derivative thereof (-CH 3 -> -CH 2 OH); (ii) where the compound of Formula I contains an alkoxy group, an hydroxy derivative thereof (-OR -> -OH); (iii) where the compound of Formula I contains a tertiary amino group, a secondary amino derivative thereof (-NR a R b -> -NHR a or -NHR b ); (iv) where the compound of Formula I contains a secondary amino group, a primary derivative thereof (-NHR -> -NH 2 ); (v) where the compound of Formula I contains a phenyl moiety, a phenol derivative thereof (-Ph - -PhOH); and (vi) where the compound of Formula I contains an amide group, a carboxylic acid derivative thereof (-CONH 2 -> -COOH).
  • Compounds of Formula I containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of Formula I contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ("tautomerism") can occur. This can take the form of proton tautomerism in compounds of Formula I containing, for example, an imino, keto, or oxime group, or so- called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
  • racemate or a racemic precursor
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of Formula I contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2 to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine.
  • Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art.
  • the present invention includes all pharmaceutically acceptable isotopically-labeled compounds of Formula I wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 1 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 l and 125 l, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopically-labeled compounds of Formula I for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • radioactive isotopes tritium ( 3 H) and 1 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium ( 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Substitution with positron-emitting isotopes, such as 11 C, 18 F, 1s O and 3 N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Isotopically-labeled compounds of Formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, d 6 -acetone, or d 6 -DMSO.
  • Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products.
  • the compounds of the invention may be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • excipient is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • the compounds of the invention may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof).
  • compounds of Formula I may be used in co-therapies, partially or completely, in place of other conventional antiinflammatory therapies, such as together with other IKK-2 inhibitors, steroids, NSAIDs, COX-2 selective inhibitors, matrix metalloproteinase inhibitors, 5- lipoxygenase inhibitors, LTB 4 antagonists and LTA 4 hydrolase inhibitors.
  • Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art.
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays and liquid formulations.
  • Liquid formulations include suspensions, solutions, syrups and elixirs.
  • Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents.
  • Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents, 11(6), 981-986 (2001 ).
  • the drug may make up from 1 to 80 wt.% of the dosage form, more typically from 5 to 60 wt.% of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolido ⁇ e, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate.
  • the disintegrant will comprise from 1 to 25 wt.%, preferably from 5 to 20 wt.% of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose.
  • Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 to 5 wt.% of the tablet, and glidants may comprise from 0.2 to 1 wt.% of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally comprise from 0.25 to 10 wt.%, preferably from 0.5 to 3 wt.% of the tablet.
  • Other possible ingredients include anti-oxidants, colorants, flavoring agents, preservatives and taste-masking agents.
  • Exemplary tablets contain up to about 80% drug, from about 10 to about 90 wt.% binder, from about 0 to about 85 wt.% diluent, from about 2 to about 10 wt.% disintegrant, and from about 0.25 to about 10 wt.% lubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting.
  • the final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
  • Consumable oral films for human or veterinary use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of Formula I, a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabilizer or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function.
  • the compound of Formula I may be water-soluble or insoluble.
  • a water-soluble compound typically comprises from 1 to 80 wt.%, more typically from 20 to 50 wt.%, of the solutes.
  • Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 wt.% of the solutes.
  • the compound of Formula I may be in the form of multiparticulate beads.
  • the film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 wt.%, more typically in the range 30 to 80 wt.%.
  • Other possible ingredients include anti-oxidants, colorants, flavorings and flavor enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents.
  • Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming.
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- and programmed-release.
  • Suitable modified release formulations for the purposes of the invention are described in U.S. Patent No. 6,106,864.
  • the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrastemal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • a suitable vehicle such as sterile, pyrogen-free water.
  • the preparation of parenteral formulations under sterile conditions for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • the solubility of compounds of Formula I used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility- enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- and programmed-release.
  • compounds of the invention may be formulated as a solid, semi- solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and poly(dl-lactic-coglycolic)acid (PGLA) microspheres.
  • PGLA poly(dl-lactic-coglycolic)acid
  • the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Penetration enhancers may be incorporated; see, e.g., Finnin and Morgan, J Pharm Sci. 88(10), 955-958 (1999).
  • Topical administration includes delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. PowderjectTM, BiojectTM, etc.) injection.
  • Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- and programmed-release.
  • the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • a surfactant such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, is micronized to a size suitable for delivery by inhalation (typically less than 5 ⁇ M).
  • Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • a suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 ⁇ g to 20 mg of the compound of the invention per actuation and the actuation volume may vary from 1 to 100 ⁇ L.
  • a typical formulation may comprise a compound of Formula I, propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Suitable flavors such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- and programmed-release.
  • the dosage unit is determined by means of a valve which delivers a metered amount.
  • Units in accordance with the invention are typically arranged to administer a metered dose or "puff' containing from 20 to 1000 ⁇ g of the compound of Formula I.
  • the overall daily dose will typically be in the range 100 ⁇ g to 10 mg which may be administered in a single dose or, more usually, as divided doses throughout the day, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.
  • the compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- and programmed-release. [00318]
  • the compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline.
  • formulations suitable for ocular and aural administration include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- or programmed-release.
  • the compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • Drug-cyclodextrin complexes for example, are found to be generally useful for most dosage forms and administration routes.
  • the cyclodextrin may be used as an auxiliary additive, i.e., as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma- cyclodextrins, such as those described in PCT Publication No. WO 98/55148.
  • kits comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of Formula I in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • kits are particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit typically comprises directions for administration and may be provided with a so-called memory aid.
  • the amount of therapeutically active compounds that are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the inflammation or inflammation related disorder, the route and frequency of administration, and the particular compound employed, and thus may vary widely.
  • the pharmaceutical compositions may contain active ingredients in the range of about 0.1 to 1000 mg, preferably in the range of about 7.0 to 350 mg.
  • the daily dose can be administered in one to four doses per day. In the case of skin conditions, it may be preferable to apply a topical preparation of compounds of this invention to the affected area two to four times a day.
  • DMF N,N-dimethylformamide.
  • DMSO dimethylsulfoxide.
  • ESI electrospray ionization Mass spectrometry.
  • HATU 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
  • HBTU 0-benzotriazolo-1-yl)-N,N,N', N'-tetramethyluronium.
  • HRMS high resolution mass spectrometry.
  • NMR nuclear magnetic resonance.
  • Ac is acetyl.
  • OAc is acetate.
  • Ph phenyl.
  • i.d is inner diameter.
  • the 2- carboxamido-3-ureidothiophene is prepared via conventional procedures for urea formation such as reaction with sodium cyanate in acetic acid. Nitration may produce a mixture of isomers from which the desired 5-nitro compound can be separated. Reduction of the nitro derivative can be achieved for example by reaction with tin in hydrochloric acid.
  • the resulting ammonium salt is treated under standard coupling conditions with a carboxylic acid and an appropriate coupling reagent, such as HBTU tetrafluoroborate, in the presence of a tertiary amine base.
  • This ester is hydrolyzed by conventional methods, as, for example, by saponification, giving, in this instance, a carboxylate salt, which can be isolated, or directly transformed into the carboxylic acid by treatment with acid.
  • This 2-ureido-3-carboxamido-thiophene-5-carboxylic acid can be coupled with amines using certain coupling agents such as HBTU tetrafluoroborate to produce 2-ureido-3-carboxamido-5- carboxamidothiophenes. Heating may be necessary depending on the type of amine being coupled, as in the case of certain anilines.
  • Scheme IIIB Synthesis of 2-ureido-3-carboxamido thiophene-5-carboxamides via direct carbonylation to amides
  • a transition metal catalyst such as a palladium compound, for example palladium (II) acetate
  • an added ligand for example, a phosphine, such as 1,1'-bis(diphenylphosphino)ferrocene in an appropriate solvent, such as DMF, containing the desired amine and a tertiary amine, gives an amide such as 2-ureido-3-carbox
  • Cyanation is achieved using zinc cyanide with a transition metal catalyst such as a palladium compound, for example, tris(dibenzylideneacetone) dipalladium, in a DMF-benzonitrile solvent system with an added ligand such as 1 ,1 '-bis(diphenylphosphino)ferrocene, preferentially at temperatures above room temperature.
  • a transition metal catalyst such as a palladium compound, for example, tris(dibenzylideneacetone) dipalladium
  • a DMF-benzonitrile solvent system with an added ligand such as 1 ,1 '-bis(diphenylphosphino)ferrocene, preferentially at temperatures above room temperature.
  • the obtained 2-ureido-3-carboxamido-5-cyanothiophene can be treated with dry HCl in methanol to give an imidate ester, which can be further transformed into the methyl ester.
  • This ester is hydrolyzed by conventional methods, as, for example, by saponification, giving, in this instance, a carboxylate salt, which can be isolated, or directly transformed into the carboxylic acid by treatment with acid.
  • This 2-ureido-3- carboxamido-thiophene-5-carboxylic acid can be coupled with amines using certain coupling agents such as HBTU tetrafluoroborate to produce 2-ureido-3-carboxamido-5-carboxamidothiophenes. Heating may be necessary depending on the type of amine being coupled, as in the case of certain anilines.
  • Scheme HID Synthesis of 2-ureido-3-carboxamido thiophene-5-carboxamides via nitriles
  • Cyanation is achieved using zinc cyanide with a transition metal catalyst such as a palladium compound, for example, tris(dibenzylideneacetone) dipalladium, in a DMF-benzonitrile solvent system with an added ligand such as 1 ,1 '-bis(diphenylphosphino)ferrocene, preferentially at temperatures above room temperature.
  • a transition metal catalyst such as a palladium compound, for example, tris(dibenzylideneacetone) dipalladium
  • a DMF-benzonitrile solvent system with an added ligand such as 1 ,1 '-bis(diphenylphosphino)ferrocene, preferentially at temperatures above room temperature.
  • the obtained 2-ureido-3-carboxamido-5-cyanothiophene can be treated with dry HCl in an appropriate solvent and further treated with amines to produce 2-ureido-3-carboxamido-5-carboxamidothiophen
  • the 2- carboxamido-3-ureidothiophene is prepared via conventional procedures for urea formation such as reaction with sodium cyanate in acetic acid. Bromination using standard conditions may produce a mixture of isomers, from which the desired 5-bromo derivative can be separated.
  • This ester is hydrolyzed by conventional methods, as, for example, by saponification, giving, in this instance, a carboxylate salt, which can be isolated, or directly transformed into the carboxylic acid by treatment with acid.
  • This 2-ureido-3- carboxamido-thiophene-5-carboxylic acid can be coupled with amines using certain coupling agents such as HBTU tetrafluoroborate to produce 2-carboxamido-3-ureido-5-carboxamidothiophenes. Heating may be necessary depending on the type of amine being coupled, as in the case of certain anilines.
  • the 2- carboxamido-3-ureidothiophene is prepared via conventional procedures for urea formation such as reaction with sodium cyanate in acetic acid. Bromination using standard conditions may produce a mixture of isomers, from which the desired 5-bromo derivative can be separated.
  • a transition metal catalyst such as a palladium compound, for example palladium (II) acetate
  • an added ligand for example, a phosphine, such as 1,1'-bis(diphenylphosphino)ferrocene in an appropriate solvent, such as DMF, containing the desired amine and a tertiary amine, gives an amide such as 2-carboxamido-3 ⁇ ure
  • the 2- carboxamido-3-ureidothiophene is prepared via conventional procedures for urea formation such as reaction with sodium cyanate in acetic acid. Bromination using standard conditions may produce a mixture of isomers, from which the desired 5-bromo derivative can be separated. Cyanation is achieved using zinc cyanide with a transition metal catalyst such as a palladium compound, for example, tris(dibenzylideneacetone) dipalladium, in a DMF-benzonitrile solvent system with an added ligand such as 1 ,1 '-bis(diphenylphosphino)ferrocene, preferentially at temperatures above room temperature.
  • a transition metal catalyst such as a palladium compound, for example, tris(dibenzylideneacetone) dipalladium
  • the obtained 2-ureido-3-carboxamido-5-cyanothiophene can be treated with dry HCl in methanol to give an imidate ester, which can be further transformed into the methyl ester.
  • This ester is hydrolyzed by conventional methods, as, for example, by saponification, giving, in this instance, a carboxylate salt, which can be isolated, or directly transformed into the carboxylic acid by treatment with acid.
  • This 2-ureido-3- carboxamido-thiophene-5-carboxylic acid can be coupled with amines using certain coupling agents such as HBTU tetrafluoroborate to produce 2-ureido-3-carboxamido-5-carboxamidothiophenes. Heating may be necessary depending on the type of amine being coupled, as in the case of certain anilines.
  • the 2- carboxamido-3-ureidothiophene is prepared via conventional procedures for urea formation such as reaction with sodium cyanate in acetic acid. Bromination using standard conditions may produce a mixture of isomers, from which the desired 5-bromo derivative can be separated.
  • Cyanation is achieved using zinc cyanide with a transition metal catalyst such as a palladium compound, for example, tris(dibenzylideneacetone) dipalladium, in a DMF-benzonitrile solvent system with an added ligand such as 1 ,1 '-bis(diphenylphosphino)ferrocene, preferentially at temperatures above room temperature.
  • a transition metal catalyst such as a palladium compound, for example, tris(dibenzylideneacetone) dipalladium
  • a DMF-benzonitrile solvent system with an added ligand such as 1 ,1 '-bis(diphenylphosphino)ferrocene, preferentially at temperatures above room temperature.
  • the obtained 2-ureido-3-carboxamido-5-cyanothiophene can be treated with dry HCl in an appropriate solvent and further treated with amines to produce 2-ureido-3-carboxamido-5-carboxamidothiophen
  • Example 2A Preparation of 2-[(aminocarbonyl)amino]-5-aminothiophene-3- carboxamide
  • 2-[(aminocarbonyl)amino]-5-nitrothiophene-3-carboxamide from Example 1 (0.189 g, 0.821 mmol) and concentrated HCl (1 .8 mL, 22 mmol) were combined and placed in a water bath at 21 °C. Then tin powder (0.202 g, 1.70 mmol) was slowly added. After 2.5 hours the mixture was filtered, the solid washed twice with the filtrate, followed by 10 mL of methanol and 30 mL of diethyl ether.
  • Example 2B Preparation of 2-[(aminocarbonyl)amino]-5-aminothiophene-3- carboxamide
  • 2-[(aminocarbonyl)amino]-5-nitrothiophene-3-carboxamide from Example 1 (2.62 g, 11.4 mmol) and concentrated HCl (25.0 mL, 299 mmol) were combined and placed in a water bath at 21 °C. Then tin powder (2.70 g, 22.7 mmol) was slowly added over 2.0 hours keeping the temperature below 30°C. After 30 min. the mixture was filtered, the solid washed twice with 6 mL portions of concentrated HCl, followed by 6 mL diethyl ether. The solid was then dried under vacuum.
  • Example 2C Preparation of 2-[(aminocarbonyI)amino]-5-aminothiophene-3- carboxamide
  • 2-[(aminocarbonyl)amino]-5-nitrothiophene-3-carboxamide from Example 1 (2.62 g, 11.4 mmol) and concentrated HCl (25.0 mL, 299 mmol) were combined and placed in a water bath at 21 °C. Then tin powder (2.70 g, 22.7 mmol) was slowly added over 2.0 hours keeping the temperature below 30°C. An additional 5 mL HCl was added to aid stirring. After 30 min. the mixture was filtered, and the solid was dried under vacuum.
  • Example 3 2-[(aminocarbonyl)amino]-5- ⁇ [(3-chlorophenyl)acetyl]amino ⁇ thiophene-3- carboxamide
  • Example 18 2-[(aminocarbonyl)amino]-5- ⁇ [(3-fluorophenyl)acetyl]amino ⁇ thiophene-3- carboxamide
  • Example 19 N- ⁇ 4-(Aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2-yl ⁇ -5- methylthiophene-2-carboxamide
  • Example 29 N- ⁇ 4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2-yl ⁇ -1- methylprolinamide
  • Example 31 A 2-[(aminocarbony!)amino]-5-(1 ,3-dioxo-1 ,3-dihydro-2H-isoindol-2- yl)thiophene-3-carboxamide
  • Example 31 B 2-[(aminocarbonyl)amino]-5-(1 ,3-dioxo-1 ,3-dihydro-2H-isoindol-2- yl)thiophene-3-carboxamide
  • 2-cyanobenzoic acid 0.574 g, 3.9 mmol
  • stirring was for 3.5 hours
  • the residue was trituated in 45 mL H 2 0, in 25 mL CH 3 OH:CH 3 CN (4:1), in 10 mL H z O with 1.5 g anhydrous K 2 C0 3 , and then in 10 mL chloroform.
  • Example 32 N- ⁇ 4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2-yl ⁇ -3-chloro-1 - benzothiophene-2-carboxamide
  • Example 33 N- ⁇ 4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2-yl ⁇ -1- benzothiophene-2-carboxamide
  • Example 34 2-[(Aminocarbonyl)amino]-5- ⁇ [4-(benzyloxy)benzoyl]amino ⁇ thiophene-3- carboxamide
  • Example 35 2-[(Aminocarbonyl)amino]-5-[(3-cyanobenzoyl)amino]thiophene-3- carboxamide
  • Example 36 2-[(Aminocarbonyl)amino]-5-[(4-cyanobenzoyl)amino]thiophene-3- carboxamide
  • Example 37 2-[(Aminocarbonyl)amino]-5-[(2-fluorobenzoyl)amino]thiophene-3- carboxamide
  • Example 38 2-[(Aminocarbonyl)amino]-5-[(3-fluorobenzoyl)amino]thiophene-3- carboxamide
  • campJe_39 2-[(Aminocarbonyl)amino]-5-[(4-fluorobenzoyl)amino]thiophene-3- carboxamide
  • BcampJe 40 2-[(Aminocarbonyl)amino]-5-[(3-methoxybenzoyl)amino]thiophene-3- carboxamide [00409]
  • the crude solid salt of 2-[(aminocarbonyl)amino]-5-aminothiophene-3-carboxamide (0.293 g) was combined with m-anisic acid (0.264 g, 1.74 mmol), HBTU (BF 4 ) (0.553 g, 1.72 mmol), N,N-dimethylethyIamine (1.3 mL, 12 mmol), and DMSO (1.7 mL).
  • Example 41 2-[(Aminocarbonyl)amino]-5- ⁇ [2-(trifluoromethyl)benzoyl]amino ⁇ thiophene- 3-carboxamide
  • Example 42 2-[(Aminocarbonyl)amino]-5-[(2-chlorobenzoyl)amino]thiophene-3- carboxamide [00416] Prepared according to Example 40 (substituting 2-chlorobenzoic acid for the m-anisic acid), except that stirring was maintained for 3.5 hrs., and after the initial water trituration, the residue was then triturated in 13 wt% aqueous K 2 C0 3 solution, CDCI 3 , and finally diethyl ether. The solid was then dissolved in DMF, added to H 2 0, and the precipitate filtered, washed with H z O, and then dried under vacuum to afford a gray solid.
  • Example 43 2-[(Aminocarbonyl)amino]-5-[(3-chlorobenzoyl)amino]thiophene-3- carboxamide
  • Example 44 2-[(Aminocarbonyl)amino]-5-[(2-methoxybenzoyl)amino]thiophene-3- carboxamide
  • Example 47 2-[(AminocarbonyI)amino]-5-[(4-chlorobenzoyl)amino]thiophene-3- carboxamide repare accor ng o xample 40 (substituting 4-chlorobenzoic acid for the m-anisic acid), except that after the DMF/H 2 0 slurry was filtered and the solid washed with 10 mL H 2 0, the solid was then sonicated in 10 mL CHCI 3 , and then in 5 mL CH 3 OH. The product was then dried under vacuum. The title compound is a brown solid.
  • Example 48 2-[(Aminocarbonyl)amino]-5- ⁇ [3-(trifluoromethyl)benzoyl]amino ⁇ thiophene- 3-carboxamide
  • Example 50 Methyl 3-[( ⁇ 4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2- yl ⁇ amino)carbonyl]benzoate
  • Example 51 2-[(aminocarbonyl)amino]-5-[(1 ,1'-biphenyl-2-ylcarbonyl)amino]thiophene-
  • the residue was triturated in 120 mL H z O, then triturated and sonicated in 50 mL 20:80 CH 3 OH:H 2 0, followed by sonication in 25 mL CH 3 OH, filtering, and washing with 25 mL CH 3 OH.
  • the combined methanol filtrate and wash was stripped of solvent, the residue sonicated in 100 mL H 2 0, filtered, washed with 25 mL H z O, then triturated in 50 mL diethyl ether, triturated again in 25 mL diethyl ether, filtered, and washed with 25 mL diethyl ether.
  • the product was then dried under vacuum.
  • the title compound was a brown solid.
  • Example 52 2-[(Aminocarbonyl)amino]-5-[(1 ,1'-biphenyl-4-ylcarbonyl)amino]thiophene-
  • Example 53 2-[(Aminocarbonyl)amino]-5-[(1 ,1 '-biphenyl-3-yIcarbonyl)amino]thiophene- 3-carboxamide
  • Example 51 Prepared according to Example 51 (substituting 3-biphenylcarboxylic acid for the 2- biphenylcarboxylic acid), except 0.401 g of the solid salt prepared according to Example 2C was used and the other reagents were scaled accordingly. Then, after the DMF was stripped off, the residue was sonicated in 50 mL H 2 0, filtered, washed with 25 mL H 2 0, sonicated with 50 mL saturated sodium bicarbonate solution, filtered, washed with 25 mL H 2 0, triturated and sonicated in 25 mL CH 2 CI 2 , filtered, and washed with 25 mL CH 2 CI 2 .
  • Examples 55-73 shown in Table VII below, were prepared analogously to Example 54, substituting the appropriate carboxylic acid for the 2,3,5-trifluorobenzoic acid.
  • Example 74 4-F(l4-(Aminocarbonvl)-5-r(aminocarbonyl)amino1thien-2- yl ⁇ amino)carbonyl]-2,5-dichlorobenzoic acid
  • Example 75 4-[( ⁇ 4-(Aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2- yl ⁇ amino)carbonyl]-2,5-dibromobenzoic acid [00459] Prepared similarly to Example 74 (substituting 2,5-dibromo-4-carboxybenzoic acid for the 2,5-dichloro-4-carboxybenzoic acid). H NMR (CD 3 OD)/d 6 -DMSO (4:1): 5 6.91 (s, 1 H), 7.88 (s 1H),
  • Example 77 Methyl 4-[( ⁇ 4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2- yl ⁇ amino)carbonyl]-2,5-dibromobenzoate
  • Example 76 Prepared according to Example 76 (substituting 4-[( ⁇ 4-(Aminocarbonyl)-5- [(aminocarbonyl)amino]thien-2-yl ⁇ amino)carbonyl]-2,5-dibromobenzoic acid (Example 75) for the 4-[( ⁇ 4- (Aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2-yl ⁇ amino)carbonyl]-2,5-dichlorobenzoic acid).
  • Example 78 2-[(Aminocarbonyl)amino]-5- ⁇ [3-(chloromethyl)benzoyl]amino ⁇ thiophene-3- carboxamide
  • Example 79 2-[(Aminocarbonyl)amino]-5- ⁇ [3-(piperidin-1- ylmethyl)benzoyl]amino ⁇ thiophene-3-carboxamide
  • Example 80 2-[(aminocarbonyl)amino]-5-(4-chlorobenzyl)thiophene-3-carboxamide
  • Examples 81-100 (shown in Table VIII, below) were prepared by parallel synthesis, substituting the appropriate zinc chloride reagent.
  • the parallel synthesis apparatus consists of an aluminum block, which can be heated or cooled to the appropriate temperature, with a set of wells for 20- 50 mL glass vessels.
  • the parallel reactor blocks can be used under reflux conditions and inert atmosphere (obtained from J-KEM Scientific, Inc., St. Louis, MO, USA or ChemGlass Inc., Vineland, NJ, USA).
  • Analytical LCMS reverse phase chromatography was carried out using a C18 column 2.1 mm inner diameter x 30 mm and a linear gradient of 5% acetonitrile in 0.1 % TFA/H 2 0 to 95% acetonitrile in 0.1 % TFA/H 2 0 over 4.5 min. at a flow rate of 1 mL/min.
  • the eluent composition was held at 95% acetonitrile in 0.1% TFA/H 2 0 from 4.5 min to 6 min.
  • the LCMS was equipped with a diode array detector, a mass spectral detector (MSD) and an evaporative light scattering detector (ELS).
  • a flow splitter was attached after the UV diode array detector to allow flow to the MSD and ELS.
  • Mass spectra were obtained using an Agilent MSD in electrospray positive mode.
  • Preparative reverse phase chromatography was carried out using a C18 column 41.4 mm i.d. of 50 mm, 100 mm or 300 mm length.
  • the HPLC retention time was determined using analytical LCMS reverse phase analysis and represents the time obtained for the compound having the desired molecular ion. The retention time is based on the observed time in the UV chromatogram.
  • the molecular ion listed in the table is the baseline (100%) peak, unless otherwise noted.
  • Purity of the compounds prepared by parallel synthesis was determined by detection of the peak of the desired molecular ion and integration of the corresponding peak detected either by UV at 254 nm or by ELS.
  • Example 101 2-[(aminocarbonyl)amino]-5-(2-naphthoylamino)thiophene-3- carboxamide
  • Example 102 2-[(aminocarbonyl)amino]-5-(1 -naphthoylamino)thiophene-3- carboxamide
  • Example 103 2-[(aminocarbonyl)amino]-5-[(1 ,2-dihydroacenaphthylen-5- ylcarbonyl)amino]thiophene-3-carboxamide [00485] Prepared analogously to Example 101.
  • Mass of Molecular Ion 381 (M + 1).
  • Example 104 4-[( ⁇ 4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2- yl ⁇ amino)carbonyl]cyclohexane carboxylic acid
  • Example 105 Butyl 4-[( ⁇ 4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2- yl ⁇ amino)carbonyl]cyclohexane carboxylate
  • Example 109 4-[( ⁇ 4-(Aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2- yl ⁇ amino)carbonyl]cyclohexane carboxylic acid (cis isomer)
  • Example 110 2-methoxyethyl 4-[( ⁇ 4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2- yl ⁇ amino)carbonyl]cyclohexanecarboxylate
  • Example 110.1 Butyl 4-[( ⁇ 4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2- yl ⁇ amino)carbonyl] cyclohexanecarboxylate
  • Examples 111-115 shown in Table IX below, were prepared analogously to Example 109.
  • Example 116 2-[(aminocarbonyl)amino]-5- ⁇ [(4-tert- butylcyclohexyl)carbonyl]amino ⁇ thiophene-3-carboxamide
  • Examples 117-212 are reported in Table X. Examples 117-193 were prepared via parallel synthesis analogously to the procedure of Example 116. Examples 194-212 were prepared via parallel synthesis analogously to Example 116 with the following exceptions: To 0.402 mmol of corresponding acid was added 0.152 g (0.401 mmol) of 2-(1 H-benzotriazole-1-yl)-1, 1 ,3,3- tetramethyluronium hexafiuorophosphate, 0.100 g (0.423 mmol) of 5-amino-2- [(aminocarbonyl)amino]thiophene-3-carboxamide hydrochloride, 0.465 mL (4.230 mmol) 4- methylmorpholine, and 1.5 mL DMSO.
  • the parallel synthesis apparatus consisted of an aluminum block (obtained from J-KEM Scientific, Inc., St. Louis, MO, USA or ChemGlass Inc., Vineland, NJ, USA), which can be heated or cooled to the appropriate temperature, with a set of wells for 20-50 mL glass vessels.
  • the parallel reactor blocks can be used under reflux conditions and inert atmosphere.
  • the HPLC retention time was determined using analytical LCMS reverse phase analysis and represents the time obtained for the compound having the desired molecular ion. The retention time is based on the observed time in the UV chromatogram.
  • the molecular ion listed in Table X is the baseline (100%) peak, unless otherwise noted.
  • Analytical LCMS reverse phase chromatography was carried out using a C18 column 2.1 mm i.d. x 30 mm and a linear gradient of 5% acetonitrile in 0.1 % TFA/water to 95% acetonitrile in 0.1 % TFA/water over 4.5 min. at a flow rate of 1 mL/min.
  • the eluant composition was held at 95% acetonitrile in 0.1% TFA/water from 4.5 min to 6 min.
  • the LCMS was equipped with a diode array detector, a mass spectral detector (MSD) and an evaporative light scattering detector (ELS).
  • a flow splitter was attached after the UV diode array detector to allow flow to the MSD and ELS.
  • Mass spectra were obtained using an Agilent MSD in electrospray positive mode.
  • Preparative reverse phase chromatography was carried out using a C18 column 41.4 mm i.d. of 50 mm, 100
  • Example 213 2-[(Aminocarbonyl)amino]-5- ⁇ [(4- aminocyclohexyl)carbonyl]amino ⁇ thiophene-3-carboxamide Hydrochloride (trans-isomer)
  • Example 214 2-[(aminocarbonyl)amino]-5-[( ⁇ 4- [(phenylacetyl)amino]cyclohexyl ⁇ carbonyl)amino]thiophene-3-carboxamide (trans-isomer)
  • Example 214.1 2-[(aminocarbonyl)amino]-5- ⁇ [(4- ⁇ [(4- chlorophenyl)acetyl]amino ⁇ cyclohexyl)carbonyl] amino ⁇ thiophene-3-carboxamide
  • Example 214.2 2-[(aminocarbonyl)amino]-5-[( ⁇ 4-[(3,3- dimethylbutanoyl)amino]cyclohexyl ⁇ carbonyl)amino] thiophene-3-carboxamide (trans-isomer)
  • Example 214.3 2-[(aminocarbonyl)amino]-5- ⁇ [(4- ⁇ [(4- chlorophenyl)acetyl]amino ⁇ cyclohexyl) carbonyl]amino ⁇ thiophene-3-carboxamide (trans-isomer)
  • Example 215 2-[(Aminocarbonyl)amino]-5- ⁇ [(4- aminocyclohexyl)carbonyl]amino ⁇ thiophene-3-carboxamide Hydrochloride (cis-isomer)
  • Example 216 N- ⁇ 4-(aminocarbonyI)-5-[(aminocarbonyl)amino]thien-2-yl ⁇ -7- azabicyclo[2.2.1] heptane-2-carboxamide trifluoroacetate
  • Example 218 5-(beta-alanylamino)-2-[(aminocarbonyl)amino]thiophene-3-carboxamide
  • Example 300 Methyl 4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thiophene-2- carboxylate
  • the tube was placed in an oil bath at 80°C, and CO was bubbled for 6 hours under vigorous stirring.
  • the reaction mixture was filtered through celite, washed with 10 mL of DMF. Most of the liquids were removed under reduced pressure, and 60 mL of methylene chloride was added to the residue.
  • the mixture was triturated for 2 hours, filtered, and dried.
  • the solid was triturated with water (60 mL) for 5 hours, filtered, dried, and triturated with 25 mL of ethanol overnight, to give the desired product after filtration and drying.
  • Example 302 4-(Aminocarbonyl)-5-[(aminocarbonyl)amino]thiophene-2-carboxylic acid
  • Example 303 5-[(Aminocarbonyl)amino]-N-2-(3-chlorophenyl)thiophene-2,4- dicarboxamide
  • Example 304 Methyl 4-[( ⁇ 4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2- yl ⁇ carbonyl)amino]benzoate
  • Example 305 5-[(Aminocarbonyl)amino]-N-2-(3-chlorophenyl)-N-2-methylthiophene- 2,4-dicarboxamide
  • Example 306 5-[(Aminocarbonyl)amino]-N-2-(3-chlorobenzyl)thiophene-2,4- dicarboxamide
  • Example 307 5-[(Aminocarbonyl)amino]-N-2-(2-chlorobenzyI)thiophene-2,4- dicarboxamide
  • Example 308 5-[(Aminocarbonyl)amino]-N-2-(4-chlorobenzyl)thiophene-2,4- dicarboxamide
  • Example 309 5-[(Aminocarbony!amino]-N-2-[(1 R,2R)-2-phenylcyclopropyl]thiophene- 2,4-dicarboxamide
  • [00568] [00569] 2-[(aminocarbonyl)amino]-5-bromothiophene-3-carboxamide (4.48 g, 18 mmol), Zn(CN) 2 (1.247 g, 10.9 mmol), DPPF (1,1'-bis(diphenylphosphino)ferrocene) (1.308 g, 2.35 mmol), DMF (N,N-dimethylformamide) (39 mL), and benzonitrile (13 mL) were combined in a flask containing a stir-bar.
  • Example 312 5-[(aminocarbonyl)amino] thiophene-2,4-dicarboxamide
  • SAM 2 TM 96 Biotin capture plates were from Promega.
  • Anti-FLAG affinity resin, FLAG- peptide, NP-40 (Nonidet P-40), BSA, ATP, ADP, AMP, LPS (E. coli serotype 0111 :B4), and dithiothreitol were obtained from Sigma Chemicals.
  • Antibodies specific for NEMO (IKK- ) (FL-419), IKK-1 (H-744), IKK- 2(H-470) and l cB ⁇ (C-21) were purchased from Santa Cruz Biotechnology.
  • Ni-NTA resin was purchased from Qiage ⁇ .
  • Peptides were purchased from American Peptide Company.
  • Protease inhibitor cocktail tablets were from Boehringer Mannheim.
  • Sephacryl S-300 column was from Pharmacia LKB Biotechnology. Centriprep-10 concentrators with a molecular weight cutoff of 10 kDa and membranes with molecular weight cut-off of 30 kDa were obtained from Amicon. [Y- 33 P] ATP (2500 Ci/mmol) and [Y- 32 P] ATP (6000 Ci/mmol) were purchased from Amersham. The other reagents used were of the highest grade commercially available.
  • cDNAs of human IKK-1 and IKK-2 were amplified by reverse transcriptase-polymerase chain reaction from human placental RNA (Clonetech).
  • hlKK-1 was subcloned into pFastBac HTa (Life Technologies) and expressed as N-terminal His s -tagged fusion protein.
  • the hlKK-2 cDNA was amplified using a reverse oligonucleotide primer which incorporated the peptide sequence for a FLAG-epitope tag at the C-terminus of the IKK-2 coding region (DYKDDDDKD).
  • the hlKK-2:FLAG cDNA was subcloned into the baculovirus vector pFastBac.
  • the rhlKK-2 (S177S, E177E) mutant was constructed in the same vector used for wild type rh IKK-2 using a QuikChangeTM mutagenesis kit (Stratagene). Viral stocks of each construct were used to infect insect cells grown in 40L suspension culture. The cells were lysed at a time that maximal expression and rhlKK activity were demonstrated. Cell lysates were stored at -80°C until purification of the recombinant proteins was undertaken as described below.
  • buffer A 20 mM Tris-HCI, pH 7.6, containing 50 mM NaCl, 20 mM NaF, 20 mM /?-Glycerophosphate, 500 uM sodium orthovanadate, 2.5 mM metabisulfite, 5 mM benzamidine, 1 mM EDTA, 0.5 mM EGTA, 10% glycerol, 1 mM DTT, 1X CompleteTM protease inhibitors; buffer B: same as buffer A, except 150 mM NaCl, and buffer C: same as buffer A, except 500 mM NaCl.
  • the cells were microfluidized and centrifuged at 100,000 X g for 45 min. The supernatant was collected, imidazole added to the final concentration of 10 mM and incubated with 25 ml of Ni-NTA resin for 2 hrs.
  • the suspension was poured into a 25 ml column and washed with 250 ml of buffer C and then with 125 ml of 50 mM imidazole in buffer C.
  • rh IKK-1 homodimer was eluted using 300 mM imidazole in buffer C.
  • BSA and NP-40 were added to>the enzyme fractions to the final concentration of 0.1 %.
  • the enzyme was dialyzed against buffer B, aliquoted and stored at -80°C.
  • Washed resin was poured into a column and rhlKK-2 homodimer was eluted using 5 bed volumes of buffer B containing FLAG peptide. 5 mM DTT, 0.1 % NP-40 and BSA (concentrated to 0.1 % in final amount) was added to the eluted enzyme before concentrating in using an Amicon membrane with a molecular weight cut-off of 30 kDa. Enzyme was aliquoted and stored at -80°C. ⁇
  • the protein-resin slurry was poured into a 25 ml column and washed with 250 ml of buffer A containing 10 mM imidazole followed by 125 ml of buffer A containing 50 mM imidazole. Buffer A, containing 300 mM imidazole, was then used to elute the protein. A 75 ml pool was collected and NP-40 was added to a final concentration of 0.1%. The protein solution was then dialyzed against buffer B. The dialyzed heterodimer enzyme was then allowed to bind to 25 ml of anti- FLAG M2 agarose affinity gel overnight with constant mixing. The protein-resin slurry was then centrifuged for 5 min at 2,000 rpm.
  • the supernatant was collected and the resin re-suspended in 100 ml of buffer C containing 0.1 % NP-40. The resin was washed with 375 ml of buffer C containing 0.1 % NP-40. The protein-resin was poured into a 25 ml column and the enzyme eluted using buffer B containing FLAG peptide. Enzyme fractions (100 ml) were collected and concentrated to 20 ml using an Amicon membrane with molecular weight cut-off of 30 kDa. Bovine serum albumin was added to the concentrated enzyme to final concentration of 0.1 %. The enzyme was then aliquoted and stored at -80°C.
  • Pre-B cells were stimulated by the addition of 10 ⁇ g/ml LPS for varying lengths of time ranging from 0-4 hr.
  • THP-1 cells were stimulated by the addition of 1 ⁇ g/ml LPS for 45 minutes.
  • Cells were pelleted, washed with cold 50 mM sodium phosphate buffer, pH 7.4 containing 0.15 M NaCl and lysed at 4°C in 20 mM Hepes buffer, pH 7.6 containing 50 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1 mM sodium orthovanadate, 10 mM -glycerophosphate, 1 mM NaF, 1 mM PMSF, 1 mM DTT and 0.5 % NP40 (lysis buffer).
  • the cytosolic fractions obtained following centrifugation at 10,000 X g were stored at -80°C until used.
  • SF9 cells paste containing rhlKKs were centrifuged (100,000 X g, 10 min) to remove debris.
  • rhlKKs were immunoprecipitated (100 ⁇ g of cell paste) from the cell supernatant using 3 ⁇ g of anti- NEMO antibody (FL-419), followed by coupling to protein A sepharose beads.
  • rhlKKs were also immunoprecipitated from affinity chromatography purified protein preparations (1 ⁇ g) using anti-FLAG, anti-His or anti-NEMO antibodies (1-4 ⁇ g) followed by protein A sepharose coupling.
  • the native, human IKK complex was immunoprecipitated from THP-1 cell homogenates (300 ⁇ g/condition) using the anti- NEMO antibody. Immune complexes were pelleted and washed 3 times with 1 ml cold lysis buffer.
  • Immunoprecipitated rhlKKs were chromatographed by SDS-PAGE (8% Tris-glycine) and transferred to nitrocellulose membranes (Novex) and detected by chemiluminescense (SuperSignal) using specific anti- IKK antibodies (IKK-2 H-470, IKK-1 H-744).
  • Native IKK-2, kB ⁇ , and NEMO proteins from cytosolic lysates (20-80 ⁇ g) were separated by SDS-PAGE and visualized by chemiluminescense using specific antibodies.
  • IKK-1 SAM Enzyme Assay [00583] IKK-1 kinase activity was measured using a biotinylated ⁇ Ba peptide (Gly-Leu-Lys-Lys- Glu-Arg-Leu-Leu-Asp-Asp-Arg-His-Asp-Ser 32 -Gly-Leu-Asp-Ser 36 -Met-Lys-Asp-Glu-Glu), a SAM 2 TM 96 Biotin capture plate and a vacuum system.
  • the standard reaction mixture contained 5 ⁇ M biotinylated l/cB ⁇ peptide, 1 ⁇ M [ ⁇ - 33 P] ATP (about 1 X 10 5 cpm), 1 M DTT, 50 mM KCI, 2 mM MgCI 2 , 2 mM MnCI 2 , 10 mM NaF, 25 mM Hepes buffer, pH. 7.6 and enzyme solution (1-10 ⁇ l) in a final volume of 50 ⁇ l. After incubation at 25°C for 30 min, 25 ⁇ l of the reaction mixture was withdrawn and added to a SAM 2 TM 96 Biotin capture 96-well plate.
  • rhlKK-1 homodimer For K m determination of rhlKK-1 homodimer, due to its low activity and higher K m for ⁇ Ba peptide, rhlKK-1 homodimer (0.3 ⁇ g) was assayed with 125 ⁇ M ⁇ Ba peptide and a 5-fold higher specific activity of ATP (from 0.1 to 10 ⁇ M) for ATP K m experiments and a 5-fold higher specific activity of 5 ⁇ M ATP and ⁇ Ba peptide (from 5 to 200 ⁇ M) for l/cB ⁇ peptide K m experiments.
  • IKK heterodimer Resin Enzyme Assay [00584] IKK heterodimer kinase activity was measured using a biotinylated l cB ⁇ peptide (Gly- Leu-Lys-Lys-Glu-Arg-Leu-Leu-Asp-Asp-Arg-His-Asp-Ser 32 -Gly-Leu-Asp-Ser 33 -Met-Lys-Asp-Glu-Glu) (American Peptide Co.).
  • 20 ul of the standard reaction mixture contained 5 ⁇ M biotinylated ⁇ Ba peptide, 0.1 ⁇ Ci/reaction [ - 33 R] ATP (Amersham) (about 1 X 10 5 cpm), 1 ⁇ M ATP (Sigma), 1 mM DTT (Sigma), 2 mM MgCI 2 (Sigma), 2 mM MnCI 2 (Sigma), 10 mM NaF (Sigma), 25 mM Hepes (Sigma) buffer, pH 7.6 and 20 ⁇ l enzyme solution and 10 ⁇ l inhibitor in a final volume of 50 ⁇ l.
  • IKK-2 Resin Enzyme Assay [00585] IKK-2 kinase activity was measured using a biotinylated ⁇ Ba peptide (Gly-Leu-Lys-Lys- Glu-Arg-Leu-Leu-Asp-Asp-Arg-His-Asp-Ser 32 -Gly-Leu-Asp-Ser 36 -Met-Lys-Asp-Glu-Glu) (American Peptide Co.).
  • 20 ul of the standard reaction mixture contained 5 ⁇ M biotinylated B ⁇ peptide, 0.1 ⁇ Ci/reaction [y- 33 P] ATP (Amersham) (about 1 X 10 5 cpm), 1 ⁇ M ATP (Sigma), 1 mM DTT (Sigma), 2 mM MgCI 2 (Sigma), 2 mM MnCI 2 (Sigma), 10 mM NaF (Sigma), 25 mM Hepes (Sigma) buffer, pH 7.6 and 20 ⁇ l enzyme solution and 10 ul inhibitor in a final volume of 50 ⁇ l.

Abstract

IKK-2-inhibiting compounds of Formula I: wherein R, X, Y, Z, R3, R4, R5, and are as defined herein, are disclosed.

Description

SUBSTITUTED THIOPHENE AMIDE COMPOUNDS FOR THξ TREATMENT OF INFLAMMATION
FIELD OF THE INVENTION [0001] This invention generally relates to anti-inflammatory pharmaceutical agents and specifically relates to thiophene compounds as inhibitors of IKK-2, an kB kinase. The invention is further related to compositions comprising such compounds, and methods for treating cancer, inflammation, and inflammation-associated disorders such as arthritis.
BACKGROUND OF THE INVENTION [0002] Rheumatoid arthritis is a common inflammatory disease affecting approximately 1 % of the population. The disease is characterized by multiple painful swollen joints that severely limit the patient's daily function, and can progress to the destruction of the affected joints. A common treatment for rheumatoid arthritis is anti-inflammatory steroids. Steroids are clinically very effective, but are limited in their use because of multiple severe side-effects. Thus, a need exists for an anti- rheumatoid arthritis treatment that offers the potency of steroids without the associated toxicity. One of the mechanisms by which steroids exert their broad spectrum anti-inflammatory action is by inhibiting the activation of the transcription factor NF-/ B. NF-κB plays a prominent role in immune and inflammatory responses by regulating the transcription of many early, inducible genes in a variety of cells including inflammatory enzymes such as COX-2 and iNOS. NF-κB is sequestered in an inactive form in the cytoplasm by a member of the kB family of inhibitory proteins, and this prevents gene transcription of these responsive genes in the nucleus. Stimulation of cells leads to the phosphorylation, ubiquination and degradation of kB thereby releasing NF- B to the nucleus for activation of gene transcription. Chronic activation of NF-/ B has been demonstrated in vascular endothelium and synovial lining cells from patients with RA. Recently the kB kinases (IKK-1 and IKK-2), which phosphorylate kB and thereby initiate its degradation, have been cloned and initially characterized; these kinases appear to represent the critical, common denominator in the activation of NF-/cB since antisense or dominant-negative IKK constructs block NF- B nuclear translocation and inhibit NF-κB linked reported genes. Therefore, IKK-1 and/or IKK-2 represent novel and powerful targets for drug development. [0003] It has been reported that selective IKK-2 inhibitors could be useful for the treatment of inflammatory diseases. See, e.g., Karin et al.. Nat. Revs. 3. 17-26, 2004. [0004] PCT Publication No. WO 01/58890 describes thiophenecarboxamides as inhibitors of IKK-2. [0005] PCT Publication No. WO 02/30353 describes 2-aminothiophene-3-carboxamides as NF-κB inhibitors. [0006] PCT Publication No. WO 03/10163 describes ureido-carboxamido thiophene compounds as inhibitors of IKK-2 kinase. [0007] PCT Publication No. WO 03/29242 describes ureido-thiophenecarboxamide derivatives as NF-ΛB inhibitors.
SUMMARY OF THE INVENTION [0008] This invention provides for, in part, IKK-2-inhibiting compounds of Formula I:
Figure imgf000003_0001
[0010] wherein R is selected from the group consisting of:
Figure imgf000003_0002
[0012] wherein X is selected from the group consisting of a bond, alkyl, cycloalkyl, alkenyl, and heterocycloalkyl; [0013] wherein Y is O or S; [0014] wherein Z is selected from the group consisting of hydrido, halo, alkyl, cyano, and haloalkyl; [0015] wherein R1 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, or where R1 and R2 together with the atoms to which they are attached form a heterocyclic moiety, or where R1 and R1a together with the nitrogen to which they are attached form a heterocyclic moiety; [0016] wherein R is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-alkylamino, N,N-dialkylamino, N-arylamino, N-alkyl-N-arylamino, N- hydroxyamino, N-alkyl-N-hydroxyamino, N-aryl-N-hydroxyamino, halo, cyano, keto, hydroxyl, alkyl, haloalkyl, cycloalkyl, alkoxy, alkenyl, alkenyloxy, aryl, aryloxy, aralkyl, aralkylcarbonyl, aralkylcarbonylamino, heteroarylcarbonyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, alkoxycarbonyl, aryloxycarbonyl, carboxyl, alkoxyalkoxycarbonyl, alkoxycarbonylamino, heterocycloalkyl, heterocycloalkylalkyl, thiol, oxidosulfanyl, sulfino, alkylthio, alkylsulfinyl, alkylsulfonyl, cycloalkylthio, cycloalkylsulfinyl, cycloalkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, heterocycloalkylthio, heterocycloalkylsulfinyl, heterocycloalkylsulfonyl, heteroarylthio, heteroarylsulfinyl, and heteroarylsulfonyl; [0017] wherein R1a is selected from the group consisting of hydrido, hydroxyl, alkoxy, alkyl, haloalkyl, aryl, and heteroaryl, or where R1a and R1 together with the nitrogen to which they are attached form a heterocyclic moiety; [0018] wherein R2 is selected from the group consisting of hydrido, hydroxyl, alkoxy, alkyl, haloalkyl, aryl, and heteroaryl, or R2 and R1 together with the atoms to which they are attached form a heterocyclic moiety; [0019] wherein R3 is selected from the group consisting of alkyl, haloalkyl, and -NR7R8; and [0020] wherein R4, R5, R6, R7, and R8 are independently selected from the group consisting of hydrido, hydroxyl, alkoxy, alkyl, haloalkyl, aryl, and heteroaryl; [0021 ] or a pharmaceutically acceptable salt thereof. [0022] The instant invention is also directed to pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically-acceptable salt thereof, as defined above, and a pharmaceutically acceptable carrier, diluent, or adjuvant. [0023] The instant invention is also directed to a method of treating or preventing inflammation or an inflammation-associated disorder, the method comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need of such treatment or susceptible to such inflammation or inflammation-associated disorder. [0024] Other objects of the invention will be in part apparent and in part pointed out hereinafter.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS [0025] In accordance with the present invention, Applicants have discovered a class of IKK-2- inhibiting compounds of Formula 1:
Figure imgf000004_0001
[0027] wherein R, Y, Z, R3, R4, R5, and R6 are defined as shown above. [0028] Compounds of Formula I may be useful for treating, among other things, inflammation in a subject, such as, as an analgesic in the treatment of pain and headaches, or as an antipyretic for the treatment of fever. For example, compounds of the present invention may be useful to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, psoriatic arthritis, and pyogenic arthritis. [0029] Compounds of the invention may be further useful in the treatment of frailty, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, menstrual cramps (e.g., dysmenorrhea), premature labor, tendinitis, bursitis, dermatological conditions such as psoriasis, eczema, bums, sunburn, dermatitis, pancreatitis, hepatitis, and from post-operative inflammation including from ophthalmic surgery such as cataract surgery and refractive surgery. Compounds of the invention also would be useful to treat , gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. Compounds of the invention would be useful for the prevention or treatment of cancer, such as colorectal cancer, and cancer of the breast, lung, prostate, bladder, cervix and skin, as well as treatment of cancer stem cells. Compounds of the invention would be useful in treating inflammation and tissue damage in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular junction disease including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, nephritis, hypersensitivity, swelling occurring after injury, myocardial ischemia, and the like. [0030] The compounds would also be useful in the treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis. The compounds would also be useful for the treatment of certain central nervous system disorders, such as cortical dementias including Alzheimer's disease, and central nervous system damage resulting from stroke, ischemia and trauma. The compounds of the invention are useful as anti-inflammatory agents, such as for the treatment of arthritis, with the additional benefit of having significantly less harmful side effects. These compounds would also be useful in the treatment of allergic rhinitis, respiratory distress syndrome, and atherosclerosis. The compounds would also be useful in the treatment of pain, but not limited to postoperative pain, dental pain, muscular pain, and pain resulting from cancer. The compounds would be useful for the prevention of dementias, such as Alzheimer's disease. [0031] Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats. [0032] The present compounds may also be used in co-therapies, partially or completely, in place of other conventional antiinflammatory therapies, such as together with steroids, NSAIDs, COX-2 selective inhibitors, 5-lipoxygenase inhibitors, LTB antagonists and LTA4 hydrolase inhibitors. [0033] Other conditions in which the compounds of the present invention may provide an advantage include cardiovascular ischemia, diabetes (type I or type II), congestive heart failure, myocarditis, atherosclerosis, migraine, glaucoma, aortic aneurysm, reflux esophagitis, diarrhea, irritable bowel syndrome, cystic fibrosis, emphysema, asthma, bronchiectasis, hyperalgesia (allodynia), and cerebral ischemia (both focal ischemia, thrombotic stroke and global ischemia (for example, secondary to cardiac arrest). [0034] The compounds of the present invention may also be useful in the treatment of pain including somatogenic (either nociceptive or neuropathic), both acute and chronic. A compound of the present invention could be used in any situation including neuropathic pain that a common NSAID or opioid analgesic would traditionally be administered. [0035] Conjunctive treatment of a compound of the present invention with an antineoplastic agent may produce a beneficial effect or alternatively reduce the toxic side effects associated with chemotherapy by reducing the therapeutic dose of the side effect-causing agent needed for therapeutic efficacy or by directly reducing symptoms of toxic side effects caused by the side effect-causing agent. A compound of the present invention may further be useful as an adjunct to radiation therapy to reduce side effects or enhance efficacy. In the present invention, another agent which can be combined therapeutically with a compound of the present invention includes any therapeutic agent which is capable of inhibiting the enzyme cyclooxygenase-2 ("COX-2"). Preferably such COX-2 inhibiting agents inhibit COX-2 selectively relative to the enzyme cyclooxygenase-1 ("COX-1"). Such a COX-2 inhibitor is known as a "COX-2 selective inhibitor". More preferably, a compound of the present invention can be therapeutically combined with a COX-2 selective inhibitor wherein the COX-2 selective inhibitor selectively inhibits COX-2 at a ratio of at least 10:1 relative to inhibition of COX-1 , more preferably at least 30:1 , and still more preferably at least 50:1 in an In vitro test. COX-2 selective inhibitors useful in therapeutic combination with the compounds of the present invention include celecoxib, valdecoxib, deracoxib, etoricoxib, rofecoxib, ABT- 963 (2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl-3(2H)- pyridazinone; described in PCT Publication No. WO 00/24719), or meloxicam. A compound of the present invention can also be advantageously used in therapeutic combination with a prodrug of a COX-2 selective inhibitor, for example parecoxib. [0036] Another chemotherapeutic agent which may be useful in combination with a compound of the present invention can be selected, for example, from the following non-comprehensive and non- limiting list: Alpha-difluoromethylomithine (DFMO), 5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, Lilly DATHF, Merrill Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N-(2'-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropyl pyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim, methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661 , NCI NSC-612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, Taiho UFT, uricytin, Shionogi 254-S, aldo-phosphamide analogues, altretamine, anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitane, Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)2, diphenylspiromustine, diplatinum cytostatic, Erba distamycin derivatives, Chugai DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517, estramustine phosphate sodium, fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfamide, iproplatin, lomustiπe, mafosfamide, mitolactol, Nippon Kayaku NK-121 , NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine, Prater PTT-119, ranimustine, semustine, SmithKline SK&F- 101772, Yakult Honsha SN-22, spiromus-tine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone, tetraplatin, trimelamol, Taiho 4181 -A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456, aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate, bryostatin-1 , Taiho C-1027, calichemycin, chromoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko .DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1 , Kyowa Hakko DC92-B, ditrisarubicin B, Shionogi DOB-41 , doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin, esperamicin-A1, esperamicin-Alb, Erbamont FCE-21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, mitoxantrone, SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01 , SRI International NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin, pirarubicin, porothramycin, pyrindamycin A, Tobishi RA-I, rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 zorubicin, alpha-carotene, alpha- difluoromethyl-arginine, acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile, amsacrine, Angiostat, ankinomycin, anti-neoplaston A10, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1 , Henkel APD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin, benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene, Bristo-Myers BMY- 40481 , Vestar boron-10, bromofosfamide, Wellcome BW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride, Ajinomoto CDAF, chlorsulfaquinoxalone, Chemex CHX-2053, Chemex CHX- 100, Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICN compound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate, dacarbazine, datelliptinium, didemnin-B, dihaematoporphyrin ether, dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, elliprabin, elliptinium acetate, Tsumura EPMTC, ergotamine, etoposide, etretinate, fenretinide, Fujisawa FR-57704, gallium nitrate, genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, grifolan NMF-5N, hexadecylphosphocholine, Green Cross HO-221 , homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin, lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin, Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyanine derivatives, methylanilinoacridine, Molecular Genetics MGI-136, minactivin, mitonafide, mitoquidone, mopidamol, motretinide, Zenyaku Kogyo MST-16, N-(retinoyl)amino acids, Nisshin Flour Milling N-021, N-acylated- dehydroalanines, nafazatrom, Taisho NCU-190, nocodazole derivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI NSC-95580, octreotide, Ono ONO-112, oquizanocine, Akzo Org-10172, pancratistatin, pazelliptine, Warner-Lambert PD-111707, Warner-Lambert PD-115934, Wamer-Lambert PD-131141 , Pierre Fabre PE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreic acid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitron protease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS, restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976, SmithKline SK&F-104864, Sumitomo SM- 108, Kuraray SMANCS, SeaPharm SP-10094, spatol, spirocyclopropane derivatives, spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone, Stypoldione, Suntory SUN 0237, Suntory SUN 2071 , superoxide dismutase, Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29, tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN- 1028, ukrain, Eastman Kodak USB-006, vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides, Yamanouchi YM-534, uroguanylin, combretastatin, dolastatin, idarubicin, epirubicin, estramustine, cyclophosphamide, 9-amino-2-(S)-camptothecin, topotecan, irinotecan (Camptosar), exemestane, decapeptyl (tryptorelin), or an omega-3 fatty acid. [0037] Examples of radioprotective agents which may be used in a combination therapy with the compounds of this invention include AD-5, adchnon, amifostine analogues, detox, dimesna, 1-102, MM- 159, N-acylated-dehydroalanines, TGF-Genentech, tiprotimod, amifostine, WR-151327, FUT-187, ketoprofen transdermal, nabumetone, superoxide dismutase (Chiron) and superoxide dismutase Enzon. [0038] The compounds of the present invention may also be useful in treatment or prevention of angiogenesis-related disorders or conditions, for example, tumor growth, metastasis, macular degeneration, and atherosclerosis. [0039] In a further embodiment, the present invention also provides therapeutic combinations for the treatment or prevention of ophthalmic disorders or conditions such as glaucoma. For example the present inventive compounds advantageously may be used in therapeutic combination with a drug which reduces the intraocular pressure of patients afflicted with glaucoma. Such intraocular pressure-reducing drugs include without limitation latanoprost, travoprost, bimatoprost, or unoprostol. The therapeutic combination of a compound of the present invention plus an intraocular pressure-reducing drug may be useful because each is believed to achieve its effects by affecting a different mechanism. [0040] In another combination of the present invention, the present inventive compounds can be used in therapeutic combination with an antihyperlipidemic or cholesterol-lowering drug such as a benzothiepine or a benzothiazepine antihyperlipidemic drug. Examples of benzothiepine antihyperlipidemic drugs useful in the present inventive therapeutic combination can be found in U.S. Patent No. 5,994,391, herein incorporated by reference. Some benzothiazepine antihyperlipidemic drugs are described in PCT Publication No. WO 93/16055. Alternatively, the antihyperlipidemic or cholesterol-lowering drug useful in combination with a compound of the present invention can be an HMG Co-A reductase inhibitor. Examples of HMG Co-A reductase inhibitors useful in the present therapeutic combination include, individually, benfluorex, fluvastatin, lovastatin, pravastatin, simvastatin, atorvastatin, cerivastatin, bervastatin, ZD-9720 (described in PCT Publication No. WO 97/06802), ZD-4522 (CAS No. 147098-20-2 for the calcium salt; CAS No. 147098-18-8 for the sodium salt; described in European Patent No. EP 521471), BMS 180431 (CAS No. 129829-03-4), or NK-104 (CAS No. 141750-63-2). The therapeutic combination of a compound of the present invention plus an antihyperlipidemic or cholesterol-lowering drug may be useful, for example, in reducing the risk of formation of atherosclerotic lesions in blood vessels. For example, atherosclerotic lesions often initiate at inflamed sites in blood vessels. It is established that antihyperlipidemic or cholesterol-lowering drug reduce risk of formation of atherosclerotic lesions by lowering lipid levels in blood. Without limiting the invention to a single mechanism of action, it is believed that one way the compounds of the present combination may work in concert to provide improved control of atherosclerotic lesions by, for example, reducing inflammation of the blood vessels in concert with lowering blood lipid levels. [0041] In another embodiment of the invention, the present compounds can be used in combination with other compounds or therapies for the treatment of central nervous conditions or disorders such as migraine. For example, the present compounds can be used in therapeutic combination with caffeine, a 5-HT-1 B/1 D agonist (for example, a triptan such as sumatriptan, naratriptan, zolmitriptan, rizatriptan, almotriptan, or frovatriptan), a dopamine D4 antagonist (e.g., sonepiprazole), aspirin, acetaminophen, ibuprofen, indomethacin, naproxen sodium, isometheptene, dichloralphenazone, butalbital, an ergot alkaloid (e.g., ergotamine, dihydroergotamine, bromocriptine, ergonovine, or methyl ergonovine), a tricyclic antidepressant (e.g., amitriptyline or nortriptyline), a serotonergic antagonist (e.g., methysergide or cyproheptadine), a beta-andrenergic antagonist (e.g., propranolol, timolol, atenolol, nadolol, or metprolol), or a monoamine oxidase inhibitor (e.g., phenylzine or isocarboxazid). [0042] The present invention includes compounds that selectively inhibit IKK-2 over other kinases. Such other kinases include, but are not limited to, Abl(h), Abl(T315l), Abl(T315l), AMPK, Aurora- A, BTK, CaMKII, CaMKIV, CDK1/cyclinB, CDK2, CDK2/cyclin A, CDK2/cyclinE, CHK1 , CHK2, CK1 , CK1(y), CK , CK2, c-RAF(h), CSK, cSRC(h), DYRKIa, ERK2, Fyn, GSK3β, IGF-1 R, IKK1 , IKKi, IKK2(h), JNK SAPK1C, JNK1, JNK1σ1(h), JNK2, JNK2σ2(h), JNK3, Lck, MAPK1(h), MAPK2(h), MAPK2/ERK2, MAPKAP-K1 a, MAPKAP-K2, MEK1 , MK-2, MK-3, MKK1 , MKK4, MKK6, MKK7, MKK7β(h), MNK,
MRSK2/APKAPk1b, MSK, MSK1 , NEK2a, NEK6, p38 alpha, p38 beta, p38 delta, p38 gamma, p70 S6K, PAK2, PDGFRβ, PDK1, PHK, PKA, PKBΔph, PKCf, PKCσ, PKCy, PKC£, PKCe, PRAK, ROCK-II, Rsk1, Rsk2, RSKB, SAPK2a/p38, SAPK2b, SAPK2b/p38β2, SAPK3, SAPK3/p38g, SAPK4, SAPK4/p38d, SGK, TBK-1 , and ZAP-70. The compounds may have an IKK-2 IC50 of less than about 10 μM, preferably less than about 1 μM, and have a selectivity ratio of IKK-2 inhibition over IKK-1 inhibition of at least 50, or at least 100. The compounds may have an IKK-1 IC50 of greater than 10 μM, or greater than 100 μM. [0043] In one preferred embodiment, the compound of Formula I is a compound of Formula IA:
Figure imgf000009_0001
[0044] IA [0045] wherein R is selected from the group consisting of:
Figure imgf000009_0002
[0047] wherein X is selected from the group consisting of a bond, alkyl, cycloalkyl, alkenyl, and heterocycloalkyl; [0048] wherein Z is selected from the group consisting of hydrido, halo, alkyl, cyano, and haloalkyl; [0049] wherein R1 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, or where R1 and R2 together with the atoms to which they are attached form a heterocyclic moiety, or where R1 and R1a together with the nitrogen to which they are attached form a heterocyclic moiety; [0050] wherein R1 is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-alkylamino, N,N-dialkylamino, N-arylamino, N-alkyl-N-arylamino, N- hydroxyamino, N-alkyl-N-hydroxyamino, N-aryl-N-hydroxyamino, halo, cyano, keto, hydroxyl, alkyl, haloalkyl, cycloalkyl, alkoxy, alkenyl, alkenyloxy, aryl, aryloxy, aralkyl, aralkylcarbonyl, aralkylcarbonylamino, heteroarylcarbonyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, alkoxycarbonyl, aryloxycarbonyl, carboxyl, alkoxyalkoxycarbonyl, alkoxycarbonylamino, heterocycloalkyl, heterocycloalkylalkyl, thiol, oxidosulfanyl, sulfino, alkylthio, alkylsulfinyl, alkylsulfonyl, cycloalkylthio, cycloalkylsulfinyl, cycloalkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, heterocycloalkylthio, heterocycloalkylsulfinyl, heterocycloalkylsulfonyl, heteroarylthio, heteroarylsulfinyl, and heteroarylsulfonyl; [0051] wherein R1a is selected from the group consisting of hydrido, hydroxyl, alkoxy, alkyl, haloalkyl, aryl, and heteroaryl, or where R1a and R1 together with the nitrogen to which they are attached form a heterocyclic moiety; [0052] wherein R2 is selected from the group consisting of hydrido, hydroxyl, alkoxy, alkyl, haloalkyl, aryl, and heteroaryl, or R2 and R1 together with the atoms to which they are attached form a heterocyclic moiety; [0053] wherein R3 is selected from the group consisting of alkyl, haloalkyl, and -NR7R8; and [0054] wherein R4, R5, R6, R7, and R8 are independently selected from the group consisting of hydrido, hydroxyl, alkoxy, alkyl, haloalkyl, aryl, and heteroaryl; [0055] or a pharmaceutically acceptable salt thereof. [0056] In one preferred embodiment, the compound of Formula IA is a compound wherein X is selected from the group consisting of a bond, C^ alkyl, C3-12 cycloalkyl, C2-β alkenyl, and 3- to 12- membered heterocycloalkyl; [0057] wherein Z is selected from the group consisting of hydrido, halo, Cι.6 alkyl, cyano, and C1-6 haloalkyl; [0058] wherein R ,1 is selected from the group consisting of C^ alkyl, C -12 cycloalkyl, C2-6 alkenyl, C3.12 cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, C3.12 aryl, C4- 8 aralkyl, 3- to 12-membered heteroaryl, and 4- to 18-membered heteroaralkyl, or where R1 and R2 together with the atoms to which they are attached form a 3- to 12-membered heterocyclic moiety, or where R1 and R1a together with the nitrogen to which they are attached form a 3- to 12-membered heterocyclic moiety; [0059] wherein R is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-(C1-6 alkyl)amino, N,N-di(C1_6 alkyl)amino, N-(C3-12 aryl)amino, N- (C-ι-6 alkyl)-N-(C3-12 aryl)amino, N-hydroxyamino, N-(C1-6 alkyl)-N-hydroxyamino, N-(C3-12 aryl)-N- hydroxyamino, halo, cyano, keto, hydroxyl, C1-6 alkyl, C1-β haloalkyl, C3.β cycloalkyl, C^e alkoxy, C2.6 alkenyl, C2.6 alkenyloxy, C^^ aryl, C3-ι2 aryloxy, C4_20 aralkyl, C4-2o aralkylcarbonyl, C4-20 aralkylcarbonylamino, 3- to 14-membered heteroarylcarbonyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 3- to 12-membered heteroaryl, C2.7 alkoxycarbonyl, C3-12 aryloxycarbonyl, carboxyl, C2-15 alkoxyalkoxycarbonyl, C2-7 alkoxycarbonylamino, 3- to 12-membered heterocycloalkyl, 4- to 18-membered heterocycloalkylalkyl, thiol, oxidosulfanyl, sulfino, Cι_6 alkylthio, Cι_6 alkylsulfinyl, Cι-S alkylsulfonyl, C3.12 cycloalkylthio, C3-12 cycloalkylsulfinyl, C3-12 cycloalkylsulfonyl, C3.12 arylthio, C3.12 arylsulfinyl, C3-12 arylsulfonyl, 3- to 12-membered heterocycloalkylthio, 3- to 12-membered heterocycloalkylsulfinyl, 3- to 12-membered heterocycloalkylsulfonyl, 3- to 12-membered heteroarylthio, 3- to 12-membered heteroarylsulfinyl, 3- to 12-membered and heteroarylsulfonyl; [0060] wherein R1a is selected from the group consisting of hydrido, hydroxyl, C,_6 alkoxy, C-i_6 alkyl, C1-8 haloalkyl, C3-12 aryl, and 3- to 12-membered heteroaryl, or where R1a and R1 together with the nitrogen to which they are attached form a 3- to 12-membered heterocyclic moiety; [0061] wherein R2 is selected from the group consisting of hydrido, hydroxyl, Cι.β alkoxy, Cι-6 alkyl, Cι-6 haloalkyl, C3-12 aryl, and 3- to 12-membered heteroaryl, or R2 and R1 together with the atoms to which they are attached form a 3- to 12-membered heterocyclic moiety; [0062] wherein R3 is selected from the group consisting of Cι-s alkyl, C-,.6 haloalkyl, and -NR7R8; and [0063] wherein R4, R5, R6, R7, and R8 are independently selected from the group consisting of hydrido, hydroxyl, C1-6 alkoxy, C1-6 alkyl, C-|.6 haloalkyl, C3-ι2 aryl, and 3- to 12-membered heteroaryl. [0064] In one particularly preferred embodiment, the compound of Formula IA is a compound wherein X is selected from the group consisting of a bond, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, propenyl, butenyl, pentenyl, and heterocycloalkyl; [0065] wherein Z is selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyano, and haloalkyl; [0066] wherein R1 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, propenyl, butenyl, pentenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, isoindolyl, dihydroindolyl, isoindolinyl, dihydrothiophenyl, dihydropyrrolyl, dihydrofuryl, dihydropyrazolyl, dihydroimidazolyl, dihydroisoxazolyl, dihydrooxazolyl, phenyl, biphenyl, naphthyl, indenyl, benzyl, phenylethyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isoindoledionyl, pyridinylmethyl, pyridinylethyl, benzothiophenylmethyl, benzothiophenylethyl, indolylmethyl, indolylethyl, isoquinolinylmethyl, isoquinolinylethyl, quinolinylmethyl, quinolinylethyl, thienylmethyl, thienylethyl, pyrrolylmethyl, pyrrolylethyl, furylmethyl, furylethyl, pyrazolylmethyl, pyrazolylethyl, imidazolylmethyl, imidazolylethyl, isoxazolylm ethyl, isoxazolylethyl, oxazolylmethyl, oxazolylethyl, isoindoledionylmethyl, and isoindoledionylethyl, or where R1 and R2 together with the atoms to which they are attached form pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isoindoledionyl, isoindolyl, dihydroindolyl, isoindolinyl, dihydrothiophenyl, dihydropyrrolyl, dihydrofuryl, dihydropyrazolyl, dihydroimidazolyl, dihydroisoxazolyl, dihydrooxazolyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, or oxazolidinyl, or where R1 and R1a together with the atoms to which they are attached form a cyclic moiety selected from the group consisting of piperidinonyl, dihydropyridinonyl, pyridinonyl, dihydroindolonyl, octahydroindolonyl, dihydroisoindolonyl, octahydroisoindolonyl, isoquinolinonyl, dihydroisoquinolinonyl, quinolinonyl, dihydroquinolinonyl, pyrrolidinonyl, and pyrazolidinonyl; [0067] wherein R1 is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-methylamino, N-ethylamino, N-propylamino, N,N-dimethylamino, N- methyl-N-ethylamino, N-methyl-N-propylamino, N,N-diethylamino, N-ethyl-N-propylamino, N,N- dipropylamino, N-phenylamino, N-biphenylamino, N-naphthylamino, N-methyl-N-phenylamino, N-ethyl-N- phenylamino, N-propyl-N-pheπylamino, N-hydroxyamino, N-methyl-N-hydroxyamino, N-ethyl-N- hydroxyamino, N-propyl-N-hydroxyamino, N-phenyl-N-hydroxyamino, N-biphenyl-N-hydroxyamino, N- naphthyl-N-hydroxyamino, chloro, fluoro, bromo, iodo, cyano, keto, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, butoxy, ethenyl, propenyl, butenyl, pentenyl ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, phenyl, biphenyl, naphthyl, indenyl, phenoxy, biphenoxy, naphthyloxy, indenyloxy, benzyl, phenylethyl, benzylcarbonyl, phenylethylcarbonyl, benzylcarbonylamino, phenylethylcarbonylamino, pyridinylcarbonyl, benzothiophenylcarbonyl, indolylcarbonyl, isoquinolinylcarbonyl, quinolinylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl, furylcarbonyl, pyrazolylcarbonyl, imidazolylcarbonyl, isoxazolylcarbonyl, oxazolylcarbonyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isoindoledionyl, isoindolyl, dihydroindolyl, isoindolinyl, dihydrothiophenyl, dihydropyrrolyl, dihydrofuryl, dihydropyrazolyl, dihydroimidazolyl, dihydroisoxazolyl, dihydrooxazolyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, phenoxycarbonyl, biphenoxycarbonyl, naphthyloxycarbonyl, indenyloxycarbonyl, carboxyl, methoxymethoxycarbonyl, methoxyethoxycarbonyl, ethoxymethoxycarbonyl, ethoxyethoxycarbonyl, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, piperidinylmethyl, piperidinylethyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrazolidinylmethyl, pyrazolidinylethyl, imidazolidinylmethyl, imidazolidinylethyl, isoxazolidinylmethyl, isoxazolidinylethyl, oxazolidinylmethyl, oxazolidinylethyl, thiol, oxidosulfanyl, sulfino, methylthio, ethylthio, propylthio, butylthio, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, phenylthio, biphenylthio, naphthylthio, phenylsulfinyl, biphenylsulfinyl, naphthylsulfinyl, phenylsulfonyl, biphenylsulfonyl, naphthylsulfonyl, piperidinylthio, pyrrolidinylthio, pyrazolidinylthio, imidazolidinylthio, isoxazolidinylthio, oxazolidinylthio, piperidinylsulfinyl, pyrrolidinylsulfinyl, pyrazol id inyls u If iny I , imidazolidinylsulfinyl, isoxazolidinylsulfinyl, oxazolidinylsulfinyl, piperidinylsulfonyl, pyrrolidinylsuifonyl, pyrazolidinylsulfonyl, imidazolidinylsulfonyl, isoxazolidinylsulfonyl, oxazolidinylsulfonyl, pyridinylthio, benzothiophenylthio, indolylthio, isoquinolinylthio, quinolinylthio, thienylthio, pyrrolylthio, furylthio, pyrazolylthio, imidazolylthio, isoxazolylthio, oxazolylthio, isoindoledionylthio, pyridinylsulfinyl, benzothiophenylsulfinyl, indolylsulfinyl, isoquinolinylsulfinyl, quinolinylsulfinyl, thienylsulfinyl, pyrrolylsulfinyl, furylsulfinyl, pyrazolylsulfinyl, imidazolylsulfinyl, isoxazolylsulfinyl, oxazolylsulfinyl, isoindoledionylsulfinyl, pyridinylsulfonyl, benzothiophenylsulfonyl, indolylsulfonyl, isoquinolinylsulfonyl, quinolinylsulfonyl, thienylsulfonyl, pyrrolylsulfonyl, furylsulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl, isoxazolylsulfonyl, oxazolylsulfonyl, and isoindoledionylsulfonyl; [0068] wherein R1a is selected from the group consisting of hydrido, hydroxyl, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, phenyl, biphenyl, naphthyl, indenyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and isoindoledionyl, or where R1a and R1 together with the nitrogen to which they are attached form pyridine, piperidine, indole, indoline, isoindole, isoindolinyl, isoquinoline, quinoline, pyrrole, pyrrolidine, pyrazole, pyrazolidine, imidazole, imidazolidine, isoxazole, isoxazolidine, oxazole, or oxazolidine; [0069] wherein R2 is selected from the group consisting of hydrido, hydroxyl, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, phenyl, biphenyl, naphthyl, indenyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isoindoledionyl, or Rz and R1 together with the atoms to which they are attached form a cyclic moiety selected from the group consisting of piperidinonyl, dihydropyridinonyl, pyridinonyl, dihydroindolonyl, octahydroindolonyl, dihydroisoindolonyl, octahydroisoindolonyl, isoquinolinonyl, dihydroisoquinolinonyl, quinolinonyl, dihydroquinolinonyl, pyrrolidinonyl, and pyrazolidinonyl; [0070] wherein R3 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and -NR7R8; and [0071] wherein R4, R5, R6, R7, and R8 are independently selected from the group consisting of hydrido, hydroxyl, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, phenyl, biphenyl, naphthyl, indenyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and isoindoledionyl. [0072] In a particularly preferred embodiment, the compound of Formula I is a compound of Formula IIA:
Figure imgf000012_0001
[0074] wherein Z is selected from the group consisting of hydrido, halo, alkyl, cyano, and haloalkyl; [0075] wherein R9 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, or where R9 and R10 together with the atoms to which they are attached form a heterocyclic moiety; [0076] wherein R9 is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-alkylamino, N,N-dialkylamino, N-arylamino, N-alkyl-N-arylamino, N- hydroxyamino, N-alkyl-N-hydroxyamino, N-aryl-N-hydroxyamino, halo, cyano, keto, hydroxyl, alkyl, haloalkyl, cycloalkyl, alkoxy, alkenyl, alkenyloxy, aryl, aryloxy, aralkyl, aralkylcarbonyl, aralkylcarbonylamino, heteroarylcarbonyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, alkoxycarbonyl, aryloxycarbonyl, carboxyl, alkoxyalkoxycarbonyl, alkoxycarbonylamino, heterocycloalkyl, heterocycloalkylalkyl, thiol, oxidosulfanyl, sulfino, alkylthio, alkylsulfinyl, alkylsulfonyl, cycloalkylthio, cycloalkylsulfinyl, cycloalkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, heterocycloalkylthio, heterocycloalkylsulfinyl, heterocycloalkylsulfonyl, heteroarylthio, heteroarylsulfinyl, and heteroarylsulfonyl; [0077] wherein Ri0 is selected from the group consisting of hydrido, hydroxyl, alkoxy, alkyl, haloalkyl, aryl, and heteroaryl, or R10 and R9 together with the atoms to which they are attached form a heterocyclic moiety; [0078] wherein R11 and R12 are independently selected from the group consisting of hydrido, hydroxyl, alkoxy, alkyl, haloalkyl, aryl, and heteroaryl; [0079] or a pharmaceutically acceptable salt thereof. [0080] In one preferred embodiment, the compound of Formula IIA is a compound wherein Z is selected from the group consisting of hydrido, halo, C1-6 alkyl, cyano, and C1-s haloalkyl; [0081] wherein R9 is selected from the group consisting of C1-6 alkyl, C3- 2 cycloalkyl, C2.6 alkenyl, C3-12 cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, C3.12 aryl, C4-18 aralkyl, 3- to 12-membered heteroaryl, and 4- to 18-membered heteroaralkyl, or where R9 and R10 together with the atoms to which they are attached form a 3- to 12-membered heterocyclic moiety; [0082] wherein R9 is optionally substituted by one or more substituents independently selected from the group consisting of amino, N^C^s alkyl)amino, N,N-di(C1-β alkyl)amino, N-(C3. 2 aryl)amino, N- alkyl)-N-(C3-12 aryl)amino, N-hydroxyamino, N-(Cι-s alkyl)-N-hydroxyamino, N-(C3.-t2 aryl)-N- hydroxyamino, halo, cyano, keto, hydroxyl, Cι-6 alkyl, C1J3 haloalkyl, C3.6 cycloalkyl, C1-β alkoxy, C2-s alkenyl, C2.6 alkenyloxy, C3.12 aryl, C3.12 aryloxy, C4.20 aralkyl, C4_20 aralkylcarbonyl, C4.2o aralkylcarbonylamino, 3- to 14-membered heteroarylcarbonyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 3- to 12-membered heteroaryl, C2-7 alkoxycarbonyl, C3-12 aryloxycarbonyl, carboxyl, C2-ι5 alkoxyalkoxycarbonyl, C2.7 alkoxycarbonylamino, 3- to 12-membered heterocycloalkyl, 4- to 18-membered heterocycloalkylalkyl, thiol, oxidosulfanyl, sulfino, C1-β alkylthio, C1-6 alkylsulfinyl, alkylsulfonyl, C3-12 cycloalkylthio, C3. 2 cycloalkylsulfinyl, C3-ι2 cycloalkylsulfonyl, C3- 2 arylthio, C3.12 arylsulfinyl, C3.ι2 arylsulfonyl, 3- to 12-membered heterocycloalkylthio, 3- to 12-membered heterocycloalkylsulfinyl, 3- to 12-membered heterocycloalkylsulfonyl, 3- to 12-membered heteroarylthio, 3- to 12-membered heteroarylsulfinyl, and 3- to 12-membered heteroarylsulfonyl; [0083] wherein R10 is selected from the group consisting of hydrido, hydroxyl, C1-8 alkoxy, C1-6 alkyl, Cι-S haloalkyl, C3.12 aryl, and 3- to 12-membered heteroaryl, or R10 and R9 together with the atoms to which they are attached form a 3- to 12-membered heterocyclic moiety; [0084] wherein R11 and R12 are independently selected from the group consisting of hydrido, hydroxyl, C1-6 alkoxy, C1-β alkyl, C^ haloalkyl, C3-12 aryl, and 3- to 12-membered heteroaryl. [0085] In one particularly preferred embodiment, the compound of Formula IIA is a compound wherein Z is selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyano, and haloalkyl; [0086] wherein R9 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, propenyl, butenyl, pentenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, isoindolyl, dihydroindolyl, isoindolinyl, dihydrothiophenyl, dihydropyrrolyl, dihydrofuryl, dihydropyrazolyl, dihydroimidazolyl, dihydroisoxazolyl, dihydrooxazolyl, phenyl, biphenyl, naphthyl, indenyl, benzyl, phenylethyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isoindoledionyl, pyridinylmethyl, pyridinylethyl, benzothiophenylmethyl, benzothiophenylethyl, indolylmethyl, indolylethyl, isoquinolinylmethyl, isoquinolinylethyl, quinolinylmethyl, quinolinylethyl, thienylmethyl, thienylethyl, pyrrolylmethyl, pyrrolylethyl, furylmethyl, furylethyl, pyrazolylmethyl, pyrazolylethyl, imidazolylmethyl, imidazolylethyl, isoxazolylmethyl, isoxazolylethyl, oxazolylmethyl, oxazolylethyl, isoindoledionylmethyl, and isoindoledionylethyl, or where R9 and R10 together with the atoms to which they are attached form pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isoindoledionyl, isoindolyl, dihydroindolyl, isoindolinyl, dihydrothiophenyl, dihydropyrrolyl, dihydrofuryl, dihydropyrazolyl, dihydroimidazolyl, dihydroisoxazolyl, dihydrooxazolyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, or oxazolidinyl; [0087] wherein Rs is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-methylamino, N-ethylamino, N-propylamino, N,N-dimethylamino, N- methyl-N-ethylamino, N-methyl-N-propylamino, N,N-diethylamino, N-ethyl-N-propylamino, N,N- dipropylamino, N-phenylamino, N-biphenylamino, N-naphthylamino, N-methyl-N-phenylamino, N-ethyl-N- phenylamino, N-propyl-N-phenylamino, N-hydroxyamino, N-methyl-N-hydroxyamino, N-ethyl-N- hydroxyamino, N-propyl-N-hydroxyamino, N-phenyl-N-hydroxyamino, N-biphenyl-N-hydroxyamiπo, N- naphthyl-N-hydroxyamino, chloro, fluoro, bromo, iodo, cyano, keto, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, butoxy, ethenyl, propenyl, butenyl, pentenyl ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, phenyl, biphenyl, naphthyl, indenyl, phenoxy, biphenoxy, naphthyloxy, indenyloxy, benzyl, phenylethyl, benzylcarbonyl, phenylethylcarbonyl, benzylcarbonylamino, phenylethylcarbonylamino, pyridinylcarbonyl, benzothiophenylcarbonyl, indolylcarbonyl, isoquinolinylcarbonyl, quinolinylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl, furylcarbonyl, pyrazolylcarbonyl, imidazolylcarbonyl, isoxazolylcarbonyl, oxazolylcarbonyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isoindoledionyl, isoindolyl, dihydroindolyl, isoindolinyl, dihydrothiophenyl, dihydropyrrolyl, dihydrofuryl, dihydropyrazolyl, dihydroimidazolyl, dihydroisoxazolyl, dihydrooxazolyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, phenoxycarbonyl, biphenoxycarbonyl, naphthyloxycarbonyl, indenyloxycarbonyl, carboxyl, methoxymethoxycarbonyl, methoxyethoxycarbonyl, ethoxymethoxycarbonyl, ethoxyethoxycarbonyl, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, piperidinylmethyl, piperidinylethyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrazolidinylmethyl, pyrazolidinylethyl, imidazolidinylmethyl, imidazolidinylethyl, isoxazolidinylmethyl, isoxazolidinylethyl, oxazolidinylmethyl, oxazolidinylethyl, thiol, oxidosulfanyl, sulfino, methylthio, ethylthio, propylthio, butylthio, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, phenylthio, biphenylthio, naphthylthio, phenylsulfinyl, biphenylsulfinyl, naphthylsulfinyl, phenylsulfonyl, biphenylsulfonyl, naphthylsulfonyl, piperidinylthio, pyrrolidinylthio, pyrazolidinylthio, imidazolidinylthio, isoxazolidinylthio, oxazolidinylthio, piperidinylsulfinyl, pyrrolidinylsulfinyl, pyrazolidinylsulfinyl, imidazolidinylsulfinyl, isoxazolidinylsulfinyl, oxazolidinylsulfinyl, piperidinylsulfonyl, pyrrolidinylsulfonyl, pyrazolidinylsulfonyl, imidazolidinylsulfonyl, isoxazolidinylsulfonyl, oxazolidinylsulfonyl, pyridinylthio, benzothiophenylthio, indolylthio, isoquinolinylthio, quinolinylthio, thienylthio, pyrrolylthio, furylthio, pyrazolylthio, imidazolylthio, isoxazolylthio, oxazolylthio, isoindoledionylthio, pyridinylsulfinyl, benzothiophenylsulfinyl, indolylsulfinyl, isoquinolinylsulfinyl, quinolinylsulfinyl, thienylsulfinyl, pyrrolylsulfinyl, furylsulfinyl, pyrazolylsulfinyl, imidazolylsulfinyl, isoxazolylsulfinyl, oxazolylsulfinyl, isoindoledionylsulfinyl, pyridinylsulfonyl, benzothiophenylsulfonyl, indolylsulfonyl, isoquinolinylsulfonyl, quinolinylsulfonyl, thienylsulfonyl, pyrrolylsulfonyl, furylsulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl, isoxazolylsulfonyl, oxazolylsulfonyl, and isoindoledionylsulfonyl; [0088] wherein R10 is selected from the group consisting of hydrido, hydroxyl, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, phenyl, biphenyl, naphthyl, indenyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isoindoledionyl, or R10 and R9 together with the atoms to which they are attached form a cyclic moiety selected from the group consisting of piperidinonyl, dihydropyridinonyl, pyridinonyl, dihydroindolonyl, octahydroindolonyl, dihydroisoindolonyl, octahydroisoindolonyl, isoquinolinonyl, dihydroisoquinolinonyl, quinolinonyl, dihydroquinolinonyl, pyrrolidinonyl, and pyrazolidinonyl; [0089] wherein R 1 and R12 are independently selected from the group consisting of hydrido, hydroxyl, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, phenyl, biphenyl, naphthyl, indenyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and isoindoledionyl. [0090] In a particularly preferred embodiment, the compound of Formula I is a compound of Formula MB:
Figure imgf000015_0001
[0092] wherein Z, R9, R10, R11, and R12 are as defined above for Formula IIA; or a pharmaceutically acceptable salt thereof. [0093] In a particularly preferred embodiment, the compound of Formula I is a compound of Formula IIC:
Figure imgf000016_0001
[0095] wherein Z is selected from the group consisting of hydrido, halo, alkyl, cyano, and haloalkyl; [0096] wherein R9 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, or where R9 and R9a together with the nitrogen to which they are attached form a heterocyclic moiety; [0097] wherein R9 is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-alkylamino, N,N-dialkylamino, N-arylamino, N-alkyl-N-arylamino, N- hydroxyamino, N-alkyl-N-hydroxyamino, N-aryl-N-hydroxyamino, halo, cyano, keto, hydroxyl, alkyl, haloalkyl, cycloalkyl, alkoxy, alkenyl, alkenyloxy, aryl, aryloxy, aralkyl, aralkylcarbonyl, aralkylcarbonylamino, heteroarylcarbonyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, alkoxycarbonyl, aryloxycarbonyl, carboxyl, alkoxyalkoxycarbonyl, alkoxycarbonylamino, heterocycloalkyl, heterocycloalkylalkyl, thiol, oxidosulfanyl, sulfino, alkylthio, alkylsulfinyl, alkylsulfonyl, cycloalkylthio, cycloalkylsulfinyl, cycloalkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, heterocycloalkylthio, heterocycloalkylsulfinyl, heterocycloalkylsulfonyl, heteroarylthio, heteroarylsulfinyl, and heteroarylsulfonyl; [0098] wherein R9a is selected from the group consisting of hydrido, hydroxyl, alkoxy, alkyl, haloalkyl, aryl, and heteroaryl, or where R9a and R9 together with the nitrogen to which they are attached form a heterocyclic moiety; [0099] wherein R11 and R12 are independently selected from the group consisting of hydrido, hydroxyl, alkoxy, alkyl, haloalkyl, aryl, and heteroaryl; [00100] or a pharmaceutically acceptable salt thereof. [00101] In one preferred embodiment, the compound of Formula IIC is a compound wherein Z is selected from the group consisting of hydrido, halo, C-|.e alkyl, cyano, and C1-6 haloalkyl; [00102] wherein R9 is selected from the group consisting of C-i-6 alkyl, C3-12 cycloalkyl, C2.B alkenyl, C3-12 cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, C3_ι2 aryl, C4-18 aralkyl, 3- to 12-membered heteroaryl, and 4- to 18-membered heteroaralkyl, or where R9 and R9a together with the nitrogen to which they are attached form a 3- to 12-membered heterocyclic moiety; [00103] wherein R9 is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-(Cι.6 alkyl)amino, N,N-di(C1.6 alkyl)amino, N-(C3.12 ary|)amino, N- (C1-s alkyl)-N-(C3-12 aryl)amino, N-hydroxyamino, N-(C -8 alkyl)-N-hydroxyamino, N-(C3-12 aryl)-N- hydroxyamino, halo, cyano, keto, hydroxyl, C^ alkyl, C1-δ haloalkyl, C3.6 cycloalkyl, C1-6 alkoxy, C2-6 alkenyl, C2.6 alkenyloxy, C3-ι2 aryl, C3_ι2 aryloxy, C4-20 aralkyl, C4.20 aralkylcarbonyl, C4-20 aralkylcarbonylamino, 3- to 14-membered heteroarylcarbonyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 3- to 12-membered heteroaryl, C2-7 alkoxycarbonyl, C3.12 aryloxycarbonyl, carboxyl, C2.15 alkoxyalkoxycarbonyl, C2-7 alkoxycarbonylamino, 3- to 12-membered heterocycloalkyl, 4- to 18-membered heterocycloalkylalkyl, thiol, oxidosulfanyl, sulfino, C1-B alkylthio, C1-β alkylsulfinyl, Ct_6 alkylsulfonyl, C3- 2 cycloalkylthio, C3.12 cycloalkylsulfinyl, C3-12 cycloalkylsulfonyl, C3-12 arylthio, C3-12 arylsulfinyl, C3.12 arylsulfonyl, 3- to 12-membered heterocycloalkylthio, 3- to 12-membered heterocycloalkylsulfinyl, 3- to 12-membered heterocycloalkylsulfonyl, 3- to 12-membered heteroarylthio, 3- to 12-membered heteroarylsulfinyl, and 3- to 12-membered heteroarylsulfonyl; [00104] wherein R9a is selected from the group consisting of hydrido, hydroxyl, C-,.6 alkoxy, Cι_s alkyl, Cι.6 haloalkyl, C3_12 aryl, and 3- to 12-membered heteroaryl, or where R9a and R9 together with the nitrogen to which they are attached form a 3- to 12-membered heterocyclic moiety; [00105] wherein R11 and R12 are independently selected from the group consisting of hydrido, hydroxyl, C1-s alkoxy, C1-s alkyl, C -6 haloalkyl, C3-ι2 aryl, and 3- to 12-membered heteroaryl. [00106] In one particularly preferred embodiment, the compound of Formula IIC is a compound wherein Z is selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyano, and haloalkyl; [00107] wherein R9 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, propenyl, butenyl, pentenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, isoindolyl, dihydroindolyl, isoindolinyl, dihydrothiophenyl, dihydropyrrolyl, dihydrofuryl, dihydropyrazolyl, dihydroimidazolyl, dihydroisoxazolyl, dihydrooxazolyl, phenyl, biphenyl, naphthyl, indenyl, benzyl, phenylethyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isoindoledionyl, pyridinylmethyl, pyridinylethyl, benzothiophenylmethyl, benzothiophenylethyl, indolylmethyl, indolylethyl, isoquinolinylmethyl, isoquinolinylethyl, quinolinylmethyl, quinolinylethyl, thienylmethyl, thienylethyl, pyrrolylmethyl, pyrrolylethyl, furylmethyl, furylethyl, pyrazolylmethyl, pyrazolylethyl, imidazolylmethyl, imidazolylethyl, isoxazolylmethyl, isoxazolylethyl, oxazolylmethyl, oxazolylethyl, isoindoledionylmethyl, and isoindoledionylethyl, or where R9 and R9a together with the atoms to which they are attached form a cyclic moiety selected from the group consisting of piperidinonyl, dihydropyridinonyl, pyridinonyl, dihydroindolonyl, octahydroindolonyl, dihydroisoindolonyl, octahydroisoindolonyl, isoquinolinoπyl, dihydroisoquinolinonyl, quinolinonyl, dihydroquinolinonyl, pyrrolidinonyl, and pyrazolidinonyl; [00108] wherein R9 is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-methylamino, N-ethylamino, N-propylamino, N,N-dimethylamino, N- methyl-N-ethylamino, N-methyl-N-propylamino, N,N-diethylamino, N-ethyl-N-propylamino, N,N- dipropylamino, N-phenylamino, N-biphenylamino, N-naphthylamino, N-methyl-N-phenylamino, N-ethyl-N- phenylamino, N-propyl-N-phenylamino, N-hydroxyamino, N-methyl-N-hydroxyamino, N-ethyl-N- hydroxyamino, N-propyl-N-hydroxyamino, N-phenyl-N-hydroxyamino, N-biphenyl-N-hydroxyamino, N- naphthyl-N-hydroxyamino, chloro, fluoro, bromo, iodo, cyano, keto, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, butoxy, ethenyl, propenyl, butenyl, pentenyl ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, phenyl, biphenyl, naphthyl, indenyl, phenoxy, biphenoxy, naphthyloxy, indenyloxy, benzyl, phenylethyl, benzylcarbonyl, phenylethylcarbonyl, benzylcarbonylamino, phenylethylcarbonylamino, pyridinylcarbonyl, benzothiophenylcarbonyl, indolylcarbonyl, isoquinolinylcarbonyl, quinolinylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl, furylcarbonyl, pyrazolylcarbonyl, imidazolylcarbonyl, isoxazolylcarbonyl, oxazolylcarbonyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isoindoledionyl, isoindolyl, dihydroindolyl, isoindolinyl, dihydrothiophenyl, dihydropyrrolyl, dihydrofuryl, dihydropyrazolyl, dihydroimidazolyl, dihydroisoxazolyl, dihydrooxazolyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, phenoxycarbonyl, biphenoxycarbonyl, naphthyloxycarbonyl, indenyloxycarbonyl, carboxyl, methoxymethoxycarbonyl, methoxyethoxycarbonyl, ethoxymethoxycarbonyl, ethoxyethoxycarbonyl, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, piperidinylmethyl, piperidinylethyl, pyrrolidinylmethyl, pyrrolid inyl ethyl , pyrazolidinylmethyl, pyrazolidinylethyl, imidazolidinylmethyl, imidazolidinylethyl, isoxazolidinylmethyl, isoxazolidinylethyl, oxazolidinylmethyl, oxazolidinylethyl, thiol, oxidosulfanyl, sulfino, methylthio, ethylthio, propylthio, butylthio, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopeπtylsulfonyl, cyclohexylsulfonyl, phenylthio, biphenylthio, naphthylthio, phenylsulfinyl, biphenylsulfmyl, naphthylsulfinyl, phenylsulfonyl, biphenylsulfonyl, naphthylsulfonyl, piperidinylthio, pyrrol idinylthio, pyrazolidinylthio, imidazolidinylthio, isoxazolidinylthio, oxazolidinylthio, piperidinylsulfinyl, pyrrolidinylsulfinyl, pyrazolidinylsulfinyl, imidazolidinylsulfinyl, isoxazolidinylsulfinyl, oxazolidinylsulfinyl, piperidinylsulfonyl, pyrrolidinylsulfonyl, pyrazolidinylsulfonyl, imidazolidinylsulfonyl, isoxazolidinylsulfonyl, oxazolidinylsulfonyl, pyridinylthio, benzothiophenylthio, indolylthio, isoquinolinylthio, quinolinylthio, thienyjthio, pyrrolylthio, furylthio, pyrazolylthio, imidazolylthio, isoxazolylthio, oxazolylthio, isoindoledionylthio, pyridinylsulfinyl, benzothiophenylsulfinyl, indolylsulfinyl, isoquinolinylsulfinyl, quinolinylsulfinyl, thienylsulfinyl, pyrrolylsulfinyl, furylsulfinyl, pyrazolylsulfinyl, imidazolylsulfinyl, isoxazolylsulfinyl, oxazolylsulfinyl, isoindoledionylsulfinyl, pyridinylsulfonyl, benzothiophenylsulfonyl, indolylsulfonyl, isoquinolinylsulfonyl, quinolinylsulfonyl, thienylsulfonyl, pyrrolylsulfonyl, furylsulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl, isoxazolylsulfonyl, oxazolylsulfonyl, and isoindoledionylsulfonyl; [00109] wherein R9a is selected from the group consisting of hydrido, hydroxyl, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, phenyl, biphenyl, naphthyl, indenyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and isoindoledionyl, or where R9a and R9 together with the nitrogen to which they are attached form pyridine, piperidine, indole, indoline, isoindole, isoindolinyl, isoquinoline, quinoline, pyrrole, pyrrolidine, pyrazole, pyrazolidine, imidazole, imidazolidine, isoxazole, isoxazolidine, oxazole, or oxazolidine; [00110] wherein R11 and R12 are independently selected from the group consisting of hydrido, hydroxyl, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, phenyl, biphenyl, naphthyl, indenyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and isoindoledionyl. [00111] In a particularly preferred embodiment, the compound of Formula I is a compound of Formula IID:
Figure imgf000019_0001
[00113] wherein Z, R9, R9a, R 1, and R12 are as defined above for Formula IIC; or a pharmaceutically acceptable salt thereof. [00114] In a particularly preferred embodiment, the compound of Formula I is a compound of Formula HE:
Figure imgf000019_0002
[00116] wherein Z is selected from the group consisting of hydrido, halo, alkyl, cyano, and haloalkyl; [00117] wherein R is selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; [00118] wherein R is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-alkylamino, N,N-dialkylamino, N-arylamino, N-alkyl-N-arylamino, N- ι hydroxyamino, N-alkyl-N-hydroxyamino, N-aryl-N-hydroxyamino, halo, cyano, keto, hydroxyl, alkyl, haloalkyl, cycloalkyl, alkoxy, alkenyl, alkenyloxy, aryl, aryloxy, aralkyl, aralkylcarbonyl, aralkylcarbonylamino, heteroarylcarbonyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, alkoxycarbonyl, aryloxycarbonyl, carboxyl, alkoxyalkoxycarbonyl, alkoxycarbonylamino, heterocycloalkyl, , heterocycloalkylalkyl, thiol, oxidosulfanyl, sulfino, alkylthio, alkylsulfinyl, alkylsulfonyl, cycloalkylthio, cycloalkylsulfinyl, cycloalkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, heterocycloalkylthio, heterocycloalkylsulfinyl, heterocycloalkylsulfonyl, heteroarylthio, heteroarylsulfinyl, and heteroarylsulfonyl; [00119] wherein R11 and R12 are independently selected from the group consisting of hydrido, hydroxyl, alkoxy, alkyl, haloalkyl, aryl, and heteroaryl; [00120] or a pharmaceutically acceptable salt thereof. [00121] In one preferred embodiment, the compound of Formula HE is a compound wherein Z is selected from the group consisting of hydrido, halo, C1-6 alkyl, cyano, and C^ haloalkyl; [00122] wherein R is selected from the group consisting of C^s alkyl, C3-12 cycloalkyl, C2-6 alkenyl, C3-12 cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, C3.12 aryl, C4-18 aralkyl, 3- to 12-membered heteroaryl, and 4- to 18-membered heteroaralkyl; [00123] wherein R1 is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-(C1.6 alkyl)amino, N,N-di(Cι.s alkyl)amino, N-(C3-12 aryl)amino, N- (C^e alkyl)-N-(C3-12 aryl)amino, N-hydroxyamino, N-(C1-β alkyl)-N-hydroxyamino, N-(C3.12 aryl)-N- hydroxyamino, halo, cyano, keto, hydroxyl, C1-6 alkyl, Cι.6 haloalkyl, C3.6 cycloalkyl, C1-β alkoxy, C2-S alkenyl, C2.β alkenyloxy, C3.-|2 aryl, C3- 2 aryloxy, C4.20 aralkyl, C4.20 aralkylcarbonyl, C -20 aralkylcarbonylamino, 3- to 14-membered heteroarylcarbonyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 3- to 12-membered heteroaryl, C2_7 alkoxycarbonyl, C3-12 aryloxycarbonyl, carboxyl, C2_15 alkoxyalkoxycarbonyl, C2-7 alkoxycarbonylamino, 3- to 12-membered heterocycloalkyl, 4- to 18-membered heterocycloalkylalkyl, thiol, oxidosulfanyl, sulfino, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C3-12 cycloalkylthio, C3.12 cycloalkylsulfinyl, C3_ι2 cycloalkylsulfonyl, C3.12 arylthio, C3_12 arylsulfinyl, C3-12 arylsulfonyl, 3- to 12-membered heterocycloalkylthio, 3- to 12-membered heterocycloalkylsulfinyl, 3- to 12-membered heterocycloalkylsulfonyl, 3- to 12-membered heteroarylthio, 3- to 12-membered heteroarylsulfinyl, and 3- to 12-membered heteroarylsulfonyl; [00124] wherein R1 and R 2 are independently selected from the group consisting of hydrido, hydroxyl, C1-6 alkoxy, C -6 alkyl, C^ haloalkyl, C3.12 aryl, and 3- to 12-membered heteroaryl. [00125] In one particularly preferred embodiment, the compound of Formula HE is a compound wherein Z is selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyano, and haloalkyl; [00126] wherein R1 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, propenyl, butenyl, pentenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, isoindolyl, dihydroindolyl, isoindolinyl, dihydrothiophenyl, dihydropyrrolyl, dihydrofuryl, dihydropyrazolyl, dihydroimidazolyl, dihydroisoxazolyl, dihydrooxazolyl, phenyl, biphenyl, naphthyl, indenyl, benzyl, phenylethyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isoindoledionyl, pyridinylmethyl, pyridinylethyl, benzothiophenylmethyl, benzothiophenylethyl, indolylmethyl, indolylethyl, isoquinolinylmethyl, isoquinolinylethyl, quinolinylmethyl, quinolinylethyl, thienyl methyl, thienylethyl, pyrrolylmethyl, pyrrolylethyl, furylmethyl, furylethyl, pyrazolylmethyl, pyrazolylethyl, imidazolylmethyl, imidazolylethyl, isoxazolylmethyl, isoxazolylethyl, oxazolylmethyl, oxazolylethyl, isoindoledionylmethyl, and isoindoledionylethyl; [00127] wherein R1 is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-methylamino, N-ethylamino, N-propylamino, N,N-dimethyIamino, N- methyl-N-ethylamino, N-methyl-N-propylamino, N,N-diethylamino, N-ethyl-N-propylamino, N,N- dipropylamino, N-phenylamino, N-biphenylamino, N-πaphthylamino, N-methyl-N-phenylamino, N-ethyl-N- phenylamino, N-propyl-N-phenylamino, N-hydroxyamino, N-methyl-N-hydroxyamino, N-ethyl-N- hydroxyamino, N-propyl-N-hydroxyamino, N-phenyl-N-hydroxyamino, N-biphenyl-N-hydroxyamino, N- naphthyl-N-hydroxyamino, chloro, fluoro, bromo, iodo, cyano, keto, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, butoxy, ethenyl, propenyl, butenyl, pentenyl ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, phenyl, biphenyl, naphthyl, indenyl, phenoxy, biphenoxy, naphthyloxy, indenyloxy, benzyl, phenylethyl, benzylcarbonyl, phenylethylcarbonyl, benzylcarbonylamino, phenylethylcarbonylamino, pyridinylcarbonyl, benzothiophenylcarbonyl, indolylcarbonyl, isoquinolinylcarbonyl, quinolinylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl, furylcarbonyl, pyrazolylcarbonyl, imidazolylcarbonyl, isoxazolylcarbonyl, oxazolylcarbonyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isoindoledionyl, isoindolyl, dihydroindolyl, isoindolinyl, dihydrothiophenyl, dihydropyrrolyl, dihydrofuryl, dihydropyrazolyl, dihydroimidazolyl, dihydroisoxazolyl, dihydrooxazolyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, methoxycarbonyl, ethoxycarbonyl, propoxycarboπyl, butoxycarbonyl, phenoxycarbonyl, biphenoxycarbonyl, naphthyloxycarbonyl, indenyloxycarbonyl, carboxyl, methoxymethoxycarbonyl, methoxyethoxycarbonyl, ethoxymethoxycarbonyl, ethoxyethoxycarbonyl, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, piperidinylmethyl, piperidinylethyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrazolidinylmethyl, pyrazolidinylethyl, imidazolidinylmethyl, imidazolidinylethyl, isoxazolidinylmethyl, isoxazolidinylethyl, oxazolidinylmethyl, oxazolidinylethyl, thiol, oxidosulfanyl, sulfino, methylthio, ethylthio, propylthio, butylthio, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, phenylthio, biphenylthio, naphthylthio, phenylsulfinyl, biphenylsulfinyl, naphthylsulfinyl, phenylsulfonyl, biphenylsulfonyl, naphthylsulfonyl, piperidinylthio, pyrrolidinylthio, pyrazolidinylthio, imidazolidinylthio, isoxazolidinylthio, oxazolidinylthio, piperidinylsulfinyl, pyrrolidinylsulfinyl, pyrazolidinylsulfinyl, imidazolidinylsulfinyl, isoxazolidinylsulfinyl, oxazolidinylsulfinyl, piperidinylsulfonyl, pyrrolidinylsulfonyl, pyrazolidinylsulfonyl, imidazolidinylsulfonyl, isoxazolidinylsulfonyl, oxazolidinylsulfonyl, pyridinylthio, benzothiophenylthio, indolylthio, isoquinolinylthio, quinolinylthio, thienylthio, pyrrolylthio, furylthio, pyrazolylthio, imidazolylthio, isoxazolylthio, oxazolylthio, isoindoledionylthio, pyridinylsulfinyl, benzothiophenylsulfinyl, indolylsulfinyl, isoquinolinylsulfinyl, quinolinylsulfinyl, thienylsulfinyl, pyrrolylsulfinyl, furylsulfinyl, pyrazolylsulfinyl, imidazolylsulfinyl, isoxazolylsulfinyl, oxazolylsulfinyl, isoindoledioπylsulfinyl, pyridinylsulfonyl, benzothiophenylsulfonyl, indolylsulfonyl, isoquinolinylsulfonyl, quinolinylsulfonyl, thienylsuifonyl, pyrrolylsulfonyl, furylsulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl, isoxazolylsulfonyl, oxazolylsulfonyl, and isoindoledionylsulfonyl; [00128] wherein R11 and R12 are independently selected from the group consisting of hydrido, hydroxyl, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, phenyl, biphenyl, naphthyl, indenyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and isoindoledionyl. [00129] In a particularly preferred embodiment, the compound of Formula I is a compound of Formula I IF:
Figure imgf000021_0001
[00131] wherein Z, R1, R11, and R12 are as defined above for Formula HE; or a pharmaceutically acceptable salt thereof. [00132] In a particularly preferred embodiment, the compound of Formula I is a compound of Formula III:
[00133]
Figure imgf000022_0001
[00134] wherein X is a bond or alkyl; [00135] wherein Ra is selected from the group consisting of halo, cyano, alkyl, cycloalkyl, haloalkyl, alkoxy, aryl, aryloxy, aralkoxy, alkoxycarbonyl, carboxyl, heterocycloalkylalkyl, and alkylsulfonyl, or wherein Ra and R10 together with the atoms to which they are attached form a heterocyclic moiety; [00136] wherein Rb, Rc, Rd, and Re are independently selected from the group consisting of halo, cyano, alkyl, cycloalkyl, haloalkyl, alkoxy, aryl, aryloxy, aralkoxy, alkoxycarbonyl, carboxyl, heterocycloalkylalkyl, and alkylsulfonyl; [00137] wherein R10 is selected from the group consisting of hydrido and alkyl, or R10 and Ra together with the atoms to which they are attached form a heterocyclic moiety; and [00138] wherein R11 and R12 are independently selected from the group consisting of hydrido and alkyl; [00139] wherein Ra and Rb, or R and Rc, or Rc and Rd, or Rd and Re may form a ring moiety fused to the phenyl ring to which they are both attached, said ring moiety selected from the group consisting of cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl, and heteroaryl, wherein said ring moiety may be substituted by one or more substituents selected from the group consisting of halo, keto, alkyl, hydroxy, alkoxy, aralkyl, and aralkoxy; [00140] or a pharmaceutically acceptable salt thereof. [00141] In one preferred embodiment, the compound of Formula III is a compound wherein X is a bond or C1-β alkyl; [00142] wherein Ra is selected from the group consisting of halo, cyano, C1-6 alkyl, cycloalkyl, C-,.15 haloalkyl, Cι-6 alkoxy, C3-12 aryl, C3.12 aryloxy, C3-12 aralkoxy, C2.6 alkoxycarbonyl, carboxyl, 3- to 18- membered heterocycloalkylalkyl, and C-ι.6 alkylsulfonyl, or wherein Ra and R10 together with the atoms to which they are attached form a 3- to 12-membered heterocyclic moiety; [00143] wherein Rb, R°, Rd, and Re are independently selected from the group consisting of halo, cyano, C^.β alkyl, cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C3.12 aryl, C3-12 aryloxy, C3.12 aralkoxy, C2-B alkoxycarbonyl, carboxyl, 3- to 18-membered heterocycloalkylalkyl, and Cι.a alkylsulfonyl; [00144] wherein R10 is selected from the group consisting of hydrido and Cι.β alkyl, or R10 and Ra together with the atoms to which they are attached form a 3- to 12-membered heterocyclic moiety; and [00145] wherein R11 and R 2 are independently selected from the group consisting of hydrido and Cι-6 alkyl; [00146] wherein Ra and Rb, or R and Rc, or Rc and Rd, or Rd and Re may form a ring moiety fused to the phenyl ring to which they are both attached, said ring moiety selected from the group consisting of C3-12 cycloalkyl, C3^2 cycloalkenyl, C3-12 aryl, 3- to 12-membered heterocycloalkyl, 3- to 12- membered heterocycloalkenyl, and 3- to 12-membered heteroaryl, wherein said ring moiety may be substituted by one or more substituents selected from the group consisting of halo, keto, Cι_g alkyl, hydroxy, C1-s alkoxy, C3.12 aralkyl, and C3.12 aralkoxy. [00147] In one particularly preferred embodiment, the compound of Formula III is a compound wherein X is selected from the group consisting of a bond, methyl, ethyl, and propyl; [00148] wherein Ra is selected from the group consisting of chloro, fluoro, bromo, cyano, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, chloromethyl, trifluoromethyl, methoxy, phenyl, phenoxy, benzyloxy, methoxycarbonyl, carboxyl, piperidinylmethyl, methylsulfonyl, benzyloxyphenyl, and methylpiperazinylmethyl, or wherein Ra and R10 together with the atoms to which they are attached form an isoindoledionyl group; [00149] wherein R , Rc, Rd, and Re are independently selected from the group consisting of chloro, fluoro, bromo, cyano, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, chloromethyl, trifluoromethyl, methoxy, phenyl, phenoxy, benzyloxy, methoxycarbonyl, carboxyl, piperidinylmethyl, methylsulfonyl, benzyloxyphenyl, and methylpiperazinylmethyl; [00150] wherein R10 is selected from the group consisting of hydrido and methyl, or R 0 and Ra together with the atoms to which they are attached form an isoindoledionyl group; and [00151] wherein R11 and R12 are independently selected from the group consisting of hydrido and methyl; [00152] wherein Ra and Rb, or Rb and Rc, or R° and Rd, or Rd and Re may form a ring moiety fused to the phenyl ring to which they are both attached, said ring moiety selected from the group consisting of cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, phenyl, pyridinyl, thienyl, pyrrolyl, furyl, and pyrazolyl, wherein said ring moiety may be substituted by one or more substituents selected from the group consisting of chloro, fluoro, bromo, keto, methyl, methoxy, benzyl, and benzyloxy. [00153] In another particularly preferred embodiment, the compound of Formula I is a compound of Formula IV:
[00154]
Figure imgf000023_0001
[00155] wherein X is alkyl; [00156] wherein Ra, Rb, Rc, Rd, and Re are independently selected from the group consisting of halo, cyano, alkyl, haloalkyl, alkoxy, aryl, and aralkoxy; and [00157] wherein R11 and R12 are independently selected from the group consisting of hydrido and alkyl; [00158] wherein Ra and R , or Rb and R°, or Rc and Rd, or Rd and Re may form an aryl moiety fused to the phenyl ring to which they are both attached, wherein said aryl moiety may be substituted by one or more substituents selected from the group consisting of halo, alkyl, and alkoxy; [00159] or a pharmaceutically acceptable salt thereof. [00160] In one preferred embodiment, the compound of Formula IV is a compound wherein X is
C,.s alkyl; [00161] wherein Ra, Rb, Rc, Rd, and Re are independently selected from the group consisting of halo, cyano, C -3 alkyl, C -6 haloalkyl, Cι-S alkoxy, C3.12 aryl, and C4.14 aralkoxy; and [00162] wherein R11 and R12 are independently selected from the group consisting of hydrido and d.6 alkyl; [00163] wherein Ra and Rb, or Rb and Rc, or Rc and Rd, or Rd and Re may form an C3.12 aryl moiety fused to the phenyl ring to which they are both attached, wherein said aryl moiety may be substituted by one or more substituents selected from the group consisting of halo, C1-3 alkyl, and C-|.8 alkoxy. [00164] In one particularly preferred embodiment, the compound of Formula IV is a compound wherein X is selected from the group consisting of methyl, ethyl, and propyl; [00165] wherein Ra, Rb, Rc, Rd, and Re are independently selected from the group consisting of chloro, bromo, fluoro, cyano, methyl, trifluoromethyl, methoxy, phenyl, and benzyloxy; and [[0000166] wherein R11 and R12 are independently selected from the group consisting of hydrido and methyl [00167] wherein Ra and Rb, or Rb and Rc, or Rc and Rd, or Rd and Re, together with the phenyl ring to which they are attached, may form a naphthyl ring, wherein said naphthyl ring may be optionally substituted by one or more substituents selected from the group consisting of bromo, chloro, fluoro, methyl, and methoxy. [00168] In another particularly preferred embodiment, the compound of Formula I is a compound of Formula V:
Figure imgf000024_0001
[00170] wherein X is a bond or alkyl; [00171] wherein R is a 5- to 12-membered heterocyclic moiety; [00172] wherein R is optionally substituted by one or more substituents independently selected from the group consisting of halo, alkyl, alkoxycarbonyl, carboxyl, and heteroarylalkyl; [00173] wherein R10, R 1, and R12 are independently selected from the group consisting of hydrido and alkyl; [00174] or a pharmaceutically acceptable salt thereof. [00175] In one preferred embodiment, the compound of Formula V is a compound wherein X is a bond or Cι_β alkyl; [00176] wherein R is optionally substituted by one or more substituents independently selected from the group consisting of halo, C1-s alkyl, Cι_7 alkoxycarbonyl, carboxyl, and 3- to 12-membered heteroarylalkyl; [00177] wherein R 0, R11, and R12 are independently selected from the group consisting of hydrido and C1-6 alkyl. [00178] In one particularly preferred embodiment, the compound of Formula V is a compound wherein X is selected from the group consisting of a bond, methyl, ethyl, and propyl; [00179] wherein R is a heterocyclic moiety selected from the group consisting of pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, 7-azabicyclo[2.2.1]heptane, isoindolinyl, piperidinyl, and pyrrolidinyl; [00180] wherein R is optionally substituted by one or more substituents independently selected from the group consisting of bromo, chloro, fluoro, methyl, methoxycarbonyl, propoxycarbonyl, carboxyl, and pyridinyl methyl; [00181] wherein R10, R11, and R12 are independently selected from the group consisting of hydrido and methyl. [00182] In another particularly preferred embodiment, the compound of Formula I is a compound of Formula VII:
Figure imgf000025_0001
[00184] wherein X is alkyl; [00185] wherein R is selected from the group consisting of alkyl, alkenyl, C3.12 cycloalkyl, and C3-ι2 cycloalkenyl; [00186] wherein R is optionally substituted by one or more substituents independently selected from the group consisting of cyano, keto, alkyl, alkoxy, haloalkyl, alkylcarbonyl, aryl, cycloalkyl, aralkylcarbonyl, aralkylcarbonylamino, heteroarylcarbonyl, alkoxycarbonyl, carboxyl, and alkoxyalkoxycarbonyl; and [00187] wherein R11 and R12 are independently selected from the group consisting of hydrido and alkyl; [00188] or a pharmaceutically acceptable salt thereof. [00189] In one preferred embodiment, the compound of Formula VII is a compound wherein X is C1-3 alkyl; [00190] wherein R is selected from the group consisting of Cι-6 alkyl, C2-6 alkenyl, C3-ι2 cycloalkyl, and C3-12 cycloalkenyl; [00191] wherein R is optionally substituted by one or more substituents independently selected from the group consisting of cyano, keto, Cι_6 alkyl, C -6 alkoxy, d.6 haloalkyl, C2.7 alkylcarbonyl, C3.12 aryl, C3-12 cycloalkyl, C4.18 aralkylcarbonyl, C _18 aralkylcarbonylamino, 3- to 12-membered heteroarylcarbonyl, C2- alkoxycarbonyl, carboxyl, and C3-18 alkoxyalkoxycarbonyl; and [00192] wherein R11 and R12 are independently selected from the group consisting of hydrido and C^s alkyl. [00193] In one particularly preferred embodiment, the compound of Formula VII is a compound wherein X is selected from the group consisting of methyl, ethyl, and propyl; [00194] wherein R is selected from the group consisting of methyl, ethyl, propyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthyl, octahydroindyl, octahydropentalene, bicyclo[2 2.1]heptyl, tricyclo[2.2.1.0~2,6~]heptyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, decahydronaphthenyl, hexahydroindenyl, hexahydropentalenyl, bicyclo[2.2.1]heptenyl, and bicyclo[3.1.1]heptenyl; [00195] wherein R is optionally substituted by one or more substituents independently selected from the group consisting of cyano, keto, methyl, ethyl, propyl, cyclopentyl, cyclohexyl, trifluoromethyl, methylcarbonyl, propylcarbonyl, pentylcarbonyl, phenyl, benzylcarbonyl, benzylcarbonylamino, thienylcarbonyl, propoxycarbonyl, butoxycarbonyl, carboxyl, and methoxyethoxycarbonyl; and [00196] wherein R11 and R12 are independently selected from the group consisting of hydrido and methyl. [00197] In a particularly preferred embodiment, the compound of Formula I is selected from the group of compounds consisting of the compounds shown in Tables I, II, III, and IV, below:
Table
Figure imgf000026_0002
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000027_0002
Figure imgf000027_0003
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0004
Figure imgf000031_0003
Figure imgf000031_0001
Table II
Figure imgf000031_0005
Figure imgf000031_0007
Figure imgf000031_0002
Figure imgf000031_0006
Figure imgf000032_0003
Figure imgf000032_0001
Figure imgf000032_0002
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Table III
Figure imgf000037_0002
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000038_0002
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Table IV
Figure imgf000046_0002
Figure imgf000046_0003
Figure imgf000046_0004
Figure imgf000047_0002
Figure imgf000047_0001
Figure imgf000048_0002
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0002
Figure imgf000056_0001
DEFINITIONS [00198] The term "hydrido" denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals may be attached to a carbon atom to form a methylene (-CH2-) radical. [00199] The term "halo" denotes halogen atoms such as fluorine, chlorine, bromine, or iodine. [00200] The term "carbonyl", whether used alone or with other terms such as "alkylcarbonyl", denotes -(C=0)-. [00201] The terms "carboxy" or "carboxyl", whether used alone or with other terms, such as "carboxyalkyl", denotes -C02H. [00202] The term "sulfonyl," whether used alone or linked to other terms such as alkylsulfonyl, denotes the divalent radical -S02-. [00203] The term "amido" when used by itself or with other terms such as "amidoalkyl", "N- monoalkylamido", "N-monoarylamido", "N,N-dialkylamido", "N-alkyl-N-arylamido", "N-alkyl-N- hydroxyamido" and "N-alkyl-N-hydroxyamidoalkyl", embraces a carbonyl radical substituted with an amino radical. [00204] The terms "N-alkylamido" and "N,N-dialkylamido" denote amido groups which have been substituted with one alkyl radical and with two alkyl radicals, respectively. [00205] The terms "N-monoarylamido" and "N-alkyl-N-arylamido" denote amido radicals substituted, respectively, with one aryl radical, and one alkyl and one aryl radical. [00206] The term "N-alkyl-N-hydroxyamido" embraces amido radicals substituted with a hydroxyl radical and with an alkyl radical. [00207] The terms "sulfamyl" or "sulfonamidyl" denotes a sulfonyl radical substituted with an amino radical, forming a sulfonamide (-S02NH2). The amino radical may be substituted with alkyl and/or aryl moieties to form, e.g., "N-alkylsulfamyl", "N-arylsulfamyl", "N,N-dialkylsulfamyI," and "N-alkyl-N- arylsulfamyl" radicals. [00208] The term "amidino" denotes a -C(=NH)NH2 radical. [00209] The term "cyanoamidino" denotes a -C(=N-CN)NH2 radical. [00210] The term "alkyl," used alone or within other terms such as "haloalkyl" and
"alkylsulfonyl," embraces linear or branched radicals having one to about twenty carbon atoms. More preferred are "lower alkyl" radicals having one to about eight carbon atoms. Examples of alkyl radicals include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, and t-butyl), pentyl (including n-pentyl and isoamyl), hexyl, octyl and the like. [00211] The term "cycloalkyl" embraces radicals having three to ten carbon atoms, and includes monocyclic, bicyclic, and tricyclic radicals. Examples of cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decahydronaphthyl, octahydroindyl, octahydropentalene, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, and bicyclo[4.2.2]decyI. [00212] The term "alkylcarbonyl" embraces radicals having a carbonyl radical substituted with an alkyl radical. An example of an alkylcarbonyl radical is acetyl. [00213] The term "alkylthio" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. An example of an alkylthio radical is methylthio (CH3S-). [00214] The term "alkylsulfinyl" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent -S(=0)- radical. An example of an alkylsulfinyl radical is methylsulfinyl (CH3S(=0)-). [00215] The term "alkylsulfonyl" embraces alkyl radicals as defined above attached to a divalent sulfonyl radical, -S02-. [00216] The term "amidoalkyl" embraces alkyl radicals substituted with amido radicals. [00217] The term "N-alkyl-N-hydroxyamidoalkyl" embraces alkyl radicals substituted with an N- alkyl-N-hydroxyamido radical. [00218] The term "aminoalkyl" embraces alkyl radicals substituted with amino radicals. [00219] The term "carboxyalkyl" embraces radicals having a carboxyl moiety attached to an alkyl radical. [00220] The term "haloalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl, and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have a bromo, chloro, or a fluoro atom within the radical. Dihaloalkyl radicals may have two of the same halo atoms or a combination of different halo radicals; polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. [00221] The term "hydroxyalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms, any of which may be substituted with one or more hydroxyl radicals. [00222] The terms "N-alkylamino" and "N, N-dialkylamino" denote amino groups which have been substituted with one alkyl radical and with two alkyl radicals, respectively. [00223] The term "alkoxy" embraces linear or branched oxy-containing alkyl radicals having one to about ten carbon atoms. Examples of "alkoxy" radicals include methoxy and butoxy. [00224] The term "alkoxyalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms substituted by one or more alkoxy radicals each having one to about ten carbon atoms. [00225] "Alkoxy" or "alkoxyalkyl" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro, or bromo, to provide "haloalkoxy" or "haloalkoxyalkyl" radicals. [00226] The term "alkoxycarbonyl" means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical. Examples of such alkoxycarbonyl radicals include methoxycarbonyl and t-butoxycarbonyl. [00227] The term "alkoxycarbonylalkyl" embraces radicals having alkoxycarbonyl moiety, as defined above substituted to an alkyl radical. Examples of such alkoxycarbonylalkyl radicals include methoxycarbonylethyl (-(CH2)2(0=)COCH3) and t-butoxycarbonylethyl (-(CH2)2(0=)COC(CH3)3). [00228] The term "alkylaminoalkyl" embraces aminoalkyl radicals wherein the nitrogen atom is substituted with an alkyl radical. [00229] The term "alkylcarbonylalkyl" denotes an alkyl radical substituted with an "alkylcarbonyl" radical. [00230] The term "alkenyl," used alone or within other terms such as "haloalkenyl," embraces unsaturated linear or branched radicals having two to about twenty carbon atoms and containing at least one carbon-carbon double bond. Examples of alkenyl radicals include ethenyl, propenyl butenyl, pentenyl, and the like. [00231] The term "cycloalkenyl" embraces unsaturated radicals having three to ten carbon atoms and containing at least one carbon-carbon double bond, and includes monocyclic, bicyclic, and tricyclic radicals. Examples of cycloalkenyl radicals include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, decahydronaphthenyl, hexahydroindenyl, hexahydropentalenyl, bicyclo[2.1.0]pentenyl, bicyclo[1.1.1]pentenyl, bicyclo[2.1.1]hexenyl, bicyclo[2.2.1]heptenyl, bicyclo[3.1.1]heptenyl, bicyclo[3.2.1]octenyl, bicyclo[2.2.2]octenyl, and bicyclo[4.2.2]decenyl. [00232] The term "alkynyl," used alone or within other terms such as "haloalkynyl," embraces unsaturated linear or branched radicals having two to about twenty carbon atoms and containing at least one carbon-carbon triple bond. Examples of alkynyl radicals include ethynyl, propynyl butynyl, pentynyl, and the like. [00233] The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one, two, or three rings wherein at least one of the rings is aromatic, and wherein such rings may be attached together in a pendant manner or may be fused. Examples of aryl radicals include phenyl, naphthyl, tetrahydronapthyl, indyl, and biphenyl. Aryl moieties, alone or in combination, may be optionally substituted by one or more substituents selected from the group consisting of amino, halo, cyano, hydroxyl, alkyl, alkoxy, and carboxyl. [00234] The term "aralkyl" embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenethyl, and diphenethyl. [00235] The term "arylsulfonyl" embraces aryl radicals as defined above attached to a sulfonyl radical. [00236] The term "acyl," whether used alone or within a term such as "acylamino," denotes a radical provided by the residue after removal of hydroxyl from an organic acid. [00237] The term "acylamino" embraces an amino radical substituted with an acyl group. An examples of an "acylamino" radical is acetylamino (CH3C(=0) H-). [00238] The term "heterocyclic" or "heterocycle" means a saturated or unsaturated mono- or multi-ring carbocyclic system wherein one or more carbon atoms in the system are replaced by nitrogen, sulfur, phosphorous, and/or oxygen. The term "heterocyclic" embraces "heteroaryl" groups, which means a carbocyclic aromatic system containing one, two, or three rings wherein at least one of the rings is aromatic, wherein such rings may be attached together in a pendant manner or may be fused, and wherein one or more carbon atoms in the system are replaced by nitrogen, sulfur, phosphorous, and/or oxygen. "Heterocyclic" includes, for example, the following structures:
Figure imgf000059_0001
[00240] wherein Z, ∑ Z2, and Z3 are independently carbon, sulfur, phosphorous, oxygen, or nitrogen, with the proviso that one of Z, Z1, Z2, or Z3 is other than carbon, but is not oxygen or sulfur when attached to another Z atom by a double bond or when attached to another oxygen or sulfur atom.
Furthermore, the optional substituents are understood to be attached to Z, Z1, Z2, or Z3 only when each is carbon. For example, the term "heterocyclyl" embraces each of the following groups, although this listing is not meant to limit the definition to these groups only: furanyl; thienyl; pyrrolyl; 2-isopyrrolyl; 3-isopyrrolyl; pyrazolyl; 2-isoimidazolyl; 1,2,3-triazolyl; 1 ,2,4-triazolyl; 1,2-dithiolyl; 1,3-dithiolyl; 1 ,2,3-oxathiolyl; isoxazolyl; oxazolyl; thiazolyl; isothiazolyl; 1 ,2,3-oxadiazolyl; 1 ,2,4-oxadiazolyl; 1 ,2,5-oxadiazolyl; 1,3,4- oxadiazolyl; 1,2,3,4-oxatriazolyl; 1 ,2,3,5-oxatriazolyl; 1 ,2,3-dioxazolyl; 1 ,2,4-dioxazolyl; 1 ,3,2-dioxazolyl;
1,3,4-dioxazolyl; 1 ,2,5-oxathiazolyl; 1 ,3-oxathiolyl; 1 ,2-pyranyl; 1 ,4-pyranyl; 1 ,2-pyranonyl; 1,4-pyranonyl;
1 ,2-dioxinyl; 1 ,3-dioxinyl; pyridyl; pyridazyl; pyrimidyl; pyrazinyl; piperazyl; 1,3,5-triazinyl; 1 ,2,4-triazinyI; 1,2,3-triazinyl; 1,2,4-oxazinyl; 1 ,3,2-oxazinyl; 1 ,3,6-oxazinyl; 1,2,6-oxazinyl; 1 ,4-oxazinyl; o-isoxazinyl; p- isoxazinyl; 1,2,5-oxathiazinyl; 1 ,4-oxazinyl; o-isoxazinyl; p-isoxazinyl; 1 ,2,5-oxathiainzyl; 1 ,2,6-oxathiainzyl;
1 ,4,2-oxadiainzyl; 1 ,3,5,2-oxadiainzyl; morpholino; azepinyl; oxepinyl; thiepinyl; 1,2,4-diazepinyl; benzofuranyl; isobenzofuranyl; benzothiofuranyl; isobenzothiofuranyl; indolyl; indoleninyl; 2-isobenzazolyl;
1,5-pyrindinyl; pyrano[3,4-b]pyrrolyl; isόindazolyl; indoxazinyl; benzoxazolyl; anthranilyl; 1,2-benzopyranyl; quinolyl; isoquinolyl; cinnolyl; quinazolyl; naphthyridyl; pyrido[3,4-b]pyridyl; pyrido[3,2-b]pyridyl; pyrido[4,3- b]pyridyl; 1 ,3,2-benzoxazyl; 1 ,4,2-benzoxazyl; 2,1 ,3-benzoxazyl; 3,1 ,4-benzoxazyl; 1 ,2-benzoisoxazyl; 1 ,4- benzoisoxazyl; carbazolyl; xanthenyl; acridinyl; purinyl; thiazolidyl; piperidyl; pyrrolidyl; 1 ,2-dihydroazinyl;
1,4-dihydroazinyl; 1 ,2,3,6-tetrahydro-1,3-diazinyl; perhydro-1 ,4-diazinyl; 1 ,2-thiapyranyl; and 1,4- thiapyranyl. Heterocyclic moieties, alone or in combination, may be optionally substituted by one or more substituents selected from the group consisting of amino, halo, cyano, hydroxyl, alkyl, alkoxy, and carboxyl. [00241] The term "heteroaryl" also embraces radicals where heterocyclic radicals are fused with aryl radicals as defined herein. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. [00242] The term "heterocycloalkyl" embraces heterocyclic-substituted alkyl radicals such as pyridylmethyl and thienylmethyl. [00243] The terms benzyl and phenylmethyl are interchangeable. [00244] The phrases "combination therapy", "co-administration", "administration with", or "co- therapy", in defining the use of a selective IKK-2 inhibitory agent in combination with another therapeutic agent such as another analgesic agent, is intended to embrace administration of each agent in a sequential manner in a regimen that may provide beneficial effects of the drug combination, and is ' intended as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single capsule or dosage device having a fixed ratio of these active agents or in multiple, separate capsules or dosage devices for each agent, where the separate capsules or dosage devices can be taken together contemporaneously, or taken within a period of time sufficient to receive a beneficial effect from both of the constituent agents of the combination. [00245] The term "subject" for purposes of treatment includes any human or animal subject who is in need of the prevention of, or who has pain, inflammation and/or any one of the known inflammation- associated disorders. The subject is typically a human subject. [00246] The phrase "therapeutic combination" as used herein refers to the combination of two or more therapeutic compounds and, optionally, one or more pharmaceutically acceptable carrier used to provide dosage forms that produce a beneficial effect of each therapeutic compound in the subject at the desired time, .whether the therapeutic compounds are administered substantially simultaneously, or sequentially. [00247] The phrase "therapeutically effective" as used herein refers to an amount of a therapeutic compound, or amounts of combined therapeutic compounds in combination therapy. The amount or combined amounts achieve one or more of the goals of preventing, inhibiting, reducing or eliminating the inflammation or inflammation-related disease or condition. A "therapeutically-effective" amount of each agent in a combination therapy is expected to be less than an amount used in treatment using agent by itself, thus while avoiding adverse side effects typically associated with alternative therapies, namely higher dose monotherapy of each agent by itself. [00248] The terms "treating" or "to treat" means to alleviate symptoms, eliminate the causation either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms in a subject. The term "treatment" includes alleviation, elimination of causation of or prevention of pain and/or inflammation associated with, but not limited to, any of the diseases or disorders described above. [00249] Pharmaceutically acceptable salts of the compounds of Formula I include the acid addition and base salts thereof. [00250] Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotiπate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts. [00251] Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. [00252] Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. [00253] Pharmaceutically acceptable salts of compounds of Formula I may be prepared by one or more of three methods: (i) by reacting the compound of Formula I with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of Formula I or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by converting one salt of the compound of Formula I to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column. All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the resulting salt may vary from completely ionized to almost non-ionized. [00254] The compounds of the invention may exist in both unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term "hydrate" is employed when said solvent is water. [00255] Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized; or non-ionized. For a review of such complexes, see Haleblian, J. Pharnrt. ScL 64(8), 1269-1288 (1975). [00256] Hereinafter all references to compounds of Formula I include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof. [00257] The compounds of the invention include compounds of Formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of Formula I. [00258] As indicated, so-called prodrugs of the compounds of Formula I are also within the scope of the invention. The term "prodrug" refers to a compound that is a drug precursor which, following . administration to a subject and subsequent absorption, is converted to an active species in vivo via some process, such as a metabolic process. Other products from the conversion process are easily disposed of by the body. The more preferred prodrugs are those involving a conversion process that produces products that are generally accepted as safe. [00259] Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of Formula I with certain moieties known to those skilled in the art as "pro-moieties." [00260] Some examples of prodrugs in accordance with the invention include: (i) where the compound of Formula I contains a carboxylic acid functionality (-C02H), an ester thereof, for example, a compound wherein the hydrogen of the carboxylic acid functionality of the compound of Formula I is replaced by C^Ca alkyl; (ii) where the compound of Formula I contains an alcohol functionality (-OH), an ether thereof, for example, a compound wherein the hydrogen of the alcohol functionality of the compound of Formula I is replaced by CrC6 alkanoyloxymethyl; and (iii) where the compound of Formula I contains a primary or secondary amino functionality (-NH2 or -NHR where R ≠H), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound of Formula I is/are replaced by CrC10 alkanoyl. [00261] Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references. [00262] Moreover, certain compounds of Formula I may themselves act as prodrugs of other compounds of Formula I. [00263] Also included within the scope of the invention are metabolites of compounds of Formula I, that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites in accordance with the invention include: (i) where the compound of Formula I contains a methyl group, an hydroxymethyl derivative thereof (-CH3 -> -CH2OH); (ii) where the compound of Formula I contains an alkoxy group, an hydroxy derivative thereof (-OR -> -OH); (iii) where the compound of Formula I contains a tertiary amino group, a secondary amino derivative thereof (-NRaRb -> -NHRa or -NHRb); (iv) where the compound of Formula I contains a secondary amino group, a primary derivative thereof (-NHR -> -NH2); (v) where the compound of Formula I contains a phenyl moiety, a phenol derivative thereof (-Ph - -PhOH); and (vi) where the compound of Formula I contains an amide group, a carboxylic acid derivative thereof (-CONH2 -> -COOH). [00264] Compounds of Formula I containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of Formula I contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ("tautomerism") can occur. This can take the form of proton tautomerism in compounds of Formula I containing, for example, an imino, keto, or oxime group, or so- called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism. [00265] Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of Formula I, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, d-lactate or l-lysine, or racemic, for example, dl- tartrate or dl-arginine. [00266] Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization. [00267] Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (chiral HPLC). [00268] Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of Formula I contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person. [00269] Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2 to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture. [00270] Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art. [00271] The present invention includes all pharmaceutically acceptable isotopically-labeled compounds of Formula I wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature. [00272] Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 1 C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123l and 125l, nitrogen, such as 13N and 15N, oxygen, such as 150, 170 and 180, phosphorus, such as 32P, and sulphur, such as 35S. [00273] Certain isotopically-labeled compounds of Formula I, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium (3H) and 1 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. [00274] Substitution with heavier isotopes such as deuterium (2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. [00275] Substitution with positron-emitting isotopes, such as 11C, 18F, 1sO and 3N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. [00276] Isotopically-labeled compounds of Formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed. [00277] Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D20, d6-acetone, or d6-DMSO. [00278] Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose. [00279] Generally, the compounds of the invention may be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. [00280] The compounds of the invention may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). For example, compounds of Formula I may be used in co-therapies, partially or completely, in place of other conventional antiinflammatory therapies, such as together with other IKK-2 inhibitors, steroids, NSAIDs, COX-2 selective inhibitors, matrix metalloproteinase inhibitors, 5- lipoxygenase inhibitors, LTB4 antagonists and LTA4 hydrolase inhibitors. [00281] Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. [00282] The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. [00283] Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays and liquid formulations. [00284] Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet. [00285] The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents, 11(6), 981-986 (2001 ). [00286] For tablet dosage forms, depending on dose, the drug may make up from 1 to 80 wt.% of the dosage form, more typically from 5 to 60 wt.% of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidoπe, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 to 25 wt.%, preferably from 5 to 20 wt.% of the dosage form. [00287] Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. [00288] Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 to 5 wt.% of the tablet, and glidants may comprise from 0.2 to 1 wt.% of the tablet. [00289] Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 to 10 wt.%, preferably from 0.5 to 3 wt.% of the tablet. [00290] Other possible ingredients include anti-oxidants, colorants, flavoring agents, preservatives and taste-masking agents. [00291] Exemplary tablets contain up to about 80% drug, from about 10 to about 90 wt.% binder, from about 0 to about 85 wt.% diluent, from about 2 to about 10 wt.% disintegrant, and from about 0.25 to about 10 wt.% lubricant. [00292] Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated. [00293] Consumable oral films for human or veterinary use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of Formula I, a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabilizer or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function. [00294] The compound of Formula I may be water-soluble or insoluble. A water-soluble compound typically comprises from 1 to 80 wt.%, more typically from 20 to 50 wt.%, of the solutes. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 wt.% of the solutes. Alternatively, the compound of Formula I may be in the form of multiparticulate beads. [00295] The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 wt.%, more typically in the range 30 to 80 wt.%. [00296] Other possible ingredients include anti-oxidants, colorants, flavorings and flavor enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents. [00297] Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming. [00298] Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- and programmed-release. [00299] Suitable modified release formulations for the purposes of the invention are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Verma et al., Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in PCT Publication No. WO 00/35298. [00300] The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrastemal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques. [00301] Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. [00302] The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art. [00303] The solubility of compounds of Formula I used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility- enhancing agents. [00304] Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- and programmed-release. Thus compounds of the invention may be formulated as a solid, semi- solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and poly(dl-lactic-coglycolic)acid (PGLA) microspheres. [00305] The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated; see, e.g., Finnin and Morgan, J Pharm Sci. 88(10), 955-958 (1999). [00306] Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection. [00307] Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- and programmed-release. [00308] The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer
(preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. [00309] The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid. [00310] Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5μM). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying. [00311] Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. [00312] A suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 μg to 20 mg of the compound of the invention per actuation and the actuation volume may vary from 1 to 100 μL. A typical formulation may comprise a compound of Formula I, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol. [00313] Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration. [00314] Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- and programmed-release. [00315] In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or "puff' containing from 20 to 1000 μg of the compound of Formula I. The overall daily dose will typically be in the range 100 μg to 10 mg which may be administered in a single dose or, more usually, as divided doses throughout the day, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time. [00316] The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. [00317] Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- and programmed-release. [00318] The compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis. [00319] Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- or programmed-release. [00320] The compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration. [00321] Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e., as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma- cyclodextrins, such as those described in PCT Publication No. WO 98/55148. [00322] Inasmuch as it may desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions. [00323] Such kits comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of Formula I in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like. [00324] Such kits are particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid. [00325] The amount of therapeutically active compounds that are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the inflammation or inflammation related disorder, the route and frequency of administration, and the particular compound employed, and thus may vary widely. The pharmaceutical compositions may contain active ingredients in the range of about 0.1 to 1000 mg, preferably in the range of about 7.0 to 350 mg. A daily dose of about 0.01 to 100 mg/kg body weight, preferably between about 0.1 and about 50 mg/kg body weight and most preferably between about 0.5 to 30 mg/kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day. In the case of skin conditions, it may be preferable to apply a topical preparation of compounds of this invention to the affected area two to four times a day. [00326] It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy. [00327] These dosages are based on an average human subject having a weight of about 60 to 70 kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly. [00328] For the avoidance of doubt, references herein to "treatment" include references to curative, palliative and prophylactic treatment. [00329] "dba" is dibenzylideneacetone. [00330] "DMF" is N,N-dimethylformamide. [00331] "DMSO" is dimethylsulfoxide. [00332] "ESI" is electrospray ionization Mass spectrometry. [00333] "HATU" is 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate. [00334] "HBTU" is 0-benzotriazolo-1-yl)-N,N,N', N'-tetramethyluronium. [00335] "HRMS" is high resolution mass spectrometry. [00336] "NMR" is nuclear magnetic resonance. [00337] "Ac" is acetyl. [00338] "OAc" is acetate. [00339] "Ph" is phenyl. [00340] "i.d." is inner diameter.
REACTION SCHEMES • [00341] Compounds of Formula I may be prepared according to the reaction schemes set forth below.
Scheme I Synthesis of 2-ureido-3-carboxamido thiophene-5-carboxamides
Figure imgf000069_0001
Figure imgf000069_0002
χyχχn HN R12 [00342] Condensation of 2,5-dihydroxy-1 ,4-dithiane with an appropriate cyanoacetamide gives a 2-aminothiophene-3-carboxamide. Conversion to the 2-ureido-3-carboxamidothiophene is achieved by the standard methods for urea formation, such as the use of sodium cyanate in acetic acid. Careful nitration using nitric acid in acetic anhydride produces the 5-nitro derivative. Reduction of the nitro derivative with tin in hydrochloric acid produces the 2-ureido-3-carboxamido-5-aminothiophene as a salt. Finally, the 5-amide is produced by reaction with carboxylic acids using standard coupling reagents such as HBTU tetrafluoroborate and tertiary amine as base. Scheme II Synthesis of 2-carboxamido-3-ureido thiophene-5-amides
Figure imgf000070_0001
Figure imgf000070_0002
[00343] Starting from commercially available 2-carboxamido-3-aminothiophene, the 2- carboxamido-3-ureidothiophene is prepared via conventional procedures for urea formation such as reaction with sodium cyanate in acetic acid. Nitration may produce a mixture of isomers from which the desired 5-nitro compound can be separated. Reduction of the nitro derivative can be achieved for example by reaction with tin in hydrochloric acid. The resulting ammonium salt is treated under standard coupling conditions with a carboxylic acid and an appropriate coupling reagent, such as HBTU tetrafluoroborate, in the presence of a tertiary amine base.
Scheme MIA Synthesis of 2-ureido-3-carboxamido thiophene-5-carboxamides from esters via carbonylation
Figure imgf000071_0001
Figure imgf000071_0002
Figure imgf000071_0003
[00344] Condensation of 2,5-dihydroxy-1 ,4-dithiane with an appropriate cyanoacetamide gives a 2-aminothiophene-3-carboxamide. Conversion to the 2-ureido-3-carboxamidothiophene is achieved by the standard methods for urea formation, such as the use of sodium cyanate in acetic acid. Bromination can be effected by, for example, bromine in acetic acid to produce the desired 5-bromo derivative. Carbonylation of the 5-bromo derivative using carbon monoxide, with a transition metal catalyst, such as a palladium compound, for example palladium (II) acetate, optionally in the presence of an added ligand, for example, a phosphine, such as 1 ,1'-bis(diphenylphosphino)ferrocene in an alcohol, such as methanol, as solvent gives an ester, such as methyl 2-ureido-3-carboxamido-thiophene-5-carboxylate. This ester is hydrolyzed by conventional methods, as, for example, by saponification, giving, in this instance, a carboxylate salt, which can be isolated, or directly transformed into the carboxylic acid by treatment with acid. This 2-ureido-3-carboxamido-thiophene-5-carboxylic acid can be coupled with amines using certain coupling agents such as HBTU tetrafluoroborate to produce 2-ureido-3-carboxamido-5- carboxamidothiophenes. Heating may be necessary depending on the type of amine being coupled, as in the case of certain anilines. Scheme IIIB Synthesis of 2-ureido-3-carboxamido thiophene-5-carboxamides via direct carbonylation to amides
Figure imgf000072_0001
Figure imgf000072_0002
[00345] Condensation of 2,5-dihydroxy-1 ,4-dithiane with an appropriate cyanoacetamide gives the 2-aminothiophene-3-carboxamide. Conversion to the 2-ureido-3-carboxamidothiophene is achieved by the standard methods for urea formation, such as the use of sodium cyanate in acetic acid. Bromination can be effected by, for example, bromine in acetic acid to produce the desired 5-bromo derivative. Carbonylation of the 5-bromo derivative using carbon monoxide, with a transition metal catalyst, such as a palladium compound, for example palladium (II) acetate, optionally in the presence of an added ligand, for example, a phosphine, such as 1,1'-bis(diphenylphosphino)ferrocene in an appropriate solvent, such as DMF, containing the desired amine and a tertiary amine, gives an amide such as 2-ureido-3-carboxamido- 5-carboxamidothiophene.
Scheme IIIC Synthesis of 2-ureido-3-carboxamido thiophene-5-carboxamides via nitriles
Figure imgf000073_0001
Figure imgf000073_0002
[00346] Condensation of 2,5-dihydroxy-1 ,4-dithiane with an appropriate cyanoacetamide gives the 2-aminothiophene-3~carboxamide. Conversion to the 2-ureido-3-carboxamidothiophene is achieved by the standard methods for urea formation, such as the use of sodium cyanate in acetic acid. Bromination with bromine in acetic acid produces the desired 5-bromo derivative. Cyanation is achieved using zinc cyanide with a transition metal catalyst such as a palladium compound, for example, tris(dibenzylideneacetone) dipalladium, in a DMF-benzonitrile solvent system with an added ligand such as 1 ,1 '-bis(diphenylphosphino)ferrocene, preferentially at temperatures above room temperature. The obtained 2-ureido-3-carboxamido-5-cyanothiophene can be treated with dry HCl in methanol to give an imidate ester, which can be further transformed into the methyl ester. This ester is hydrolyzed by conventional methods, as, for example, by saponification, giving, in this instance, a carboxylate salt, which can be isolated, or directly transformed into the carboxylic acid by treatment with acid. This 2-ureido-3- carboxamido-thiophene-5-carboxylic acid can be coupled with amines using certain coupling agents such as HBTU tetrafluoroborate to produce 2-ureido-3-carboxamido-5-carboxamidothiophenes. Heating may be necessary depending on the type of amine being coupled, as in the case of certain anilines. Scheme HID Synthesis of 2-ureido-3-carboxamido thiophene-5-carboxamides via nitriles
Figure imgf000074_0001
Figure imgf000074_0002
[00347] Condensation of 2,5-dihydroxy-1 ,4-dithiane with an appropriate cyanoacetamide gives the 2-aminothiophene-3-carboxamide. Conversion to the 2-ureido-3-carboxamidothiophene is achieved by the standard methods for urea formation, such as the use of sodium cyanate in acetic acid. Bromination with bromine in acetic acid produces the desired 5-bromo derivative. Cyanation is achieved using zinc cyanide with a transition metal catalyst such as a palladium compound, for example, tris(dibenzylideneacetone) dipalladium, in a DMF-benzonitrile solvent system with an added ligand such as 1 ,1 '-bis(diphenylphosphino)ferrocene, preferentially at temperatures above room temperature. The obtained 2-ureido-3-carboxamido-5-cyanothiophene can be treated with dry HCl in an appropriate solvent and further treated with amines to produce 2-ureido-3-carboxamido-5-carboxamidothiophenes.
Scheme IVA Synthesis of 2-carboxamido-3-ureido thiophene-5-amides from esters via carbonylation
Figure imgf000074_0003
Figure imgf000074_0004
[00348] Starting from commercially available 2-carboxamido-3-aminothiophene, the 2- carboxamido-3-ureidothiophene is prepared via conventional procedures for urea formation such as reaction with sodium cyanate in acetic acid. Bromination using standard conditions may produce a mixture of isomers, from which the desired 5-bromo derivative can be separated. Carbonylation of the 5-bromo derivative using carbon monoxide, with a transition metal catalyst, such as a palladium compound, for example palladium (II) acetate, optionally in the presence of an added ligand, for example, a phosphine, such as 1 ,1'-bis(diphenylphosphino)ferrocene in an alcohol, such as methanol, as solvent gives an ester, such as methyl 2-ureido-3-carboxamido-thiophene-5-carboxylate. This ester is hydrolyzed by conventional methods, as, for example, by saponification, giving, in this instance, a carboxylate salt, which can be isolated, or directly transformed into the carboxylic acid by treatment with acid. This 2-ureido-3- carboxamido-thiophene-5-carboxylic acid can be coupled with amines using certain coupling agents such as HBTU tetrafluoroborate to produce 2-carboxamido-3-ureido-5-carboxamidothiophenes. Heating may be necessary depending on the type of amine being coupled, as in the case of certain anilines.
Scheme IVB Synthesis of 2-carboxamido-3-ureido thiophene-5-amides via direct carbonylation to amides
Figure imgf000075_0001
[00349] Starting from commercially available 2-carboxamido-3-aminothiophene, the 2- carboxamido-3-ureidothiophene is prepared via conventional procedures for urea formation such as reaction with sodium cyanate in acetic acid. Bromination using standard conditions may produce a mixture of isomers, from which the desired 5-bromo derivative can be separated. Carbonylation of the 5-bromo derivative using carbon monoxide, with a transition metal catalyst, such as a palladium compound, for example palladium (II) acetate, optionally in the presence of an added ligand, for example, a phosphine, such as 1,1'-bis(diphenylphosphino)ferrocene in an appropriate solvent, such as DMF, containing the desired amine and a tertiary amine, gives an amide such as 2-carboxamido-3~ureido-5- carboxamidothiophene.
Scheme IVC Synthesis of 2-carboxamido-3-ureido thiophene-5-amides from nitriles
Figure imgf000076_0001
-
Figure imgf000076_0002
1
Figure imgf000076_0003
11
[00350] Starting from commercially available 2-carboxamido-3-aminothiophene, the 2- carboxamido-3-ureidothiophene is prepared via conventional procedures for urea formation such as reaction with sodium cyanate in acetic acid. Bromination using standard conditions may produce a mixture of isomers, from which the desired 5-bromo derivative can be separated. Cyanation is achieved using zinc cyanide with a transition metal catalyst such as a palladium compound, for example, tris(dibenzylideneacetone) dipalladium, in a DMF-benzonitrile solvent system with an added ligand such as 1 ,1 '-bis(diphenylphosphino)ferrocene, preferentially at temperatures above room temperature. The obtained 2-ureido-3-carboxamido-5-cyanothiophene can be treated with dry HCl in methanol to give an imidate ester, which can be further transformed into the methyl ester. This ester is hydrolyzed by conventional methods, as, for example, by saponification, giving, in this instance, a carboxylate salt, which can be isolated, or directly transformed into the carboxylic acid by treatment with acid. This 2-ureido-3- carboxamido-thiophene-5-carboxylic acid can be coupled with amines using certain coupling agents such as HBTU tetrafluoroborate to produce 2-ureido-3-carboxamido-5-carboxamidothiophenes. Heating may be necessary depending on the type of amine being coupled, as in the case of certain anilines. Scheme IVD Synthesis of 2-carboxamido-3-ureido thiophene-5-amides from nitriles
Figure imgf000077_0001
Figure imgf000077_0002
[00351] Starting from commercially available 2-carboxamido-3-aminothiophene, the 2- carboxamido-3-ureidothiophene is prepared via conventional procedures for urea formation such as reaction with sodium cyanate in acetic acid. Bromination using standard conditions may produce a mixture of isomers, from which the desired 5-bromo derivative can be separated. Cyanation is achieved using zinc cyanide with a transition metal catalyst such as a palladium compound, for example, tris(dibenzylideneacetone) dipalladium, in a DMF-benzonitrile solvent system with an added ligand such as 1 ,1 '-bis(diphenylphosphino)ferrocene, preferentially at temperatures above room temperature. The obtained 2-ureido-3-carboxamido-5-cyanothiophene can be treated with dry HCl in an appropriate solvent and further treated with amines to produce 2-ureido-3-carboxamido-5-carboxamidothiophenes.
EXAMPLES
Figure imgf000077_0003
[00354] 2-[(aminocarbonyl)amino]thiophene-3-carboxamide (3.00 g, 16.2 mmol) and acetic anhydride (112 mL) were combined and placed in an ice/water/acetone bath and cooled to 0°C. Separately, acetic anhydride (22 mL) and 70% nitric acid (3.8 mL) were combined at 0°C and the solution was added with vigorous stirring to the reaction mixture over 13 minutes, keeping the temperature between -1 °C and 2°C. After 15 minutes, ice water (100 mL) was slowly added keeping the temperature below 12°C. After an additional half hour, more ice water (50 mL) was added and the mixture filtered cold, keeping the filtrate cold in an ice bath during filtration. The solid product was washed twice with 10 mL portions of water and dried under vacuum. The title compound is a brown solid. 1H NMR (d6-DMSO): δ 6.77-8.40 (2s + br s, 4H), 8.54 (s, 1 H), 11.56 (s, 1 H). ESI mass spectrum for C6H7N4θ4S+: 231 (M + 1).
[00355] Example 2A: Preparation of 2-[(aminocarbonyl)amino]-5-aminothiophene-3- carboxamide
Figure imgf000078_0001
[00357] 2-[(aminocarbonyl)amino]-5-nitrothiophene-3-carboxamide from Example 1 (0.189 g, 0.821 mmol) and concentrated HCl (1 .8 mL, 22 mmol) were combined and placed in a water bath at 21 °C. Then tin powder (0.202 g, 1.70 mmol) was slowly added. After 2.5 hours the mixture was filtered, the solid washed twice with the filtrate, followed by 10 mL of methanol and 30 mL of diethyl ether. ESI mass spectrum for C6H9N402S+: 201 (M + 1 ). Anal. Calc'd. for C12H18CI6N8θ4S2Sn(H20)1,3: C, 19.03; H, 2.74; Cl, 28.09, N, 14.80. Found: C, 19.27; H, 2.33; Cl, 27.75, N, 14.73.
[00358] Example 2B: Preparation of 2-[(aminocarbonyl)amino]-5-aminothiophene-3- carboxamide [00359] 2-[(aminocarbonyl)amino]-5-nitrothiophene-3-carboxamide from Example 1 (2.62 g, 11.4 mmol) and concentrated HCl (25.0 mL, 299 mmol) were combined and placed in a water bath at 21 °C. Then tin powder (2.70 g, 22.7 mmol) was slowly added over 2.0 hours keeping the temperature below 30°C. After 30 min. the mixture was filtered, the solid washed twice with 6 mL portions of concentrated HCl, followed by 6 mL diethyl ether. The solid was then dried under vacuum.
[00360] Example 2C: Preparation of 2-[(aminocarbonyI)amino]-5-aminothiophene-3- carboxamide [00361] 2-[(aminocarbonyl)amino]-5-nitrothiophene-3-carboxamide from Example 1 (2.62 g, 11.4 mmol) and concentrated HCl (25.0 mL, 299 mmol) were combined and placed in a water bath at 21 °C. Then tin powder (2.70 g, 22.7 mmol) was slowly added over 2.0 hours keeping the temperature below 30°C. An additional 5 mL HCl was added to aid stirring. After 30 min. the mixture was filtered, and the solid was dried under vacuum. [00362] Example 3: 2-[(aminocarbonyl)amino]-5-{[(3-chlorophenyl)acetyl]amino}thiophene-3- carboxamide
Figure imgf000078_0002
[00364] The crude solid salt of 2-[(aminocarbonyl)amino]-5-aminothiophene-3-carboxamide (0.24 g) (prepared according to either Example 2A or Example 2B) was combined with 1 mmol of (3- chlorophenyl)acetic acid, HBTU (BF4) (1 mmol), N,N-dimethylethylamine (1.0 mL, 9 mmol), and DMSO (1.0 mL). The mixture was stirred for 1 hour and most of liquids were stripped off. The residue was triturated in 100 mL CH2CI2 for 6 hours. The slurry was filtered, triturated with H20 (100 mL) overnight, filtered, and washed with 20 mL ether. Then the product was dried under reduced pressure. 1H NMR (CD3OD): δ 3.66 (s, 2H), 6.83 (s, 1 H), 7.20-7.38 (m, 3H), 7.37 (s, 1 H). ESI mass spectrum for C14Hi4CIN4θ3S+: 353 (M + 1 ). [00365] Examples 4-17. shown in Table V below, were prepared analogously to Example 3, substituting the appropriate carboxylic acid for the (3-chlorophenyl)acetic acid.
Table V
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0004
[00366] Example 18: 2-[(aminocarbonyl)amino]-5-{[(3-fluorophenyl)acetyl]amino}thiophene-3- carboxamide
Figure imgf000082_0001
[00368] The crude solid salt of 2-[(aminocarbonyl)amino]-5-aminothiophene-3-carboxamide (0.24 g) (prepared according to either Example 2A or Example 2B) was combined with 1 mmol of (3- fluorophenyl)acetic acid, HBTU (BF4) (1 mmol), N,N-dimethylethylamine (1.0 mL, 9 mmol), and DMSO (1.0 mL). The mixture was stirred for 1 hour and most of liquids were stripped off. The residue was triturated in 50 mL H20 for 3 hours. The slurry was filtered, triturated with K2C03 solution (0.15 g K2C03 in 50 mL H20) overnight, filtered, and washed with H20 and ether. The product was dried under reduced pressure. H NMR (CD3OD): δ 3.30 (s, 2H), 6.83 (s, 1 H), 6.95 (t, 1 H, J = 7.88 Hz), 7.08 (d, 1 H, J = 9.74 Hz), 7.14 (d, 1 H, J = 7.55 Hz), 7.23 (d,d, 1 H, J = 7.55 Hz, J = 6.55 Hz). ESI mass spectrum for C14H14FN403S+: 337 (M + 1).
[00369] Example 19: N-{4-(Aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2-yl}-5- methylthiophene-2-carboxamide
Figure imgf000082_0002
[00371] The crude solid salt of 2-[(aminocarbonyl)amino]-5-aminothiophene-3-carboxamide (0.24 g) (prepared according to either Example 2A or Example 2B) was combined with 1 mmol of 5- methylthiophene-2-carboxylic acid, HBTU (BF4) (1 mmol), N,N-dimethylethylamine (1.0 mL, 9 mmol), and DMSO (1.0 mL). The mixture was stirred for 1 hour, then most of the liquids were stripped off. The residue was triturated in 100 mL CH2CI2 for 6 hours. The slurry was filtered, triturated with H20 (100 mL) overnight, filtered, washed with 20 mL ether, and triturated with 2 mL CH3OH for 30 minutes. The product was filtered and dried under reduced pressure. 1H NMR (CD3OD): δ 2.57 (s, 3H), 6.85 (d, 1 H, J = 3 Hz), 6.93 (s, 1 H), 7.64 (d, 1 H, J = 3 Hz). ESI mass spectrum for
Figure imgf000082_0003
325 (M + 1). [00372] Examples 20-28. shown in Table VI below, were prepared analogously to Example 19, substituting the appropriate carboxylic acid for the 5-methylthiophene-2-carboxylic acid.
Table VI
Figure imgf000083_0001
Figure imgf000084_0002
[00373] Example 29: N-{4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2-yl}-1- methylprolinamide
Figure imgf000084_0001
[00375] The crude solid salt of 2-[(aminocarbonyl)amino]-5-aminothiophene-3-carboxamide (0.1 g) (prepared according to either Example 2A or Example 2B) was combined with 0.4 mmol of an amino acid, PS-carbodiimide (1 g), PS-diethylenetriamine (2.62 g), and DMF (10 mL). The mixture was stirred overnight, then filtered and the solid was washed with DMF. The DMF was stripped off, and the residue was washed with CH2CI2, dried, and extracted with CH3OH (50 mL x 2). After removing methanol, the solid was triturated in 5 mL of a saturated solution of sodium bicarbonate for 3 hours. The slurry was filtered, and most of it was dissolved in CH3OH and filtered again. The CH3OH was removed, and the product was dried under reduced pressure. 1H NMR (CD3OD): δ 1.80-1.96 (m, 3H), 2.18-2.30 (m, 1 H), 2.34-2.46 (m, 4H), 2.96-3.04 (m, 1 H), 3.14-3.22 (m, 1 H), 6.95 (s, 1 H). ESI mass spectrum for C12H18N503S+: 312 (M + 1). [00376] Example 30: N-{4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2-yl}-1- methylpiperidine-4-carboxamide
[00377] H
Figure imgf000085_0001
[00378] Prepared analogously to Example 29. 1H NMR (CD3OD/d6-DMSO (4:1 )): δ 1.60-1.78 (m, 4H), 1.88-2.04 (m, 2H), 2.15 (s, 3H), 2.19-2.30 (m, 1H), 2.82 (dm, 2H, J = 11.8 Hz), 6.68 (s, 1 H). Mass of the Molecular ion: 326 (M + 1 ).
[00379] Example 31 A: 2-[(aminocarbony!)amino]-5-(1 ,3-dioxo-1 ,3-dihydro-2H-isoindol-2- yl)thiophene-3-carboxamide
Figure imgf000085_0002
[00381] The crude solid salt of 2-[(aminocarbonyl)amino]-5-aminothiophene-3-carboxamide
(0.1 g) (prepared according to Example 2B) was combined with mono-methyl phthalate (0.311 g, 1.73 mmol), HBTU (BF4) (0.554 g, 1.73 mmol), N,N-dimethylethyIamine (1.3 mL, 12 mmol), and DMSO (1.7 mL). The mixture was stirred for two hours and then most of the DMSO was stripped off. The residue was then triturated in 100 mL H20, followed by continued trituration after the addition of anhydrous K2C03 (0.71 g, 5.1 mmol) to the water. The slurry was then filtered, and the solid washed with 5 mL H20. The solid was then dissolved in 5 mL DMF, slowly added to 200 ml H20, then triturated overnight. The precipitate was then filtered and washed with 10 mL H20. The product was then dried under vacuum. 1H NMR (dβ-DMSO): 56.96 (br s, 2H), 7.25 (br s, 1 H), 7.43 (s, 1 H), 7.70 (br s, 1H), 7.84-7.89 (m, 2H), 7.90- 7.95 (m, 2H), 11.09 (s, 1 H). HRMS C14HnN404S+: theoretical: 331.0496; found: 331.0523 (M + 1 ).
[00382] Example 31 B: 2-[(aminocarbonyl)amino]-5-(1 ,3-dioxo-1 ,3-dihydro-2H-isoindol-2- yl)thiophene-3-carboxamide [00383] Made similarly to Example 31 A, except on a 2.6 mmole scale, 2-cyanobenzoic acid (0.574 g, 3.9 mmol) was used in place of mono-methyl phthalate, stirring was for 3.5 hours, the residue was trituated in 45 mL H20, in 25 mL CH3OH:CH3CN (4:1), in 10 mL HzO with 1.5 g anhydrous K2C03, and then in 10 mL chloroform. The product was then dissolved in DMF, precipitated with CH3CN, triturated in 10 mL H20, and dried under vacuum. [00384] Example 32: N-{4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2-yl}-3-chloro-1 - benzothiophene-2-carboxamide
Figure imgf000086_0001
[00386] The crude solid salt of 2-[(aminocarbonyl)amino]-5-aminothiophene-3-carboxamide (0.1 g) (prepared according to Example 2C) was combined with 3-chlorobenzo[b]thiophene-2-carboxylic acid (0.364 g, 1.71 mmol), PS-carbodiimide resin (2.49 g, 3.44 mmol), PS-diethylenetriamine (6.51 g, 17.1 mmol), and DMF (45.0 mL). The mixture was stirred overnight, filtered, and washed with 45 mL DMF. The DMF was stripped from the filtrate/wash and the residue triturated in 100 mL H20, followed by sonication in 10 mL CH3OH and drying under vacuum. 1H NMR (d6-DMSO): 56.84 (br s, 2H), 7.04 (s, 1H), 7.17 (br s, 1H), 7.61 (br s, 3H), 7.92 (br s, 1H), 8.14 (br s, 1H), 10.89 (s, 1 H), 11.33 (s, 1 H).
[00387] Example 33: N-{4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2-yl}-1- benzothiophene-2-carboxamide
Figure imgf000086_0002
[00389] The crude solid salt of 2-[(aminocarbonyl)amino]-5-aminothiophene-3-carboxamide
(0.1 g) (prepared according to Example 2C) was combined with benzo[b]thiophene-2-carboxylic acid (0.305 g, 1.71 mmol), HATU (0.652 g, 1.71 mmol), DMF (10 mL) and triethylamine (1.6 mL, 11.5 mmol). The mixture was then stirred overnight and the DMF stripped off. The residue was then triturated in 120 mL H20, triturated and sonicated in 50 mL 20:80 CH3OH:H20, sonicated in 25 mL CH3OH three times, and then dried under vacuum. 1H NMR (d6-DMSO): 56.82 (br s, 2H), 7.00 (s, 1 H), 7.17 (br s, 1H), 7.41-7.50 (m, 2H), 7.63 (br s, 1H), 7.96-8.07 (m, 2H), 8.30 (s, 1 H), 10.88 (s, 1H), 11.45 (s, 1 H). ESI mass spectrum for C15H13N4θ3S2 +: 361 (M + 1).
[00390] Example 34: 2-[(Aminocarbonyl)amino]-5-{[4-(benzyloxy)benzoyl]amino}thiophene-3- carboxamide
Figure imgf000086_0003
[00392] The crude solid salt of 2-[(aminocarbonyl)amino]-5-aminothiophene-3-carboxamide
(prepared according to Example 2A) was combined with 4-benzyloxybenzoic acid (0.293 g, 1.28 mmol), HATU (0.493 g, 1.30 mmol), triethylamine (1.2 mL, 8.6 mmol), and DMF (5.0 mL). The mixture was stirred overnight, and then added to H20 (50 mL). The precipitate was filtered, washed with H20, triturated in H20, and then dried under vacuum. The title compound is a gray solid. 1H NMR (d6-DMSO): 55.17 (s, 2H), 6.77 (br s, 2H), 6.91 (s, 1H), 7.04-7.22 (d + br s, 3H), 7.27-7.62 (m, 6H), 7.92 (d, 2H, J = 8.7 Hz), 10.82 (s, 1 H), 11.97 (s, 1 H). ESI mass spectrum for C20H19N4O4S+: 411 (M + 1 ).
[00393] Example 35: 2-[(Aminocarbonyl)amino]-5-[(3-cyanobenzoyl)amino]thiophene-3- carboxamide
Figure imgf000087_0001
[00395] Prepared according to Example 34 (substituting 3-cyanobenzoic acid for the 4- benzyloxybenzoic acid), except the reaction mixture was filtered, the solid washed with HzO and then triturated in H20, and the solid dried under vacuum. The title compound is a light brown solid. 1H NMR (d6- DMSO): 56.80 (br s, 2H), 6.98 (s, 1 H), 7.16 (br s, 1H), 7.61 (br s, 1 H), 7.73 (t, 1 H, J = 7.8 Hz), 8.03 (d, 1H, J = 7.7 Hz), 8.22 (d, 1 H, J = 8.1 Hz), 8.37 (s, 1 H), 10.87 (s, 1H), 11.33 (s, 1 H). ESI mass spectrum for C14H12N5θ3S+: 330 (M + 1 ).
[00396] Example 36: 2-[(Aminocarbonyl)amino]-5-[(4-cyanobenzoyl)amino]thiophene-3- carboxamide
Figure imgf000087_0002
[00398] Prepared according to Example 34 (substituting 4-cyanobenzoic acid for the 4- benzyloxybenzoic acid), except the reaction mixture was filtered, the solid washed with H20 and then triturated twice in H20, and the solid dried under vacuum. The title compound is a brown solid. 1H NMR (dβ-DMSO): 56.80 (br s, 2H), 6.99 (s, 1 H), 7.16 (br s, 1 H), 7.61 (br s, 1 H), 7.99 (d, 2H, J = 8.6 Hz), 8.09 (d, 2H, J = 8.5 Hz), 10.86 (s, 1H), 11.41 (s, 1H). HRMS C14H12N503S+: theoretical: 330.0655, found: 330.0644 (M + 1).
[00399] Example 37: 2-[(Aminocarbonyl)amino]-5-[(2-fluorobenzoyl)amino]thiophene-3- carboxamide
Figure imgf000087_0003
[00401] Prepared according to Example 34 (substituting 2-fluorobenzoic acid for the 4- benzyloxybenzoic acid), except 20 mL DMF was used, and the reaction mixture was filtered. The filtrate was then stripped of DMF, the residue triturated in H20, then triturated in CH3OH, and dried under vacuum. The title compound is a brown solid. 1H NMR (d6-DMSO): 56.79 (br s, 2H), 6.90 (s, 1H), 7.13 (br s, 1 H), 7.27-7.35 (m, 2H), 7.51-7.66 (m, 3H), 10.85 (s, 1H), 11.18 (s, 1 H). ESI mass spectrum for C13H12FN403S+: 323 (M + 1).
[00402] Example 38: 2-[(Aminocarbonyl)amino]-5-[(3-fluorobenzoyl)amino]thiophene-3- carboxamide
Figure imgf000088_0001
[00404] Prepared according to Example 34 (substituting 3-fluorobenzoic acid for the 4- benzyloxybenzoic acid), except 20 mL DMF was used, and the reaction mixture was filtered. The filtrate was then stripped of DMF, the residue triturated twice in H20, then triturated in CH3OH, and dried under vacuum. The title compound is a brown solid. 1H NMR (d6-DMSO): 56.79 (br s, 2H), 6.97 (s, 1H), 7.14 (br s, 1 H), 7.39-7.45 (m, 1 H), 7.51-7.65 (m + br s, 2H), 7.72-7.82 (m, 2H), 10.85 (s, 1H), 11.21 (s, 1 H). ESI mass spectrum for C13H12FN403S+: 323 (M + 1).
[00405] campJe_39: 2-[(Aminocarbonyl)amino]-5-[(4-fluorobenzoyl)amino]thiophene-3- carboxamide
Figure imgf000088_0002
[00407] Prepared according to Example 34 (substituting 4-fluorobenzoic acid for the 4- benzyloxybeπzoic acid), except 20 mL DMF was used, and the reaction mixture was filtered. The filtrate was then stripped of DMF, the residue triturated in H20, then triturated in CH3OH, then triturated in 3 wt% aqueous K2C03 solution followed by water washes, and then dried under vacuum. The title compound is a brown solid. 1H NMR (d6-DMSO): 56.78 (br s, 2H), 6.95 (s, 1H), 7.14 (br s, 1 H), 7.30-7.39 (m, 2H), 7.57 (br s, 1 H), 7.97-8.06 (m, 2H), 10.84 (s, 1 H), 11.15 (s, 1 H). ESI mass spectrum for C13H12FN403S+: 323 (M + 1 ).
[00408] BcampJe 40: 2-[(Aminocarbonyl)amino]-5-[(3-methoxybenzoyl)amino]thiophene-3- carboxamide [00409]
Figure imgf000089_0001
[00410] The crude solid salt of 2-[(aminocarbonyl)amino]-5-aminothiophene-3-carboxamide (0.293 g) (prepared according to Example 2B) was combined with m-anisic acid (0.264 g, 1.74 mmol), HBTU (BF4) (0.553 g, 1.72 mmol), N,N-dimethylethyIamine (1.3 mL, 12 mmol), and DMSO (1.7 mL). The mixture was stirred for two hours and then most of the DMSO was stripped off. The residue was then triturated in 100 mL H20,' followed by continued trituration after the addition of anhydrous K2C03 (0.71 g, 5.1 mmol) to the water. The slurry was then filtered, and the solid washed with 5 mL H20. The solid was then dissolved in 5 mL DMF, slowly added to 200 ml H20, then triturated overnight. The precipitate was then filtered and washed with 10 mL H20. The product was then dried under vacuum to afford a tan solid. 1H NMR (dB-DMSO): 53.80 (s, 3H), 6.78 (br s, 2H), 6.95 (s, 1H), 7.04-7.23 (m+br s, 2H), 7.41 (t, 1 H, J = 7.9 Hz), 7.44-7.48 (m, 1 H), 7.49-7.64 (m + br s, 2H), 10.83 (s, 1H), 11.08 (s, 1 H). HRMS C14H15N404S+: theoretical: 335.0809, found: 335.0833 (M+1).
[00411] Example 41 : 2-[(Aminocarbonyl)amino]-5-{[2-(trifluoromethyl)benzoyl]amino}thiophene- 3-carboxamide
Figure imgf000089_0002
[00413] Prepared according to Example 40 (substituting 2-trifluoromethylbenzoic acid for the m- anisic acid), except stirring was maintained for 3.5 hrs., and after the initial water trituration, the residue was then triturated in 13 wt% aqueous K2C03 solution, CDCI3, and finally diethyl ether. The product was then dried under vacuum to afford a brownish gray solid. 1H NMR (d6-DMSO): 56.79 (br s, 2H), 6.85 (s, 1 H), 7.11 (br s, 1 H), 7.48-7.71 (m + br s, 3H), 7.75 (t, 1H, J = 7.5 Hz), 7.81 (d, 1 H, J = 7.8 Hz), 10.85 (s, 1 H), 11.36 (s, 1 H). ESI mass spectrum for C14H12F3N403S+: 373 (M + 1).
[00414] Example 42: 2-[(Aminocarbonyl)amino]-5-[(2-chlorobenzoyl)amino]thiophene-3- carboxamide
Figure imgf000090_0001
[00416] Prepared according to Example 40 (substituting 2-chlorobenzoic acid for the m-anisic acid), except that stirring was maintained for 3.5 hrs., and after the initial water trituration, the residue was then triturated in 13 wt% aqueous K2C03 solution, CDCI3, and finally diethyl ether. The solid was then dissolved in DMF, added to H20, and the precipitate filtered, washed with HzO, and then dried under vacuum to afford a gray solid. 1H NMR (d6-DMSO): 56.80 (br s, 2H), 6.86 (s, 1H), 7.12 (br s, 1 H), 7.37- 7.70 (m + br s, 5H), 10.85 (s, 1 H), 11.30 (s, 1 H). ESI mass spectrum for C13H12CIN403S+ 339 (M + 1 ).
[00417] Example 43: 2-[(Aminocarbonyl)amino]-5-[(3-chlorobenzoyl)amino]thiophene-3- carboxamide
Figure imgf000090_0002
[00419] Prepared according to Example 40 (substituting 3-chlorobenzoic acid for the m-anisic acid). The title compound is a light tan solid. 1H NMR (d6-DMSO): 56.79 (br s, 2H), 6.96 (s, 1 H), 7.14 (br s, 1 H), 7.45-7.73 (m + br s, 3H), 7.89 (d, 1 H, J = 7.8 Hz), 7.98 (s, 1 H), 10.85 (s, 1 H), 11.24 (s, 1 H). HRMS C13H12CIN403S+: theoretical: 339.0313, found: 339.0311 (M+1 ).
[00420] Example 44: 2-[(Aminocarbonyl)amino]-5-[(2-methoxybenzoyl)amino]thiophene-3- carboxamide
Figure imgf000090_0003
[00422] Prepared according to Example 40 (substituting 2-methoxybenzoic acid for the m-anisic acid). The title compound is a light brown solid. 1H NMR (d6-DMSO): 53.86 (s, 3H), 6.78 (br s, 2H), 6.89 (s, 1 H), 7.03 (td, 1 H, J = 7.5, 0.8 Hz), 7.11 + 7.15 (overlapping br s + d, 2H, J = 8.2 Hz), 7.42-7.58 (m + br s, 2H), 7.60-7.65 (m, 1H), 10.70 (s, 1 H), 10.80 (s, 1 H). HRMS C14H15N404S+: theoretical: 335.0809, found: 335.0773 (M+1). [00423] Example 45: 2-[(Aminocarbonyl)amino]-5-[(4-methoxybenzoyl)amino]thiophene-3- carboxamide
Figure imgf000091_0001
[00425] Prepared according to Example 40 (substituting 4-metfιoxybenzoic acid for the m-anisic acid), except that after the K2C03 trituration and water wash, the solid was then triturated in 25 mL CH2CI2. The title compound is a light brown solid. 1H NMR (d6-DMSO): 53.80 (s, 3H), 6.76 (br s, 2H), 6.91 (s, 1 H), 7.00-7.05 (m, 2H), 7.12 (br s, 1 H), 7.53 (br s, 1 H), 7.90-7.95 (m, 2H), 10.82 (s, 1 H), 10.95 (s, 1H). HRMS C14H15N404S+: theoretical: 335.0809, found: 335.0803 (M+1 ). [00426] Example 46: Methyl 4-[({4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2- yl}amino)carbonyl]benzoate
Figure imgf000091_0002
[00428] Prepared according to Example 40 (substituting 4-(methoxycarbonyl)benzoic acid for the m-anisic acid), except that after the DMF/H20 slurry was filtered and the solid washed with 10 mL H20, the solid was sonicated in CHCI3. After filtration, the solid was triturated in 1.0 mL DMF and most of the dissolved portion precipitated with 50 mL CHCI3. After filtration the solid was triturated in 25 mL anhydrous diethyl ether followed by washing with 8 mL anhydrous diethyl ether. The product was then dried under vacuum. The title compound is a light brown solid. 1H NMR (ds-DMSO): 53.86 (s, 3H), 6.80 (br s, 2H), 6.99 (s, 1 H), 7.16 (br s, 1 H), 7.59 (br s, 1H), 8.06 (s, 4H), 10.86 (s, 1 H), 11.35 (s, 1 H). ESI mass spectrum for C15H15N405S+: 363 (M + 1 ).
[00429] Example 47: 2-[(AminocarbonyI)amino]-5-[(4-chlorobenzoyl)amino]thiophene-3- carboxamide
Figure imgf000092_0001
repare accor ng o xample 40 (substituting 4-chlorobenzoic acid for the m-anisic acid), except that after the DMF/H20 slurry was filtered and the solid washed with 10 mL H20, the solid was then sonicated in 10 mL CHCI3, and then in 5 mL CH3OH. The product was then dried under vacuum. The title compound is a brown solid. 1H NMR (d6-DMSO): 56.79 (br s, 2H), 6.96 (s, 1 H), 7.15 (br s, 1 H), 7.52-7.72 (m + br s, 3H), 7.97 (d, 2H, J = 8.5 Hz), 10.85 (s, 1 H), 11.22 (s, 1 H). ESI mass spectrum for C13H12CIN403S+: 339 (M + 1).
[00432] Example 48: 2-[(Aminocarbonyl)amino]-5-{[3-(trifluoromethyl)benzoyl]amino}thiophene- 3-carboxamide
Figure imgf000092_0002
[00434] Prepared according to Example 40 (substituting 3-trifluoromethylbenzoic acid for the m- anisic acid), except that after the DMF/H20 slurry was filtered and the solid washed with 10 mL H20, the solid was sonicated in 10 mL CHCI3. The solid was sonicated in 5 mL CH30H, and 3 mL H20 was added to precipitate most of the dissolved product. The precipitate was then filtered, washed with 5 mL 1 :1 CH3OH:H20, and dried under vacuum. The title compound is a brown solid. 1H NMR (d6-DMSO): 56.81 (br s, 2H), 7.00 (s, 1 H), 7.16 (br s, 1 H), 7.59 (br s, 1 H), 7.77 (t, 1 H, J = 7.7 Hz), 7.94 (d, 1 H, J = 7.5 Hz), 8.24 (d, 1 H, J = 7.7 Hz), 8.28 (s, 1H), 10.86 (s, 1H), 11.36 (s, 1 H). ESI mass spectrum for C14H12F3N4θ3S+: 373 (M + 1).
[00435] <anτρJe_49: 2-[(Aminocarbonyl)amino]-5-{[4-(trifluoromethyl)benzoyl]amino}thiophene- 3-carboxamide
Figure imgf000092_0003
[00437] Prepared according to Example 40 (substituting 4-trifluoromethylbenzoic acid for the m- anisic acid), except that after the DMF/H20 slurry was filtered and the solid washed with 10 mL H20, the solid was sonicated in 10 mL CHCI3. Then the solid was dissolved in 5 mL CH3OH. H20 (2 L) was added to precipitate most of the dissolved product. The precipitate was then filtered, washed with 5 mL CH3OH, dried under vacuum. The title compound is a brown solid. 1H NMR (dB-DMSO): 56.80 (br s, 2H), 7.00 (s, 1 H), 7.16 (br s, 1 H), 7.60 (br s, 1 H), 7.90 (d, 2H, J = 8.2 Hz), 8.14 (d, 2H, J = 8.1 Hz), 10.87 (s, 1 H), 11.38 (s, 1H). ESI mass spectrum for C14H12F3N 03S+: 373 (M + 1 ).
[00438] Example 50: Methyl 3-[({4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2- yl}amino)carbonyl]benzoate
Figure imgf000093_0001
[00440] Prepared according to Example 40 (substituting 3-(methoxycarbonyl)benzoic acid for the m-anisic acid), except that the product was additionally sonicated in CHCI3, filtered, partially dissolved and triturated in 1.0 mL DMF, followed by the addition of 50 mL CHCI3 to precipitate the product, and then filtered. The product was then triturated in 25 mL diethyl ether, filtered, washed with 8 L diethyl ether, sonicated in 5 mL CH3OH, triturated in 5 mL diethyl ether, and then dried under vacuum. The title compound was a brown solid. 1H NMR (d6-DMSO): 53.90 (s, 3H), 6.82 (br s, 2H), 7.01 (s, 1 H), 7.18 (br s, 1 H), 7.59 (br s, 1 H), 7.69 (t, 1 H, J = 7.8 Hz), 8.14 (d, 1 H, J = 7.9 Hz), 8.22 (d, 1 H, J = 7.9 Hz), 8.55 (s, 1 H), 10.86 (s, 1 H), 11.37 (s, 1 H). ESI mass spectrum for C15H15N4θ5S+: 363 (M + 1 ).
[00441] Example 51 : 2-[(aminocarbonyl)amino]-5-[(1 ,1'-biphenyl-2-ylcarbonyl)amino]thiophene-
3-carboxamide
Figure imgf000093_0002
[00443] The crude solid salt of 2-[(aminocarbonyl)amino]-5-aminothiophene-3-carboxamide (0.428 g) (prepared according to Example 2C) was combined with 2-biphenylcarboxylic acid (0.339 g, 1.71 mmol), HATU (0.652 g, 1.71 mmol), DMF (10 mL) and triethylamine (1.6 mL, 11.5 mmol). The mixture was then stirred overnight and the DMF stripped off. The residue was triturated in 120 mL HzO, then triturated and sonicated in 50 mL 20:80 CH3OH:H20, followed by sonication in 25 mL CH3OH, filtering, and washing with 25 mL CH3OH. The combined methanol filtrate and wash was stripped of solvent, the residue sonicated in 100 mL H20, filtered, washed with 25 mL HzO, then triturated in 50 mL diethyl ether, triturated again in 25 mL diethyl ether, filtered, and washed with 25 mL diethyl ether. The product was then dried under vacuum. The title compound was a brown solid. 1H NMR (d6-DMSO): 56.70 (s, 1 H), 6.76 (br s, 2H), 7.07 (br s, 1 H), 7.24-7.59 (m, 10H), 10.81 (s, 1 H), 11.09 (s, 1 H). ESI mass spectrum for C19H17N403S+: 381 (M + 1).
[00444] Example 52: 2-[(Aminocarbonyl)amino]-5-[(1 ,1'-biphenyl-4-ylcarbonyl)amino]thiophene-
3-carboxamide
Figure imgf000094_0001
[00446] Prepared according to Example 51 (substituting 4-biphenylcarboxylic acid for the 2- biphenylcarboxylic acid), except the combined methanol filtrate and wash were discarded and the solid was then sonicated in 100 mL H20, filtered, and washed with 25 mL H20. Then the solid was sonicated in 50 mL CHCI3, filtered, washed with 15 mL CHCI3, sonicated with 30 mL saturated sodium bicarbonate solution, filtered, washed twice with 30 mL H20, sonicated again with 25 mL saturated sodium bicarbonate solution, filtered, and washed with 20 mL HzO. The product was then dried under vacuum to afford a brown solid. 1H NMR (d6-DMSO): 56.79 (br s, 2H), 6.98 (s, 1 H), 7.14 (br s, 1H), 7.37-7.43 (m, 1H), 7.46- 7.52 (m, 2H), 7.58 (br s, 1H), 7.71-7.77 (m, 2H), 7.82 (d, 2H, J = 8.6 Hz), 8.05 (d, 2H, J = 8.5 Hz), 10.85 (s, 1H), 11.20 (s, 1 H). ESI mass spectrum for C19H17N403S+: 381 (M + 1).
[00447] Example 53: 2-[(Aminocarbonyl)amino]-5-[(1 ,1 '-biphenyl-3-yIcarbonyl)amino]thiophene- 3-carboxamide
Figure imgf000094_0002
[00449] Prepared according to Example 51 (substituting 3-biphenylcarboxylic acid for the 2- biphenylcarboxylic acid), except 0.401 g of the solid salt prepared according to Example 2C was used and the other reagents were scaled accordingly. Then, after the DMF was stripped off, the residue was sonicated in 50 mL H20, filtered, washed with 25 mL H20, sonicated with 50 mL saturated sodium bicarbonate solution, filtered, washed with 25 mL H20, triturated and sonicated in 25 mL CH2CI2, filtered, and washed with 25 mL CH2CI2. The product was then dried under vacuum to afford a brown solid. 1H NMR (d6-DMSO): 56.80 (br s, 2H), 7.00 (s, 1 H), 7.15 (br s, 1 H), 7.37-7.43 (m, 1 H), 7.47-7.64 (m, 4H), 7.73-7.77 (m, 2H), 7.84-7.89 (m, 1 H), 7.90-7.95 (m, 1 H), 8.20-8.23 (m, 1 H), 10.84 (s, 1 H), 11.21 (s, 1H). ESI mass spectrum for C19Hι7N4θ3S+: 381 (M + 1). [00450] Example 54: 2-[(Aminocarbonyl)amino]-5-[(2,3,5-trifluorobenzoyl)amino]thiophene-3- carboxamide
Figure imgf000095_0001
[00452] The crude solid salt of 2-[(aminocarbonyl)amiπo]-5-aminothiophene-3-carboxamide (0.24 g) (prepared according to Example 2A or Example 2B) was combined with 1 mmol of 2,3,5- trifluorobenzoic acid, HBTU (BF4) (1 mmol), N,N-dimethylethylamine (1.0 mL, 9 mmol), and DMSO (1.0 mL). The mixture was stirred for 1 hour, then most of the liquids were stripped off. The residue was triturated in 100 mL CH2CI2 for 6 hours. The slurry was filtered, triturated with HzO (100 mL) overnight, filtered, washed with 20 mL ether, and triturated with 2 mL CH3OH for 30 minutes. Then the product was filtered and dried under reduced pressure to afford a brown solid. 1H NMR (CD3OD): 6.89 (s, 1 H), 7.28- 7.36 (m, 1H), 7.37-7.45 (m, 1H). ESI mass spectrum for C13H10F3N4O3S+: 359 (M + 1).
[00453] Examples 55-73, shown in Table VII below, were prepared analogously to Example 54, substituting the appropriate carboxylic acid for the 2,3,5-trifluorobenzoic acid.
Table VII
Figure imgf000095_0002
Figure imgf000096_0001
Example Name and Structure 1H NMR MS(ES+) (M+1) [(3- (CD3OD): 56.94 (s, 1H), 7.25- 357 7.32 (m, 1H), 7.61-7.68 (m, 2H). ide
[(3- (CD3OD): 5 1.29 (t, 3H, J = 7.5 358 Hz), 3.01 (q, 2H, J = 7.5 Hz), 6.94 (s, 1 H), 7.49 (t, 1 H, J = 7.7 Hz ), 7.75 (dd, 1H, J = 7.7, 1.2 Hz), 7.82 (dd, 1H, J = 7.7, 1.2 Hz).
Figure imgf000097_0001
2-[(Aminocarbonyl) amino]-5-[(2,5- (CD3OD): 56.97 (s, 1H), 7.24- 341 difluorobenzoyl) amino]thiophene-3- 7.38 (m, 2H), 7.46-7.54 (m, 1 H). carboxamide
Figure imgf000097_0002
2-[(Aminocarbonyl) amino]-5-[(2,6- (CD3OD): 56.96 (s, 1H), 7.06- 341 difluorobenzoyl) amino]thiophene-3- 7.16 (m, 2H), 7.48-7.60 (m, 1 H). carboxamide
Figure imgf000097_0003
Example Name and Structure 1HNMR MS(ES+) (M+1) (CD3OD): 57.03 (s, 1H), 7.48 (d, 357 1H, J=7.4Hz), 7.68 (d, 1H,J = 7.4 Hz), 7.85 (s, 1H).
Figure imgf000098_0001
2-[(Aminocarbonyl)amino]-5-[(3,4- (CD3OD): 57.01 (s, 1H), 7.40- 341 ene-3- 7.54 (m, 1 H), 7.68-7.98 (m, 2H).
Figure imgf000098_0002
2-[(Aminocarbonyl)amino]-5-[(2,3- (CD3OD): 57.00 (s, 1H), 7.28- 341 difluorobenzoyl)amino]thiophene-3- 7.38 (m, 1H), 7.42-7.60 (m, 2H). carboxamide
Figure imgf000098_0003
2-[(Aminocarbonyl) amino]-5-[(3,5- (CD3OD): 56.98 (s, 1H), 7.16- 341 ne-3- 7.24 (m, 1H), 7.51-7.59 (m, 2H).
Figure imgf000098_0004
Figure imgf000099_0001
Figure imgf000100_0001
[00454] Example 74: 4-F(l4-(Aminocarbonvl)-5-r(aminocarbonyl)amino1thien-2- yl}amino)carbonyl]-2,5-dichlorobenzoic acid
Figure imgf000100_0002
[00456] The crude solid salt of 2-[(aminocarbonyl)amino]-5-aminothiophene-3-carboxamide (0.24 g) (prepared according to Example 2A or Example 2B) was combined with 2 mmol of 2,5-dichloro-4- carboxybenzoic acid, HBTU (BF4) (2 mmol), N,N-dimethylethylamine (2.0 mL, 18 mmol), and DMSO (2.0 mL). The mixture was stirred for 1 hour, then most of the liquids were stripped off. The residue was triturated in 100 mL CH2CI2 for 6 hours. The slurry was filtered, triturated with H20 (100 mL) overnight, filtered, washed with 20 mL ether, and triturated with 5 mL CH3OH for 30 minutes. Then the product was filtered and dried under reduced pressure. 1H NMR (CD3OD)/ds-DMSO (4:1 ): 56.98 (s, 1 H), 7.77 (s 1 H), 7.98 (s 1H). ESI mass spectrum for Cι4H10CI2N4θ5S+: 417,(M + 1).
[00457] Example 75: 4-[({4-(Aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2- yl}amino)carbonyl]-2,5-dibromobenzoic acid
Figure imgf000101_0001
[00459] Prepared similarly to Example 74 (substituting 2,5-dibromo-4-carboxybenzoic acid for the 2,5-dichloro-4-carboxybenzoic acid). H NMR (CD3OD)/d6-DMSO (4:1): 5 6.91 (s, 1 H), 7.88 (s 1H),
7.99 (s 1H). ESI mass spectrum for C14H10Br2N4O5S+: 504 (M + 1).
[00460] 'Example 76: Methyl 4-[({4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2- yl}amino)carbonyl]-2,5-dicfιlorobenzoate
Figure imgf000101_0002
[00462] 4-[({4-(Aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2-yl}amino)carbonyl]-2,5- dichlorobenzoic acid (Example 74 0.2 mmol) was combined with 0.1 mL (2.5 mmol) of CH3OH, HBTU
(BF4) (0.3 mmol), N,N-dimethylethylamine (0.2 mL, 2 mmol), and DMSO (0.6 mL). The mixture was stirred for 1 hour, then most of the liquids were stripped off. The residue was triturated in 100 mL CH2CI2 for 6 hours. The slurry was filtered, triturated with H20 (100 mL) overnight, filtered, washed with 20 mL ether, and triturated with 5 mL CH3OH for 30 minutes. Then the product was filtered and dried under reduced pressure. 1H NMR (CD3OD)/ds-DMSO (4:1): 53.82 (s, 3H), 6.88 (s, 1 H), 7.68 (s 1 H), 7.88 (s 1 H). ESI mass spectrum for C15H12CI2N405S+: 431 (M + 1).
[00463] Example 77: Methyl 4-[({4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2- yl}amino)carbonyl]-2,5-dibromobenzoate
Figure imgf000101_0003
[00465] Prepared according to Example 76 (substituting 4-[({4-(Aminocarbonyl)-5- [(aminocarbonyl)amino]thien-2-yl}amino)carbonyl]-2,5-dibromobenzoic acid (Example 75) for the 4-[({4- (Aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2-yl}amino)carbonyl]-2,5-dichlorobenzoic acid). 1H NMR (CD3OD)/ds-DMSO (4:1 ): 53.83 (s, 3H), 6.83 (s, 1H), 7.79 (s 1 H), 7.98 (s 1 H). ESI mass spectrum for C15H12Br2N405S+: 519 (M + 1).
[00466] Example 78: 2-[(Aminocarbonyl)amino]-5-{[3-(chloromethyl)benzoyl]amino}thiophene-3- carboxamide
Figure imgf000102_0001
[00468] Made similarly to Example 54 (substituting 3-chloromethylbenzoic acid for the 2,3,5- trifluorobenzoic acid), except that instead of N,N-dimethylethylamine, 1 mL N,N-diisopropylethylamine was used. 1H NMR (CD3OD): 54.75 (s, 2H), 6.97 (s, 1H), 7.54 (t, 1 H, J = 7.6 Hz), 7.66 (d, 1 H, J = 7.7 Hz), 7.88 (d, 1H, J = 7.8 Hz), 7.88 (s, 1 H). ESI mass spectrum for C14H13CIN403S+: 353 (M + 1 ).
[00469] Example 79: 2-[(Aminocarbonyl)amino]-5-{[3-(piperidin-1- ylmethyl)benzoyl]amino}thiophene-3-carboxamide
Figure imgf000102_0002
[00471] 2-[(Aminocarbonyl)amino}-5-{[3-(chloromethyl)benzoyl]amino}thiophene-3-carboxamide (Example 78, 0.1 g, 0.28 mmol) was mixed with 1 mL piperidine and 1 mL DMF, and heated overnight with stirring. The DMF and the excess piperidine were removed under reduced pressure, the residue was washed with 10 mL ether, triturated with 2 mL CH3OH, then filtered and dried. 1H NMR (CD3OD): 5 1.20- 2.00 (m, 6H), 4.18 (s, 2H), 2.61-2.99 (m, 2H), 3.20-3.43 (m, 2H), 6.68 (s, 1H), 7.35-7.45 (m, 1 H), 7.46- 7.56 (m, 1H), 7.60-7.74 (m, 2H). ESI mass spectrum for C19H23N503S+: 402 (M + 1).
[00472] Example 80: 2-[(aminocarbonyl)amino]-5-(4-chlorobenzyl)thiophene-3-carboxamide
Figure imgf000102_0003
[00474] To 0.150 g (0.568 mmol) of 2-[(aminocarbonyl)amino]-5-bromothiophene-3- carboxamide was added 0.013 g (0.057 mmol) of palladium (II) acetate, 0.030 g (0.114 mmol) triphenylphosphine, and 11.36 mL (5.680 mmol) of a 0.5M solution of 4-chlorobenzylzinc chloride. The reaction mixture was heated under nitrogen to 40°C overnight and the reaction progress was monitored by HPLC. Quenched reaction mixture with 10 L 2N HCl and added 30 mL ethyl acetate and 20 mL H20. The organic layer was washed with H20, dried over Na2S04, filtered, and concentrated to afford a yellow oil which was purified by reverse phase chromatography. Concentration of the desired fractions afforded a yellow solid. H NMR (d6-DMSO/400 MHz) 53.92 (s, 2H), 6.80 (br s, 2H), 7.00 (s, 1H), 7.12 (br s, 1 H), 7.24 (d, 2H, J = 8.4 Hz), 7.35 (d, 2H, J = 8.0Hz), 7.53 (br s, 1 H), 10.86 (s, 1 H). HRMS C13H13CIN302S+: theoretical 310.0412, found 310.0405.
[00475] Examples 81-100 (shown in Table VIII, below) were prepared by parallel synthesis, substituting the appropriate zinc chloride reagent. The parallel synthesis apparatus consists of an aluminum block, which can be heated or cooled to the appropriate temperature, with a set of wells for 20- 50 mL glass vessels. The parallel reactor blocks can be used under reflux conditions and inert atmosphere (obtained from J-KEM Scientific, Inc., St. Louis, MO, USA or ChemGlass Inc., Vineland, NJ, USA). [00476] Analytical LCMS reverse phase chromatography was carried out using a C18 column 2.1 mm inner diameter x 30 mm and a linear gradient of 5% acetonitrile in 0.1 % TFA/H20 to 95% acetonitrile in 0.1 % TFA/H20 over 4.5 min. at a flow rate of 1 mL/min. The eluent composition was held at 95% acetonitrile in 0.1% TFA/H20 from 4.5 min to 6 min. The LCMS was equipped with a diode array detector, a mass spectral detector (MSD) and an evaporative light scattering detector (ELS). A flow splitter was attached after the UV diode array detector to allow flow to the MSD and ELS. Mass spectra were obtained using an Agilent MSD in electrospray positive mode. Preparative reverse phase chromatography was carried out using a C18 column 41.4 mm i.d. of 50 mm, 100 mm or 300 mm length. The HPLC retention time was determined using analytical LCMS reverse phase analysis and represents the time obtained for the compound having the desired molecular ion. The retention time is based on the observed time in the UV chromatogram. The molecular ion listed in the table is the baseline (100%) peak, unless otherwise noted. Purity of the compounds prepared by parallel synthesis was determined by detection of the peak of the desired molecular ion and integration of the corresponding peak detected either by UV at 254 nm or by ELS.
Table VIII
Figure imgf000103_0001
Example Name and Structure LC (min) MS HRMS (ES+)
83 2.469 290 290.0926
84 2.283 294 294.0751
85 2.265 294 294.074
86 2.265 294 294.0746
87 2.396 310 310.0421
88 2.457 310 310.0453
Figure imgf000104_0001
Figure imgf000105_0001
Example Name and Structure LC (min) MS HRMS (ES+)
95 2-[(aminocarbonyl)amino]-5-(2,6-dichlorobenzyl) 2.583 344 344.0015
Figure imgf000106_0001
96 2-[(aminocarbonyl)amino]-5-(2-chloro-6-fluorobenzyl) 2.423 328 328.0315
Figure imgf000106_0002
97 2-[(aminocarbonyl)amino]-5-(2,6-difluorobenzyl) 2.272 312 312.0622
98 2.355 290 290.097
99 2.273 306 306.0909
100 2.202 306 306.0907
Figure imgf000106_0003
[00477] Example 101: 2-[(aminocarbonyl)amino]-5-(2-naphthoylamino)thiophene-3- carboxamide
Figure imgf000107_0001
[00479] The solid salt of 2-[(aminocarbonyl)amino]-5-aminothiophene-3-carboxamide (0.428 g) (prepared according to Example 2C) was combined with 2-naphthoic acid (0.296 g, 1.72 mmol), HATU (0.652 g, 1.71 mmol), DMF (10 mL) and triethylamine (1.6 mL, 11.5 mmol). The mixture was then stirred overnight and the DMF stripped off. The residue was triturated in 120 mL H20, then triturated and sonicated in 50 mL 20:80 CH3OH:H20, followed by two cycles of sonication in 25 mL CH3OH, filtering, and washing with 25 mL CH3OH. The product was then dried under vacuum. 1H NMR (d6-DMSO): 56.80 (br s, 2H), 7.01 (s, 1H), 7.16 (br s, 1 H), 7.56-7.66 (m, 3H), 7.96-8.08 (m, 4H), 8.56 (s, 1 H), 10.86 (s, 1 H), 11.30 (s, 1H). ESI Mass Spectrum CιrH15N403S+: 355 (M + 1).
[00480] Example 102: 2-[(aminocarbonyl)amino]-5-(1 -naphthoylamino)thiophene-3- carboxamide
Figure imgf000107_0002
[00482] Prepared similarly to Example 101 (substituting 1-naphthoic acid (0.295 g, 1.71 mmol) for the 2-naphthoic acid), except that after sonication once in 25 mL CH3OH, filtering, and washing with 25 mL CH3OH, the methanol filtrate and wash were combined with 25 mL H20 and then partially stripped to remove some of the methanol. The resulting precipitate was filtered and washed with 25 mL H20, then sonicated in 15 mL CH3OH, 30 mL H20 was added, the precipitate filtered, washed with H20, and dried under vacuum. 1H NMR (d6-DMSO): 56.81 (br s, 2H), 6.91 (s, 1 H), 7.14 (br s, 1 H), 7.54-7.63 (m, 4H), 7.72 (dd, 1 H, J = 7.1 Hz, J = 1.2 Hz), 7.98-8.02 (m, 1 H), 8.06 (d, 1 H, J = 8.3 Hz), 8.14-8.19 (m, 1H), 10.88 (s, 1H), 11.40 (s, 1H). ESI Mass Spectrum C17H15N403S*: 355 (M + 1). [00483] Example 103: 2-[(aminocarbonyl)amino]-5-[(1 ,2-dihydroacenaphthylen-5- ylcarbonyl)amino]thiophene-3-carboxamide
Figure imgf000108_0001
[00485] Prepared analogously to Example 101. 1H NMR (CD3OD/d6-DMSO (4:1 )): 53.38 (s, 4H), 6.84 (s, 1H), 7.32 (d, 2H, J = 7.04 Hz), 7.49 (t, 1 H, J = 6.95 Hz), 7.76 (d, 1 H, J = 7.15 Hz), 8.46 (d, 1 H, J = 8.46 Hz). Mass of Molecular Ion: 381 (M + 1).
[00486] Example 104: 4-[({4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2- yl}amino)carbonyl]cyclohexane carboxylic acid
Figure imgf000108_0002
[00488] The solid salt of 2-[(aminocarbonyl)amino]-5-aminothiophene-3-carboxamide (0.15 g) (prepared according to either Example 2A or Example 2B) was combined with 0.18 g (1.045 mmol) of trans-1 ,4-cyclohexanedicarboxylic acid, HBTU (BF4) (0.32 g, 1 mmol), N,N-dimethylethylamine (1.6 mL) and DMSO (1.5 mL). The mixture was stirred for 1 hour, then most of the liquids were stripped off. The residue was triturated in 100 mL CH2CI2 for 6 hours. The slurry was filtered, triturated with H20 (100 mL) overnight, filtered, washed with 20 mL ether, and triturated with 5 mL CH3OH for 30 minutes. Then the product was filtered and dried under reduced pressure to give the product. H NMR (CD3OD/d6-
DMSO(4:1 )): 5 1.39-1.69 (m, 4H), 1.90-2.12 (m, 4H), 2.22-2.44 (m, 2H), 6.90 (s, 1 H). ESI Mass
Spectrum C14H19N405S+: 355 (M + 1 ).
[00489] Example 105: Butyl 4-[({4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2- yl}amino)carbonyl]cyclohexane carboxylate
Figure imgf000108_0003
[00491] 4-[({4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2- yl}amino)carbonyl]cyclohexanecarboxylic acid (Example 115, 0.12 g, 0.34 mmol) was combined with 0.1 mL (2.5 mmol) of CH3OH, HBTU (BF4) 0.17 g (0.5 mmol), N,N-dimethylethylamine (0.7 mL), and DMSO (1.0 mL). The mixture was stirred overnight, then most of the liquids were stripped off. The residue was triturated in 100 mL CH2CI2 for 6 hours. The slurry was filtered, triturated with H20 (100 mL) overnight, filtered, triturated with 50 mL a saturated solution of sodium bicarbonate, filtered, washed with H20. Then the product was dried under reduced pressure to give the desired ester. 1H NMR (CD3OD): 50.95 (t, 3H, J = 7.35 Hz), 1.33-1.68 (m, 8H), 1.89-2.12 (m, 4H), 2.28-2.42 (m, 2H), 4.08 (t, 2H, J = 6.55 Hz), 6.89 (s, 1H). ESI Mass Spectrum C18H27N405S+: 411 (M + 1).
[00492] Example 109: 4-[({4-(Aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2- yl}amino)carbonyl]cyclohexane carboxylic acid (cis isomer)
Figure imgf000109_0001
[00494] The crude solid salt of 2-[(aminocarbonyl)amino]-5-aminothiophene-3-carboxamide (0.15 g) (prepared according to either Example 2A or Example 2B) was combined with 1.5 mmol of carboxylic acid, HBTU (BF4) (0.32 g, 1 mmol), N,N-dimethylethylamine (1.6 mL) and DMSO (1.5 mL). The mixture was stirred for 1 hour, then most of the liquids were stripped off. The residue was triturated in 100 mL of CH2CI2 for 6 hours. The slurry was filtered, triturated with water (100 mL) overnight, filtered, washed with 20 mL of ether, and triturated with 5 mL of methanol for 30 minutes. Then the product was filtered and dried under reduced pressure to give a solid. 1H NMR (CD3OD): 5 1.54-1.82 (m, 6H), 2.10- 2.24 (m, 2H), 2.36-2.50 (m, 1 H), 2.54-2.64 (m,1H), 6.89 (s, 1H). Mass of molecular ion: 355 (M + 1 ).
[00495] Example 110: 2-methoxyethyl 4-[({4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2- yl}amino)carbonyl]cyclohexanecarboxylate
Figure imgf000109_0002
[00497] 4-[({4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2- yl}amino)carbonyl]cyclofιexanecarboxylic acid (Example 109, 0.12 g, 0.34 mmol) was combined with 2.5 mmol of 2-methoxyethanol, HBTU (BF4) 0.17 g (0.5 mmol), N,N-dimethylethylamine (0.7 mL), and DMSO (1.0 mL). The mixture was stirred overnight, then most of the liquids were stripped off. The residue was triturated in 100 mL of CH2CI2 for 6 hours. The slurry was filtered, triturated with water (100 mL) overnight, filtered, triturated with 50 mL of a saturated solution of sodium bicarbonate, filtered, washed with water. Then the product was dried under reduced pressure to give the desired ester. 1H NMR (CD3OD): 5 1.40-1.68 (m, 4H), 1.89-2.08 (m, 2H), 2.10-2.13 (m, 2H), 2.28-2.46 (m, 2H),3.58-3.63 (m, 2H), 4.18-4.24 (m, 2H), 3.40 (s, 3H), 6.89 (s, 1H). Mass of molecular ion: 413 (M + 1).
[00498] Example 110.1 : Butyl 4-[({4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2- yl}amino)carbonyl] cyclohexanecarboxylate
Figure imgf000110_0001
[00500] Prepared analogously to Example 110. 1H NMR (CD3OD): 50.95 (t, 3H, J = 7.35 Hz), 1.33-1.68 (m, 8H), 1.89-2.12 (m, 4H), 2.28-2.42 (m, 2H), 4.08 (t, 2H, J = 6.55 Hz), 6.89 (s, 1 H). Mass of molecular ion: 411 (M + 1 ).
[00501] Examples 111-115. shown in Table IX below, were prepared analogously to Example 109.
Table IX
Figure imgf000110_0002
Figure imgf000111_0001
Figure imgf000112_0002
[00502] Example 116: 2-[(aminocarbonyl)amino]-5-{[(4-tert- butylcyclohexyl)carbonyl]amino}thiophene-3-carboxamide
Figure imgf000112_0001
[00504] To 4-tert-butylcyclohexane carboxylic acid (0.064 g, 0.348 mmol) in a 2 dram vial was added 2-(1 H-Benzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafiuorophosphate (0.127 g, 0.333 mmol), 5-amino-2-[(aminocarbonyl)amino]thiophene-3-carboxamide hydrochloride (0.050 g, 0.211 mmol), 4- methylmorpholine (0.232 mL, 2.110 mmol), and 1.0 mL of DMSO. The reaction mixture was stirred overnight at room temperature and the reaction progress was monitored by HPLC. Volatiles were removed via nitrogen stream and the crude reaction mixture was purified by reverse phase chromatography. Concentration of the desired fractions afforded an orange solid. 1H NMR (dβ-DMSO, 400 MHz) (mixture of cis and trans isomers) 5 0.79 (s, 9H, minor isomer), 0.82 (s, 9H, major isomer), 0.94 ( , 2H), 1.21-1.52 (m, 3H), 1.80 (m, 2H), 2.02 (d, 1 H, J = 12.4 Hz, minor isomer), 2.21 (t, 1H, J = 12.0 Hz, major isomer), 6.71 (m, 3H), 7.08 (brs, 1 H), 7.51 (brs, 1 H), 10.43 (s, 1 H, minor isomer), 10.54 (s, 1 H, major isomer), 10.77 (m, 1 H); MS (ES+) 367 (M+1 ); HRMS (ES+) m/z calc'd for (C17H26N403S) 367.1798, found 367.1778; LC (min) 2.810 (100%).
[00505] Examples 117-212 are reported in Table X. Examples 117-193 were prepared via parallel synthesis analogously to the procedure of Example 116. Examples 194-212 were prepared via parallel synthesis analogously to Example 116 with the following exceptions: To 0.402 mmol of corresponding acid was added 0.152 g (0.401 mmol) of 2-(1 H-benzotriazole-1-yl)-1, 1 ,3,3- tetramethyluronium hexafiuorophosphate, 0.100 g (0.423 mmol) of 5-amino-2- [(aminocarbonyl)amino]thiophene-3-carboxamide hydrochloride, 0.465 mL (4.230 mmol) 4- methylmorpholine, and 1.5 mL DMSO. [00506] The parallel synthesis apparatus consisted of an aluminum block (obtained from J-KEM Scientific, Inc., St. Louis, MO, USA or ChemGlass Inc., Vineland, NJ, USA), which can be heated or cooled to the appropriate temperature, with a set of wells for 20-50 mL glass vessels. The parallel reactor blocks can be used under reflux conditions and inert atmosphere. The HPLC retention time was determined using analytical LCMS reverse phase analysis and represents the time obtained for the compound having the desired molecular ion. The retention time is based on the observed time in the UV chromatogram. The molecular ion listed in Table X is the baseline (100%) peak, unless otherwise noted. Analytical LCMS reverse phase chromatography was carried out using a C18 column 2.1 mm i.d. x 30 mm and a linear gradient of 5% acetonitrile in 0.1 % TFA/water to 95% acetonitrile in 0.1 % TFA/water over 4.5 min. at a flow rate of 1 mL/min. The eluant composition was held at 95% acetonitrile in 0.1% TFA/water from 4.5 min to 6 min. The LCMS was equipped with a diode array detector, a mass spectral detector (MSD) and an evaporative light scattering detector (ELS). A flow splitter was attached after the UV diode array detector to allow flow to the MSD and ELS. Mass spectra were obtained using an Agilent MSD in electrospray positive mode. Preparative reverse phase chromatography was carried out using a C18 column 41.4 mm i.d. of 50 mm, 100 mm or 300 mm length.
Table X Example Name and Structure LC (min) MS (ES+) HRMS
1 17 2.126 390.0 390.0459 -
Figure imgf000113_0001
118 5- 2.009 311.1 311.1201 thiophene-3-
Figure imgf000113_0002
Example Name and Structure LC (min) MS (ES ) HRMS
119 2-[(aminocarbonyl)amino]-5-{[(3- 2.228 325.1 325.1291 methylcyclohexyl) carbonyl]amino}thiophene- 3-carboxamide
Figure imgf000114_0001
120 2-[(aminocarbonyl)amino]-5-[(2- 1.910 319.1 319.0880 methylbenzoyl) amino]thiophene-3- carboxamide
121 ,8- 2.324 359.1 359.1134 )amino]
Figure imgf000114_0002
122 2-[(aminocarbonyl)amino]-5~{[(4-{[(4- 2.202 480.1 480.1363 methylphenyl) sulfonyljamino} cyclohexyl)carbonyl] am ino}thiophene-3- carboxamide
Figure imgf000114_0003
Example Name and Structure LC (min) MS (ES+) HRMS
123 2-[(aminocarbonyl)amino]-5- 1.940 311.1 311.1173 [(cyclohexylcarbonyl) amino]thiophene-3- carboxamide
124 1.510 283.1 283.0839
Figure imgf000115_0001
125 2-[(aminocarbonyl)amino]-5-{[(2- 2.200 325.1 325.1290 methylcyclohexyl) carbonyl]amino}thiophene- 3-carboxamide
Figure imgf000115_0002
126 2-[(aminocarbonyl)amino]-5-{[3- 1.616 383.1 383.0483 (methylsulfonyl) benzoyl]amino}thiophene-3- carboxamide
Figure imgf000115_0003
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Example Name and Structure LC (min) MS (ES+) HRMS
148 2.650 353.2 353.1658 oxamide
Figure imgf000121_0001
149 2-[(aminocarbonyl)amino]-5-[(2-fluoro-5- 2.009 337.1 337.0738 methy!benzoyl)amino] thiophene-3- carboxamide
150 1 S,2S)-2- 2.211 345.1 345.1029 ino)
Figure imgf000121_0002
151 2-[(aminocarbonyl)amino]-5-{[(4- 2.498 339.1 339.1472 ethylcyclohexyl) carbonyl]amino}thiophene-3- carboxamide
Figure imgf000121_0003
Example Name and Structure LC (min) MS (ES+) HRMS
152 2.349 387.1 387.0697 ino)
Figure imgf000122_0001
153 2-[(aminocarbonyl)amino]-5-[(4- 2.010 319.1 319.0860 methylbenzoyl) amino]thiophene-3- carboxamide
Figure imgf000122_0002
154 2-[(aminocarbonyl)amino]-5-[(2,3-dihydro-1 H- 2.130 345.1 345.1047 inden-2-ylcarbonyl)am ino] thiophene-3- carboxamide
155 1.699 341.1 341.1258 oxamide
Figure imgf000122_0003
Example Name and Structure LC (min) MS (ES HRMS
156 2-[(aminocarbonyl)amino]-5- 0.722 269.1 269.0673 [(cyclopropylcarbonyl) amino]thiophene-3- carboxamide
157 1.684 341.1 341.1231
Figure imgf000123_0001
158 2-[(aminocarbonyl)amino]-5-({4-[(1,1- 1.390 452.1 452.1082 dioxidothiomorpholin-4- yl)methyl]benzoyl}amino) thiophene-3- carboxamide
Figure imgf000123_0002
159 N-{4-(aminocarbonyl)-5- 1.562 306.1 306.0612 [(aminocarbonyl)amino] thien-2-yl}pyridine-2- carboxamide
Figure imgf000123_0003
Figure imgf000124_0001
Figure imgf000125_0001
Example Name and Structure LC (min) MS (ES ) HRMS
168 2-[(aminocarbonyl Jam ino]-5-{[( 1 -methyl-1 H- 2.179 372.1 372.1150 indol-3-yl)acetyl]amino} thiophene-3- carboxamide
169 - 2.961 367.2 367.1772 }thiophene-3-
170 1.432 413.1 413.1398 -yl}-2,5- 1 H-pyrrole-3-
Figure imgf000126_0001
171 - 2.845 421.1 421.1059
Figure imgf000126_0002
Example Name and Structure LC (min) MS (ES+) HRMS
172 N-{4-(aminocarbonyl)-5- 1 .721 340.0 340.0293 [(aminocarbonyl)amino] thien-2-yl}-2- chloroϊsonicotinamide
Figure imgf000127_0001
173 2-[(aminocarbonyl)amino]-5-[(2- 2.339 369.1 369.1014 naphthylacetyl) amino]thiophene-3- carboxamide
Figure imgf000127_0002
174 2-[(aminocarbonyl)amino]-5-({[4- 2.631 425.1 425.1243 (benzyloxy)phenyl] acetyl}amino)thiophene-3- carboxamide
Figure imgf000127_0003
175 2-[(aminocarbonyl)amino]-5-{[(4- 3.180 381.2 381.1945 pentylcyclohexyl) carbonyl]amino}thiophene- 3-carboxamide
Figure imgf000127_0004
Example Name and Structure LC (min) MS (ES+) HRMS
176 N-{4-(am inocarbonyl )-5- 1.859 356.1 356.0826 [(aminocarbonyl)amino] thien-2-yl}quinoline- 8-carboxamide
Figure imgf000128_0001
177 2-[(aminocarbonyl)amino]-5-{[(4-phenylthien- 2.268 387.1 387.0562 3-yl)carbonyl]amino} thiophene-3- carboxamide
Figure imgf000128_0002
178 2-[(aminocarbonyl)amino]-5-{[(4,5- 2.116 339.1 339.0543 dimethylthien-3-yl)carbonyl]amino} thiophene- 3-carboxamide
179 2.292 421.1 421.0965
Figure imgf000128_0003
Example Name and Structure LC (min) MS (ES+) HRMS
180 0.952 417.2 417.1701 )
Figure imgf000129_0001
181 2.194 424.2 424.1667 mino) e-7-
Figure imgf000129_0002
182 2-[(aminocarbonyl)amino]-5-{[(1- 1.193 294.1 294.0679 cyanocyclopropyl) carbonyl]amino}thiophene- 3-carboxamide
183 1.586 285.1 285.1032 e-3-
Figure imgf000129_0003
184 2-[(aminocarbonyl)amino]-5-[(3-chloro-2,2- 1.687 319.1 319.0591 dimethylpropanoyl)amino] thiophene-3- carboxamide
Figure imgf000129_0004
Figure imgf000130_0001
Example Name and Structure LC (min) MS (ES+) HRMS
189 2-[(aminocarbonyl)amino]-5-[(2,2- 2.358 327.2 327.1487 dimethylhexanoyl) amino]thiophene-3- carboxamide
Figure imgf000131_0001
190 2-[(aminocarbonyl)amino]-5-(propionylamino) 0.814 257.1 257.0722
191 1.725 337.1 337.0572 nyl}
Figure imgf000131_0002
192 2-[(aminocarbonyl)amino]-5-[(4,4,4-trifluoro- 1.715 339.1 339.0735 2-methylbutanoyl)amino] thiophene-3- carboxamide
Figure imgf000131_0003
193 2-[(aminocarbonyl)amino]-5-{[(4- 2.595 387.1 387.1535 phenylcyclohexyl) carbonyl]amino}thiophene- 3-carboxamide
Figure imgf000131_0004
Figure imgf000132_0001
Figure imgf000133_0001
Example Name and Structure LC (min) MS (ES+) HRMS
206 2-[(aminocarbonyI)amino]-5-{[(2R,5S)- 2.234 349.1 349.132 hexahydro-2,5-methanopentalen-3a(1 H)- ylcarbonyl]amino} thiophene-3-carboxamide
Figure imgf000135_0001
207 2-[(aminocarbonyl)amino]-5-{[(4-pentylbicyclo 3.292 407.2 407.214 [2.2.2]oct-1 -yl)carbonyl] amino}thiophene-3- carboxamide
Figure imgf000135_0002
208 5-{[6-(acetylamino) hexanoyl]amino}-2- 1.269 356.1 356.139 [(aminocarbonyl)amino] thiophene-3- carboxamide
Figure imgf000135_0003
Example Name and Structure LC (min) MS (ES+) HRMS
209 2-[(aminocarbonyl)amino]-5-[(5- 0.929 313.1 313.099 oxohexanoyl)amino] thiophene-3- carboxamide
Figure imgf000136_0001
210 methyl 6-({4-(aminocarbonyl)-5- 1.616 343.1 343.106 [(aminocarbonyl)amino] thien-2-yl}amino)-6- oxohexanoate
Figure imgf000136_0002
211 2-[(aminocarbonyl)amino]-5- 2.185 325.1 325.136 [(cyclohexylacetyl) amino]thiophene-3- carboxamide
Figure imgf000136_0003
Figure imgf000137_0003
[00507] Example 213: 2-[(Aminocarbonyl)amino]-5-{[(4- aminocyclohexyl)carbonyl]amino}thiophene-3-carboxamide Hydrochloride (trans-isomer)
Figure imgf000137_0001
[00509] Three mL of concentrated HCl was added dropwise at room temperature for 3 minutes to 0.1 g of tert-butyl 4-[({4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2- yl}amino)carbonyl]cyclohexylcarbamate (trans-isomer) (Example 111). The suspension was stirred for 15 minutes, filtered, and washed with 10 mL of chloroform to give the desired product after drying under reduced pressure. 1H NMR (CD3OD): δ 1.39-1.59 (m, 2H), 1.60-1.82 (m, 2H), 1.99-2.15 (m, 4H), 2.38-2.52 (m, 1 H), 3.09-3.26 (m, 1H), 6.83 (s, 1 H). Mass of Molecular Ion: 326 (M + 1).
[00510] Example 214: 2-[(aminocarbonyl)amino]-5-[({4- [(phenylacetyl)amino]cyclohexyl}carbonyl)amino]thiophene-3-carboxamide (trans-isomer)
Figure imgf000137_0002
[00512] The trans-isomer of 2-[(AminocarbonyI)amino]-5-{[(4- aminocyclohexyl)carbonyl]amino}thiophene-3-carboxamide (Example 213, 0.07 g, 0.215 mmol) was combined with 0.5 mmol of substituted acetic acid, HBTU (BF4) 0.17 g (0.5 mmol), N,N- dimethylethylamine (0.3 mL), and DMSO (1.0 mL). The mixture was stirred overnight then most of the liquids were stripped off. The residue was triturated in 80 mL of CH2CI2 for 6 hours. The slurry was filtered, triturated with water (40 mL) overnight, filtered, triturated with 20 mL of a 10% solution of sodium bicarbonate, filtered, washed with water. Then the product was dried under reduced pressure to give the desired amide. 1H NMR (CD3OD/d6-DMSO(4:1)): δ 1.08-1.30 (m, 2H), 1.41-1.57 (m, 2H), 1.74-1.92 (m, 4H), 2.14-2.26 (m, 1 H), 3.28 (s, 2H), 3.40-3.60 (m, 1 H), 6.63 (s, 1 H), 7.05-7.30 (m, 5H). Mass of molecular ion: 444 (M + 1).
[00513] Example 214.1 : 2-[(aminocarbonyl)amino]-5-{[(4-{[(4- chlorophenyl)acetyl]amino}cyclohexyl)carbonyl] amino}thiophene-3-carboxamide
Figure imgf000138_0001
[00515] Prepared analogously to Example 214. 1H NMR (CD3OD/ds-DMSO(4:1)): δ 1.04-1.26
(m, 2H), 1.39-1.58 (m, 2H), 1.74-1.92 (m, 4H), 2.14-2.28 (m, 1H), 3.38 (s, 2H), 3.40-3.60 (m, 1 H), 6.62 (s, 1 H), 7.10-7.32 (m, 5H). Mass of Molecular Ion: 478 (M + 1).
[00516] Example 214.2: 2-[(aminocarbonyl)amino]-5-[({4-[(3,3- dimethylbutanoyl)amino]cyclohexyl}carbonyl)amino] thiophene-3-carboxamide (trans-isomer)
Figure imgf000138_0002
[00518] Prepared analogously to Example 214. H NMR (CD3OD/ds-DMSO(4:1)): δ 0.90 (s, 9H), 1.20-1.40 (m, 2H), 1.50-1.74 (m, 2H), 1.88-2.08 (m, 6H), 2.25-2.38 (m, 1H), 3.58-3.68 (m, 1H), 6.65 (s, 1 H). Mass of Molecular Ion: 424 (M + 1 ).
[00519] Example 214.3: 2-[(aminocarbonyl)amino]-5-{[(4-{[(4- chlorophenyl)acetyl]amino}cyclohexyl) carbonyl]amino} thiophene-3-carboxamide (trans-isomer)
Figure imgf000139_0001
[00521] Prepared analogously to Example 214. 1H NMR (CD3OD/d6-DMSO(4:1 )): δ 1.04-1.26 (m, 2H), 1.39-1.58 (m, 2H), 1 .74-1.92 (m, 4H), 2.14-2.28 (m, 1 H), 3.38 (s, 2H), 3.40-3.60 (m, 1 H), 6.62 (s, 1 H), 7.10-7.32 (m, 5H). Mass of Molecular Ion: 478 (M + 1 ).
[00522] Example 215: 2-[(Aminocarbonyl)amino]-5-{[(4- aminocyclohexyl)carbonyl]amino}thiophene-3-carboxamide Hydrochloride (cis-isomer)
Figure imgf000139_0002
[00524] Prepared according to Example 213. 1H NMR (CD3OD): δ 1.70-1.84 (m, 2H), 1.85-1.94 (m, 4H), 1.98-2.10 (m, 2H), 2.61-2.72 (m, 1 H), 3.24-3.36 (m, 1 H), 6.79 (s, 1 H). Mass of Molecular Ion: 326 (M + 1 ).
[00525] Example 216: N-{4-(aminocarbonyI)-5-[(aminocarbonyl)amino]thien-2-yl}-7- azabicyclo[2.2.1] heptane-2-carboxamide trifluoroacetate
Figure imgf000139_0003
[00527] To tert-butyl 2-[({4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2- yl}amino)carbonyl]-7-azabicyclo[2.2.1]heptane-7-carboxylate (Example 181 , 760.069 g, 0.163 mmol) in a 2 dram vial was added 2.0 mL trifluoroacetic acid and 2.0 mL dichloromethane. The reaction mixture was stirred for one hour at room temperature and the reaction progress was monitored by HPLC. Volatiles were removed via nitrogen stream and the crude reaction mixture was dried under high vacuum overnight to afford a mauve solid. 1H NMR (dδ-DMSO, 400 MHz) δ 1.63 (m, 2H), 1.81 (m, 2H), 1.93-2.05 (m, 2H), 2.92 (dd, 1H, J = 8.8 Hz, J = 5.2 Hz), 4.14 (s, 1H), 4.32 (s, 1 H), 6.76 (s, 3H), 7.16 (brs, 1 H), 7.59 (brs, 1H), 8.06 (d, 1 H, J = 8.4 Hz), 9.03 (d, 1 H, J = 8.8 Hz), 10.82 (s, 1 H), 11.07 (s, 1 H); 19F NMR (d6-DMSO) δ -7 A (CF3, s); LC (min) 0.380 (100%); MS (ES+) 324 (M+1 ); HRMS (ES+) m/z calc'd for (C13H17N503S) 324.1125, found 324.1110. [00528] Example 217: N-{4-(aminocarbonyI)-5-[(aminocarbonyl)amino]thien-2-yl}piperidine-3- carboxamide
Figure imgf000140_0001
[00530] Prepared analogously to Example 216. LC (min) 0.355 (100%); MS (ES+) 312 (M+1); HRMS (ES+) m/z found 312.1144.
[00531] Example 218: 5-(beta-alanylamino)-2-[(aminocarbonyl)amino]thiophene-3-carboxamide
Figure imgf000140_0002
[00533] Prepared analogously to Example 216. LC (min) 0.196 (100%); MS (ES+) 272 (M+1);
HRMS (ES+) m/z found 272.0811.
[00534] Example 300: Methyl 4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thiophene-2- carboxylate
Figure imgf000140_0003
[00536] 2-[(aminocarbonyl)amino]-5-bromothiophene-3-carboxamide (1.70 g, 6.4 mmol), DPPF (1 ,1'-bis(diphenylphosphino)ferrocene) (0.382 g, 0.6 mmol), DMF (N,N-dimethylformamide) (24 mL), and methanol (20 mL) were combined in a tube containing a stir-bar. Nitrogen was bubbled through the solution for 30 minutes to remove oxygen, after that Pd(OAc)2 (0.166 g, 0.74 mmol) was added, and the tube with reaction mixture was purged with nitrogen. The tube was placed in an oil bath at 80°C, and CO was bubbled for 6 hours under vigorous stirring. The reaction mixture was filtered through celite, washed with 10 mL of DMF. Most of the liquids were removed under reduced pressure, and 60 mL of methylene chloride was added to the residue. The mixture was triturated for 2 hours, filtered, and dried. The solid was triturated with water (60 mL) for 5 hours, filtered, dried, and triturated with 25 mL of ethanol overnight, to give the desired product after filtration and drying. H NMR (αVDMSO): δ 3.78 (s, 3H), 6.82-7.35 (br s, 2H), 7.39 (brs, 1H), 7.72 (br s, 1H), 8.16 (s, 1H), 11.30 (s, 1H). ESI mass spectrum for C8H9N304S+: 244 (M + 1). ). [00537] Example 301 : Sodium 4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thiophene-2- carboxylate
Figure imgf000141_0001
[00539] Methyl 4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thiophene-2-carboxylate (Example 300, 0.60 g, 2.5 mmol), 4.8 mL of 1 NaOH, and 1 mL of CH3OH were placed in a flask containing a stir- bar. The mixture was stirred overnight at room temperature. Liquids were removed under reduced pressure, solid was dried and triturated with 30 mL of ethanol for 6 hours to give the desired salt after filtration and drying. 1H NMR (D20): δ 7.43 (s, 1 H). ESI mass spectrum for C7HsN304S+: 230 (M + 1).
[00540] Example 302: 4-(Aminocarbonyl)-5-[(aminocarbonyl)amino]thiophene-2-carboxylic acid
Figure imgf000141_0002
[00542] 4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thiophene-2-carboxylic acid, sodium salt (Example 301 , 0.45 g, 1.8 mmol) was dissolved in a minimal amount of H20, and 6N HCl was added to adjust the pH to 3. The precipitate was filtered, washed with sodium bicarbonate solution and water. After drying, the desired acid was obtained. 1H NMR (αVDMSO): δ 6.88-7.23 (br s, 2H), 7.35 (br s, 1 H), 7.73 (br s, 1 H), 8.06 (s, 1 H), 11.24 (s, 1 H), 12.02-13.22 (br s, 1 H). ESI mass spectrum for C7H6N304S+: 230 (M + 1 ).
[00543] Example 303: 5-[(Aminocarbonyl)amino]-N-2-(3-chlorophenyl)thiophene-2,4- dicarboxamide
Figure imgf000141_0003
[00545] 4-(Aminocarbonyl)-5-[(aminocarbonyl)amino]thiophene-2-carboxyIic acid (Example 302, 0.1 g, 0.43 mmol) was combined with 1.5 mmol of an aniline derivative, HBTU (BF4) (1.5 mmol), N,N- dimethylethylamine (0.5 mL, 4.5 mmol), and DMSO (1.0 mL). The mixture was stirred for 20 hours at 50°C, then most of the liquids were stripped off. The residue was triturated in 60 mL of CH2CI for 6 hours. The slurry was filtered, triturated with saturated sodium bicarbonate solution (60 mL) overnight, washed with water, filtered, and triturated with 5 mL of ethanol. After filtration the product was dried under reduced pressure. The title compound is a solid. 1H NMR (CD3OD)/d6-DMSO (4:1 ): δ 7.07 (dd, 1 H, J = 8.8, 1.20 Hz), 7.28 (t, 1 H, J = 8.1 Hz), 7.57 (dd, 1 H, J = 7.1 , 1.0 Hz), 7.83 (t, 1 H, J = 2.0 Hz), 7.98 (s, 1 H). ESI mass spectrum for C13H11CIN403S+: 339 (M + 1 ).
[00546] Example 304: Methyl 4-[({4-(aminocarbonyl)-5-[(aminocarbonyl)amino]thien-2- yl}carbonyl)amino]benzoate
Figure imgf000142_0001
[00548] Prepared analogously to Example 303. The title compound is a solid. 1H NMR (CD3OD)/dβ-DMSO (4:1 ): δ 3.79 (s, 3H), 7.79 (d, 2H, J = 8.9 Hz), 7.97-8.38 (m, 3H). ESI mass spectrum for C15H14N405S+: 363 (M + 1 ).
[00549] Example 305: 5-[(Aminocarbonyl)amino]-N-2-(3-chlorophenyl)-N-2-methylthiophene- 2,4-dicarboxamide
Figure imgf000142_0002
[00551] Prepared analogously to Example 303. The title compound is a solid. 1H NMR (CD3OD)/dβ-DMSO (4:1): δ 3.33 (s, 3H), 7.11-7.20 (m, 1 H), 7.25-8.38 (m, 4H). ESI mass spectrum for C14H13C1N403S+: 353 (M + 1 ).
[00552] Example 306: 5-[(Aminocarbonyl)amino]-N-2-(3-chlorobenzyl)thiophene-2,4- dicarboxamide
Figure imgf000142_0003
[00554] 4-(Aminocarbonyl)-5-[(aminocarbonyl)amino]thiophene-2-carboxylic acid (Example 302, 0.1 g, 0.43 mmol) was combined with 1.5 mmol of an alkyl- or alkylaryl- amine, HBTU (BF4) (1.5 mmol), N,N-diisopropylethylamine (0.5 mL, 4.5 mmol), and DMSO (1.0 mL). The mixture was stirred for 20 hours at room temperature, then most of liquids were stripped off. The residue was triturated in 60 mL of CH2CI2 for 6 hours. The slurry was filtered, triturated with saturated sodium bicarbonate solution (60 mL) overnight, washed with water, filtered, and triturated with 5 mL of ethanol. After filtration the product was dried under reduced pressure. The title compound is a solid. 1H NMR (CD3OD)/ds-DMSO (4:1 ): δ 3.89 (s, 2H), 7.18-7.24 (m, 4H), 7.69 (s, 1 H). ESI mass spectrum for C14H13CIN403S+: 353 (M + 1 ).
[00555] Example 307: 5-[(Aminocarbonyl)amino]-N-2-(2-chlorobenzyI)thiophene-2,4- dicarboxamide
Figure imgf000143_0001
[00557] Prepared analogously to Example 306. The title compound is a solid. 1 H NMR d6-
DMSO: 4.46 (d, 2H, J = 5.6 Hz), 7.07 (br s, 2H), 7.20-7.48 (m, 5H), 7.93 (s, 1 H), 8.60 (t, 1 H, J = 5.7 Hz), 11.05 (s, 1 H). ESI mass spectrum for C14H13C!N403S+: 353 (M + 1 ).
[00558] Example 308: 5-[(Aminocarbonyl)amino]-N-2-(4-chlorobenzyl)thiophene-2,4- dicarboxamide
Figure imgf000143_0002
[00560] Prepared analogously to Example 306. The title compound is a solid. 1H NMR d6- DMSO: δ 4.36 (d, 2H, J = 5.6 Hz), 7.06 (br s, 2H), 7.29 (d, 2H, J = 8.2 Hz), 7.38 (d, 2H, J = 8.3 Hz), 7.89 (s, 1 H), 8.64 (t, 1 H, J = 5.6 Hz), 11.04 (s, 1 H). ESI mass spectrum for C14H13CIN403S+: 353 (M + 1 ).
[00561] Example 309: 5-[(Aminocarbony!)amino]-N-2-[(1 R,2R)-2-phenylcyclopropyl]thiophene- 2,4-dicarboxamide
Figure imgf000143_0003
[00563] Prepared analogously to Example 306. The title compound is a solid. 1H NMR (CD3OD)/d6-DMSO (4:1 ): δ 1.20-1.35 (m, 2H), 2.00-2.18 (m, 1 H), 2.81 -2.98 (m, 1 H), 7.01 -7.30 (m, 5H), 7.68 (s, 1 H). ESI mass spectrum for C16H16N403S+: 345 (M + 1 ). [00564] Example 310: 5-[(Aminocarbonyl)amino]-N-2-1,2,3,4-tetrahydronaphthalen-1- ylthiophene-2,4-dicarboxamide
Figure imgf000144_0001
[00566] Prepared analogously to Example 306. The title compound is a solid. 1H NMR (CD3OD): δ 1.80-2.18 (m, 4H), 2.72-2.98 (m, 2H), 5.25 (t, 1H, J = 6.8 Hz), 7.08-7.30 (m, 4H), 7.69 (s, 1H). ESI mass spectrum for C17H18N403S+: 359 (M + 1 ).
[00567] Example 311 : 2-r(aminocarbonvl)aminol-5-cvanothiophene-3-carboxamide
Figure imgf000144_0002
[00568] [00569] 2-[(aminocarbonyl)amino]-5-bromothiophene-3-carboxamide (4.48 g, 18 mmol), Zn(CN)2 (1.247 g, 10.9 mmol), DPPF (1,1'-bis(diphenylphosphino)ferrocene) (1.308 g, 2.35 mmol), DMF (N,N-dimethylformamide) (39 mL), and benzonitrile (13 mL) were combined in a flask containing a stir-bar. Nitrogen was bubbled through the solution for 30 minutes to remove oxygen, after that Pd2(dba)3 (0.97 g, 1.04 mmol) was added, and the flask with reaction mixture was purged with nitrogen. The flask was placed in an oil bath at 90°C for 6 hours with vigorous stirring. The reaction mixture was filtered through celite, washed with 10 mL of DMF. Most of the liquids were removed under reduced pressure, and 100 mL of methylene chloride was added to the residue. The mixture was triturated for 1 hour, filtered, and dried. The solid was triturated with water (100 mL) for 3 hours, filtered and dried. The solid was placed in a flask containing half the amount of the above used reagents and solvents, and the reaction was repeated under the same conditions, including work up, to give the desired product after trituration with methanol (50 mL), filtration and drying. 1H NMR (CD3OD): 7.90 (s, 1H). ESI mass spectrum for C7H6N402S+: 211 (M + 1). ).
[00570] Example 312: 5-[(aminocarbonyl)amino] thiophene-2,4-dicarboxamide
Figure imgf000144_0003
[00572] 2-[(aminocarbonyl)amino]-5-cyanothiophene-3-carboxamide (Example 311 , 0.21 g, 1.0 mmol), 2 mL of 1 N NaOH, and 1 mL of CH3OH were placed in a flask containing a stir-bar. The mixture was stirred overnight at room temperature. Liquids were removed under reduced pressure, solid was dried and triturated with 10 mL of ethanol for 6 hours to give the desired amide, after filtration and drying. 1H NMR d6-DMSO: δ 5.20 (s, 2H), 6.39 (s, 1 H), 6.41-7.00 (br s, 3H), 7.67 (s, 1H), 9.90 (s, 1 H). ESI mass spectrum for C7H8N403S+: 229 (M + 1). [00573] Example 400: IKK-2 IC50 determination
Materials [00574] SAM2 ™ 96 Biotin capture plates were from Promega. Anti-FLAG affinity resin, FLAG- peptide, NP-40 (Nonidet P-40), BSA, ATP, ADP, AMP, LPS (E. coli serotype 0111 :B4), and dithiothreitol were obtained from Sigma Chemicals. Antibodies specific for NEMO (IKK- ) (FL-419), IKK-1 (H-744), IKK- 2(H-470) and l cBσ(C-21) were purchased from Santa Cruz Biotechnology. Ni-NTA resin was purchased from Qiageπ. Peptides were purchased from American Peptide Company. Protease inhibitor cocktail tablets were from Boehringer Mannheim. Sephacryl S-300 column was from Pharmacia LKB Biotechnology. Centriprep-10 concentrators with a molecular weight cutoff of 10 kDa and membranes with molecular weight cut-off of 30 kDa were obtained from Amicon. [Y-33P] ATP (2500 Ci/mmol) and [Y-32P] ATP (6000 Ci/mmol) were purchased from Amersham. The other reagents used were of the highest grade commercially available.
Cloning and Expression [00575] cDNAs of human IKK-1 and IKK-2 were amplified by reverse transcriptase-polymerase chain reaction from human placental RNA (Clonetech). hlKK-1 was subcloned into pFastBac HTa (Life Technologies) and expressed as N-terminal Hiss-tagged fusion protein. The hlKK-2 cDNA was amplified using a reverse oligonucleotide primer which incorporated the peptide sequence for a FLAG-epitope tag at the C-terminus of the IKK-2 coding region (DYKDDDDKD). The hlKK-2:FLAG cDNAwas subcloned into the baculovirus vector pFastBac. The rhlKK-2 (S177S, E177E) mutant was constructed in the same vector used for wild type rh IKK-2 using a QuikChange™ mutagenesis kit (Stratagene). Viral stocks of each construct were used to infect insect cells grown in 40L suspension culture. The cells were lysed at a time that maximal expression and rhlKK activity were demonstrated. Cell lysates were stored at -80°C until purification of the recombinant proteins was undertaken as described below.
Enzyme Isolation [00576] All purification procedures were carried out at 4°C unless otherwise noted. Buffers used are: buffer A: 20 mM Tris-HCI, pH 7.6, containing 50 mM NaCl, 20 mM NaF, 20 mM /?-Glycerophosphate, 500 uM sodium orthovanadate, 2.5 mM metabisulfite, 5 mM benzamidine, 1 mM EDTA, 0.5 mM EGTA, 10% glycerol, 1 mM DTT, 1X Complete™ protease inhibitors; buffer B: same as buffer A, except 150 mM NaCl, and buffer C: same as buffer A, except 500 mM NaCl.
Isolation of rhlKK-1 homodimer [00577] Cells from an 8-liter fermentation of baculovirus-expressed IKK-1 tagged with His peptide were centrifuged and the cell pellet (MOI 0.1, l=72 hr) was re-suspended in 100 ml of buffer C.
The cells were microfluidized and centrifuged at 100,000 X g for 45 min. The supernatant was collected, imidazole added to the final concentration of 10 mM and incubated with 25 ml of Ni-NTA resin for 2 hrs.
The suspension was poured into a 25 ml column and washed with 250 ml of buffer C and then with 125 ml of 50 mM imidazole in buffer C. rh IKK-1 homodimer was eluted using 300 mM imidazole in buffer C. BSA and NP-40 were added to>the enzyme fractions to the final concentration of 0.1 %. The enzyme was dialyzed against buffer B, aliquoted and stored at -80°C.
Isolation of rhlKK-2 homodimer [00578] A 10-liter culture of baculovirus-expressing IKK-2 tagged with FLAG peptide was centrifuged and the cell pellet (MOI=0.1 and l=72 hrs) was re-suspended in buffer A. These cells were microfluidized, and centrifuged at 100,000 X g for 45 min. Supernatant was passed over a G-25 column equilibrated with Buffer A. Protein peak was collected and incubated with anti-FLAG affinity resin on a rotator overnight in buffer B. The resin was washed in batch with 10-15 bed volumes of buffer C. Washed resin was poured into a column and rhlKK-2 homodimer was eluted using 5 bed volumes of buffer B containing FLAG peptide. 5 mM DTT, 0.1 % NP-40 and BSA (concentrated to 0.1 % in final amount) was added to the eluted enzyme before concentrating in using an Amicon membrane with a molecular weight cut-off of 30 kDa. Enzyme was aliquoted and stored at -80°C. <
Isolation of rhlKK-1/IKK-2 heterodimer [00579] The heterodimer enzyme was produced by coinfection in a baculovirus system (FLAG IKK-2/IKK-1 His; MOI=0.1 and l=72 hrs). Infected cells were centrifuged and the cell pellet (10.0 g) was suspended in 50 ml of buffer A. The protein suspension was microfluidized and centrifuged at 100,000 X g for 45 min. Imidazole was added to the supernatant to a final concentration of 10 mM. The protein was allowed to bind 25 ml of Ni-NTA resin by mixing for 2 hrs. The protein-resin slurry was poured into a 25 ml column and washed with 250 ml of buffer A containing 10 mM imidazole followed by 125 ml of buffer A containing 50 mM imidazole. Buffer A, containing 300 mM imidazole, was then used to elute the protein. A 75 ml pool was collected and NP-40 was added to a final concentration of 0.1%. The protein solution was then dialyzed against buffer B. The dialyzed heterodimer enzyme was then allowed to bind to 25 ml of anti- FLAG M2 agarose affinity gel overnight with constant mixing. The protein-resin slurry was then centrifuged for 5 min at 2,000 rpm. The supernatant was collected and the resin re-suspended in 100 ml of buffer C containing 0.1 % NP-40. The resin was washed with 375 ml of buffer C containing 0.1 % NP-40. The protein-resin was poured into a 25 ml column and the enzyme eluted using buffer B containing FLAG peptide. Enzyme fractions (100 ml) were collected and concentrated to 20 ml using an Amicon membrane with molecular weight cut-off of 30 kDa. Bovine serum albumin was added to the concentrated enzyme to final concentration of 0.1 %. The enzyme was then aliquoted and stored at -80°C.
Cell Culture [00580] The wild type (wt) human pre-B cell line, 70Z/3, and its mutant, 1.3E2, were generously provided by Dr. Carol Sibley. Wt 70Z/3 and 1.3E2 cells were grown in RPMI 1640 (Gibco) supplemented with 7 % defined bovine serum (Hyclone) and 50 μM 2-mercaptoethanol. Human monocytic leukemia THP-1 cells, obtained from ATCC, were cultured in RPMI 1640 supplemented with 10% defined bovine serum, 10 mM HEPES, 1.0 mM sodium pyruvate and 50 μM 2-mercaptoethanol. For experiments, cells were plated in 6 well plates at 1x106 cells/ml in fresh media. Pre-B cells were stimulated by the addition of 10 μg/ml LPS for varying lengths of time ranging from 0-4 hr. THP-1 cells were stimulated by the addition of 1 μg/ml LPS for 45 minutes. Cells were pelleted, washed with cold 50 mM sodium phosphate buffer, pH 7.4 containing 0.15 M NaCl and lysed at 4°C in 20 mM Hepes buffer, pH 7.6 containing 50 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1 mM sodium orthovanadate, 10 mM -glycerophosphate, 1 mM NaF, 1 mM PMSF, 1 mM DTT and 0.5 % NP40 (lysis buffer). The cytosolic fractions obtained following centrifugation at 10,000 X g were stored at -80°C until used.
Immunoprecipitation and Western Blotting [00581] SF9 cells paste containing rhlKKs were centrifuged (100,000 X g, 10 min) to remove debris. rhlKKs were immunoprecipitated (100 μg of cell paste) from the cell supernatant using 3 μg of anti- NEMO antibody (FL-419), followed by coupling to protein A sepharose beads. rhlKKs were also immunoprecipitated from affinity chromatography purified protein preparations (1 μg) using anti-FLAG, anti-His or anti-NEMO antibodies (1-4 μg) followed by protein A sepharose coupling. The native, human IKK complex was immunoprecipitated from THP-1 cell homogenates (300 μg/condition) using the anti- NEMO antibody. Immune complexes were pelleted and washed 3 times with 1 ml cold lysis buffer.
Immunoprecipitated rhlKKs were chromatographed by SDS-PAGE (8% Tris-glycine) and transferred to nitrocellulose membranes (Novex) and detected by chemiluminescense (SuperSignal) using specific anti- IKK antibodies (IKK-2 H-470, IKK-1 H-744). Native IKK-2, kBσ, and NEMO proteins from cytosolic lysates (20-80 μg) were separated by SDS-PAGE and visualized by chemiluminescense using specific antibodies.
Phosphatase Treatment [00582] Immunoprecipitated rhlKKs were washed 2 times in 50 mM Tris-HCI, pH 8.2 containing 0.1 mM EDTA, 1 mM DTT, 1 mM PMSF and 2 mM MnCI2 and resuspended in 50 μl. Phosphatase (ΛPPase, 1000 U) was pre-diluted in the same buffer and added to the IKK samples. Following incubation at room temperature for 30 minutes with intermittent mixing, cold lysis buffer was added to the tubes to stop the reaction. After several washes, 10 % of the beads were removed for Western analysis, and the remaining material was pelleted and resuspended in 100 μl of the buffer used for the in vitro kinase assay.
IKK-1 SAM Enzyme Assay [00583] IKK-1 kinase activity was measured using a biotinylated \κBa peptide (Gly-Leu-Lys-Lys- Glu-Arg-Leu-Leu-Asp-Asp-Arg-His-Asp-Ser32-Gly-Leu-Asp-Ser36-Met-Lys-Asp-Glu-Glu), a SAM2™ 96 Biotin capture plate and a vacuum system. The standard reaction mixture contained 5 μM biotinylated l/cBσ peptide, 1 μM [γ-33P] ATP (about 1 X 105 cpm), 1 M DTT, 50 mM KCI, 2 mM MgCI2, 2 mM MnCI2, 10 mM NaF, 25 mM Hepes buffer, pH. 7.6 and enzyme solution (1-10 μl) in a final volume of 50 μl. After incubation at 25°C for 30 min, 25 μl of the reaction mixture was withdrawn and added to a SAM2 ™ 96 Biotin capture 96-well plate. Each well was then washed successively with 800 μl 2 M NaCl, 1.2 ml of NaCl containing 1% H3P04, 400 μl HzO, and 200 μl 95% ethanol. The plate was allowed to dry in a hood at 25°C for 1 hr and then 25 μl of scintillation fluid (Microscint 20) was added to each well. Incorporation of [ -33P] ATP was measured using a Top-Count NXT (Packard). Under each assay condition, the degree of phosphorylation of Bσ peptide substrate was linear with time and concentration for all purified enzymes. Results from the biotinylated peptide assay were confirmed by SDS-PAGE analysis of kinase reaction utilizing a GST- Bcr^ and [γ-32P] ATP. The resulting radiolabeled substrate was quantitated by
Phosphoimager (Molecular Dynamics). An ion exchange resin assay was also employed using [ -33P] ATP and GST- Bσ^ fusion protein as the substrates. Each assay system yielded consistent results in regard to Km and specific activities for each of the purified kinase isoforms. One unit of enzyme activity was defined as the amount required to catalyze the transfer of 1 nmole of phosphate from ATP to \κBa peptide per min. Specific activity was expressed as units per mg of protein. For experiments related to Km determination of purified enzymes, various concentrations of ATP or 1 cBσ peptide were used in the assay at either a fixed 1/cBσ or ATP concentration. For Bσ peptide Km, assays were carried out with 0.1 μg of enzyme, 5 μM ATP and \κBa peptide from 0.5 to 20μM. For ATP Km, assays were carried out with 0.1 μg of enzyme, 10 μM \κBa peptide and ATP from 0.1 to 10μM. For Km determination of rhlKK-1 homodimer, due to its low activity and higher Km for \κBa peptide, rhlKK-1 homodimer (0.3 μg) was assayed with 125 μM \κBa peptide and a 5-fold higher specific activity of ATP (from 0.1 to 10 μM) for ATP Km experiments and a 5-fold higher specific activity of 5 μM ATP and \κBa peptide (from 5 to 200 μM) for l/cBσ peptide Km experiments.
IKK heterodimer Resin Enzyme Assay [00584] IKK heterodimer kinase activity was measured using a biotinylated l cBσ peptide (Gly- Leu-Lys-Lys-Glu-Arg-Leu-Leu-Asp-Asp-Arg-His-Asp-Ser32-Gly-Leu-Asp-Ser33-Met-Lys-Asp-Glu-Glu) (American Peptide Co.). 20 ul of the standard reaction mixture contained 5 μM biotinylated \κBa peptide, 0.1 μCi/reaction [ -33R] ATP (Amersham) (about 1 X 105 cpm), 1 μM ATP (Sigma), 1 mM DTT (Sigma), 2 mM MgCI2 (Sigma), 2 mM MnCI2 (Sigma), 10 mM NaF (Sigma), 25 mM Hepes (Sigma) buffer, pH 7.6 and 20 μl enzyme solution and 10 μl inhibitor in a final volume of 50 μl. After incubation at 25°C for 30 min, 150 μl resin (Dowex an ion-exchange resin AG1X8 200-400 mesh) in 900 mM formate, pH 3.0 was added to each well to stop the reaction. Resin was allowed to settle for one hour and 50 ul of supernatant was removed to a Micolite-2 flat bottom plate (Dynex). 150 μl of scintillation fluid (Microscint 40) (Packard) was added to each well. Incorporation of |>-33P] ATP was measured using a Top-Count NXT (Packard). IKK-2 Resin Enzyme Assay [00585] IKK-2 kinase activity was measured using a biotinylated \κBa peptide (Gly-Leu-Lys-Lys- Glu-Arg-Leu-Leu-Asp-Asp-Arg-His-Asp-Ser32-Gly-Leu-Asp-Ser36-Met-Lys-Asp-Glu-Glu) (American Peptide Co.). 20 ul of the standard reaction mixture contained 5 μM biotinylated Bσ peptide, 0.1 μCi/reaction [y- 33P] ATP (Amersham) (about 1 X 105 cpm), 1 μM ATP (Sigma), 1 mM DTT (Sigma), 2 mM MgCI2 (Sigma), 2 mM MnCI2 (Sigma), 10 mM NaF (Sigma), 25 mM Hepes (Sigma) buffer, pH 7.6 and 20 μl enzyme solution and 10 ul inhibitor in a final volume of 50 μl. After incubation at 25°C for 30 min, 150 /I resin (Dowex anion-exchange resin AG1X8 200-400 mesh) in 900 mM formate, pH 3.0 was added to each well to stop the reaction. Resin was allowed to settle for one hour and 50 ul of supernatant was removed to a Micolite-2 flat bottom plate (Dynex). 150 μl of scintillation fluid (Microscint 40) (Packard) was added to each well. Incorporation of [γ-33P] ATP was measured using a Top-Count NXT (Packard). [00586] IKK-2 IC50 values obtained from the assay described above are shown in Table XI.
Table XI
Figure imgf000148_0001
Figure imgf000148_0002
Figure imgf000148_0003
Figure imgf000149_0001
Figure imgf000149_0002
Figure imgf000149_0003
Figure imgf000150_0001
Figure imgf000150_0002
Figure imgf000150_0003

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula IIA or Formula IIB:
Figure imgf000151_0001
wherein Z is selected from the group consisting of hydrido, halo, alkyl, cyano, and haloalkyl; wherein Rs is selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, or where R9 and R10 together with the atoms to which they are attached form a heterocyclic moiety; wherein R9 is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-alkylamino, N,N-dialkylamino, N-arylamino, N-alkyl-N-arylamino, N- hydroxyamino, N-alkyl-N-hydroxyamino, N-aryl-N-hydroxyamino, halo, cyano, keto, hydroxyl, alkyl, haloalkyl, cycloalkyl, alkoxy, alkenyl, alkenyloxy, aryl, aryloxy, aralkyl, aralkylcarbonyl, aralkylcarbonylamino, heteroarylcarbonyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, alkoxycarbonyl, aryloxycarbonyl, carboxyl, alkoxyalkoxycarbonyl, alkoxycarbonylamino, heterocycloalkyl, heterocycloalkylalkyl, thiol, oxidosulfanyl, sulfino, alkylthio, alkylsulfinyl, alkylsulfonyl, cycloalkylthio, cycloalkylsulfinyl, cycloalkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, heterocycloalkylthio, heterocycloalkylsulfinyl, heterocycloalkylsulfonyl, heteroarylthio, heteroarylsulfinyl, and heteroarylsulfonyl; wherein R10 is selected from the group consisting of hydrido, hydroxyl, alkoxy, alkyl, haloalkyl, aryl, and heteroaryl, or R10 and R9 together with the atoms to which they are attached form a heterocyclic moiety; wherein R11 and R12 are independently selected from the group consisting of hydrido, hydroxyl, alkoxy, alkyl, haloalkyl, aryl, and heteroaryl; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 wherein Z is selected from the group consisting of hydrido, halo, c^e alkyl, cyano, and Cι.s haloalkyl; wherein R9 is selected from the group consisting of c1-6 alkyl, c3- 2 cycloalkyl, c2_6 alkenyl, c3.12 cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, c3-i2 aryl, c4.18 aralkyl, 3- to 12-membered heteroaryl, and 4- to 18-membered heteroaralkyl, or where R9 and R 0 together with the atoms to which they are attached form a 3- to 12-membered heterocyclic moiety; wherein R9 is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-(C1-β alkyl)amino, N,N-di(Cι^ alkyl)amino, N-(C3. 2 aryl)amino, N-(c1.6 alkyl)- N-(C3-12 aryI)amino, N-hydroxyamino, N-(c1-6 alkyl)-N-hydroxyamino, N-(c3-12 aryl)-N-hydroxyamino, halo, cyano, keto, hydroxyl, c1-s alkyl, C-|.6 haloalkyl, C3-6 cycloalkyl, C1-B alkoxy, c2-6 alkenyl, c2.s alkenyloxy, c3.12 aryl, c3-12 aryloxy, c4-20 aralkyl, c4.20 aralkylcarbonyl, c4_20 aralkylcarbonylamino, 3- to 14-membered heteroarylcarbonyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 3- to 12- membered heteroaryl, c2-7 alkoxycarbonyl, c3.12 aryloxycarbonyl, carboxyl, c2-ιs alkoxyalkoxycarbonyl, c2-7 alkoxycarbonylamino, 3- to 12-membered heterocycloalkyl, 4- to 18-membered heterocycloalkylalkyl, thiol, oxidosulfanyl, sulfino, Cι-β alkylthio, C -6 alkylsulfinyl, C^ alkylsulfonyl, c3_ι2 cycloalkylthio, c3_ι2 cycloalkylsulfinyl, c3-12 cycloalkylsulfonyl, c3-12 arylthio, c3-ι2 arylsulfinyl, c3.ι2 arylsulfonyl, 3- to 12- membered heterocycloalkylthio, 3- to 12-membered heterocycloalkylsulfinyl, 3- to 12-membered heterocycloalkylsulfonyl, 3- to 12-membered heteroarylthio, 3- to 12-membered heteroarylsulfinyl, and 3- to 12-membered heteroarylsulfonyl; wherein R10 is selected from the group consisting of hydrido, hydroxyl, c^ alkoxy, cι-6 alkyl, c^β haloalkyl, c3-12 aryl, and 3- to 12-membered heteroaryl, or R10 and R9 together with the atoms to which they are attached form a 3- to 12-membered heterocyclic moiety; wherein R11 and R12 are independently selected from the group consisting of hydrido, hydroxyl, Cι-S alkoxy, c1-6 alkyl, Cι-6 haloalkyl, c3-12 aryl, and 3- to 12-membered heteroaryl.
3. A compound according to claim 2 wherein Z is selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyano, and haloalkyl; wherein R9 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, propenyl, butenyl, pentenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, isoindolyl, dihydroindolyl, isoindolinyl, dihydrothiophenyl, dihydropyrrolyl, dihydrofuryl, dihydropyrazolyl, dihydroimidazolyl, dihydroisoxazolyl, dihydrooxazolyl, phenyl, biphenyl, naphthyl, indenyl, benzyl, phenylethyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isoindoledionyl, pyridinylmethyl, pyridinylethyl, benzothiophenylmethyl, benzothiophenylethyl, indolylmethyl, indolylethyl, isoquinolinylmethyl, isoquinolinylethyl, quinolinylmethyl, quinolinylethyl, thienyl methyl, thienylethyl, pyrrolyl methyl, pyrrolylethyl, furylmethyl, furylethyl, pyrazolylmethyl, pyrazolylethyl, imidazolylmethyl, imidazolylethyl, isoxazolylmethyl, isoxazolylethyl, oxazolylmethyl, oxazolylethyl, isoindoledionylmethyl, and isoindoledionylethyl, or where R9 and R10 together with the atoms to which they are attached form pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isoindoledionyl, isoindolyl, dihydroindolyl, isoindolinyl, dihydrothiophenyl, dihydropyrrolyl, dihydrofuryl, dihydropyrazolyl, dihydroimidazolyl, dihydroisoxazolyl, dihydrooxazolyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, or oxazolidinyl; wherein R9 is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-methylamino, N-ethylamino, N-propylamino, N,N-dimethylamino, N-methyl-N- ethylamino, N-methyl-N-propylamino, N,N-diethylamino, N-ethyl-N-propylamino, N,N-dipropylamino, N- phenylamino, N-biphenylamino, N-naphthylamino, N-methyl-N-phenylamino, N-ethyl-N-phenylamino, N- propyl-N-phenylamino, N-hydroxyamino, N-methyl-N-hydroxyamino, N-ethyl-N-hydroxyamino, N-propyl-N- hydroxyamino, N-phenyl-N-hydroxyamino, N-biphenyl-N-hydroxyamino, N-naphthyl-N-hydroxyamino, chloro, fluoro, bromo, iodo, cyano, keto, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, butoxy, ethenyl, propenyl, butenyl, pentenyl ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, phenyl, biphenyl, naphthyl, indenyl, phenoxy, biphenoxy, naphthyloxy, indenyloxy, benzyl, phenylethyl, benzylcarbonyl, phenylethylcarbonyl, benzylcarbonylamino, phenylethylcarbonylamino, pyridinylcarbonyl, benzothiophenylcarbonyl, indolylcarbonyl, isoquinolinylcarbonyl, quinolinylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl, furylcarbonyl, pyrazolylcarbonyl, imidazolylcarbonyl, isoxazolylcarbonyl, oxazolylcarbonyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isoindoledionyl, isoindolyl, dihydroindolyl, isoindolinyl, dihydrothiophenyl, dihydropyrrolyl, dihydrofuryl, dihydropyrazolyl, dihydroimidazolyl, dihydroisoxazolyl, dihydrooxazolyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, phenoxycarbonyl, biphenoxycarbonyl, naphthyloxycarbonyl, indenyloxycarbonyl, carboxyl, methoxymethoxycarbonyl, methoxyethoxycarbonyl, ethoxymethoxycarbonyl, ethoxyethoxycarbonyl, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, piperidinylmethyl, piperidinylethyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrazolidinylmethyl, pyrazolidinylethyl, imidazolidinylmethyl, imidazolidinylethyl, isoxazolidinylmethyl, isoxazolidinylethyl, oxazolidinylmethyl, oxazolidinylethyl, thiol, oxidosulfanyl, sulfino, methylthio, ethylthio, propylthio, butylthio, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, phenylthio, biphenylthio, naphthylthio, phenylsulfinyl, biphenylsulfinyl, naphthylsulfinyl, phenylsulfonyl, biphenylsulfonyl, naphthylsulfonyl, piperidinylthio, pyrrolidinylthio, pyrazolidinylthio, imidazolidinylthio, isoxazolidinylthio, oxazolidinylthio, piperidinylsulfinyl, pyrrolidinylsulfinyl, pyrazolidinylsulfinyl, imidazolidinylsulfinyl, isoxazolidinylsulfinyl, oxazolidinylsulfinyl, piperidinylsulfonyl, pyrrolidinylsulfonyl, pyrazolidinylsulfonyl, imidazolidinylsulfonyl, isoxazolidinylsulfonyl, oxazolidinylsulfonyl, pyridinylthio, benzothiophenylthio, indolylthio, isoquinolinylthio, quinolinylthio, thienylthio, pyrrolylthio, furylthio, pyrazolylthio, imidazolylthio, isoxazolylthio, oxazolylthio, isoindoledionylthio, pyridinylsulfinyl, benzothiophenylsulfinyl, indolylsulfinyl, isoquinolinylsulfinyl, quinolinylsulfinyl, thienylsulfinyl, pyrrolylsulfinyl, furylsulfinyl, pyrazolylsulfinyl, imidazolylsulfinyl, isoxazolylsulfinyl, oxazolylsulfinyl, isoindoledionylsulfinyl, pyridinylsulfonyl, benzothiophenylsulfonyl, indolylsulfonyl, isoquinolinylsulfonyl, quinolinylsulfonyl, thienylsulfonyl, pyrrolylsulfonyl, furylsulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl, isoxazolylsulfonyl, oxazolylsulfonyl, and isoindoledionylsulfonyl; wherein R10 is selected from the group consisting of hydrido, hydroxyl, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, phenyl, biphenyl, naphthyl, indenyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isoindoledionyl, or R10 and R9 together with the atoms to which they are attached form a cyclic moiety selected from the group consisting of piperidinonyl, dihydropyridinonyl, pyridinonyl, dihydroindolonyl, octahydroindolonyl, dihydroisoindolonyl, octahydroisoindolonyl, isoquinolinonyl, dihydroisoquinolinonyl, quinolinonyl, dihydroquinolinonyl, pyrrolidinonyl, and pyrazolidinonyl; wherein R11 and R12 are independently selected from the group consisting of hydrido, hydroxyl, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, phenyl, biphenyl, naphthyl, indenyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and isoindoledionyl.
4. A compound of Formula IIC or Formula IID:
Figure imgf000154_0001
wherein Z is selected from the group consisting of hydrido, halo, alkyl, cyano, and haloalkyl; wherein R9 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, or where R9 and R9a together with the nitrogen to which they are attached form a heterocyclic moiety; wherein R9 is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-alkylamino, N,N-dialkylamino, N-arylamino, N-alkyl-N-arylamino, N- hydroxyamino, N-alkyl-N-hydroxyamino, N-aryl-N-hydroxyamino, halo, cyano, keto, hydroxyl, alkyl, haloalkyl, cycloalkyl, alkoxy, alkenyl, alkenyloxy, aryl, aryloxy, aralkyl, aralkylcarbonyl, aralkylcarbonylamino, heteroarylcarbonyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, alkoxycarbonyl, aryloxycarbonyl, carboxyl, alkoxyalkoxycarbonyl, alkoxycarbonylamino, heterocycloalkyl, heterocycloalkylalkyl, thiol, oxidosulfanyl, sulfino, alkylthio, alkylsulfinyl, alkylsulfonyl, cycloalkylthio, cycloalkylsulfinyl, cycloalkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, heterocycloalkylthio, heterocycloalkylsulfinyl, heterocycloalkylsulfonyl, heteroarylthio, heteroarylsulfinyl, and heteroarylsulfonyl; wherein R9a is selected from the group consisting of hydrido, hydroxyl, alkoxy, alkyl, haloalkyl, aryl, and heteroaryl, or where R9a and R9 together with the nitrogen to which they are attached form a heterocyclic moiety; wherein R11 and R12 are independently selected from the group consisting of hydrido, hydroxyl, alkoxy, alkyl, haloalkyl, aryl, and heteroaryl; or a pharmaceutically acceptable salt thereof.
5. A compound according to claim 4 wherein Z is selected from the group consisting of hydrido, halo, c1-6 alkyl, cyano, and c^e haloalkyl; wherein R9 is selected from the group consisting of c1-s alkyl, c3- 2 cycloalkyl, c2-6 alkenyl, c3-12 cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, c3_12 aryl, c4.18 aralkyl, 3- to 12-membered heteroaryl, and 4- to 18-membered heteroaralkyl, or where R9 and R9a together with the nitrogen to which they are attached form a 3- to 12-membered heterocyclic moiety; wherein R9 is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-(C1.6 alkyl)amino, N,N-di(C .6 alkyl)amino, N-(C3_ι2 aryl)amino, N-(cι.6 alkyl)- N-(C3-12 aryl)amino, N-hydroxyamino, N-(c-ι-6 alkyl)-N-hydroxyamino, N-(c3. 2 aryl)-N-hydroxyamiπo, halo, cyano, keto, hydroxyl, Ct.6 alkyl, C1-6 haloalkyl, C3.6 cycloalkyl, C-t.6 alkoxy, c2_3 alkenyl, c2.6 alkenyloxy, c3-ι2 aryl, c3.12 aryloxy, c4.20 aralkyl, c -20 aralkylcarbonyl, c4-2o aralkylcarbonylamino, 3- to 14-membered heteroarylcarbonyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 3- to 12- membered heteroaryl, c2-7 alkoxycarbonyl, c3.12 aryloxycarbonyl, carboxyl, c2-i5 alkoxyalkoxycarbonyl, c2-7 alkoxycarbonylamino, 3- to 12-membered heterocycloalkyl, 4- to 18-membered heterocycloalkylalkyl, thiol, oxidosulfanyl, sulfino, C1-6 alkylthio, C|.6 alkylsulfinyl, .S alkylsulfonyl, c3.12 cycloalkylthio, c3-12 cycloalkylsulfinyl, c3.-ι2 cycloalkylsulfonyl, c3-12 arylthio, c3-ι2 arylsulfinyl, c3.12 arylsulfonyl, 3- to 12- membered heterocycloalkylthio, 3- to 12-membered heterocycloalkylsulfinyl, 3- to 12-membered heterocycloalkylsulfonyl, 3- to 12-membered heteroarylthio, 3- to 12-membered heteroarylsulfinyl, and 3- to 12-membered heteroarylsulfonyl; wherein R9a is selected from the group consisting of hydrido, hydroxyl, c-|.6 alkoxy, c1-6 alkyl, cι-β haloalkyl, c3-12 aryl, and 3- to 12-membered heteroaryl, or where R9a and R9 together with the nitrogen to which they are attached form a 3- to 12-membered heterocyclic moiety; wherein R11 and R12 are independently selected from the group consisting of hydrido, hydroxyl, c -β alkoxy, Cι-S alkyl, c1-6 haloalkyl, c3-ι2 aryl, and 3- to 12-membered heteroaryl. 6. A compound according to claim 5 wherein Z is selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyano, and haloalkyl; wherein R9 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, propenyl, butenyl, pentenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, isoindolyl, dihydroindolyl, isoindolinyl, dihydrothiophenyl, dihydropyrrolyl, dihydrofuryl, dihydropyrazolyl, dihydroimidazolyl, dihydroisoxazolyl, dihydrooxazolyl, phenyl, biphenyl, naphthyl, indenyl, benzyl, phenylethyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isoindoledionyl, pyridinylmethyl, pyridinylethyl, benzothiophenylmethyl, benzothiophenylethyl, indolylmethyl, indolylethyl, isoquinolinylmethyl, isoquinolinylethyl, quinolinylmethyl, quinolinylethyl, thienylmethyl, thienylethyl, pyrrolylmethyl, pyrrolyiethyl, furylmethyl, furylethyl, pyrazolylmethyl, pyrazolylethyl, imidazolylmethyl, imidazolylethyl, isoxazolylmethyl, isoxazolylethyl, oxazolylmethyl, oxazolylethyl, isoindoledionylmethyl, and isoindoledionylethyl, or where R9 and R9a together with the atoms to which they are attached form a cyclic moiety selected from the group consisting of piperidiπonyl, dihydropyridinonyl, pyridinonyl, dihydroindolonyl, octahydroindolonyl, dihydroisoindolonyl, octahydroisoindolonyl, isoquinolinonyl, dihydroisoquinolinonyl, quinolinonyl, dihydroquinolinonyl, pyrrolidinonyl, and pyrazolidinonyl; wherein R9 is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-methylamino, N-ethylamino, N-propylamino, N,N-dimethylamino, N-methyl-N- ethylamino, N-methyl-N-propylamino, N,N-diethylamino, N-ethyl-N-propylamino, N,N-dipropylamino, N- phenylamino, N-biphenylamino, N-naphthylamino, N-methyl-N-phenylamino, N-ethyl-N-phenylamino, N- propyl-N-phenylamino, N-hydroxyamino, N-methyl-N-hydroxyamino, N-ethyl-N-hydroxyamino, N-propyl-N- hydroxyamino, N-phenyl-N-hydroxyamino, N-biphenyl-N-hydroxyamino, N-naphthyl-N-hydroxyamino, chloro, fluoro, bromo, iodo, cyano, keto, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, butoxy, ethenyl, propenyl, butenyl, pentenyl ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, phenyl, biphenyl, naphthyl, indenyl, phenoxy, biphenoxy, naphthyloxy, indenyloxy, benzyl, phenylethyl, benzylcarbonyl, phenylethylcarbonyl, benzylcarbonylamino, phenylethylcarbonylamino, pyridinylcarbonyl, benzothiophenylcarbonyl, indolylcarbonyl, isoquinolinylcarbonyl, quinolinylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl, furylcarbonyl, pyrazolylcarbonyl, imidazolylcarbonyl, isoxazolylcarbonyl, oxazolylcarbonyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isoindoledionyl, isoindolyl, dihydroindolyl, isoindolinyl, dihydrothiophenyl, dihydropyrrolyl, dihydrofuryl, dihydropyrazolyl, dihydroimidazolyl, dihydroisoxazolyl, dihydrooxazolyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, phenoxycarbonyl, biphenoxycarbonyl, naphthyloxycarbonyl, indenyloxycarbonyl, carboxyl, methoxymethoxycarbonyl, methoxyethoxycarbonyl, ethoxymethoxycarbonyl, ethoxyethoxycarbonyl, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, piperidinylmethyl, piperidinylethyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrazolidinylmethyl, pyrazolidinylethyl, imidazolidinylmethyl, imidazolidinylethyl, isoxazolidinylmethyl, isoxazolidinylethyl, oxazolidinylmethyl, oxazolidinylethyl, thiol, oxidosulfanyl, sulfino, methylthio, ethylthio, propylthio, butylthio, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, cycldpropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, phenylthio, biphenylthio, naphthylthio, phenylsulfinyl, biphenylsulfinyl, naphthylsulfinyl, phenylsulfonyl, biphenylsulfonyl, naphthylsulfonyl, piperidinylthio, pyrrolidinylthio, pyrazolidinylthio, imidazolidinylthio, isoxazolidinylthio, oxazolidinylthio, piperidinylsulfinyl, pyrrolidinylsulfinyl, pyrazolidinylsulfinyl, imidazolidinylsulfinyl, isoxazolidinylsulfinyl, oxazolidinylsulfinyl, piperidinylsulfonyl, pyrrolidinylsulfonyl, pyrazolidinylsulfonyl, imidazolidinylsulfonyl, isoxazolidinylsulfonyl, oxazolidinylsulfonyl, pyridinylthio, benzothiophenylthio, indolylthio, isoquinolinylthio, quinolinylthio, thienylthio, pyrrolylthio, furylthio, pyrazolylthio, imidazolylthio, isoxazolylthio, oxazolylthio; isoindoledionylthio, pyridinylsulfinyl, benzothiophenylsulfinyl, indolylsulfinyl, isoquinolinylsulfinyl, quinolinylsulfinyl, thienylsulfinyl, pyrrolylsulfinyl, furylsulfinyl, pyrazolylsulfinyl, imidazolylsulfinyl, isoxazolylsulfinyl, oxazolylsulfinyl, isoindoledionylsulfinyl, pyridinylsulfonyl, benzothiophenylsulfonyl, indolylsulfonyl, isoquinolinylsulfonyl, quinolinylsulfonyl, thienylsulfonyl, pyrrolylsulfonyl, furylsulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl, isoxazolylsulfonyl, oxazolylsulfonyl, and isoindoledionylsulfonyl; wherein R9a is selected from the group consisting of hydrido, hydroxyl, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, phenyl, biphenyl, naphthyl, indenyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and isoindoledionyl, or where R9a and R9 together with the nitrogen to which they are attached form pyridine, piperidine, indole, indoline, isoindole, isoindolinyl, isoquinoline, quinoline, pyrrole, pyrrolidine, pyrazole, pyrazolidine, imidazole, imidazolidine, isoxazole, isoxazolidine, oxazole, or oxazolidine; wherein R11 and R12 are independently selected from the group consisting of hydrido, hydroxyl, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, phenyl, biphenyl, naphthyl, indenyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and isoindoledionyl.
A compound of Formula HE or IIF:
Figure imgf000156_0001
wherein Z is selected from the group consisting of hydrido, halo, alkyl, cyano, and haloalkyl; wherein R1 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; wherein R1 is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-alkylamino, N,N-dialkylamino, N-arylamino, N-alkyl-N-arylamino, N- hydroxyamino, N-alkyl-N-hydroxyamino, N-aryl-N-hydroxyamino, halo, cyano, keto, hydroxyl, alkyl, haloalkyl, cycloalkyl, alkoxy, alkenyl, alkenyloxy, aryl, aryloxy, aralkyl, aralkylcarbonyl, aralkylcarbonylamino, heteroarylcarbonyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, alkoxycarbonyl, aryloxycarbonyl, carboxyl, alkoxyalkoxycarbonyl, alkoxycarbonylamino, heterocycloalkyl, heterocycloalkylalkyl, thiol, oxidosulfanyl, sulfino, alkylthio, alkylsulfinyl, alkylsulfonyl, cycloalkylthio, cycloalkylsulfinyl, cycloalkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, heterocycloalkylthio, heterocycloalkylsulfinyl, heterocycloalkylsulfonyl, heteroarylthio, heteroarylsulfinyl, and heteroarylsulfonyl; wherein R11 and R12 are independently selected from the group consisting of hydrido, hydroxyl, alkoxy, alkyl, haloalkyl, aryl, and heteroaryl; or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 7 wherein Z is selected from the group consisting of hydrido, halo, c^ alkyl, cyano, and c1-8 haloalkyl; wherein R1 is selected from the group consisting of c1-6 alkyl, c3- 2 cycloalkyl, c2-6 alkenyl, C3_12 cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, c3.12 aryl, c4.ι8 aralkyl, 3- to 12-membered heteroaryl, and 4- to 18-membered heteroaralkyl; wherein R1 is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-(C1-β alkyl)amino, N,N-di(C1.6 alkyl)amino, N-(C3_ι2 aryl)amino, N-(c1-6 alkyl)- N-(C3-12 aryl)amino, N-hydroxyamino, N- -e alkyl)-N-hydroxyamino, N-(c3-12 aryl)-N-hydroxyamino, halo, cyano, keto, hydroxyl, c^ alkyl, c^ haloalkyl, C3.6 cycloalkyl, c1-6 alkoxy, c2.8 alkenyl, c2.6 alkenyloxy, c3-12 aryl> c3-ι2 aryloxy, c4-20 aralkyl, c -20 aralkylcarbonyl, c4-20 aralkylcarbonylamino, 3- to 14-membered heteroarylcarbonyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, 3- to 12- membered heteroaryl, c2-7 alkoxycarbonyl, c3-12 aryloxycarbonyl, carboxyl, c2-15 alkoxyalkoxycarbonyl, c2-7 alkoxycarbonylamino, 3- to 12-membered heterocycloalkyl, 4- to 18-membered heterocycloalkylalkyl, thiol, oxidosulfanyl, sulfino, C1-6 alkylthio, C,.6 alkylsulfinyl, C1-B alkylsulfonyl, c3-12 cycloalkylthio, c3-12 cycloalkylsulfinyl, c3-12 cycloalkylsulfonyl, c3.12 arylthio, c3-12 arylsulfinyl, c3-12 arylsulfonyl, 3- to 12- membered heterocycloalkylthio, 3- to 12-membered heterocycloalkylsulfinyl, 3- to 12-membered heterocycloalkylsulfonyl, 3- to 12-membered heteroarylthio, 3- to 12-membered heteroarylsulfinyl, and 3- to 12-membered heteroarylsulfonyl; wherein R11 and R 2 are independently selected from the group consisting of hydrido, hydroxyl, c1-6 alkoxy, c1-6 alkyl, c1-6 haloalkyl, C3_12 aryl, and 3- to 12-membered heteroaryl.
9. A compound according to claim 8 wherein Z is selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyano, and haloalkyl; wherein R1 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, propenyl, butenyl, pentenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, isoindolyl, dihydroindolyl, isoindolinyl, dihydrothiophenyl, dihydropyrrolyl, dihydrofuryl, dihydropyrazolyl, dihydroimidazolyl, dihydroisoxazolyl, dihydrooxazolyl, phenyl, biphenyl, naphthyl, indenyl, benzyl, phenylethyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isoindoledionyl, pyridinylmethyl, pyridinylethyl, benzothiophenylmethyl, benzothiophenylethyl, indolylmethyl, indolylethyl, isoquinolinylmethyl, isoquinolinylethyl, quinolinylmethyl, quinolinylethyl, thienylmethyl, thienylethyl, pyrrolylmethyl, pyrrolyiethyl, furylmethyl, furylethyl, pyrazolylmethyl, pyrazolylethyl, imidazolylmethyl, imidazolylethyl, isoxazolylmethyl, isoxazolylethyl, oxazolylmethyl, oxazolylethyl, isoindoledionylmethyl, and isoindoledionylethyl; wherein R1 is optionally substituted by one or more substituents independently selected from the group consisting of amino, N-methylamino, N-ethylamino, N-propylamino, N,N-dimethylamino, N-methyl-N- ethylamino, N-methyl-N-propylamino, N,N-diethylamino, N-ethyl-N-propylamino, N,N-dipropylamino, N- phenylamino, N-biphenylamino, N-naphthylamino, N-methyl-N-phenylamino, N-ethyl-N-phenylamino, N- propyl-N-phenylamino, N-hydroxyamino, N-methyl-N-hydroxyamino, N-ethyl-N-hydroxyamino, N-propyl-N- hydroxyamino, N-phenyl-N-hydroxyamino, N-biphenyl-N-hydroxyamino, N-naphthyl-N-hydroxyamino, chloro, fluoro, bromo, iodo, cyano, keto, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, butoxy, ethenyl, propenyl, butenyl, pentenyl ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, phenyl, biphenyl, naphthyl, indenyl, phenoxy, biphenoxy, naphthyloxy, indenyloxy, benzyl, phenylethyl, benzylcarbonyl, phenylethylcarbonyl, benzylcarbonylamino, phenylethylcarbonylamino, pyridinylcarbonyl, benzothiophenylcarbonyl, indolylcarbonyl, isoquinolinylcarbonyl, quinolinylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl, furylcarbonyl, pyrazolylcarbonyl, imidazolylcarbonyl, isoxazolylcarbonyl, oxazolylcarbonyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isoindoledionyl, isoindolyl, dihydroindolyl, isoindolinyl, dihydrothiophenyl, dihydropyrrolyl, dihydrofuryl, dihydropyrazolyl, dihydroimidazolyl, dihydroisoxazolyl, dihydrooxazolyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, phenoxycarbonyl, biphenoxycarbonyl, naphthyloxycarbonyl, indenyloxycarbonyl, carboxyl, methoxymethoxycarbonyl, methoxyethoxycarbonyl, ethoxymethoxycarbonyl, ethoxyethoxycarbonyl, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, piperidinylmethyl, piperidinylethyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrazolidinylmethyl, pyrazolidinylethyl, imidazolidinylmethyl, imidazolidinylethyl, isoxazolidinylmethyl, isoxazolidinylethyl, oxazolidinylmethyl, oxazolidinylethyl, thiol, oxidosulfanyl, sulfino, methylthio, ethylthio, propylthio, butylthio, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, phenylthio, biphenylthio, naphthylthio, phenylsulfinyl, biphenylsulfinyl, naphthylsulfinyl, phenylsulfonyl, biphenylsulfonyl, naphthylsulfonyl, piperidinylthio, pyrrolidinylthio, pyrazolidinylthio, imidazolidinylthio, isoxazolidinylthio, oxazolidinylthio, piperidinylsulfinyl, pyrrolidinylsulfinyl, pyrazolidinylsulfinyl, imidazolidinylsulfinyl, isoxazolidinylsulfinyl, oxazolidinylsulfinyl, piperidinylsulfonyl, pyrrolidinylsulfonyl, pyrazolidinylsulfonyl, imidazolidinylsulfonyl, isoxazolidinylsulfonyl, oxazolidinylsulfonyl, pyridinylthio, benzothiophenylthio, indolylthio, isoquinolinylthio, quinolinylthio, thienylthio, pyrrolylthio, furylthio, pyrazolylthio, imidazolylthio, isoxazolylthio, oxazolylthio, isoindoledionylthio, pyridinylsulfinyl, benzothiophenylsulfinyl, indolylsulfinyl, isoquinolinylsulfinyl, quinolinylsulfinyl, thienylsulfinyl, pyrrolylsulfinyl, furylsulfinyl, pyrazolylsulfinyl, imidazolylsulfinyl, isoxazolylsulfinyl, oxazolylsulfinyl, isoindoledionylsulfinyl, pyridinylsulfonyl, benzothiophenylsulfonyl, indolylsulfonyl, isoquinolinylsulfonyl, quinolinylsulfonyl, thienylsulfonyl, pyrrolylsulfonyl, furylsulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl, isoxazolylsulfonyl, oxazolylsulfonyl, and isoindoledionylsulfonyl; wherein R11 and R12 are independently selected from the group consisting of hydrido, hydroxyl, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, phenyl, biphenyl, naphthyl, indenyl, pyridinyl, benzothiophenyl, indolyl, isoquinolinyl, quinolinyl, thienyl, pyrrolyl, furyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, and isoindoledionyl.
10. A compound of Formula III:
Figure imgf000159_0001
wherein X is a bond or alkyl; wherein Ra is selected from the group consisting of halo, cyano, alkyl, cycloalkyl, haloalkyl, alkoxy, aryl, aryloxy, aralkoxy, alkoxycarbonyl, carboxyl, heterocycloalkylalkyl, and alkylsulfonyl, or wherein Ra and R10 together with the atoms to which they are attached form a heterocyclic moiety; wherein Rb, Rc, Rd, and Re are independently selected from the group consisting of halo, cyano, alkyl, cycloalkyl, haloalkyl, alkoxy, aryl, aryloxy, aralkoxy, alkoxycarbonyl, carboxyl, heterocycloalkylalkyl, and alkylsulfonyl; wherein R10 is selected from the group consisting of hydrido and alkyl, or R10 and Ra together with the atoms to which they are attached form a heterocyclic moiety; and wherein R 1 and R12 are independently selected from the group consisting of hydrido and alkyl; wherein Ra and Rb, or Rb and Rc, or R° and Rd, or Rd and Re may form a ring moiety fused to the phenyl ring to which they are both attached, said ring moiety selected from the group consisting of cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl, and heteroaryl, wherein said ring moiety may be substituted by one or more substituents selected from the group consisting of halo, keto, alkyl, hydroxy, alkoxy, aralkyl, and aralkoxy; or a pharmaceutically acceptable salt thereof.
11. A compound of Formula IV:
Figure imgf000160_0001
wherein X is alkyl; wherein Ra, Rb, Rc, Rd, and Rβ are independently selected from the group consisting of halo, cyano, alkyl, haloalkyl, alkoxy, aryl, and aralkoxy; and wherein R11 and R12 are independently selected from the group consisting of hydrido and alkyl; wherein Ra and R , or Rb and Rc, or Rc and Rd, or Rd and Re may form an aryl moiety fused to the phenyl ring to which they are both attached, wherein said aryl moiety may be substituted by one or more substituents selected from the group consisting of halo, alkyl, and alkoxy; or a pharmaceutically acceptable salt thereof.
12. A compound of Formula V:
Figure imgf000160_0002
wherein X is a bond or alkyl; wherein R is a 5- to 12-membered heterocyclic moiety; wherein R is optionally substituted by one or more substituents independently selected from the group consisting of halo, alkyl, alkoxycarbonyl, carboxyl, and heteroarylalkyl; wherein R10, R11, and R12 are independently selected from the group consisting of hydrido and alky); or a pharmaceutically acceptable salt thereof.
13. A compound of Formula VI:
Figure imgf000160_0003
wherein X is alkyl; wherein R is selected from the group consisting of alkyl, alkenyl, C3- 2 cycloalkyl, and C3. 2 cycloalkenyl; wherein R is optionally substituted by one or more substituents independently selected from the group consisting of cyano, keto, alkyl, alkoxy, haloalkyl, alkylcarbonyl, aryl, cycloalkyl, aralkylcarbonyl, aralkylcarbonylamino, heteroarylcarbonyl, alkoxycarbonyl, carboxyl, and alkoxyalkoxycarbonyl; and wherein R11 and R12 are independently selected from the group consisting of hydrido and alkyl; or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a compound according to any one of claims 1-
13 or a pharmaceutically-acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or adjuvant.
15. A method of treating cancer, inflammation, or an inflammation-associated disorder in a subject, said method comprising administering to the subject having or susceptible to such cancer, inflammation, or an inflammation-associated disorder, a therapeutically-effective amount of a compound according to any one of claims 1-13.
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