EP2074107A2 - Tricyclic compounds as matrix metalloproteinase inhibitors - Google Patents

Tricyclic compounds as matrix metalloproteinase inhibitors

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Publication number
EP2074107A2
EP2074107A2 EP07839790A EP07839790A EP2074107A2 EP 2074107 A2 EP2074107 A2 EP 2074107A2 EP 07839790 A EP07839790 A EP 07839790A EP 07839790 A EP07839790 A EP 07839790A EP 2074107 A2 EP2074107 A2 EP 2074107A2
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Prior art keywords
group
methyl
sulfonamido
dibenzo
alkyl
Prior art date
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EP07839790A
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German (de)
French (fr)
Inventor
Wei Li
Jianchang Li
Yuchuan Wu
Steve Tam
Tarek Mansour
Joseph P. Sypek
Iain Mcfayden
Rajeev Hotchandani
Junjun Wu
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Wyeth LLC
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Wyeth LLC
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Publication of EP2074107A2 publication Critical patent/EP2074107A2/en
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/76—Dibenzothiophenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present teachings relate to tricyclic compounds and derivatives that can be used for inhibiting matrix metalloproteinases.
  • the present teachings also relate to methods for preparing the tricyclic compounds and derivatives, and methods of their use.
  • MMPs Matrix metalloproteinases
  • ECM extracellular matrix
  • MMPs tissue inhibitors of metalloproteinases
  • TMPs tissue inhibitors of metalloproteinases
  • MMPs have been a highly active set of targets for the design of therapeutic agents, specifically for the disease areas of arthritis and oncology (for ' reviews, see e.g., Woessner, J.F. (1991), FASEB J., 5: 2145-2154; and Coussens, L.M. (2002), Science, 295(5564): 2387-2392).
  • MMPs can be broadly classified into collagenases (MMP-I, MMP-8, and MMP- 13), gelatinases (MMP-2 and MMP-9), stromelysins (MMP-3, MMP-10, and MMP-11), elastases (MMP-7, and MMP- 12) and membrane-associated MMPs (MMP- 14 through MMP-25).
  • MMP-I collagenases
  • MMP-8 gelatinases
  • MMP-9 stromelysins
  • MMP-3 stromelysins
  • MMP-11 stromelysins
  • MMP-7 elastases
  • MMP- 14 through MMP-25 membrane-associated MMPs
  • the gelatinases have been shown to be the MMPs most intimately involved with the growth and spread of tumors, while the collagenases have been associated with the pathogenesis of arthritis. See e.g., Ellenrieder, V. et al. (2000), Int. J. Cancer, 85(1): 14-20; Singer
  • MMPs also have been implicated in various other diseases including restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, septic arthritis, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, colitis, glomerular disease of the kidney, premature rupture of fetal membranes, inflammatory bowel disease, periodontal disease, age-related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/
  • Macrophage metalloelastase, MMP- 12, like many MMPs is able to degrade many ECM components.
  • MMP- 12 is an important mediator of various diseases. For example, in studies conducted to investigate macrophage involvement in rheumatoid arthritis, elevated MMP- 12 expression levels were observed in synovial tissues and fluids from patients with rheumatoid arthritis relative to those with osteoarthritis. See Liu, M. et al. (2004), Arthritis & Rheumatism, 50(10): 3112- 3117. Other studies have linked MMP- 12 to promoting atherosclerotic plaque instability. See e.g., Johnson, J.L.
  • MMP- 12 expression might serve as a prognostic indicator for early tumor relapse. See Hofmann H. S. et al. (2005), Clin. Cancer Res., 11(3): 1086-1092.
  • Asthma and chronic obstructive pulmonary disease are chronic pulmonary diseases that are both characterized by the accumulation of inflammatory cells, airflow obstruction and airway remodeling.
  • MMPs have been implicated to be the major class of proteolytic enzymes that induce airway remodeling. See e.g., Suzuki, R. Y. et al. (2004), Treat. Respir. Med., 3: 17-27.
  • MMP- 12 in particular, has been demonstrated to play a significant role in airway inflammation and remodeling.
  • Recent studies have shown by immunohistochemistry, for example, that bronchoalveolar lavage (BAL) cells and bronchial lung biopsies from patients with moderate to severe COPD had greater MMP- 12 expression than controls. See Molet, S.
  • MMP inhibitors in particular, MMP- 12 inhibitors, can be therapeutically beneficial for treating a variety of pathologic conditions and/or disorders.
  • the present teachings also provide methods of preparing the compounds of formula I and methods of treating pathologic conditions or disorders mediated wholly or in part by matrix metalloproteinases, such as asthma and chronic obstructive pulmonary disease, including administering a therapeutically effective amount of a compound of formula I to a patient, for example, a patient in need thereof.
  • matrix metalloproteinases such as asthma and chronic obstructive pulmonary disease
  • R is an N-linked, free carboxyl or carboxyl-protected, natural or non-natural amino acid, or an N-linked amino acid derivative
  • R 2 and R 3 independently are a) H, b) oxo, c) -OR 8 , d) -S(O) m R 8 , e) -S(O) 1n OR 8 , f) -S(O) m NR 8 R 9 , g) -C(O)R 8 , h) -C(O)OR 8 , i) -C(O)NR 8 R 9 , j) -C(S)OR 8 , k) -C(S)R 8 , 1) -C(S)NR 8 R 9 , m) -C(NR 8 )NR 8 R 9 , n) a C 1-10 alkyl group,
  • R 4 and R 5 independently are a) H, b) -CN, c) -NO 2 , d) halogen, e) -OR 8 , f) -NR 8 R 9 , g) -S(O) 111 R 8 , h) -S(O) 111 OR 8 , i) -C(O)R 8 , j) -C(O)OR 8 , k) -C(O)NR 8 R 9 ,
  • R 6 is a) H, b) -S(O) m R 8 , c) -S(O) 1n OR 8 , d) -C(O)R 8 , e) -C(O)OR 8 , f) -C(O)NR 8 R 9 , g) -C(S)R 8 , h) -C(S)OR 8 , i) -C(S)NR 8 R 9 J) a Ci -10 alkyl group, k) a C 2-I0 alkenyl group, 1) a C 2-I0 alkynyl group, or m) a C M0 haloalkyl group, wherein each of j) - m) optionally is substituted with a C 6-I4 aryl group or a 5-13 membered heteroaryl group, wherein each of the C 6-I4 aryl group and the 5-13 membered heteroaryl group optionally is substituted with 1-4 -Z-R
  • R 7 at each occurrence, is a) H, b) -CN, c) -NO 2 , d) halogen, e) oxo, f) -OR 8 , g) -NR 8 R 9 , h) -N(O)R 8 R 9 , i) -S(O) m R 8 , j) -S(O) 01 O-R 8 , k) -S(O) 111 NR 8 R 9 , 1) -C(O)R 8 , m) -C(O)OR 8 , n) -C(O)NR 8 R 9 , o) -C(S)R 8 , p) -C(S)OR 8 , q) -C(S)NR 8 R 9 , r) -Si(C 1-10 alkyl) 3 , s) a C -10 alkyl group, t) a C 2 -io alkeny
  • R 8 and R 9 at each occurrence, independently are a) H, b) -OR 1 ', c) -SR 11 , d) -S(O) 111 R 1 1 , e) -S(O) m -OR", f) -S(0) m -NR"R 12 , g) -C(O)R 1 1 , h) -C(O)OR 1 1 , i) -C(O)NR 11 R 12 J) -C(S)NR 11 R 12 , k) a C 1-10 alkyl group, 1) a C 2-10 alkenyl group, m) a C 2- I 0 alkynyl group, n) a C 1-10 alkoxy group, o) a Ci -10 haloalkyl group, p) a C 3-I o cycloalkyl group, q) a C 6-I4 aryl group, r) a 3-14 membered
  • R 10 is a) halogen, b) -CN, c) -NO 2 , d) oxo, e) -0-Z-R", f) -NR 1 '-Z-R 12 , g) -N(O)R 1 '-Z-R 12 , h) -S(O) 111 R 1 ', i) -S(O) 111 O-Z-R 1 ', j) -S(O) 1n NR 1 '-Z-R 12 , k) -C(O)R 1 ', 1) -C(O)O-Z-R 1 ', m) -C(O)NR 1 '-Z-R 12 , n) -C(S)NR 1 '-Z-R 12 , o) -Si(C 1-I0 alkyl) 3 , p) a C MO alkyl group, q) a C 2- I
  • R 11 and R 12 at each occurrence, independently are a) H, b) -OH, c) -SH, d) -S(O) 2 OH, e) -C(O)OH, f) -C(O)NH 2 , g) -C(S)NH 2 , h) -OC 1-10 alkyl, i) -S(O) 01 -C 1-10 alkyl, j) -S(O) m -OC 1-10 alkyl, k) -C(O)-C 1-10 alkyl, 1) -C(O)-OCi-I 0 alkyl, m) -C(S)N(C 1- I 0 alkyl) 2 , n) -C(S)NH-C 1-10 alkyl, o) -C(O)NH-C 1-10 alkyl, p) -C(O)N(C 1-10 alkyl) 2 , q) a C
  • R 13 at each occurrence, is a) halogen, b) -CN, c) -NO 2 , d) oxo, e) -OH, f) -NH 2 , g) -NH(C 1-10 alkyl), h) -N(C 1-10 alkyl) 2 , i) -S(O) m H, j) -S(O) 111 -C 1-10 alkyl, k) -S(O) 2 OH, 1) -S(O) 01 -OC 1-10 alkyl, m) -S(O) 111 NH 2 , n) -S(O) 1n NH(C 1-10 alkyl), o) -S(O) 111 N(C 1-10 alkyl) 2 , p) -CHO, q) -C(O)-C 1-10 alkyl, r) -C(O)OH, s) -C(O)
  • X is O, S, S(O), S(O) 2 , or NR 6 ;
  • Y is S(O), S(O) 2 , or C(O);
  • Z at each occurrence, is a) a divalent C 1-10 alkyl group, b) a divalent C 2-10 alkenyl group, c) a divalent C 2-10 alkynyl group, d) a divalent Cj -10 haloalkyl group, or e) a covalent bond; and m, at each occurrence, is O, 1 , or 2.
  • compounds of formula I can be:
  • R i 1 1 , X, and Y are as defined herein.
  • R 4 and R 5 can be independently selected from H and a halogen.
  • R 4 can be H and R 5 can be H, Cl, or Br.
  • X can be O.
  • X can be S.
  • Y can be S(O) 2 .
  • R 1 can be W-V-NH-, wherein:
  • W is a) -C(O)R 14 , b) -S(O) m R 14 , c) -S(O) m OR 14 , d) -S(O) 01 NR 14 R 15 , e) -C(O)OR 14 , f) - C(O)NR 14 R 15 , g) -C(S)R 14 , h) -C(S)OR 14 , i) -NR 14 R 15 , j) -C(NR 14 )NR I4 R 15 , k) -P(O)(OR I4 ) 2 , or 1) -B(OR 14 ) 2 ;
  • R 14 and R 15 at each occurrence, independently are a) H, b) -OH, c) -SH, d) -S(O) 2 OH, e) -C(O)OH, f) -C(O)NH 2 , g) -C(S)NH 2 , h) -S(O) n -C 1-10 alkyl, i) -S(O) m -OC 1-10 alkyl, j) -C(O)-C 1-10 alkyl, k) -C(O)-OC 1-10 alkyl,
  • R 17 is a) halogen, b) -CN, c) -NO 2 , d) oxo, e) -OH, f) -NH 2 , g) -NH(C 1- IO alkyl), h) -N(Ci -10 alkyl) 2 , i) -S(O) 01 H, j) -S(O) 111 -C 1-10 alkyl, k) -S(O) 2 OH, 1) -S(O) 111 -OC 1- I 0 alkyl, m) -S(0) m NH 2 , n) -S(O) 01 NH(C 1 -10 alkyl), o) -S(O) 111 N(C 1- I 0 alkyl) 2 , p) -CHO, q) -C(O)-C 1-10 alkyl, r) -C(O)OH, s) -NH 2 , g
  • W can be -C(O)OR 14 and V can be -CR 14 R 16 -, where R 14 and R 16 are as defined herein.
  • R 1 can be an N- linked, free carboxyl or carboxyl-protected, natural or nonnatural D-alpha-amino acid.
  • R 1 can be an N-linked, free carboxyl or carboxyl- protected, natural or non-natural L-alpha-amino acid.
  • the amino acid derivative can be a natural amino acid derivative.
  • R 16 can be isopropyl.
  • R 1 can be a valine.
  • R 1 can be a D-valine.
  • R 2 and R can independently be H, oxo, -S(O) 111 OR 8 , -S(O) 1n NR 8 R 9 , -C(O)R 8 , -C(S)OR 8 , -C(S)R 8 , -C(S)NR 8 R 9 , -C(NR )NR R , a Ci-I 0 alkyl group, a C 2- I 0 alkenyl group, a C 2 - 10 alkynyl group, a Ci-io haloalkyl group, a C 3-I0 cycloalkyl group, a C 6-I4 aryl group, a 3-14 membered cycloheteroalkyl group, or a 5-13 membered heteroaryl group, wherein each of the Ci-io alkyl group, the C 2-I0 alkenyl group, the C 2-I0 alkynyl group, the Ci.
  • R 2 and R 3 can be independently selected from H, oxo, -C(O)R 8 , a C M O alkyl group, a C 2-I0 alkenyl group, a C 2-I o alkynyl group, and a C 3 . 10 cycloalkyl group, where each of the Ci.
  • R 10 alkyl groups, the C 2- 1 0 alkenyl group, the C 2-I0 alkynyl group, and the C 3-I0 cycloalkyl group can be optionally substituted with 1-4 -Z-R 10 groups.
  • R 2 and R 3 can be independently selected from H, oxo, -C(O)CH 3 , -C(O)CH 2 CH 3 , -C(O)CH(CH 3 ) 2 , a methyl group, and an ethyl group.
  • R 2 can be -C(O)OR 8 , where R 8 can be selected from H, -C(O)R 11 , -C(O)OR 1 1 , -C(O)NR 11 R 12 , a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, a Ci -I0 haloalkyl group, a C 3- io cycloalkyl group, a C 6-I4 aryl group, a 3-14 membered cycloheteroalkyl group, and a 5-13 membered heteroaryl group, where each of the C MO alkyl group, the C 2- io alkenyl group, the C 2- I 0 alkynyl group, the Ci -I0 haloalkyl group, the C 3-I0 cycloalkyl group, the C 6-H aryl group, the 3-14 membered cycloheteroal
  • R can be selected from H, a Ci -I0 alkyl group, a C 2-I0 alkenyl group, a C 2-I0 alkynyl group, and a C 6- I 4 aryl group, where each of the Ci -I0 alkyl group, the C 2-I0 alkenyl group, the C 2- io alkynyl group, and the C 6-H aryl group can be optionally substituted with 1-4 -Z-R 10 groups.
  • R 8 can be selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a butyl group, a hexyl group, and a butynyl group, each of which can be optionally substituted with 1-4 groups independently selected from a halogen, -S(O) 01 R 1 1 , -S(O) 111 O-Z-R 1 ', -S(O) 111 NR 1 '-Z-R 12 , -C(O)R 11 , -C(O)O-Z-R 1 1 , -C(O)NR"-Z-R 12 , a C 6-H aryl group, and a 5-13 membered heteroaryl group.
  • R 8 can be selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a butyl group, a hexyl group, a 3-butynyl group, a 4-butynyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a 2-bromoethyl group, a 2-methanesulfonylethyl group, a 3-chloropropyl group, and a benzyl group.
  • R 8 can be a phenyl group optionally substituted with 1-4 groups independently selected from a halogen and a C MO alkyl group.
  • R can be selected from a phenyl group, a tolyl group, a fluorophenyl group, and a chlorophenyl group.
  • R 2 can be -C(O)NR 8 R 9 , where R 8 and R 9 can be independently selected from H, a C MO alkyl group, a C 2-I0 alkenyl group, a C 2-I0 alkynyl group, a C 3-I0 cycloalkyl group, a C 6-I4 aryl group, a 3-14 membered cycloheteroalkyl group, and a 5-13 membered heteroaryl group, and each of the C MO alkyl group, the C 2 - 10 alkenyl group, the C 2 - 10 alkynyl group, the C 3-I0 cycloalkyl group, the C 6-I4 aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-13 membered heteroaryl group can be optionally substituted with 1-4 -Z-R 10 groups.
  • R 9 can be H or a C M O alkyl group.
  • R 9 can be H or a C M O
  • R can be selected from H, a C MO alkyl group, a C 3-I0 cycloalkyl group, a C 6-I4 aryl group, a 3-14 membered cycloheteroalkyl group, and a 5-13 membered heteroaryl group, and each of the Ci -I0 alkyl group, the C 3- io cycloalkyl group, the C 6- I 4 aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-13 membered heteroaryl group can be optionally substituted with 1-4 -Z-R 10 groups.
  • the -Z-R 10 group at each occurrence, can be halogen, -O-Z-R 1 ', -NR 1 '-Z-R 12 , a C MO alkyl group, a C MO alkoxy group, a C MO haloalkyl group, a 3-14 membered cycloheteroalkyl group, a 5-13 membered heteroaryl group, or a phenyl group, where each of the C M0 alkyl group, the C MO alkoxy group, the C M O haloalkyl group, the 3-14 membered cycloheteroalkyl group, the 5-13 membered heteroaryl group, or the phenyl group can be optionally substituted with 1-4 R 13 .
  • R 8 can be H or a Ci -6 alkyl group optionally substituted with 1-4 groups independently selected from halogen, a phenyl group, and a 5-6 membered heteroaryl group, where each of the phenyl group and the 5-6 membered heteroaryl group can be optionally substituted with 1-4 R 13 .
  • R 8 can be selected from H, a methyl group, an ethyl group, an isopropyl group, a cyclopentyl group, a benzyl group, a fluorobenzyl group, a phenethyl group, a thienylmethyl group, and a thienylethyl group.
  • R 8 can be a phenyl group or a 5-13 membered heteroaryl group, each of which can be optionally substituted with 1-4 -Z-R 10 groups.
  • R can be selected from a phenyl group, a 2,3- dihydrobenzo[b][l,4]dioxinyl group, a thienyl group, a pyridyl group, and an isoxazolyl group, and each of the phenyl group, the thienyl group, the pyridyl group, and the isoxazolyl group can be optionally substituted with 1 -3 groups independently selected from halogen, -O-Z-R 1 1 , -NR 1 '-Z-R 12 , a Ci -I0 alkyl group, and a Ci -I0 haloalkyl group.
  • R can be -S(O) 01 R . In some embodiments, R can be -S(O) 111 OR 8 . In certain embodiments, R 2 can be -S(O)R 8 or -SO 2 R 8 .
  • R 8 can be selected from H, a Ci-io alkyl group, a C 2- I 0 alkenyl group, a C 2 - 10 alkynyl group, a Ci -I0 haloalkyl group, a C 3-I0 cycloalkyl group, a C 6-I4 aryl group, a 3-14 membered cycloheteroalkyl group, and a 5-13 membered heteroaryl group, wherein each of the Ci.io alkyl group, the C 2- 10 alkenyl group, the C 2- 10 alkynyl group, the Cj.
  • R 8 can be selected from H, a Ci. 10 alkyl group, a C 6- I 4 aryl group, and a 5-13 heteroaryl group, and each of the C MO alkyl group, the C 6-H aryl group and the 5-13 heteroaryl group can be optionally substituted with 1-4 -Z-R 1 groups.
  • the -Z-R 10 group can independently be a halogen, a C MO alkyl group, a C MO haloalkyl group, or a phenyl group.
  • R 8 can be selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a butyl group, and a hexyl group, each of which can be optionally substituted with 1-4 groups independently selected from a halogen and a Ci -I0 haloalkyl group.
  • R 8 can be selected from a methyl group, an ethyl group, an isopropyl group, a 2-chloromethyl group, and a 2-trifluoromethyl group.
  • R can be selected from a phenyl group and a 5- or 6- membered heteroaryl group, each of which can be optionally substituted with 1-3 groups independently selected from a halogen and a C MO alkyl group.
  • the 5- or 6-membered heteroaryl group can be a thienyl group or an isoxazolyl group.
  • R can be selected from a phenyl group, a fluorophenyl group, a dimethylisoxazolyl group, and a dichlorothienyl group.
  • R 3 can be H, -S(O) 111 R 8 , -S(O) 111 OR 8 , -S(O) 01 NR 8 R 9 , -C(O)R 8 , -C(S)OR 8 , -C(S)R 8 , -C(S)NR 8 R 9 , -C(NR 8 )NR 8 R 9 , a C M0 alkyl group, a C 2-I0 alkenyl group, a C 2-I0 alkynyl group, a Ci -I0 haloalkyl group, a C 3-I o cycloalkyl group, a C 6-H aryl group, a 3-14 membered cycloheteroalkyl group, or a 5-13 membered heteroaryl group, where each of the Ci -I0 alkyl group, the C 2-I0 alkenyl group, the C 2-I0 alkynyl group, the C M
  • R can be H, -S(O) m R , or a Ci -I0 alkyl group (e.g., a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, and a heptyl group) optionally substituted with 1-4 -Z-R 10 groups.
  • R 3 is -S(O) 111 R 8
  • R 8 can be a phenyl group.
  • R 3 can be selected from H, a methyl group, an ethyl group, and a fluorophenylsulfonyl group.
  • R and R 3 together with their common nitrogen atom, can form a 3-14 membered cycloheteroalkyl group or a 5-13 membered heteroaryl group, where each of the 3-14 membered cycloheteroalkyl group and the 5-13 membered heteroaryl group can be optionally substituted with 1-4 -Z-R 10 groups.
  • the 3-14 membered cycloheteroalkyl group can exclude 3-14 membered cyclic urea groups, 3-14 membered cyclic carbamate groups, 3-14 membered cyclic sulfanamide groups, and a 3-14 membered cyclic sulfonamide groups.
  • R 2 and R 3 together with their common nitrogen atom, can form a 3-14 membered cycloheteroalkyl group, which can optionally include 1, 2, or 3 additional ring heteroatoms independently selected from O, S, and N and can be optionally substituted with 1-4 -Z-R 10 groups.
  • R 2 and R 3 together with their common nitrogen atom, can form a 5 or 6 membered cycloheteroalkyl group, each of which can be optionally substituted with 1-4 -Z-R 10 groups.
  • the 5 or 6 membered cycloheteroalkyl group can be selected from a pyrrolidinyl group, an oxazolinyl group, an thiazolinyl group, an isothiazolinyl group, an imidazolinyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, a thiomorpholinyl group, and a 1,3-oxazinanyl group and the -Z-R 10 group, at each occurrence, can be selected from halogen, oxo, and a Ci -6 alkyl group.
  • R 2 and R 3 together with their common nitrogen atom, can form a 5-13 membered heteroaryl group, which can optionally include 1, 2, 3, or 4 additional N atoms and can be optionally substituted with 1-4 -Z-R 10 groups.
  • the 5-13 membered heteroaryl group can be selected from a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolyl group, an indolyl group, a purinyl group, and a carbazolyl group.
  • R 2 and R 3 together with their common nitrogen atom, can form a 5- or 6-membered heteroaryl group optionally substituted with 1-4 -Z-R 10 .
  • the 5- or 6-membered heteroaryl group can be selected from a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, and a tetrazolyl group.
  • Z can be selected from a divalent Ci -4 alkyl group and a covalent bond.
  • R 10 can be selected from -CN, -O-Z-R 1 ', -NR 1 '-Z-R 12 , -C(O)O-Z-R 1 1 , -C(O)NR 1 '-Z-R 12 , -Si(C] -I0 alkyl) 3 , a Ci-io alkyl group, a Ci -I0 haloalkyl group, a C 3-I0 cycloalkyl group, a C 6-I4 aryl group, and a 5-13 membered heteroaryl group, where each of the Ci -I0 alkyl groups, the C 6-I4 heteroaryl group, the C 3-I0 cycloalkyl group, the C 6-H aryl group, and the 5-13 membered heteroaryl group can be optionally substituted with 1-4 R 13 groups
  • R 2 can be -C(O)OR 8 or -C(O)NR 8 R 9 , R 3
  • R O O and the R 8 portion of R 2 taken together with N A ° or N A N .R 9 to which they are attached, can form a 3-14 membered cyclic urea group or a 3-14 membered cyclic carbamate group, each of which can be optionally substituted with 1-4 -Z-R 10 groups.
  • the 3-14 membered cyclic urea group or the 3-14 membered cyclic carbamate group can be a 5-12 membered cyclic urea group or a 5- 12 membered cyclic carbamate group.
  • R can be H or a methyl group.
  • the 5-12 membered cyclic urea group or the 5-12 membered cyclic carbamate group can be a 5-membered cyclic urea group, a 6- membered cyclic urea group, a 5-membered cyclic carbamate group, or a 6- membered cyclic carbamate group.
  • R 2 can be -SOR 8 or -SO 2 R 8
  • R 3 and the R 8 portion of R 2 taken together with N and S, to which they are respectively attached, can form a 3-14 membered cyclic sulfinamide group or a 3-14 membered cyclic sulfonamide group, each of which can be optionally substituted with 1-4 -Z-R 10 groups.
  • the 3-14 membered cyclic sulfinamide group or the 3-14 membered cyclic sulfonamide group can be a 5-12 membered cyclic sulfinamide group or a 5-12 membered cyclic sulfonamide group.
  • the 5-12 membered cyclic sulfinamide group or the 5-12 membered cyclic sulfonamide group can be a S-oxoisothiazolidin-2-yl group, a S-oxothiazinan-2-yl group, a S, S- dioxoisothiazolidin-2-yl group, or a S,S-dioxothiazinan-2-yl group.
  • the present teachings can exclude certain compounds within the genus identified by formula I.
  • X is O
  • -Y-R is located in the 2-position
  • -NR R is in the 7-position
  • R is hydrogen
  • the present teachings can exclude compounds where R 3 is hydrogen, a Ci -5 alkyl group, or -C(O)Ci -5 alkyl group.
  • X is O
  • -Y-R 1 is located in the 2-position
  • -NR 2 R 3 is in the 7-position
  • the present teachings can exclude compounds where each of R and R is a Ci -5 alkyl group.
  • the present teachings can also exclude compounds where -Y-R 1 is located in the 3-position, X is O, -NR 2 R 3 is in the 7-position, R 2 is H, and R 3 is H, a Ci -5 alkyl group, or -C(O)Cj -5 alkyl group; and that -Y-R 1 is located in the 3-position, X is O, -NR 2 R 3 is in the 7-position, and each of R 2 and R 3 is a Ci -5 alkyl group. Further, the present teachings can also exclude the above specified compounds where -Y-R is located in the 2-position or the 3-position, and -NR 2 R 3 is in the 8-position. [0028] Compounds of the present teachings include the compounds presented in Table 1 below:
  • prodrugs of the compounds disclosed herein refers to a compound (“parent compound”) having a moiety that produces, generates, or releases a compound of the present teachings when administered to a mammalian subject.
  • Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either by routine manipulation or in vivo, from the parent compounds.
  • prodrugs include compounds as described herein that contain one or more molecular moieties appended to a hydroxyl, amino, sulfhydryl, or carboxyl group of the compounds, and that when administered to a mammalian subject, is/are cleaved in vivo to form the free hydroxyl, amino, sulfhydryl, or carboxyl group, respectively.
  • prodrugs can include acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present teachings. Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A. C. S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, the entire disclosures of which are incorporated by reference herein for all purposes.
  • Ester forms of the compounds according to the present teachings include pharmaceutically acceptable esters known in the art which can be metabolized into the free acid form, such as a free carboxylic acid form, in a mammal body.
  • suitable esters include alkyl esters (e.g., alkyl of 1 to 10 carbon atoms), cycloalkyl esters (e.g., 3-10 carbon atoms), aryl esters (e.g., of 6-14 carbon atoms, including of 6-10 carbon atoms), and heterocyclic analogues thereof (e.g., of 3-14 ring atoms, 1-3 of which can be selected from oxygen, nitrogen, and sulfur heteroatoms) and the alcoholic residue can carry further substituents.
  • alkyl esters e.g., alkyl of 1 to 10 carbon atoms
  • cycloalkyl esters e.g., 3-10 carbon atoms
  • aryl esters e.g., of 6-14 carbon atoms, including of
  • esters of the compounds disclosed herein can be Cj. io alkyl esters, such as methyl esters, ethyl esters, propyl esters, isopropyl esters, butyl esters, isobutyl esters, t-butyl esters, pentyl esters, isopentyl esters, neopentyl esters, hexyl esters, cyclopropylmethyl esters, and benzyl esters, C 3-I o cycloalkyl esters, such as cyclopropyl esters, cyclobutyl esters, cyclopentyl esters, and cyclohexyl esters, or aryl esters, such as phenyl esters, and tolyl ester.
  • alkyl esters such as methyl esters, ethyl esters, propyl esters, isopropyl esters, butyl esters, isobutyl esters, t
  • compositions of formula I which can have an acidic moiety, can be formed using organic or inorganic bases. Both mono and polyanionic salts are contemplated, depending on the number of acidic hydrogens available for deprotonation.
  • Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts; ammonia salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri- lower alkylamine (e.g., ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-, di-, or trihydroxy lower alkylamine (e.g., mono-, di- or triethanolamine).
  • metal salts such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts
  • ammonia salts and organic amine salts such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di
  • inorganic bases include NaHCO 3 , Na 2 CO 3 , KHCO 3 , K 2 CO 3 , Cs 2 CO 3 , LiOH, NaOH, KOH, NaH 2 PO 4 , Na 2 HPO 4 , and Na 3 PO 4 .
  • Internal salts also can be formed.
  • salts can be formed using organic and inorganic acids.
  • salts can be formed from the following acids: acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, dichloroacetic, ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric, oxalic, pamoic, pantothenic, phosphoric, phthalic, propionic, succinic, sulfuric, tartaric, toluenesulfonic, and as well as other known pharmaceutically acceptable acids.
  • compositions including at least one compound described herein and one or more pharmaceutically acceptable carriers, excipients, or diluents.
  • pharmaceutically acceptable carriers are well known to those skilled in the art and can be prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington: The Science and Practice of Pharmacy, 20th edition, Alfonoso R. Gennaro (ed.), Lippincott Williams & Wilkins, Baltimore, MD (2000), the entire disclosure of which is incorporated by reference herein for all purposes.
  • pharmaceutically acceptable refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient.
  • pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and are biologically acceptable. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.
  • Compounds of the present teachings can be useful for the treatment or inhibition of a pathological condition or disorder in a mammal, for example, a human.
  • the present teachings accordingly include a method of providing to a mammal a compound of the present teachings (or its pharmaceutically acceptable salt, hydrate, or ester) or a pharmaceutical composition that includes one or more compounds of the present teachings in combination or association with a pharmaceutically acceptable carrier.
  • Compounds of the present teachings can be administered alone or in combination with other therapeutically effective compounds or therapies for the treatment or inhibition of the pathological condition or disorder.
  • therapeutically effective refers to a substance or an amount that elicits a desirable biological activity or effect.
  • the present teachings further include use of the compounds disclosed herein as active therapeutic substances for the treatment or inhibition of a pathological condition or disorder, for example, a condition mediated wholly or in part by one or more MMPs or characterized by an MMP/TIMP imbalance, such as rheumatoid arthritis, osteoarthritis, atherosclerosis, heart failure, fibrosis, pulmonary emphysema, and tumor growth, invasion, and metastasis, and diseases characterized by the accumulation of inflammatory cells, such as chronic obstructive pulmonary disease and asthma. Accordingly, the present teachings further provide methods of treating these pathological conditions and disorders using the compounds described herein. As used herein, “treating” refers to partially or completely alleviating and/or ameliorating the condition. In some embodiments, the methods include identifying a mammal having a pathological condition or disorder characterized by an MMP/TIMP imbalance, such as rheumatoid arthritis, osteoarthritis, atherosclerosis, heart failure, fibros
  • the method includes administering to a mammal a pharmaceutical composition that comprises a compound disclosed herein in combination or association with a pharmaceutically acceptable carrier.
  • the present teachings further include use of the compounds disclosed herein as active therapeutic substances for the prevention of a pathological condition or disorder, for example, a condition mediated wholly or in part by one or more MMPs or characterized by an MMP/TIMP imbalance such as rheumatoid arthritis, osteoarthritis, atherosclerosis, multiple sclerosis, heart failure, spinal cord injuries, skin aging, fibrosis, lung cancer, skin cancer, chronic obstructive pulmonary diseases, asthma, obesity, and diabetes. Accordingly, the present teachings further provide methods of preventing these pathological conditions and disorders using the compounds described herein.
  • a pathological condition or disorder for example, a condition mediated wholly or in part by one or more MMPs or characterized by an MMP/TIMP imbalance such as rheumatoid arthritis, osteoarthritis, atherosclerosis, multiple sclerosis, heart failure, spinal cord injuries, skin aging, fibrosis, lung cancer, skin cancer, chronic obstructive pulmonary diseases, asthma, obesity
  • the methods include identifying a mammal that could potentially have a pathological condition or disorder characterized by an MMP/TIMP imbalance, and providing to the mammal a therapeutically effective amount of a compound as described herein.
  • the method includes administering to a mammal a pharmaceutical composition that includes a compound disclosed herein in combination or association with a pharmaceutically acceptable carrier.
  • Compounds of the present teachings can be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers.
  • Applicable solid carriers can include one or more substances which can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, tablet-disintegrating agents, or encapsulating materials.
  • the compounds can be formulated in conventional manner, for example, in a manner similar to that used for known antiinflammatory agents.
  • Oral formulations containing an active compound disclosed herein can include any conventionally used oral form, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions.
  • the carrier in powders, can be a finely divided solid, which is an admixture with a finely divided active compound.
  • an active compound in tablets, can be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets may contain up to 99% of the active compound.
  • Capsules can contain mixtures of active compound(s) with inert filler(s) and/or diluent(s) such as the pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.
  • inert filler(s) and/or diluent(s) such as the pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.
  • Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, and ion exchange resins.
  • pharmaceutically acceptable diluents including magnesium stearate,
  • Preferred surface modifying agents include nonionic and anionic surface modifying agents.
  • Representative examples of surface modifying agents include poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine.
  • Oral formulations herein can utilize standard delay or time-release formulations to alter the absorption of the active compound(s).
  • the oral formulation can also consist of administering an active compound in water or fruit juice, containing appropriate solubilizers or emulsifiers as needed.
  • Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups, and elixirs.
  • An active compound described herein can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture thereof, or pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators.
  • liquid carriers for oral and parenteral administration include water (particularly containing additives as described above, e.g., cellulose derivatives such as a sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil).
  • the carrier can be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
  • the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellants.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intraperitoneal, or subcutaneous injection. Sterile solutions can also be administered intravenously.
  • Compositions for oral administration can be in either liquid or solid form.
  • the pharmaceutical composition can be in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories.
  • the pharmaceutical composition can be sub-divided in unit dose(s) containing appropriate quantities of the active compound.
  • the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
  • the unit dosage form can be a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
  • Such unit dosage form may contain from about 1 mg/kg of active compound to about 500 mg/kg of active compound, and can be given in a single dose or in two or more doses.
  • Such doses can be administered in any manner useful in directing the active compound(s) to the recipient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally.
  • Such administrations can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts, hydrates, and esters thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).
  • an effective dosage can vary depending upon the particular compound utilized, the mode of administration, and/or severity of the condition being treated, as well as the various physical factors related to the individual being treated.
  • a compound of the present teachings can be provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications.
  • a compound of the present teachings can be provided to a patient that can suffer from a disease in an amount sufficient to prevent or at least delay the symptoms of the disease and its complications.
  • the dosage to be used in the treatment of a specific individual typically must be subjectively determined by the attending physician. The variables involved include the specific condition and its state as well as the size, age and response pattern of the patient.
  • the lung is the targeted organ
  • it may be desirable to administer a compound directly to the airways of the patient using devices such as metered dose inhalers, breath-operated inhalers, multidose dry-powder inhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosol dispensers, and aerosol nebulizers.
  • devices such as metered dose inhalers, breath-operated inhalers, multidose dry-powder inhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosol dispensers, and aerosol nebulizers.
  • the compounds of the present teachings can be formulated into a liquid composition, a solid composition, or an aerosol composition.
  • the liquid composition can include, by way of illustration, one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and can be administered by, for example, a pump or a squeeze-actuated nebulized spray dispenser.
  • the solvents can be, for example, isotonic saline or bacteriostatic water.
  • the solid composition can be, by way of illustration, a powder preparation including one or more compounds of the present teachings intermixed with lactose or other inert powders that are acceptable for intrabronchial use, and can be administered by, for example, an aerosol dispenser or a device that breaks or punctures a capsule encasing the solid composition and delivers the solid composition for inhalation.
  • the aerosol composition can include, by way of illustration, one or more compounds of the present teachings, propellants, surfactants, and co-solvents, and can be administered by, for example, a metered device.
  • the propellants can be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other propellants that are physiologically and environmentally acceptable.
  • CFC chlorofluorocarbon
  • HFA hydrofluoroalkane
  • Compounds described herein can be administered parenterally or intraperitoneal ⁇ . Solutions or suspensions of these active compounds or pharmaceutically acceptable salts thereof can be prepared in water suitably mixed with a surfactant such as hydroxyl-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils.
  • these preparations typically contain a preservative to inhibit the growth of microorganisms.
  • the pharmaceutical forms suitable for injection can include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form is sterile and its viscosity permits it to flow through a syringe.
  • the form preferably is stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Compounds described herein can be administered transdermally, i.e., administered across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administration can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal). Topical formulations that deliver active compound(s) through the epidermis can be useful for localized treatment of inflammation and arthritis.
  • Transdermal administration can be accomplished through the use of a transdermal patch containing an active compound and a carrier that can be inert to the active compound, can be non-toxic to the skin, and can allow delivery of the active compound for systemic absorption into the blood stream via the skin.
  • the carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
  • the creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in- water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active compound can also be suitable.
  • occlusive devices can be used to release the active compound into the blood stream, such as a semi-permeable membrane covering a reservoir containing the active compound with or without a carrier, or a matrix containing the active compound.
  • Other occlusive devices are known in the literature.
  • Compounds described herein can be administered rectally or vaginally in the form of a conventional suppository.
  • Suppository formulations can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin.
  • Water-soluble suppository bases such as polyethylene glycols of various molecular weights, can also be used.
  • Lipid formulations or nanocapsules can be used to introduce compounds of the present teachings into host cells either in vitro or in vivo. Lipid formulations and nanocapsules can be prepared by methods known in the art.
  • a compound can be desirable to combine a compound with other agents effective in the treatment of the target disease.
  • other active compounds i.e., other active ingredients or agents
  • active compounds of the present teachings can be administered with active compounds of the present teachings.
  • the other agents can be administered at the same time or at different times than the compounds disclosed herein.
  • compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present teachings also consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited processing steps.
  • a "compound” refers to the compound itself and its pharmaceutically acceptable salts, hydrates, and esters, unless otherwise understood from the context of the description or expressly limited to one particular form of the compound, i.e., the compound itself, or a pharmaceutically acceptable salt, hydrate, or ester thereof.
  • a "natural amino acid” refers to an amino acid normally occurring in natural proteins, e.g., L- ⁇ -amino acids.
  • natural amino acids include glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, lysine, hydroxylysine, histidine, phenylalanine, tyrosine, tryptophan, proline, and 4- hydroxyproline.
  • a non-natural amino acid refers to an amino acid that normally does not occur in proteins.
  • a non-natural amino acid can refer to an epimer of a natural L-amino acid, i.e., an amino acid having the D- configuration; a ⁇ -amino acid; an ⁇ , ⁇ -disubstituted amino acid; an ⁇ -amino acid where the amino acid side chain has been shortened by one or two methylene groups or lengthened by up to 10 carbon atoms such as an ⁇ -amino alkanoic acid with 5 and up to and including 10 carbon atoms in a linear chain; an unsubstituted or substituted aromatic amino acid such as phenylglycine or a substituted phenylalanine; a cyclic amino acid other than the natural cyclic amino acids; and boron analogues where a backbone methylene group is replaced by a boron group, e.g.,
  • non-natural amino acids include ⁇ -alanine, taurine, ⁇ -aminobutyric acid, ⁇ -aminoisobutyric acid, ⁇ - aminoisobutyric acid, homocysteine, homoserine, cysteinesulfinic acid, cysteic acid, felinine, isovalthine, 2,3-diaminosuccinic acid, ⁇ -hydroxyglutamic acid, ⁇ -aminoadipic acid, ⁇ , ⁇ -diaminopimelic acid, ⁇ , ⁇ -diaminopropionic acid, ⁇ , ⁇ - diaminobutyric acid, ornithine, citulline, homocitrulline, saccharopine, azetidine-2- carboxylic acid, 3-hydroyproline, pipecolic acid, 5-hydroxytryptophan, 3,4- dihydroxyphenylalanine, monoiodotyrosine, 3,5-diiodotyrosine, 3,5,3'- triio
  • an "amino acid derivative” refers to a natural or non- natural amino acid having its carboxylic acid group replaced by another chemical substituent or entity.
  • another chemical substituent or entity can include an acyl group, a thiol group, a sulfonic acid group, a sulfuric acid group, a sulfonate group, a sulfonamide group, an ester group, an amide group, an amine group, an amidine group, a phosphonic acid group, a phosphonate group, a boronic acid group, and a boronic ester group.
  • an "N-linked natural amino acid” refers to a natural amino acid where its basic amino group is lacking an amine hydrogen, which is replaced by a covalent bond to another chemical entity.
  • an "N- linked non-natural amino acid” refers to a non-natural amino acid where its basic amino group is lacking an amine hydrogen, which is replaced by a covalent bond to another chemical entity.
  • an "N-linked amino acid derivative” refers to an amino acid derivative where its basic amino group is lacking an amine hydrogen, which is replaced by a covalent bond to another chemical entity.
  • free carboxyl refers to a carboxylic acid group, e.g., a free carboxyl natural amino acid refers to a natural amino acid having a carboxylic acid group at a terminal position.
  • carboxyl-protected refers to carboxylic acid group that is protected or blocked to prevent unwanted side reactions from occurring with the carboxylic acid group. A carboxyl-protected molecule can be converted to a free carboxyl molecule under the appropriate conditions.
  • tricyclic core of compounds of formula I refers to:
  • halo or halogen refers to fluoro, chloro, bromo, and iodo.
  • alkyl refers to a straight-chain or branched saturated hydrocarbon group.
  • an alkyl group can have from 1 to 10 carbon atoms (e.g., from 1 to 6 carbon atoms).
  • alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), pentyl groups (e.g., n-pentyl, isopentyl, neopentyl), and the like.
  • alkyl groups can be substituted with up to four independently selected -Z-R or R 1 groups, where Z, R 1 , and R 13 are as described herein.
  • a lower alkyl group typically has up to 4 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl (e.g., n-propyl and isopropyl), and butyl groups (e.g., n-butyl, isobutyl, s-butyl, t-butyl).
  • alkenyl refers to a straight-chain or branched alkyl group having one or more carbon-carbon double bonds.
  • an alkenyl group can have from 2 to 10 carbon atoms (e.g., from 2 to 6 carbon atoms).
  • alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl groups, and the like.
  • the one or more carbon- carbon double bonds can be internal (such as in 2-butene) or terminal (such as in 1- butene).
  • alkenyl groups can be substituted with up to four independently selected -Z-R or R 1 groups, where Z, R 10 , and R 13 are as described herein.
  • alkynyl refers to a straight-chain or branched alkyl group having one or more carbon-carbon triple bonds.
  • an alkynyl group can have from 2 to 10 carbon atoms (e.g., from 2 to 6 carbon atoms).
  • alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, and the like.
  • the one or more carbon-carbon triple bonds can be internal (such as in 2- butyne) or terminal (such as in 1-butyne).
  • alkynyl groups can be substituted with up to four independently selected -Z-R 10 or R 13 groups, where Z, R 1 , and R 1 are as described herein.
  • alkoxy refers to an -O-alkyl group.
  • alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy groups, and the like.
  • alkylthio refers to an -S-alkyl group.
  • alkylthio groups include methylthio, ethylthio, propylthio (e.g., n-propylthio and isopropylthio), t-butylthio groups, and the like.
  • haloalkyl refers to an alkyl group having one or more halogen substituents.
  • haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CH 2 F, CCl 3 , CHCl 2 , CH 2 Cl, C 2 Cl 5 , and the like.
  • Perhaloalkyl groups i.e., alkyl groups wherein all of the hydrogen atoms are replaced with halogen atoms (e.g., CF 3 and C 2 F 5 ), are included within the definition of "haloalkyl.”
  • cycloalkyl refers to a non-aromatic carbocyclic group including cyclized alkyl, alkenyl, and alkynyl groups.
  • a cycloalkyl group can be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, and/or spiro ring systems), wherein the carbon atoms are located inside or outside of the ring system.
  • a cycloalkyl group as a whole, can have from 3 to 14 ring atoms (e.g., from 3 to 8 carbon atoms for a monocyclic cycloalkyl group and from 7 to 14 carbon atoms for a polycyclic cycloalkyl group). Any suitable ring position of the cycloalkyl group can be covalently linked to the defined chemical structure.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaryl, adamantyl, and spiro[4.5]decanyl groups, as well as their homologs, isomers, and the like.
  • cycloalkyl groups can be substituted with up to four independently selected -Z-R 10 or R 13 groups, where Z, R 10 , and R 13 are as described herein.
  • cycloalkyl groups can include substitution of one or more oxo groups.
  • heteroatom refers to an atom of any element other than carbon or hydrogen and includes, for example, nitrogen, oxygen, sulfur, phosphorus, and selenium.
  • cycloheteroalkyl refers to a non-aromatic cycloalkyl group that contains at least one (e.g., one, two, three, four, or five) ring heteroatom selected from O, N and S, and optionally contains one or more (e.g., one, two, or three) double or triple bonds.
  • a cycloheteroalkyl group can have, for example, from 3 to 14 ring atoms and contains from 1 to 5 ring heteroatoms (e.g., from 3-6 ring atoms for a monocyclic cycloheteroalkyl group and from 7 to 14 ring atoms for a polycyclic cycloheteroalkyl group).
  • One or more N or S atoms in a cycloheteroalkyl ring may be oxidized (e.g., morpholine N-oxide, thiomorpholine S- oxide, thiomorpholine S,S-dioxide).
  • nitrogen atoms of cycloheteroalkyl groups can bear a substituent, for example, a -Z-R 10 group or an R 13 group, where Z, R 10 , and R 1 as described herein.
  • Cycloheteroalkyl groups can also contain one or more oxo groups, such as phthalimidyl, piperidonyl, oxazolidinonyl, 2,4(1 //,3H)-dioxo-pyrimidinyl, pyridin-2(lH)-onyl, and the like.
  • cycloheteroalkyl groups include, among others, morpholinyl, thiomorpholinyl, pyranyl, imidazolidinyl, imidazolinyl, oxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, and the like
  • cycloheteroalkyl groups can be optionally substituted with up to four independently selected -Z-R 10 or R 13 groups, where Z, R 10 , and R 13 are as described herein.
  • cyclic urea refers to a cycloheteroalkyl group that O
  • cyclic carbamate refers to a cycloheteroalkyl group
  • cyclic sulfinamide refers to a cycloheteroalkyl group O
  • cyclic sulfonamide refers to a cycloheteroalkyl group that includes ' as a part of the cycloheteroalkyl ring and does not contain any other ring heteroatom.
  • aryl refers to an aromatic monocyclic hydrocarbon ring system or a polycyclic ring system where at least one of the rings present in the ring system is an aromatic hydrocarbon ring and any other aromatic rings present in the ring system include only hydrocarbons.
  • a monocyclic aryl group can have from 6 to 14 carbon atoms and a polycyclic aryl group can have from 8 to 14 carbon atoms. Any suitable ring position of the aryl group can be covalently linked to the defined chemical structure.
  • an aryl group can have only aromatic carbocyclic rings e.g., phenyl, 1-naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl groups, and the like.
  • an aryl group can be a polycyclic ring system in which at least one aromatic carbocyclic ring is fused (i.e., having a bond in common with) to one or more cycloalkyl or cycloheteroalkyl rings.
  • aryl groups include, among others, benzo derivatives of cyclopentane (i.e., an indanyl group, which is a 5,6-bicyclic cycloalkyl/aromatic ring system), cyclohexane (i.e., a tetrahydronaphthyl group, which is a 6,6-bicyclic cycloalkyl/aromatic ring system), imidazoline (i.e., a benzimidazolinyl group, which is a 5,6-bicyclic cycloheteroalkyl/aromatic ring system), and pyran (i.e., a chromenyl group, which is a 6,6-bicyclic cycloheteroalkyl/aromatic ring system).
  • cyclopentane i.e., an indanyl group, which is a 5,6-bicyclic cycloalkyl/aromatic ring system
  • aryl groups include benzodioxanyl, benzodioxolyl, chromanyl, indolinyl groups, and the like.
  • aryl groups optionally contain up to four independently selected -Z-R 10 or R 13 groups, where Z, R 10 , and R 13 are as described herein.
  • heteroaryl refers to an aromatic monocyclic ring system containing at least 1 ring heteroatom selected from oxygen (O), nitrogen (N) and sulfur (S) or a polycyclic ring system where at least one of the rings present in the ring system is aromatic and contains at least 1 ring heteroatom.
  • a heteroaryl group as a whole, can have, for example, from 5 to 13 ring atoms and contain 1-5 ring heteroatoms.
  • Heteroaryl groups include monocyclic heteroaryl rings fused to one or more aromatic carbocyclic rings, non-aromatic carbocyclic rings, and non- aromatic cycloheteroalkyl rings.
  • heteroaryl group can be attached to the defined chemical structure at any heteroatom or carbon atom that results in a stable structure.
  • heteroaryl rings do not contain 0-0, S-S, or S-O bonds.
  • one or more N or S atoms in a heteroaryl group can be oxidized (e.g., pyridine N-oxide, thiophene S-oxide, thiophene S,S-dioxide).
  • heteroaryl groups include, for example, the 5-membered monocyclic and 5-6 bicyclic ring systems shown below:
  • T is O, S, NH, N-Z-R 2 , or N-Z-R 8 , wherein Z, R 2 , and R 8 are as defined herein.
  • heteroaryl rings include pyrrolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, isothiazolyl, thiazolyl, thiadiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuryl, benzothienyl, quinolyl, 2-methylquinolyl, isoquinolyl, quinoxalyl, quinazolyl, benzotriazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benziso
  • heteroaryl groups include 4,5,6,7-tetrahydroindolyl, tetrahydroquinolinyl, benzothienopyridinyl, benzofuropyridinyl groups, and the like.
  • heteroaryl groups can be substituted with up to four substituents independently selected from -Z-R 10 group and -R 13 group, wherein Z, R 10 , and R 13 are as described herein.
  • the compounds of the present teachings can include a "divalent group" defined herein as a linking group capable of forming a covalent bond with two other moieties.
  • compounds described herein can include a divalent C 1-I o alkyl group, such as, for example, a methylene group.
  • substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges.
  • Ci -I0 alkyl is specifically intended to individually disclose C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 1 -C 10 , C 1 -C 9 , Ci-C 8 , C 1 -C 7 , Ci-C 6 , C J -C 5 , Ci-C 4 , Ci-C 3 , Ci-C 2 , C 2 -Ci 0 , C 2 -C 9 , C 2 -C 8 , C 2 -C 7 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 10 , C 3 -C 9 , C 3 -C 8 , C 3 -C 7 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 10 , C 3 -C 7
  • the term "5-13 membered heteroaryl group” is specifically intended to individually disclose a heteroaryl group having 5, 6, 7, 8, 9, 10, 11, 12, 13, 5-13, 5-12, 5-11, 5-10, 5-9, 5-8, 5-7, 5-6, 6-13, 6-12, 6-1 1, 6-10, 6-9, 6-8, 6-7, 7- 13, 7-12, 7-11, 7-10, 7-9, 7-8, 8-13, 8-12, 8-11, 8-10, 8-9, 9-13, 9-12, 9-11, 9-10, 10- 13, 10-12, 10-11, 11-13, 11-12, or 12-13 ring atoms; and the phrase "optionally substituted with 1-4 substituents" is specifically intended to individually disclose a chemical group that can include 0, 1, 2, 3, 4, 0-4, 0-3, 0-2, 0-1, 1-4, 1-3, 1-2, 2-4, 2- 3, and 3-4 substituents.
  • Compounds described herein can contain an asymmetric atom (also referred as a chiral center), and some of the compounds can contain one or more asymmetric atoms or centers, which can thus give rise to optical isomers
  • optical isomers can be obtained in enantiomerically enriched or pure form by standard procedures known to those skilled in the art, which include, for example, chiral separation, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis.
  • the present teachings also encompass methods for preparing cis and trans isomers of compounds containing alkenyl moieties (e.g., alkenes and imines). It is also understood that the present teachings encompass all methods for making possible regioisomers in pure form and mixtures thereof, which can include standard separation procedures known to those skilled in the art, for examples, column chromatography, thin-layer chromatography, simulated moving-bed chromatography, and high-performance liquid chromatography.
  • the compounds of the present teachings can be prepared in accordance with the procedures outlined in the scheme below, from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of the compounds described herein.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or C), infrared spectroscopy, spectrophotometry (e.g., UV -visible), or mass spectrometry, or by chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography.
  • HPLC high performance liquid chromatograpy
  • Preparation of compounds can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 4th Ed., Wiley & Sons, 2006, the entire disclosure of which is incorporated by reference herein for all purposes.
  • the reactions of the processes described herein can be carried out in suitable solvents which can be readily selected by one skilled in the art of organic synthesis.
  • Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i.e., temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected.
  • a compound of formula I can be prepared from a sulfonyl chloride intermediate i.
  • a compound of formula i can react with an amino acid or a derivative thereof to provide a compound of formula ii.
  • the -NO 2 group can be converted into an amino group, through which R 2 and R 3 can be incorporated to provide a compound of formula iv.
  • Scheme 2 depicts an exemplary synthetic route for the preparation of the sulfonyl chloride intermediate i.
  • a compound having a tricyclic core optionally substituted with R 4 and R 5 i.e., a compound of formula v
  • a compound of formula vi can be nitrated to provide a compound of formula vi, which can be sulfonated directly to provide a compound of formula i or indirectly to provide a compound of formula ix.
  • the compound of formula ix can be further nitrated to provide the compound of formula i.
  • the compound of formula v can be converted into the compound of formula i by a chlorosulfonation followed by a nitration.
  • Step 4 Preparation of (R ⁇ ert-butyl 3-methyl-2-(7-nitrodibenzo[b,dlfuran-2- sulfonamido ' jbutanoate
  • Step 6 Preparation of (RVtert-butyl 2-(7-methoxycarbonylamino-dibenzofuran-2- sulfonylamino)-3 -methyl-butyric acid
  • Step 7 Preparation of (R>2-(7-methoxycarbonylamino-dibenzofuran-2- sulfonylamino)-3-methyl-butyric acid
  • the sodium salt was prepared by treatment of (S)-2-(7- methoxycarbonylamino-dibenzofuran-2-sulfonylamino)-3 -methyl-butyric acid with 1.0 equivalent of sodium hydroxide (NaOH). The salt was obtained as a white solid.
  • Example 2 Preparation of (R)-3-methyl-2-(7-(propoxycarbonylamino)dibenzo [b,d]furan-2-sulfonamido)butanoic acid
  • Step 2 Preparation of (R * )-2-(7-(3-ethylureido)dibenzo[b,d1 furan-2-sulfonamido)-3- methylbutanoic acid
  • the sodium salt was prepared by treatment of (R)-2-(7-(3- ethylureido)dibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoic acid with 1.0 equivalent of NaOH. The salt was obtained as a white solid.
  • Step 1 Preparation of (Ry3-methyl-2-(7-(methylsulfonamido)dibenzo[b,d]furan-2- sulfonamido'lbutanoic acid tert-butyl ester
  • the sodium salt was prepared by treatment of (R)-3-methyl-2-(7- (methylsulfonamido)dibenzo[b,d]furan-2-sulfonamido)butanoic acid with 1.0 equivalent of NaOH. The salt was obtained as a white solid.
  • Step 5 Preparation of (S)-tert-butyl 2-(8-aminodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate [0134] (S)-Tert-butyl 3-methyl-2-(8-nitrodibenzo[b,d]furan-3-sulfonamido) butanoate (6.12 g) and 0.6 g of 10% Pd/C (50% water) in MeOH (150 mL) was placed in a Parr shaker under hydrogen atmosphere (50 psi) for 6 hours. The suspension was filtered through Celite ® .
  • Step 6 Preparation of (S)-2-(8-(isobutoxycarbonylaniino)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoic acid tert-butyl ester
  • Example 34 Preparation of (S)-2-(8-((but-2- ynyloxy)carbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid [0143] Following procedures analogous to those described in Example 28 and using but-2-ynyl chloroformate, (S)-2-(8-((but-2-ynyloxy) carbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid was prepared as a white solid in 100% yield. HRMS: calculated for [C 22 H 22 N 2 O 7 S + H] + 459.12205; found (ESI-FTMS, [M+H] 1+ ) 459.1216.
  • Step 1 Preparation of dibenzo[b,d]thiophene-3-sulfonyl chloride
  • Step 2 Preparation of 8-nitrodibenzo[b,d]thiophene-3-sulfonyl chloride
  • Dibenzo[b,d]thiophene-3-sulfonyl chloride (2.0 g, 7.1 mmol) was mixed with trifluoroacetic acid and the mixture was stirred at room temperature.
  • Nitric acid (>90%, Fuming, 0.29 mL) was added drop-wise. The mixture was stirred at room temperature for 3 hours and was filtered. The solid was washed with TFA and dried in the air.
  • 8-Nitrodibenzo[b,d]thiophene-3 -sulfonyl chloride was obtained (1.1 g) as an off-white solid.
  • Step 3 Preparation of (S)-tert-butyl 3-methyl-2-(8-nitrodibenzo[b,d]thiophene-3- sulfonamido)butanoate
  • Step 4 Preparation of (S)-tert-butyl 2-(8-aminodibenzo[b,d1thiophene-3- sulfonamidoV3-methylbutanoate
  • the sodium salt was prepared by treatment of (S)-2-[8- (methoxycarbonylamino) dibenzo[b,d] thiophene-3-sulfonamido]-3-methylbutanoic acid with 1.0 equivalent of NaOH. The salt was obtained as a white solid.
  • the sodium salt was prepared by treatment of (R)-2-(7- aminodibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoic acid with 1.0 equivalent of NaOH. The salt was obtained as a white solid.
  • Step 1 Preparation of 7-nitro-5-(trifluoromethyl)-5H-dibenzo[b,dlthiophenium-3- sulfonate
  • Step 4 Preparation of (SVtert-butyl 2-(7-aminodibenzo[b,dlthiophene-3- sulfonamido)-3-methylbutanoate
  • the sodium salt was prepared by treatment of (S)-2-[7-(3-cyclopentyl- ureido)-dibenzothiophene-3-sulfonylamino] -3 -methyl-butyric acid with 1.0 equivalent of NaOH. The salt was obtained as a white solid.
  • Step 1 Preparation of (RV2-(7-azido-dibenzofuran-2-sulfonylamino)-3-methyl- butyric acid methyl ester
  • (R)-2-(7-amino-dibenzofuran-2-sulfonylamino)-3-methyl- butyric acid methyl ester (1.83 g, 5 mmol) in 18% HCl (30 mL) was cooled with an ice-water batch and an aqueous NaNO 2 solution (1.0 M, 7.5 mL) was added.
  • Step 2 Preparation of (R)-2- ⁇ 7-[4-(2-hvdroxy-ethyl)-[l,2Jltriazol-l-vn- dibenzofuran-2-sulfonylamino ⁇ -3-methyl-butyric acid methyl ester
  • Step 3 Preparation of (RV2-(7-r4-(2-hvdroxy-ethylV ⁇ .2.31triazol-l-yll- dibenzofuran-2-sulfonylamino ⁇ -3-methyl-butyric acid
  • Step 1 Preparation of (S Vtert-butyl 2-(8-((2- bromoethoxy)carbonylamino)dibenzo[b,dlfuran-3-sulfonamido)-3-methylbutanoate
  • Step 2 Preparation of (S Wer/-butyl 3-methyl-2-(8-(2-oxooxazolidin-3- yl)dibenzo[b,d]furan-3-sulfonamido)butanoate
  • Step 1 Preparation of (SVtert-butyl 2-(8-(diethylamino)dibenzo[b,d1furan-3- sulfonamido)3-methylbutanoate and (S)-tert-butyl 2-(8- (ethylamino)dibenzo [b,d] furan-3 -sulfonamido)3 -methylbutanoate [0225] (S)-Tert-butyl 3-methyl-2-(8-nitrodibenzo[b,d]furan-3- sulfonamido)butanoate (560 mg) and 200 mg of Pd/C (10%) were mixed with 150 mL of MeOH and 2 mL Of CH 3 CN.
  • reaction was carried out in a Pan- shaker at room temperature under hydrogen (50 psi) overnight.
  • the reaction mixture was filtered through Celite ® . Separation of the reaction mixture gave 292 mg of (S)-tert-butyl 2-(8-(diethylamino)dibenzo[b,d]furan-3-sulfonamido)3- methylbutanoate and 235 mg of (S)-tert-butyl 2-(8-(ethylamino)dibenzo[b,d]furan-3- sulfonamido)3 -methylbutanoate, both as yellow solids.
  • Step 2 Preparation of (SV2-(8-(diethylamino)dibenzo[b,d]furan-3-sulfonamido)3- methylbutanoic acid [0226]
  • the sulfonamide t-butyl ester of the diethylated compound (126 mg) from Step 1 was mixed in 2 mL of TFA/CH2CI2 (1 :1) and stirred at room temperature for 4 hours. The solvents were removed under reduced pressure and the residue was triturated with CH 3 CN/H 2 O followed by a freeze-dry process.
  • Step 1 Preparation of f SVtert-butyl 2-(8- (ethyl(methoxycarbonyl ' )amino ' )dibenzo[b,d1furan-3-sulfonamido ' )3-methylbutanoate
  • Step 2 Preparation of (S)-2-(8-(ethyl(methoxycarbonyl)amino)dibenzo[b,d]furan-3- sulfonamido * )3-methylbutanoic acid
  • Step 2 Preparation of (S)-tert-butyl 2-( * 8-bromodibenzo[b,d]furan-3-surfonamido)-3- methylbutanoate
  • 8-Bromodibenzo[b,d]furan-3-sulfonyl chloride (3.46 g, 10 mmol)
  • (S)- tert-butyl 2-amino-3-methylbutanoate hydrochloride (2.3 g, 1.1 eq.) were mixed with 30 mL Of CH 2 Cl 2 , to which N,N-diisopropylethylamine (3.84 mL, 2.2 eq.) was added.
  • Step 3 Preparation of (S)-tert-butyl 3-methyl-2-(8-morpholinodibenzo[b,d]furan-3- sulfonamido ⁇ butanoate
  • Step 4 Preparation of (S)-2-(8-(6-methoxypyridin-3-yl)dibenzo[b,d1furan-3- sulfonamido)-3-methylbutanoic acid [0233] (S)-Tert-butyl 2-(8-(6-methoxypyridin-3-yl)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoate (16 mg) was dissolved in 2 mL of TF A/C H 2 Cl 2 (1 :1).
  • Step 1 Preparation of (SWert-butyl 3-methyl-2-(8-(3-(trifluoromethvO-lH-pyrazol- l-yDdibenzo[b,d1furan-3-ylsulfonamido)butanoate
  • Step 2 Preparation of fSV3-methyl-2-(8-(3-(trifluoromethvO-lH-pyrazol-l- vDdibenzo [b.d] furan-3 -sulfonamido)butanoic acid
  • Step 1 Preparation of CS Wer/-butyl 2-(8-(lH-pyrazol-l-yl)dibenzorb.dlfuran-3- sulfonamido)-3-methylbutanoate
  • (S)-Tert-butyl 2-(8-bromodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate 200 mg, 0.4 mmol
  • pyrazole 56 mg, 0.8 mmol
  • trans-N,W- dimethyl-l,2-cyclohexanediamine (12 mg, 0.08 mmol
  • CuI 4 mg, 0.02 mmol
  • K 3 PO 4 185 mg, 0.87 mmol
  • Step 2 Preparation of (SV2-(8-(lH-pyrazol-l-vOdibenzo[b,dlfuran-3-sulfonamido)- 3-methylbutanoic acid [0237]
  • the sulfonamide t-butyl ester (27 mg) from Step 1 was mixed in 0.5 mL of TFA/ CH 2 Cl 2 (1 :1) and stirred at room temperature for 4 hours.
  • Step 1 Preparation of (SWert-butyl 4-(7-(N-(l-fert4?utoxy-3-methyl-l-oxotuban-2- yl) sulfamoyl)dibenzo[b,d]furan-2-yl)piperazine-l-carboxylate [0238] (S)-Tert'-butyl 2-(8-bromodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate (320 mg, 0.66 mol), /er/-butyl 1 -piperazinecarboxylate (247 mg, 1.32 mmol), Pd 2 (dba) 3 (14 mg, 0.01 mmol), tri(o-tolyl) phosphine (8 mg, 0.04 mmol), and sodium /ert-butoxide (140 mg, 1.45 mmol) were mixed in 2 mL of toluene and stirred at 11O 0 C
  • reaction mixture was purified by a preparative HPLC to give 54 mg of (S)-/er?-butyl 4-(7-(/V-(l-/er/-butoxy-3-methyl- l-oxotuban-2-yl) sulfamoyl)dibenzo[b,d]furan-2-yl)piperazine-l-carboxylate as a white solid in 14% yield.
  • Step 2 Preparation of (SV3-methyl-2-( ' 8-(piperazin-l-yl)dibenzorb,d1furan-3- sulfonamido)butanoic acid [0239]
  • the sulfonamide t-butyl ester (50 mg) from Step 1 was mixed in 0.5 mL of TFA/CH 2 C1 2 (1 : 1) and stirred at room temperature for 4 hours.
  • Step 1 Preparation of (S)-tert-butyl 2-(8-(lH-imidazol-l-yl)dibenzo[b,d]furan-3- sulfonamido)-3 -methy lbutanoate [0240] (S)-Tert-butyl 2-(8-aminodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate (418 mg, 1 mmol) in MeOH (10 mL) was treated with 40% aqueous glyoxal (160 mg, 1.1 mmol) for 16 hours at room temperature.
  • Step 2 Preparation of (SV2-(8-(lH-imidazol-l-v ⁇ dibenzorb,dlfuran-3- sulfonamidoVS-methylbutanoic acid [0241]
  • the sulfonamide t-butyl ester (0.2 mmol) from Step 1 was dissolved in 2 mL of TFA/CH 2 C1 2 (1 :1). The solution was stirred at room temperature for 3 hours and concentrated under reduced pressure and the residue was triturated with CH 3 CN/H 2 O followed by a freeze-dry process.
  • Step 1 Preparation of (S)-methyl 3-methyl-2-(8-nitrc>dibenzo[b,d]furan-3- sulfonamido)butanoate
  • Step 4 Preparation of (SVmethyl 2-(8-(4-cvclohexyl-lH-1.2.3-triazol-l- vOdibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate
  • Step 5 Preparation of (SV2-f8-(4-cvclohexyl-lH-1.2.3-triazol-l- vDdibenzo[b,d]furan-3-sulfonamido>3-methylbutanoic acid
  • Step 1 Preparation of (S)-methyl 3-methyl-2-(7-nitrodibenzo( ⁇ b,d]thiophene-3- sulfonamido)butanoate
  • Step 4 Preparation of (SVmethyl 3-methyl-2-(7-(4- ⁇ -methyl-lH-pyrrol-2-vO-lH- L ⁇ J-triazol-l-vDdibenzorKdithiophene-S-sulfonamido ⁇ utanoate
  • Step 5 Preparation of (SV3-methyl-2-(7-(4-(l-methyl-lH-pyrrol-2-vn-lH-1.2.3- triazol-l-yl)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid
  • the sodium salt was prepared by treatment of (S)-3-methyl-2-(7-(4-(l- methyl- 1 H-pyrrol-2-yl)- IH-1 ,2,3-triazol- 1 -yl)dibenzo[b,d]thiophene-3- sulfonamido)butanoic acid with 1.0 equivalent of NaOH.
  • the salt was obtained as a white solid.
  • Step 1 Preparation of (R)-methyl 3-methyl-2-(7-nitrodibenzo[b,d]furan-2- sulfonamido ' lbutanoate
  • 7-Nitrodibenzo[b,d]furan-2-sulfonyl chloride (Example 1, Step 3, 570 mg, 1.83 mmol)
  • (R)-methyl 2-amino-3-methylbutanoate hydrochloride 2.0 mmol
  • 5 mL Of CH 2 Cl 2 followed by slow addition of N 5 N- diisopropylethylamine (520 mg, 4 mmol) at O 0 C.
  • Step 3 Preparation of (RVmethyl 2-(7-(4H-l,2,4-triazol-4-vDdibenzorb,d1furan-2- sulfonamidoV3-methylbutanoate
  • Step 1 Preparation of (R)-methyl 2-(7-((2- bromoethoxy)carbonylamino)dibenzo [b,d] furan-2-sulfonamido)-3 -methylbutanoate
  • Step 2 Preparation of (R)-methyl 3-methyl-2-(7-(2-oxooxazolidin-3- yl)dibenzo[b,d]furan-2-sulfonamido)butanoate
  • Step 3 Preparation of (R)-3-methyl-2-(7-(2-oxooxazolidin-3-y0dibenzo[b,d1furan- 2-sulfonamido)butanoic acid
  • Example 131 Preparation of (S)-2-(8-((3- chloropropoxy)carbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoic acid [0279] Following procedures analogous to those described in Example 28 and using chloropropyl chloroformate, (S)-2-(8-((3- chloropropoxy)carbonylamino)dibenzo [b,d] furan-3 -sulfonamido)-3 -methylbutanoic acid was obtained as a white solid. HRMS calculated for [C 21 H 23 ClN 2 O 7 S + H] + 483.09873; found (ESI-FTMS, [M+H] l+ ) 483.10066.
  • Step 1 Preparation of (RVmethyl 2-(7-(2,5-dimethyl-lH-pyrrol-l- v ⁇ dibenzo[b,dlfuran-2-sulfonamido)-3-methylbutanoate [0280] (R)-Methyl 2-(7-aminodibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoate (Example 128, Step 2, 200 mg, 0.83 mmol), hexane-2,5-dione (61 mg, 0.53 mmol), and 4-methylbenzenesulfonic acid (10 mg) were mixed with 3 mL of methanol.
  • Step 2 Preparation of rRV2-(7-(2.5-dimethyl-lH-Dyrrol-l-vndibenzorb.d1furan-2- sulfonamido)-3-methylbutanoic acid
  • Step 1 Preparation of 8-bromo-7-nitrodibenzo[b,dlfuran-2-sulfonyl chloride [0282] In a round-bottom flask was added dibenzofuran (15 g) and acetic acid (90 niL). Bromine (6.1 mL) was added via a drop funnel and the mixture was heated overnight at 55 0 C. After the reaction mixture was cooled to O 0 C, the precipitate was filtered and dried in air to give 2-bromodibenzofuran (11.3 g).
  • Step 3 Preparation of (R)-methyl 2-(8-bromo-7- (methoxycarbonylaminoMibenzo [b.dl furan-2-sulfonamido)-3 -methylbutanoate
  • Step 2 Preparation of (S)-2-(8-bromo-7-(rnethoxycarbonylamino)dibenzo[b,d1furan- 2-sulfonamido)-3 -methyl butanoic acid
  • Step 1 Preparation of (R)-methyl 2-(7-iododibenzorb,d]furan-2-sulfonamido)-3- methylbutanoate
  • (R)-Methyl 2-(7-aminodibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoate (Example 128, Step 2, 2165 mg, 5.75 mmol) was mixed with hydrochloric acid (18%, 12 mL). The solution was cooled to O 0 C and an aqueous solution of sodium nitrite (1.0 M, 9 mL) was slowly added.
  • Step 2 Preparation of (RVmethyl 3-methyl-2-(7-(4-(trifluoromethyl)thiazol-2- ylamino)dibenzo[b 1 dlfuran-2-sulfonamido ' )butanoate
  • (R)-Methyl 2-(7-iododibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoate 145 mg, 0.3 mmol
  • 3-(trifluoromethyl)pyrazole 121 mg, 0.9 mmol), /r ⁇ rts-N,N'-dimethyl-l,2-cyclohexanediamine (8.5 mg, 0.2 mmol), CuI (3 mg, 0.05 mmol), and K 3 PO 4 (133 mg, 2.1 mmol) were mixed in 2 mL of toluene.
  • the mixture was irradiated under microwave at 13O 0 C for 3 hours and purified with a preparative HP
  • Step 1 Preparation of (RVmethyl 2-(7-(lH-pyrrol-l-vndibenzorb,dlfuran-2- sulfonamido)-3-methylbutanoate [0297]
  • Step 1 Preparation of 8-bromodibenzo[b,d1furan-3-sulfonyl chloride
  • Step 3 Preparation of (SVmethyl 2-(8-bromo-7-nitrodibenzo[b,d]furan-3- sulfonamido)- 3 -methylbutanoate
  • Step 4 Preparation of (S)-methyl 2-(7-aminodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate
  • Step 5 Preparation of (S)-2-(7-aminodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoic acid
  • Step 1 Preparation of (S)-methyl 2-(7-(lH-pyrrol-l-yl)dibenzo[b,dlfuran-3- sulfonamido)-3 -methylbutanoate [0304] (S)-Methyl 2-(7-aminodibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate (Example 138, Step 4, 139 mg, 0.37 mmol) and 2,5-dimethoxytetrahydrofuran (74 mg, 0.3 mmol) were mixed with AcOH (2 mL).
  • Step 2 Preparation of (S)-2-(7-(lH-pyrrol-l-yl)dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoic acid
  • Step 2 Preparation of rSV2-(7-f2,5-dimethyl-lH-pyrrol-l-yl)dibenzo[b,dlfuran-3- sulfonamidoV3-methylbutanoic acid
  • Step 1 Preparation of (SVmethyl 2-(7-(Y2- bromoethoxy)carbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate [0308] (S)-Methyl 2-(7-aminodibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate (Example 138, Step 4, 226 mg, 0.6 mmol) and DMAP (100 mg, 0.72 mmol) were dissolved in 5 mL Of CH 2 Cl 2 , followed by the addition of methyl chloroformate (169 mg, 0.9 mmol).
  • Step 2 Preparation of (S)-methyl 3-methyl-2-(7-(2-oxooxazolidin-3- yl)dibenzo[b,d1 furan-3 -sulfonamido)butanoate [0309] To a solution of (S)-methyl 2-(7-((2- bromoethoxy)carbonylamino)dibenzo [b,d] furan-3 -sulfonamido)-3 -methylbutanoate (270 mg) in 6 mL of DMF was added 160 mg OfK 2 CO 3 .
  • Step 3 Preparation of (S)-3-methyl-2-(7-(2-oxooxazolidin-3-yl)dibenzorb,d]furan-3- sulfonamido)butanoic acid
  • Step 1 Preparation of (S Vmethyl 2-(7-iododibenzorb,d]furan-3-sulfonamido)-3- methylbutanoate
  • reaction mixture was filtered and the solid was washed with water and further purified by a column chromatography to provide 3.94 g of (S)-methyl 2-(7-iododibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate as a grey solid.
  • Step 2 Preparation of (SVmethyl 3-methyl-2-(7-(3-(trifluoromethyl)-lH-pyrazol-l- y0dibenzo[b,d]furan-3-sulfonamido)butanoate
  • Step 3 Preparation of (SV3-methyl-2-(7-(3-(trifluoromethylVlH-pyrazol-l- vDdibenzo [b,d] furan-3 -sulfonamido)butanoic acid
  • Step 1 Preparation of (S)-methyl 2-(7-amino-8-bromodibenzofb,dlfuran-3- sulfonamidoV3 -methyl butanoate [0318]
  • Step 2 Preparation of (S)-2-(7-amino-8-bromodibenzo[b,dlfuran-3-sulfonamido)-3- methylbutanoic acid
  • Step 1 Preparation of (RVmethyl 3-methyl-2-(7-nitrodibenzorb,dlfuran-3- sulfonamido)butanoate
  • Step 2 Preparation of (RV3-methyl-2-(7-nitrodibenzo[b,dlfuran-3- sulfonamido)butanoic acid
  • Step 1 Preparation of (R)-methyl 2-(7-aminodibenzofb,d1furan-3-sulfonamido)-3- methylbutanoate
  • Step 2 Preparation of (R)-methyl 2-(7-dnethoxycarbonylamino * )dibenzorb,d1furan- 3-sulfonamido)-3-methylbutanoate
  • Step 3 Preparation of (R)-2-(7-(methoxycarbonylamino)dibenzo[b,dlfuran-3- sulfbnamido)- 3 -methylbutanoic acid
  • Step 1 Preparation of (R)-methyl 2-(7-(3-(3,4- difluorophenvOureido)dibenzo[b,d1furan-3-sulfonamidoV3-rnethylbutanoate
  • Step 2 Preparation of (R>2-(7-(3-(3.4-difluorophenvOureido * )dibenzorb.d1furan-3- sulfonamido>3-methylbutanoic acid
  • Step 1 Preparation of (S)-tert-butyl 3-methyl-2-(7-nitrodibenzorb,d1furan-3- sulfonamido)butanoate
  • Step 2 Preparation of (SVtert-butyl 2-(7-aminodibenzo[b,d1furan-3-sulfonamido)-3- methylbutanoate
  • Step 4 Preparation of (S)-2-(7-(methoxycarbonylamino N )dibenzo[b,dl furan-3 - sulfonamido)-3-methylbutanoic acid
  • Step 1 Preparation of (S Vtert-butyl 3-methyl-2-(7-(3-thiophen-3- ylureido)diben2o[b,d]furan-3-sulfonamido ' )butanoate
  • Step 1 Preparation of (SVmethyl 2-(7-(ethylamino)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoate
  • Step 2 Preparation of (S)-2-(7-(ethylamino)dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoic acid
  • Step 2 Preparation of (S)-2-(7-(ethyl(methoxycarbonvDamino)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoic acid [0342]
  • Step 1 Preparation of (S)-methyl 2-(7-(ethyl(methyl)amino > )dibenzo[b,d] furan-3 - sulfonamido)-3-methylbutanoate
  • Step 1 Preparation of (RVmethyl 3-methyl-2-(7-(5-tosyl-2H-tetrazol-2- yl)dibenzo[b,d]furan-2-sulfonamido)butanoate
  • Step 2 Preparation of (R)-2-(7-(5-methoxy-2H-tetrazol-2-yl)dibenzo[b,d]furan-2- sulfonamido)-3-methylbutanoic acid and (R)-2-(7-( " 5-hydroxy-2H-tetrazol-2- yQdibenzo [b,d] furan-2-sulfonamido)-3 -methylbutanoic acid
  • Step 1 Preparation of ( " SVtert-butyl 2-(7-(benzylamino)dibenzo[b,d]thiophene-3- sulfonamido)-3-methylbutanoate
  • Step 3 Preparation of (S>2-(7-(benzyl(methyl)amino)dibenzo[b,dlthiophene-3- sulfonamido)-3-methylbutanoic acid
  • N- ⁇ [7-(l,l-Dioxidoisothiazolidin-2-yl)dibenzo[b,d]thien-3-yl]sulfonyl ⁇ -L- valine was prepared using (S)-tert-butyl 2-(7-aminodibenzo[b,d]thiophene-3- sulfonamido)-3-methylbutanoate (Example 65, Step 4) and 2-chloroethanesulfonyl chloride following procedures analogous to those described in Example 99.
  • N- ⁇ [7-(l -Oxidoisothiazolidin-2-yl)dibenzo [b,d] thien-3 -yl] sulfonyl ⁇ -L-valine was prepared following procedures analogous to those described in Example 173 and using 2-chloroethanesulfinic chloride. MS (ES+) 467.18.
  • Step 1 Preparation of (S)-tert-butyl 2-(7-formamidodibenzo[b,d]thiophene-3- sulfonamido)-3-methylbutanoate
  • acetic formic anhydride prepared by dropwise addition of 98% formic acid (450 mg, 370 ⁇ l, 3.2 mmol) to acetic anhydride (800 mg, 735 ⁇ l, 2.6 mmol) at O 0 C followed by gentle heating at 50°C for 2 h) in THF (10 mL) was added (S)-tert-butyl 2-(7-aminodibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoate (1.3 g, 3 mmol)) dissolved in THF (5 mL).
  • Step 2 Preparation of (S Vtert-butyl 3-methyl-2-(7- (methylamino)dibenzo[b 1 dlthiophene-3-sulfonamido)butanoate
  • Example 179 Preparation of (S)-2-(7-(((4- fluorophenoxy)carbonyl)(methyl)amino)dibenzo[b,d]thiophene-3-sulfonamido)- 3-methylbutanoic acid [0368] Following procedures analogous to those described in Example 176 and using 4-fluorophenyl chloroformate, (S)-2-(7-(((4- fluorophenoxy)carbonyl)(methyl)amino)dibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoic acid was obtained as a white solid.
  • the enzymatic reactions were initiated by addition of a substrate, MCA-Pro-Leu-Gly-Leu-Dpa(DNP)-Ala- Arg, containing a fluorescent group (7-methoxycoumarin, MCA) and a 2,4- dinitrophenyl group (DNP), to a final concentration of 20 ⁇ M.
  • the final DMSO concentration in the assay was 10%.
  • the reaction was monitored for 30 minutes at room temperature and the initial rate of the cleavage reaction was determined using a fluorescence plate reader ( ⁇ ex : 325 nm, ⁇ em : 395 nm). Plots of the inhibitor concentration vs.

Abstract

The present invention relates to compositions of the formula (I): and pharmaceutically acceptable salts, hydrates, or esters thereof, wherein R1, R2, R3, R4, R5, X, and Y are as defined herein. The present teachings also provide methods of making the compounds of formula I, and methods of treating pathologic conditions or disorders mediated wholly or in part by matrix metalloproteinases, such as asthma and chronic obstructive pulmonary disease, comprising administering a therapeutically effective amount of a compound of formula (I) to a mammal (e.g., a human) in need thereof.

Description

TRICYCLIC COMPOUNDS AS MATRIX METALLOPROTEINASE
INHIBITORS
Introduction
[0001] The present teachings relate to tricyclic compounds and derivatives that can be used for inhibiting matrix metalloproteinases. The present teachings also relate to methods for preparing the tricyclic compounds and derivatives, and methods of their use.
[0002] Matrix metalloproteinases (MMPs) are a family of more than 20 zinc- dependent proteases that possess the ability to degrade extracellular matrix (ECM) components associated with both normal tissue remodeling and destruction. MMP expression and activity is highly controlled because of the degradative nature of these enzymes, where an apparent loss in MMP regulation can result in the pathological destruction of connective tissue and the ensuing disease state. For example, disruption of the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs), which regulate the activity of MMPs, is observed in pathologies such as rheumatoid and osteoarthritis, atherosclerosis, heart failure, fibrosis, pulmonary emphysema, and tumor growth, invasion, and metastasis. Accordingly, MMPs have been a highly active set of targets for the design of therapeutic agents, specifically for the disease areas of arthritis and oncology (for ' reviews, see e.g., Woessner, J.F. (1991), FASEB J., 5: 2145-2154; and Coussens, L.M. (2002), Science, 295(5564): 2387-2392).
[0003] MMPs can be broadly classified into collagenases (MMP-I, MMP-8, and MMP- 13), gelatinases (MMP-2 and MMP-9), stromelysins (MMP-3, MMP-10, and MMP-11), elastases (MMP-7, and MMP- 12) and membrane-associated MMPs (MMP- 14 through MMP-25). Among these classes, the gelatinases have been shown to be the MMPs most intimately involved with the growth and spread of tumors, while the collagenases have been associated with the pathogenesis of arthritis. See e.g., Ellenrieder, V. et al. (2000), Int. J. Cancer, 85(1): 14-20; Singer, CF. et al. (2002), Breast Cancer Res. Treat., 72(l):69-77; Nikkola, J. et al. (2005), Clin. Cancer Res., 1 1 : 5158-5166; Lubbe, W.J. et al. (2006), Clin. Cancer Res., 12: 1876-1882; Dean, D.D. (1991), Sem. Arthritis Rheum., 20(6 Suppl 2): 2-1 1 ; and Jackson, C. et al. (2001), Inflamm. Res., 50: 183-186. Furthermore, there is evidence to suggest that gelatinase is involved in plaque rupture associated with atherosclerosis. See e.g., Dollery, CM. et al. (1995), Cir. Res., 77: 863-868; and Kuzuya, M. et al. (2006), Arterioscler. Thromb. Vase. Biol, 26(5): 1120-1 125. MMPs also have been implicated in various other diseases including restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, septic arthritis, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, colitis, glomerular disease of the kidney, premature rupture of fetal membranes, inflammatory bowel disease, periodontal disease, age-related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/neovascularization, and corneal graft rejection.
[0004] Macrophage metalloelastase, MMP- 12, like many MMPs is able to degrade many ECM components. Studies using different animal models of disease have provided evidence that MMP- 12 is an important mediator of various diseases. For example, in studies conducted to investigate macrophage involvement in rheumatoid arthritis, elevated MMP- 12 expression levels were observed in synovial tissues and fluids from patients with rheumatoid arthritis relative to those with osteoarthritis. See Liu, M. et al. (2004), Arthritis & Rheumatism, 50(10): 3112- 3117. Other studies have linked MMP- 12 to promoting atherosclerotic plaque instability. See e.g., Johnson, J.L. (2005), PNAS, 102(43): 15575-15580. Evidence also suggested that MMP- 12 expression might serve as a prognostic indicator for early tumor relapse. See Hofmann H. S. et al. (2005), Clin. Cancer Res., 11(3): 1086-1092.
[0005] Asthma and chronic obstructive pulmonary disease (COPD) are chronic pulmonary diseases that are both characterized by the accumulation of inflammatory cells, airflow obstruction and airway remodeling. MMPs have been implicated to be the major class of proteolytic enzymes that induce airway remodeling. See e.g., Suzuki, R. Y. et al. (2004), Treat. Respir. Med., 3: 17-27. MMP- 12, in particular, has been demonstrated to play a significant role in airway inflammation and remodeling. Recent studies have shown by immunohistochemistry, for example, that bronchoalveolar lavage (BAL) cells and bronchial lung biopsies from patients with moderate to severe COPD had greater MMP- 12 expression than controls. See Molet, S. et al. (2005), Injlamm. Res., 54(1): 31-36. Similarly, other studies have demonstrated that there is increased MMP- 12 expression and enzyme activity in induced sputum from patients with mild-moderate COPD compared to non-smokers, former smokers, or current smokers. See Demedts, I. K. et al. (2006), Thorax, 61 : 196-201.
[0006] Accordingly, MMP inhibitors, in particular, MMP- 12 inhibitors, can be therapeutically beneficial for treating a variety of pathologic conditions and/or disorders.
Summary [0007] The present teachings relate to compounds of formula I:
I and pharmaceutically acceptable salts, hydrates, and esters thereof, wherein R1, R2, R3, R4, R5, X, and Y are as defined herein.
[0008] The present teachings also provide methods of preparing the compounds of formula I and methods of treating pathologic conditions or disorders mediated wholly or in part by matrix metalloproteinases, such as asthma and chronic obstructive pulmonary disease, including administering a therapeutically effective amount of a compound of formula I to a patient, for example, a patient in need thereof. Detailed Description
[0009] In one aspect, the present teachings provide compounds of formula I:
I and pharmaceutically acceptable salts, hydrates, and esters thereof, wherein:
R is an N-linked, free carboxyl or carboxyl-protected, natural or non-natural amino acid, or an N-linked amino acid derivative;
R2 and R3 independently are a) H, b) oxo, c) -OR8, d) -S(O)mR8, e) -S(O)1nOR8, f) -S(O)mNR8R9, g) -C(O)R8, h) -C(O)OR8, i) -C(O)NR8R9, j) -C(S)OR8, k) -C(S)R8, 1) -C(S)NR8R9, m) -C(NR8)NR8R9, n) a C1-10 alkyl group,
0) a C2-Io alkenyl group, p) a C2-I0 alkynyl group, q) a CM O haloalkyl group, r) a C3-IO cycloalkyl group, s) a C6-I4 aryl group, t) a 3-14 membered cycloheteroalkyl group, or u) a 5-13 membered heteroaryl group, wherein each of n) - u) optionally is substituted with 1-4 -Z-R10 groups; or R2 and R3, together with their common nitrogen atom, form a) -N=CR7R7, b) -N=O, c) -N=N-R8, d) a 3-14 membered cycloheteroalkyl group, or e) a 5-13 membered heteroaryl group, wherein each of d) and e) optionally is substituted with 1-4 -Z-R10 groups;
R4 and R5 independently are a) H, b) -CN, c) -NO2, d) halogen, e) -OR8, f) -NR8R9, g) -S(O)111R8, h) -S(O)111OR8, i) -C(O)R8, j) -C(O)OR8, k) -C(O)NR8R9,
1) -C(S)R8, m) -C(S)OR8, n) -C(S)NR8R9, o) a C1-I0 alkyl group, p) a C2-ιo alkenyl group, q) a C2-I0 alkynyl group, r) a CMO haloalkyl group, s) a C3- io cycloalkyl group, t) a C6-I4 aryl group, u) a 3-14 membered cycloheteroalkyl group, or v) a 5-13 membered heteroaryl group, wherein each of o) - v) optionally is substituted with 1- 4 -Z-R10 groups;
R6 is a) H, b) -S(O)mR8, c) -S(O)1nOR8, d) -C(O)R8, e) -C(O)OR8, f) -C(O)NR8R9, g) -C(S)R8, h) -C(S)OR8, i) -C(S)NR8R9J) a Ci-10 alkyl group, k) a C2-I0 alkenyl group, 1) a C2-I0 alkynyl group, or m) a CM0 haloalkyl group, wherein each of j) - m) optionally is substituted with a C6-I4 aryl group or a 5-13 membered heteroaryl group, wherein each of the C6-I4 aryl group and the 5-13 membered heteroaryl group optionally is substituted with 1-4 -Z-R10 groups;
R7, at each occurrence, is a) H, b) -CN, c) -NO2, d) halogen, e) oxo, f) -OR8, g) -NR8R9, h) -N(O)R8R9, i) -S(O)mR8, j) -S(O)01O-R8, k) -S(O)111NR8R9, 1) -C(O)R8, m) -C(O)OR8, n) -C(O)NR8R9, o) -C(S)R8, p) -C(S)OR8, q) -C(S)NR8R9, r) -Si(C1-10 alkyl)3, s) a C-10 alkyl group, t) a C2-io alkenyl group, u) a C2-I0 alkynyl group, v) a CM 0 haloalkyl group, w) a C3- io cycloalkyl group, x) a C6-I4 aryl group, y) a 3-14 membered cycloheteroalkyl group, or z) a 5-13 membered heteroaryl group, wherein each of r) - z) optionally is substituted with 1 - 4 -Z-R10 groups;
R8 and R9, at each occurrence, independently are a) H, b) -OR1 ', c) -SR11, d) -S(O)111R1 1, e) -S(O)m-OR", f) -S(0)m-NR"R12, g) -C(O)R1 1, h) -C(O)OR1 1, i) -C(O)NR11R12J) -C(S)NR11R12, k) a C1-10 alkyl group, 1) a C2-10 alkenyl group, m) a C2-I0 alkynyl group, n) a C1-10 alkoxy group, o) a Ci-10 haloalkyl group, p) a C3-Io cycloalkyl group, q) a C6-I4 aryl group, r) a 3-14 membered cycloheteroalkyl group, or s) a 5-13 membered heteroaryl group, wherein each of k) - s) optionally is substituted with 1-4 -Z-R10 groups;
R10, at each occurrence, is a) halogen, b) -CN, c) -NO2, d) oxo, e) -0-Z-R", f) -NR1 '-Z-R12, g) -N(O)R1 '-Z-R12, h) -S(O)111R1 ', i) -S(O)111O-Z-R1 ', j) -S(O)1nNR1 '-Z-R12, k) -C(O)R1 ', 1) -C(O)O-Z-R1 ', m) -C(O)NR1 '-Z-R12, n) -C(S)NR1 '-Z-R12, o) -Si(C1-I0 alkyl)3, p) a CMO alkyl group, q) a C2-I0 alkenyl group, r) a C2-I0 alkynyl group, s) a Ci-10 haloalkyl group, t) a C3-I0 cycloalkyl group, u) a C6-H aryl group, v) a 3-14 membered cycloheteroalkyl group, or w) a 5-13 membered heteroaryl group, wherein each of o) - w) optionally is substituted with 1-4 R13 groups;
R11 and R12, at each occurrence, independently are a) H, b) -OH, c) -SH, d) -S(O)2OH, e) -C(O)OH, f) -C(O)NH2, g) -C(S)NH2, h) -OC1-10 alkyl, i) -S(O)01-C1-10 alkyl, j) -S(O)m-OC1-10 alkyl, k) -C(O)-C1-10 alkyl, 1) -C(O)-OCi-I0 alkyl, m) -C(S)N(C1-I0 alkyl)2, n) -C(S)NH-C1-10 alkyl, o) -C(O)NH-C1-10 alkyl, p) -C(O)N(C1-10 alkyl)2, q) a C1-I0 alkyl group, r) a C2-10 alkenyl group, s) a C2-10 alkynyl group, t) a CMO alkoxy group, u) a C1-1O haloalkyl group, v) a C3-I0 cycloalkyl group, w) a C6-14 aryl group, x) a 3-14 membered cycloheteroalkyl group, or y) a 5-13 membered heteroaryl group, wherein each of h) - y) optionally is substituted with 1-4 -R13 groups;
R13, at each occurrence, is a) halogen, b) -CN, c) -NO2, d) oxo, e) -OH, f) -NH2, g) -NH(C1-10 alkyl), h) -N(C1-10 alkyl)2, i) -S(O)mH, j) -S(O)111-C1-10 alkyl, k) -S(O)2OH, 1) -S(O)01-OC1-10 alkyl, m) -S(O)111NH2, n) -S(O)1nNH(C1-10 alkyl), o) -S(O)111N(C1-10 alkyl)2, p) -CHO, q) -C(O)-C1-10 alkyl, r) -C(O)OH, s) -C(O)-OC1-10 alkyl, t) -C(O)NH2, u) -C(O)NH-C1-10 alkyl, v) -C(O)N(C1-10 alkyl)2, w) -C(S)NH2, x) -C(S)NH-C1-J0 alkyl, y) -C(S)N(C1-10 alkyl)2, z) -Si(C1-10 alkyl)3, aa) a C1-10 alkyl group, ab) a C2-10 alkenyl group, ac) a C2-I0 alkynyl group, ad) a Ci-I0 alkoxy group, ae) a CMO alkylthio group, af) a C1-10 haloalkyl group, ag) a C3-10 cycloalkyl group, ah) a C6-14 aryl group, ai) a 3-14 membered cycloheteroalkyl group, or aj) a 5-13 membered heteroaryl group;
X is O, S, S(O), S(O)2, or NR6; Y is S(O), S(O)2, or C(O);
Z, at each occurrence, is a) a divalent C1-10 alkyl group, b) a divalent C2-10 alkenyl group, c) a divalent C2-10 alkynyl group, d) a divalent Cj-10 haloalkyl group, or e) a covalent bond; and m, at each occurrence, is O, 1 , or 2.
[0010] In some embodiments, compounds of formula I can be:
wherein R i 11, X, and Y are as defined herein.
[0011] In some embodiments, R4 and R5 can be independently selected from H and a halogen. For example, R4 can be H and R5 can be H, Cl, or Br. In some embodiments, X can be O. In other embodiments, X can be S. In some embodiments, Y can be S(O)2.
[0012] In some embodiments, R1 can be W-V-NH-, wherein:
W is a) -C(O)R14, b) -S(O)mR14, c) -S(O)mOR14, d) -S(O)01NR14R15, e) -C(O)OR14, f) - C(O)NR14R15, g) -C(S)R14, h) -C(S)OR14, i) -NR14R15, j) -C(NR14)NRI4R15, k) -P(O)(ORI4)2, or 1) -B(OR14)2;
V is a) -CR14R16-, b) -CH2CR14R16-, c) -(CH=CR14R16)-, or d) -BHR16-; R14 and R15, at each occurrence, independently are a) H, b) -OH, c) -SH, d) -S(O)2OH, e) -C(O)OH, f) -C(O)NH2, g) -C(S)NH2, h) -S(O)n-C1-10 alkyl, i) -S(O)m-OC1-10 alkyl, j) -C(O)-C1-10 alkyl, k) -C(O)-OC1-10 alkyl,
1) -C(O)NH-C1-10 alkyl, m) -C(O)N(C1-10 alkyl)2, n) -C(S)NH-C1-10 alkyl, o) -C(S)N(C1-I0 alkyl)2, p) a Ci-I0 alkyl group, q) a C2-I0 alkenyl group, r) a C2-I0 alkynyl group, s) a Ci-10 alkoxy group, t) a Ci-i0 haloalkyl group, u) a C3- io cycloalkyl group, v) a C6-M aryl group, w) a 3-14 membered cycloheteroalkyl group, or x) a 5-13 membered heteroaryl group, wherein each of the C1-10 alkyl groups, the C2-Io alkenyl group, the C2-I0 alkynyl group, the Ci-I0 alkoxy group, the C1-10 haloalkyl group, the C3-io cycloalkyl group, the C6-H aryl group, the 3-14 membered cycloheteroalkyl group, and the a 5-13 membered heteroaryl group optionally is substituted with 1-4 R17 groups; R16, at each occurrence, is H or a side chain of a natural or non-natural amino acid;
R17, at each occurrence, is a) halogen, b) -CN, c) -NO2, d) oxo, e) -OH, f) -NH2, g) -NH(C1-IO alkyl), h) -N(Ci-10 alkyl)2, i) -S(O)01H, j) -S(O)111-C1-10 alkyl, k) -S(O)2OH, 1) -S(O)111-OC1-I0 alkyl, m) -S(0)mNH2, n) -S(O)01NH(C1 -10 alkyl), o) -S(O)111N(C1-I0 alkyl)2, p) -CHO, q) -C(O)-C1-10 alkyl, r) -C(O)OH, s) -C(O)-OCi-10 alkyl, t) -C(O)NH2, u) -C(O)NH-C1-10 alkyl, v) -C(O)N(C1-10 alkyl)2, w) -C(S)NH2, x) -C(S)NH-C10 alkyl, y) -C(S)N(C-10 alkyl)2, z) -Si(C1-10 alkyl)3, aa) a C1-10 alkyl group, ab) a C2-10 alkenyl group, ac) a C2-I0 alkynyl group, ad) a C1-10 alkoxy group, ae) a C1-10 alkylthio group, af) a C1-10 haloalkyl group, ag) a C3-10 cycloalkyl group, ah) a C6-14 aryl group, ai) a 3-14 membered cycloheteroalkyl group, or aj) a 5-13 membered heteroaryl group; and m is as defined herein.
[0013] In some embodiments, W can be -C(O)OR14 and V can be -CR14R16-, where R14 and R16 are as defined herein. In some embodiments, R1 can be an N- linked, free carboxyl or carboxyl-protected, natural or nonnatural D-alpha-amino acid. In other embodiments, R1 can be an N-linked, free carboxyl or carboxyl- protected, natural or non-natural L-alpha-amino acid. In other embodiments, the amino acid derivative can be a natural amino acid derivative.
[0014] In some embodiments, R16 can be isopropyl. In certain embodiments, R1 can be a valine. In particular embodiments, R1 can be a D-valine.
[0015] In some embodiments, R2 and R can independently be H, oxo, -S(O)111OR8, -S(O)1nNR8R9, -C(O)R8, -C(S)OR8, -C(S)R8, -C(S)NR8R9, -C(NR )NR R , a Ci-I0 alkyl group, a C2-I0 alkenyl group, a C2-10 alkynyl group, a Ci-io haloalkyl group, a C3-I0 cycloalkyl group, a C6-I4 aryl group, a 3-14 membered cycloheteroalkyl group, or a 5-13 membered heteroaryl group, wherein each of the Ci-io alkyl group, the C2-I0 alkenyl group, the C2-I0 alkynyl group, the Ci.10 haloalkyl group, the C3-I0 cycloalkyl group, the C6-I4 aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-13 membered heteroaryl group can be optionally substituted with 1-4 -Z-R10 groups. In certain embodiments, R2 and R3 can be independently selected from H, oxo, -C(O)R8, a C M O alkyl group, a C2-I0 alkenyl group, a C2-Io alkynyl group, and a C3.10 cycloalkyl group, where each of the Ci.10 alkyl groups, the C2- 10 alkenyl group, the C2-I0 alkynyl group, and the C3-I0 cycloalkyl group can be optionally substituted with 1-4 -Z-R10 groups. For example, R2 and R3 can be independently selected from H, oxo, -C(O)CH3, -C(O)CH2CH3, -C(O)CH(CH3)2, a methyl group, and an ethyl group.
[0016] In some embodiment, R2 and R3, together with their common nitrogen atom, can form -N=CR7R7, -N=O, or -N=N-R8. In certain embodiments, R2 and R3, together with their common nitrogen atom, can form -N=CR7R7, where each R7 can independently be H, halogen, -OR , -NR R , a Ci-I0 alkyl group, a C2- 10 alkenyl group, a C2-io alkynyl group, a Ci-I0 haloalkyl group, a C3-I0 cycloalkyl group, a C6-I4 aryl group, a 3-14 membered cycloheteroalkyl group, or a 5-13 membered heteroaryl group, and each of the Ci-I0 alkyl group, the C2-I0 alkenyl group, the C2-I0 alkynyl group, the Ci-I0 haloalkyl group, the C3-Io cycloalkyl group, the C6-I4 aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-13 membered heteroaryl group can be optionally substituted with 1-4 -Z-R10 groups. For example, R and R , together with their common nitrogen atom, can form -N=CHR7, where R7 can be -NH2, -NH(Ci-I0 alkyl), or -N(C1-10 alkyl)2. In particular embodiments, -NR2R3 can be -NH2, -NO2, -NHC(O)CH3, -N(CH2CH2OH)C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)2, -NHCH2CH2OH, -NHCH2CH2Cl, or -N=CHN(CH3)2.
[0017] In some embodiments, R2 can be -C(O)OR8, where R8 can be selected from H, -C(O)R11, -C(O)OR1 1, -C(O)NR11R12, a C1-10 alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, a Ci-I0 haloalkyl group, a C3-io cycloalkyl group, a C6-I4 aryl group, a 3-14 membered cycloheteroalkyl group, and a 5-13 membered heteroaryl group, where each of the CMO alkyl group, the C2- io alkenyl group, the C2-I0 alkynyl group, the Ci-I0 haloalkyl group, the C3-I0 cycloalkyl group, the C6-H aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-13 membered heteroaryl group can be optionally substituted with 1-4 -Z-R10 groups. For example, R can be selected from H, a Ci-I0 alkyl group, a C2-I0 alkenyl group, a C2-I0 alkynyl group, and a C6-I4 aryl group, where each of the Ci-I0 alkyl group, the C2-I0 alkenyl group, the C2-io alkynyl group, and the C6-H aryl group can be optionally substituted with 1-4 -Z-R10 groups. In certain embodiments, R8 can be selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a butyl group, a hexyl group, and a butynyl group, each of which can be optionally substituted with 1-4 groups independently selected from a halogen, -S(O)01R1 1, -S(O)111O-Z-R1 ', -S(O)111NR1 '-Z-R12, -C(O)R11, -C(O)O-Z-R1 1, -C(O)NR"-Z-R12, a C6-H aryl group, and a 5-13 membered heteroaryl group. In particular embodiments, R8 can be selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a butyl group, a hexyl group, a 3-butynyl group, a 4-butynyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a 2-bromoethyl group, a 2-methanesulfonylethyl group, a 3-chloropropyl group, and a benzyl group. [0018] In certain embodiments, where R2 is -C(O)OR8, R8 can be a phenyl group optionally substituted with 1-4 groups independently selected from a halogen and a CMO alkyl group. In particular embodiments, R can be selected from a phenyl group, a tolyl group, a fluorophenyl group, and a chlorophenyl group.
[0019] In some embodiments, R2 can be -C(O)NR8R9, where R8 and R9 can be independently selected from H, a CMO alkyl group, a C2-I0 alkenyl group, a C2-I0 alkynyl group, a C3-I0 cycloalkyl group, a C6-I4 aryl group, a 3-14 membered cycloheteroalkyl group, and a 5-13 membered heteroaryl group, and each of the CMO alkyl group, the C2-10 alkenyl group, the C2-10 alkynyl group, the C3-I0 cycloalkyl group, the C6-I4 aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-13 membered heteroaryl group can be optionally substituted with 1-4 -Z-R10 groups. In certain embodiments, R9 can be H or a CM O alkyl group. For example, R8 can be H or a methyl group.
[0020] In some embodiments, where R is -C(O)NR R , R can be selected from H, a CMO alkyl group, a C3-I0 cycloalkyl group, a C6-I4 aryl group, a 3-14 membered cycloheteroalkyl group, and a 5-13 membered heteroaryl group, and each of the Ci-I0 alkyl group, the C3-io cycloalkyl group, the C6-I4 aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-13 membered heteroaryl group can be optionally substituted with 1-4 -Z-R10 groups. For example, the -Z-R10 group, at each occurrence, can be halogen, -O-Z-R1 ', -NR1 '-Z-R12, a CMO alkyl group, a CMO alkoxy group, a CMO haloalkyl group, a 3-14 membered cycloheteroalkyl group, a 5-13 membered heteroaryl group, or a phenyl group, where each of the CM0 alkyl group, the C MO alkoxy group, the CM O haloalkyl group, the 3-14 membered cycloheteroalkyl group, the 5-13 membered heteroaryl group, or the phenyl group can be optionally substituted with 1-4 R13. In certain embodiments, R8 can be H or a Ci-6 alkyl group optionally substituted with 1-4 groups independently selected from halogen, a phenyl group, and a 5-6 membered heteroaryl group, where each of the phenyl group and the 5-6 membered heteroaryl group can be optionally substituted with 1-4 R13. In particular embodiments, R8 can be selected from H, a methyl group, an ethyl group, an isopropyl group, a cyclopentyl group, a benzyl group, a fluorobenzyl group, a phenethyl group, a thienylmethyl group, and a thienylethyl group. In certain embodiments, R8 can be a phenyl group or a 5-13 membered heteroaryl group, each of which can be optionally substituted with 1-4 -Z-R10 groups. In particular embodiments, R can be selected from a phenyl group, a 2,3- dihydrobenzo[b][l,4]dioxinyl group, a thienyl group, a pyridyl group, and an isoxazolyl group, and each of the phenyl group, the thienyl group, the pyridyl group, and the isoxazolyl group can be optionally substituted with 1 -3 groups independently selected from halogen, -O-Z-R1 1, -NR1 '-Z-R12, a Ci-I0 alkyl group, and a Ci-I0 haloalkyl group.
[0021] In some embodiments, R can be -S(O)01R . In some embodiments, R can be -S(O)111OR8. In certain embodiments, R2 can be -S(O)R8 or -SO2R8. In some embodiments, where R2 is -S(O)R8 Or -SO2R8, R8 can be selected from H, a Ci-io alkyl group, a C2-I0 alkenyl group, a C2-10 alkynyl group, a Ci-I0 haloalkyl group, a C3-I0 cycloalkyl group, a C6-I4 aryl group, a 3-14 membered cycloheteroalkyl group, and a 5-13 membered heteroaryl group, wherein each of the Ci.io alkyl group, the C2- 10 alkenyl group, the C2- 10 alkynyl group, the Cj.10 haloalkyl group, the C3- 10 cycloalkyl group, the C6-H aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-13 membered heteroaryl group can be optionally substituted with 1-4 -Z-R10 groups. For example, R8 can be selected from H, a Ci.10 alkyl group, a C6-I4 aryl group, and a 5-13 heteroaryl group, and each of the CMO alkyl group, the C6-H aryl group and the 5-13 heteroaryl group can be optionally substituted with 1-4 -Z-R1 groups. In certain embodiments, the -Z-R10 group, at each occurrence, can independently be a halogen, a CMO alkyl group, a CMO haloalkyl group, or a phenyl group. In certain embodiments, R8 can be selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a butyl group, and a hexyl group, each of which can be optionally substituted with 1-4 groups independently selected from a halogen and a Ci-I0 haloalkyl group. In particular embodiments, R8 can be selected from a methyl group, an ethyl group, an isopropyl group, a 2-chloromethyl group, and a 2-trifluoromethyl group. In certain embodiments, R can be selected from a phenyl group and a 5- or 6- membered heteroaryl group, each of which can be optionally substituted with 1-3 groups independently selected from a halogen and a CMO alkyl group. For example, the 5- or 6-membered heteroaryl group can be a thienyl group or an isoxazolyl group. In particular embodiments, R can be selected from a phenyl group, a fluorophenyl group, a dimethylisoxazolyl group, and a dichlorothienyl group.
[0022] In some embodiments, R3 can be H, -S(O)111R8, -S(O)111OR8, -S(O)01NR8R9, -C(O)R8, -C(S)OR8, -C(S)R8, -C(S)NR8R9, -C(NR8)NR8R9, a CM0 alkyl group, a C2-I0 alkenyl group, a C2-I0 alkynyl group, a Ci-I0 haloalkyl group, a C3-Io cycloalkyl group, a C6-H aryl group, a 3-14 membered cycloheteroalkyl group, or a 5-13 membered heteroaryl group, where each of the Ci-I0 alkyl group, the C2-I0 alkenyl group, the C2-I0 alkynyl group, the CM 0 haloalkyl group, the C3-io cycloalkyl group, the C6-I4 aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-13 membered heteroaryl group can be optionally substituted with 1-4 -Z-R10 groups. For example, R can be H, -S(O)mR , or a Ci-I0 alkyl group (e.g., a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, and a heptyl group) optionally substituted with 1-4 -Z-R10 groups. In certain embodiments, where R3 is -S(O)111R8, R8 can be a phenyl group. In particular embodiments, R3 can be selected from H, a methyl group, an ethyl group, and a fluorophenylsulfonyl group.
[0023] In some embodiments, R and R3, together with their common nitrogen atom, can form a 3-14 membered cycloheteroalkyl group or a 5-13 membered heteroaryl group, where each of the 3-14 membered cycloheteroalkyl group and the 5-13 membered heteroaryl group can be optionally substituted with 1-4 -Z-R10 groups. In certain embodiments, the 3-14 membered cycloheteroalkyl group can exclude 3-14 membered cyclic urea groups, 3-14 membered cyclic carbamate groups, 3-14 membered cyclic sulfanamide groups, and a 3-14 membered cyclic sulfonamide groups. In certain embodiments, R2 and R3, together with their common nitrogen atom, can form a 3-14 membered cycloheteroalkyl group, which can optionally include 1, 2, or 3 additional ring heteroatoms independently selected from O, S, and N and can be optionally substituted with 1-4 -Z-R10 groups. In certain embodiments, R2 and R3, together with their common nitrogen atom, can form a 5 or 6 membered cycloheteroalkyl group, each of which can be optionally substituted with 1-4 -Z-R10 groups. For example, the 5 or 6 membered cycloheteroalkyl group can be selected from a pyrrolidinyl group, an oxazolinyl group, an thiazolinyl group, an isothiazolinyl group, an imidazolinyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, a thiomorpholinyl group, and a 1,3-oxazinanyl group and the -Z-R10 group, at each occurrence, can be selected from halogen, oxo, and a Ci-6 alkyl group.
[0024] In certain embodiments, R2 and R3, together with their common nitrogen atom, can form a 5-13 membered heteroaryl group, which can optionally include 1, 2, 3, or 4 additional N atoms and can be optionally substituted with 1-4 -Z-R10 groups. In certain embodiments, the 5-13 membered heteroaryl group can be selected from a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolyl group, an indolyl group, a purinyl group, and a carbazolyl group. In particular embodiments, R2 and R3, together with their common nitrogen atom, can form a 5- or 6-membered heteroaryl group optionally substituted with 1-4 -Z-R10. For example, the 5- or 6-membered heteroaryl group can be selected from a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, and a tetrazolyl group. In certain embodiments, Z can be selected from a divalent Ci-4 alkyl group and a covalent bond. In certain embodiments, R10 can be selected from -CN, -O-Z-R1 ', -NR1 '-Z-R12, -C(O)O-Z-R1 1, -C(O)NR1 '-Z-R12, -Si(C]-I0 alkyl)3, a Ci-io alkyl group, a Ci-I0 haloalkyl group, a C3-I0 cycloalkyl group, a C6-I4 aryl group, and a 5-13 membered heteroaryl group, where each of the Ci-I0 alkyl groups, the C6-I4 heteroaryl group, the C3-I0 cycloalkyl group, the C6-H aryl group, and the 5-13 membered heteroaryl group can be optionally substituted with 1-4 R13 groups
[0025] In some embodiments, where R2 can be -C(O)OR8 or -C(O)NR8R9, R3
O O and the R8 portion of R2, taken together with N A ° or N A N .R9 to which they are attached, can form a 3-14 membered cyclic urea group or a 3-14 membered cyclic carbamate group, each of which can be optionally substituted with 1-4 -Z-R10 groups. In certain embodiment, the 3-14 membered cyclic urea group or the 3-14 membered cyclic carbamate group can be a 5-12 membered cyclic urea group or a 5- 12 membered cyclic carbamate group. In certain embodiments, R can be H or a methyl group. For example, the 5-12 membered cyclic urea group or the 5-12 membered cyclic carbamate group can be a 5-membered cyclic urea group, a 6- membered cyclic urea group, a 5-membered cyclic carbamate group, or a 6- membered cyclic carbamate group.
[0026] In some embodiments, where R2 can be -SOR8 or -SO2R8, R3 and the R8 portion of R2, taken together with N and S, to which they are respectively attached, can form a 3-14 membered cyclic sulfinamide group or a 3-14 membered cyclic sulfonamide group, each of which can be optionally substituted with 1-4 -Z-R10 groups. In certain embodiments, the 3-14 membered cyclic sulfinamide group or the 3-14 membered cyclic sulfonamide group can be a 5-12 membered cyclic sulfinamide group or a 5-12 membered cyclic sulfonamide group. For example, the 5-12 membered cyclic sulfinamide group or the 5-12 membered cyclic sulfonamide group can be a S-oxoisothiazolidin-2-yl group, a S-oxothiazinan-2-yl group, a S, S- dioxoisothiazolidin-2-yl group, or a S,S-dioxothiazinan-2-yl group.
[0027] It should be understood that the present teachings can exclude certain compounds within the genus identified by formula I. For example, when X is O, -Y-R is located in the 2-position, -NR R is in the 7-position and R is hydrogen, the present teachings can exclude compounds where R3 is hydrogen, a Ci-5 alkyl group, or -C(O)Ci-5 alkyl group. When X is O, -Y-R1 is located in the 2-position and -NR2R3 is in the 7-position, the present teachings can exclude compounds where each of R and R is a Ci-5 alkyl group. The present teachings can also exclude compounds where -Y-R1 is located in the 3-position, X is O, -NR2R3 is in the 7-position, R2 is H, and R3 is H, a Ci-5 alkyl group, or -C(O)Cj-5 alkyl group; and that -Y-R1 is located in the 3-position, X is O, -NR2R3 is in the 7-position, and each of R2 and R3 is a Ci-5 alkyl group. Further, the present teachings can also exclude the above specified compounds where -Y-R is located in the 2-position or the 3-position, and -NR2R3 is in the 8-position. [0028] Compounds of the present teachings include the compounds presented in Table 1 below:
Table 1
-
b
-
[0029] Also provided in accordance with the present teachings are prodrugs of the compounds disclosed herein. As used herein, "prodrug" refers to a compound ("parent compound") having a moiety that produces, generates, or releases a compound of the present teachings when administered to a mammalian subject. Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either by routine manipulation or in vivo, from the parent compounds. Examples of prodrugs include compounds as described herein that contain one or more molecular moieties appended to a hydroxyl, amino, sulfhydryl, or carboxyl group of the compounds, and that when administered to a mammalian subject, is/are cleaved in vivo to form the free hydroxyl, amino, sulfhydryl, or carboxyl group, respectively. Examples of prodrugs can include acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present teachings. Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A. C. S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, the entire disclosures of which are incorporated by reference herein for all purposes.
[0030] Ester forms of the compounds according to the present teachings include pharmaceutically acceptable esters known in the art which can be metabolized into the free acid form, such as a free carboxylic acid form, in a mammal body. Examples of suitable esters include alkyl esters (e.g., alkyl of 1 to 10 carbon atoms), cycloalkyl esters (e.g., 3-10 carbon atoms), aryl esters (e.g., of 6-14 carbon atoms, including of 6-10 carbon atoms), and heterocyclic analogues thereof (e.g., of 3-14 ring atoms, 1-3 of which can be selected from oxygen, nitrogen, and sulfur heteroatoms) and the alcoholic residue can carry further substituents. In some embodiments, esters of the compounds disclosed herein can be Cj. io alkyl esters, such as methyl esters, ethyl esters, propyl esters, isopropyl esters, butyl esters, isobutyl esters, t-butyl esters, pentyl esters, isopentyl esters, neopentyl esters, hexyl esters, cyclopropylmethyl esters, and benzyl esters, C3-Io cycloalkyl esters, such as cyclopropyl esters, cyclobutyl esters, cyclopentyl esters, and cyclohexyl esters, or aryl esters, such as phenyl esters, and tolyl ester. [0031] Pharmaceutically acceptable salts of the compounds of formula I, which can have an acidic moiety, can be formed using organic or inorganic bases. Both mono and polyanionic salts are contemplated, depending on the number of acidic hydrogens available for deprotonation. Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts; ammonia salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri- lower alkylamine (e.g., ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-, di-, or trihydroxy lower alkylamine (e.g., mono-, di- or triethanolamine). Specific non-limiting examples of inorganic bases include NaHCO3, Na2CO3, KHCO3, K2CO3, Cs2CO3, LiOH, NaOH, KOH, NaH2PO4, Na2HPO4, and Na3PO4. Internal salts also can be formed. Similarly, when a compound disclosed herein contains a basic moiety, salts can be formed using organic and inorganic acids. For example, salts can be formed from the following acids: acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, dichloroacetic, ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric, oxalic, pamoic, pantothenic, phosphoric, phthalic, propionic, succinic, sulfuric, tartaric, toluenesulfonic, and as well as other known pharmaceutically acceptable acids.
[0032] The present teachings also provide pharmaceutical compositions including at least one compound described herein and one or more pharmaceutically acceptable carriers, excipients, or diluents. Examples of such carriers are well known to those skilled in the art and can be prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington: The Science and Practice of Pharmacy, 20th edition, Alfonoso R. Gennaro (ed.), Lippincott Williams & Wilkins, Baltimore, MD (2000), the entire disclosure of which is incorporated by reference herein for all purposes. As used herein, "pharmaceutically acceptable" refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient. Accordingly, pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and are biologically acceptable. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.
[0033] Compounds of the present teachings can be useful for the treatment or inhibition of a pathological condition or disorder in a mammal, for example, a human. The present teachings accordingly include a method of providing to a mammal a compound of the present teachings (or its pharmaceutically acceptable salt, hydrate, or ester) or a pharmaceutical composition that includes one or more compounds of the present teachings in combination or association with a pharmaceutically acceptable carrier. Compounds of the present teachings can be administered alone or in combination with other therapeutically effective compounds or therapies for the treatment or inhibition of the pathological condition or disorder. As used herein, "therapeutically effective" refers to a substance or an amount that elicits a desirable biological activity or effect.
[0034] The present teachings further include use of the compounds disclosed herein as active therapeutic substances for the treatment or inhibition of a pathological condition or disorder, for example, a condition mediated wholly or in part by one or more MMPs or characterized by an MMP/TIMP imbalance, such as rheumatoid arthritis, osteoarthritis, atherosclerosis, heart failure, fibrosis, pulmonary emphysema, and tumor growth, invasion, and metastasis, and diseases characterized by the accumulation of inflammatory cells, such as chronic obstructive pulmonary disease and asthma. Accordingly, the present teachings further provide methods of treating these pathological conditions and disorders using the compounds described herein. As used herein, "treating" refers to partially or completely alleviating and/or ameliorating the condition. In some embodiments, the methods include identifying a mammal having a pathological condition or disorder characterized by an
MMP/TIMP imbalance, and providing to the mammal a therapeutically effective amount of a compound as described herein. In some embodiments, the method includes administering to a mammal a pharmaceutical composition that comprises a compound disclosed herein in combination or association with a pharmaceutically acceptable carrier. [0035] The present teachings further include use of the compounds disclosed herein as active therapeutic substances for the prevention of a pathological condition or disorder, for example, a condition mediated wholly or in part by one or more MMPs or characterized by an MMP/TIMP imbalance such as rheumatoid arthritis, osteoarthritis, atherosclerosis, multiple sclerosis, heart failure, spinal cord injuries, skin aging, fibrosis, lung cancer, skin cancer, chronic obstructive pulmonary diseases, asthma, obesity, and diabetes. Accordingly, the present teachings further provide methods of preventing these pathological conditions and disorders using the compounds described herein. In some embodiments, the methods include identifying a mammal that could potentially have a pathological condition or disorder characterized by an MMP/TIMP imbalance, and providing to the mammal a therapeutically effective amount of a compound as described herein. In some embodiments, the method includes administering to a mammal a pharmaceutical composition that includes a compound disclosed herein in combination or association with a pharmaceutically acceptable carrier.
[0036] Compounds of the present teachings can be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances which can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, tablet-disintegrating agents, or encapsulating materials. The compounds can be formulated in conventional manner, for example, in a manner similar to that used for known antiinflammatory agents. Oral formulations containing an active compound disclosed herein can include any conventionally used oral form, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. In powders, the carrier can be a finely divided solid, which is an admixture with a finely divided active compound. In tablets, an active compound can be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets may contain up to 99% of the active compound.
[0037] Capsules can contain mixtures of active compound(s) with inert filler(s) and/or diluent(s) such as the pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.
[0038] Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, and ion exchange resins. Preferred surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine. Oral formulations herein can utilize standard delay or time-release formulations to alter the absorption of the active compound(s). The oral formulation can also consist of administering an active compound in water or fruit juice, containing appropriate solubilizers or emulsifiers as needed.
[0039] Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups, and elixirs. An active compound described herein can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture thereof, or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators. Examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as described above, e.g., cellulose derivatives such as a sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration, the carrier can be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellants.
[0040] Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intraperitoneal, or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration can be in either liquid or solid form.
[0041] The pharmaceutical composition can be in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the pharmaceutical composition can be sub-divided in unit dose(s) containing appropriate quantities of the active compound. The unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. Alternatively, the unit dosage form can be a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. Such unit dosage form may contain from about 1 mg/kg of active compound to about 500 mg/kg of active compound, and can be given in a single dose or in two or more doses. Such doses can be administered in any manner useful in directing the active compound(s) to the recipient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally. Such administrations can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts, hydrates, and esters thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).
[0042] When administered for the treatment or inhibition of a particular disease state or disorder, it is understood that an effective dosage can vary depending upon the particular compound utilized, the mode of administration, and/or severity of the condition being treated, as well as the various physical factors related to the individual being treated. In therapeutic applications, a compound of the present teachings can be provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. In preventive applications, a compound of the present teachings can be provided to a patient that can suffer from a disease in an amount sufficient to prevent or at least delay the symptoms of the disease and its complications. The dosage to be used in the treatment of a specific individual typically must be subjectively determined by the attending physician. The variables involved include the specific condition and its state as well as the size, age and response pattern of the patient.
[0043] In some cases, for example those in which the lung is the targeted organ, it may be desirable to administer a compound directly to the airways of the patient, using devices such as metered dose inhalers, breath-operated inhalers, multidose dry-powder inhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosol dispensers, and aerosol nebulizers. For administration by intranasal or intrabronchial inhalation, the compounds of the present teachings can be formulated into a liquid composition, a solid composition, or an aerosol composition. The liquid composition can include, by way of illustration, one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and can be administered by, for example, a pump or a squeeze-actuated nebulized spray dispenser. The solvents can be, for example, isotonic saline or bacteriostatic water. The solid composition can be, by way of illustration, a powder preparation including one or more compounds of the present teachings intermixed with lactose or other inert powders that are acceptable for intrabronchial use, and can be administered by, for example, an aerosol dispenser or a device that breaks or punctures a capsule encasing the solid composition and delivers the solid composition for inhalation. The aerosol composition can include, by way of illustration, one or more compounds of the present teachings, propellants, surfactants, and co-solvents, and can be administered by, for example, a metered device. The propellants can be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other propellants that are physiologically and environmentally acceptable. [0044] Compounds described herein can be administered parenterally or intraperitoneal^. Solutions or suspensions of these active compounds or pharmaceutically acceptable salts thereof can be prepared in water suitably mixed with a surfactant such as hydroxyl-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils.
Under ordinary conditions of storage and use, these preparations typically contain a preservative to inhibit the growth of microorganisms.
[0045] The pharmaceutical forms suitable for injection can include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In preferred embodiments, the form is sterile and its viscosity permits it to flow through a syringe. The form preferably is stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
[0046] Compounds described herein can be administered transdermally, i.e., administered across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administration can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal). Topical formulations that deliver active compound(s) through the epidermis can be useful for localized treatment of inflammation and arthritis.
[0047] Transdermal administration can be accomplished through the use of a transdermal patch containing an active compound and a carrier that can be inert to the active compound, can be non-toxic to the skin, and can allow delivery of the active compound for systemic absorption into the blood stream via the skin. The carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in- water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active compound can also be suitable. A variety of occlusive devices can be used to release the active compound into the blood stream, such as a semi-permeable membrane covering a reservoir containing the active compound with or without a carrier, or a matrix containing the active compound. Other occlusive devices are known in the literature.
[0048] Compounds described herein can be administered rectally or vaginally in the form of a conventional suppository. Suppository formulations can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin. Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, can also be used.
[0049] Lipid formulations or nanocapsules can be used to introduce compounds of the present teachings into host cells either in vitro or in vivo. Lipid formulations and nanocapsules can be prepared by methods known in the art.
[0050] To increase the effectiveness of compounds of the present teachings, it can be desirable to combine a compound with other agents effective in the treatment of the target disease. For inflammatory diseases, other active compounds (i.e., other active ingredients or agents) effective in their treatment, and particularly in the treatment of asthma and arthritis, can be administered with active compounds of the present teachings. The other agents can be administered at the same time or at different times than the compounds disclosed herein.
[0051] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present teachings also consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited processing steps.
[0052] In the application, where an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components and can be selected from a group consisting of two or more of the recited elements or components.
[0053] The use of the term "include," "includes," "including," "have," "has," or "having" should be generally understood as open-ended and non-limiting unless specifically stated otherwise.
[0054] The use of the singular herein includes the plural (and vice versa) unless specifically stated otherwise. In addition, where the use of the term "about" is before a quantitative value, the present teachings also include the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term "about" refers to a ±5% variation from the nominal value.
[0055] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present teachings remain operable. Moreover, two or more steps or actions may be conducted simultaneously.
[0056] As used herein, a "compound" refers to the compound itself and its pharmaceutically acceptable salts, hydrates, and esters, unless otherwise understood from the context of the description or expressly limited to one particular form of the compound, i.e., the compound itself, or a pharmaceutically acceptable salt, hydrate, or ester thereof.
[0057] As used herein, a "natural amino acid" refers to an amino acid normally occurring in natural proteins, e.g., L-α-amino acids. Examples of natural amino acids include glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, lysine, hydroxylysine, histidine, phenylalanine, tyrosine, tryptophan, proline, and 4- hydroxyproline.
[0058] As used herein, a "non-natural amino acid" refers to an amino acid that normally does not occur in proteins. For example, a non-natural amino acid can refer to an epimer of a natural L-amino acid, i.e., an amino acid having the D- configuration; a β-amino acid; an α,α-disubstituted amino acid; an α-amino acid where the amino acid side chain has been shortened by one or two methylene groups or lengthened by up to 10 carbon atoms such as an α-amino alkanoic acid with 5 and up to and including 10 carbon atoms in a linear chain; an unsubstituted or substituted aromatic amino acid such as phenylglycine or a substituted phenylalanine; a cyclic amino acid other than the natural cyclic amino acids; and boron analogues where a backbone methylene group is replaced by a boron group, e.g., -BHR'-, where R' is a side chain of a natural or non-natural amino acid. Examples of non-natural amino acids include β-alanine, taurine, α-aminobutyric acid, γ-aminoisobutyric acid, β- aminoisobutyric acid, homocysteine, homoserine, cysteinesulfinic acid, cysteic acid, felinine, isovalthine, 2,3-diaminosuccinic acid, γ-hydroxyglutamic acid, α-aminoadipic acid, α,ε-diaminopimelic acid, α,β-diaminopropionic acid, α,γ- diaminobutyric acid, ornithine, citulline, homocitrulline, saccharopine, azetidine-2- carboxylic acid, 3-hydroyproline, pipecolic acid, 5-hydroxytryptophan, 3,4- dihydroxyphenylalanine, monoiodotyrosine, 3,5-diiodotyrosine, 3,5,3'- triiodothyronine, thyroxine, and azaserine.
[0059] As used herein, an "amino acid derivative" refers to a natural or non- natural amino acid having its carboxylic acid group replaced by another chemical substituent or entity. Such another chemical substituent or entity can include an acyl group, a thiol group, a sulfonic acid group, a sulfuric acid group, a sulfonate group, a sulfonamide group, an ester group, an amide group, an amine group, an amidine group, a phosphonic acid group, a phosphonate group, a boronic acid group, and a boronic ester group.
[0060] As used herein, an "N-linked natural amino acid" refers to a natural amino acid where its basic amino group is lacking an amine hydrogen, which is replaced by a covalent bond to another chemical entity. As used herein, an "N- linked non-natural amino acid" refers to a non-natural amino acid where its basic amino group is lacking an amine hydrogen, which is replaced by a covalent bond to another chemical entity. As used herein, an "N-linked amino acid derivative" refers to an amino acid derivative where its basic amino group is lacking an amine hydrogen, which is replaced by a covalent bond to another chemical entity. [0061] As used herein, "free carboxyl" refers to a carboxylic acid group, e.g., a free carboxyl natural amino acid refers to a natural amino acid having a carboxylic acid group at a terminal position. As used herein, "carboxyl-protected" refers to carboxylic acid group that is protected or blocked to prevent unwanted side reactions from occurring with the carboxylic acid group. A carboxyl-protected molecule can be converted to a free carboxyl molecule under the appropriate conditions.
[0062] As used herein, the "tricyclic core" of compounds of formula I refers to:
where X is as defined herein. [0063] As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.
[0064] As used herein, "oxo" refers to a double-bonded oxygen (i.e., =0).
[0065] As used herein, "alkyl" refers to a straight-chain or branched saturated hydrocarbon group. In some embodiments, an alkyl group can have from 1 to 10 carbon atoms (e.g., from 1 to 6 carbon atoms). Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), pentyl groups (e.g., n-pentyl, isopentyl, neopentyl), and the like. In some embodiments, alkyl groups can be substituted with up to four independently selected -Z-R or R1 groups, where Z, R1 , and R13 are as described herein. A lower alkyl group typically has up to 4 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl (e.g., n-propyl and isopropyl), and butyl groups (e.g., n-butyl, isobutyl, s-butyl, t-butyl).
[0066] As used herein, "alkenyl" refers to a straight-chain or branched alkyl group having one or more carbon-carbon double bonds. In some embodiments, an alkenyl group can have from 2 to 10 carbon atoms (e.g., from 2 to 6 carbon atoms). Examples of alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl groups, and the like. The one or more carbon- carbon double bonds can be internal (such as in 2-butene) or terminal (such as in 1- butene). In some embodiments, alkenyl groups can be substituted with up to four independently selected -Z-R or R1 groups, where Z, R10, and R13 are as described herein.
[0067] As used herein, "alkynyl" refers to a straight-chain or branched alkyl group having one or more carbon-carbon triple bonds. In some embodiments, an alkynyl group can have from 2 to 10 carbon atoms (e.g., from 2 to 6 carbon atoms). Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, and the like. The one or more carbon-carbon triple bonds can be internal (such as in 2- butyne) or terminal (such as in 1-butyne). In some embodiments, alkynyl groups can be substituted with up to four independently selected -Z-R10 or R13 groups, where Z, R1 , and R1 are as described herein.
[0068] As used herein, "alkoxy" refers to an -O-alkyl group. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy groups, and the like.
[0069] As used herein, "alkylthio" refers to an -S-alkyl group. Examples of alkylthio groups include methylthio, ethylthio, propylthio (e.g., n-propylthio and isopropylthio), t-butylthio groups, and the like.
[0070] As used herein, "haloalkyl" refers to an alkyl group having one or more halogen substituents. Examples of haloalkyl groups include CF3, C2F5, CHF2, CH2F, CCl3, CHCl2, CH2Cl, C2Cl5, and the like. Perhaloalkyl groups, i.e., alkyl groups wherein all of the hydrogen atoms are replaced with halogen atoms (e.g., CF3 and C2F5), are included within the definition of "haloalkyl."
[0071] As used herein, "cycloalkyl" refers to a non-aromatic carbocyclic group including cyclized alkyl, alkenyl, and alkynyl groups. A cycloalkyl group can be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, and/or spiro ring systems), wherein the carbon atoms are located inside or outside of the ring system. A cycloalkyl group, as a whole, can have from 3 to 14 ring atoms (e.g., from 3 to 8 carbon atoms for a monocyclic cycloalkyl group and from 7 to 14 carbon atoms for a polycyclic cycloalkyl group). Any suitable ring position of the cycloalkyl group can be covalently linked to the defined chemical structure. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaryl, adamantyl, and spiro[4.5]decanyl groups, as well as their homologs, isomers, and the like. In some embodiments, cycloalkyl groups can be substituted with up to four independently selected -Z-R10 or R13 groups, where Z, R10, and R13 are as described herein. For example, cycloalkyl groups can include substitution of one or more oxo groups.
[0072] As used herein, "heteroatom" refers to an atom of any element other than carbon or hydrogen and includes, for example, nitrogen, oxygen, sulfur, phosphorus, and selenium.
[0073] As used herein, "cycloheteroalkyl" refers to a non-aromatic cycloalkyl group that contains at least one (e.g., one, two, three, four, or five) ring heteroatom selected from O, N and S, and optionally contains one or more (e.g., one, two, or three) double or triple bonds. A cycloheteroalkyl group, as a whole, can have, for example, from 3 to 14 ring atoms and contains from 1 to 5 ring heteroatoms (e.g., from 3-6 ring atoms for a monocyclic cycloheteroalkyl group and from 7 to 14 ring atoms for a polycyclic cycloheteroalkyl group). One or more N or S atoms in a cycloheteroalkyl ring may be oxidized (e.g., morpholine N-oxide, thiomorpholine S- oxide, thiomorpholine S,S-dioxide). In some embodiments, nitrogen atoms of cycloheteroalkyl groups can bear a substituent, for example, a -Z-R10 group or an R13 group, where Z, R10, and R1 as described herein. Cycloheteroalkyl groups can also contain one or more oxo groups, such as phthalimidyl, piperidonyl, oxazolidinonyl, 2,4(1 //,3H)-dioxo-pyrimidinyl, pyridin-2(lH)-onyl, and the like. Examples of cycloheteroalkyl groups include, among others, morpholinyl, thiomorpholinyl, pyranyl, imidazolidinyl, imidazolinyl, oxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, and the like In some embodiments, cycloheteroalkyl groups can be optionally substituted with up to four independently selected -Z-R10 or R13 groups, where Z, R10, and R13 are as described herein. [0074] As used herein, "cyclic urea" refers to a cycloheteroalkyl group that O
includes 'ΛfW "1^ as a part of the cycloheteroalkyl ring and does not contain any other ring heteroatom.
[0075] As used herein, "cyclic carbamate" refers to a cycloheteroalkyl group
that includes as a part of the cycloheteroalkyl ring and does not contain any other ring heteroatom.
[0076] As used herein, "cyclic sulfinamide" refers to a cycloheteroalkyl group O
that includes "^" as a part of the cycloheteroalkyl ring and does not contain any other ring heteroatom.
[0077] As used herein, "cyclic sulfonamide" refers to a cycloheteroalkyl group that includes ' as a part of the cycloheteroalkyl ring and does not contain any other ring heteroatom.
[0078] As used herein, "aryl" refers to an aromatic monocyclic hydrocarbon ring system or a polycyclic ring system where at least one of the rings present in the ring system is an aromatic hydrocarbon ring and any other aromatic rings present in the ring system include only hydrocarbons. In some embodiments, a monocyclic aryl group can have from 6 to 14 carbon atoms and a polycyclic aryl group can have from 8 to 14 carbon atoms. Any suitable ring position of the aryl group can be covalently linked to the defined chemical structure. In some embodiments, an aryl group can have only aromatic carbocyclic rings e.g., phenyl, 1-naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl groups, and the like. In other embodiments, an aryl group can be a polycyclic ring system in which at least one aromatic carbocyclic ring is fused (i.e., having a bond in common with) to one or more cycloalkyl or cycloheteroalkyl rings. Examples of such aryl groups include, among others, benzo derivatives of cyclopentane (i.e., an indanyl group, which is a 5,6-bicyclic cycloalkyl/aromatic ring system), cyclohexane (i.e., a tetrahydronaphthyl group, which is a 6,6-bicyclic cycloalkyl/aromatic ring system), imidazoline (i.e., a benzimidazolinyl group, which is a 5,6-bicyclic cycloheteroalkyl/aromatic ring system), and pyran (i.e., a chromenyl group, which is a 6,6-bicyclic cycloheteroalkyl/aromatic ring system). Other examples of aryl groups include benzodioxanyl, benzodioxolyl, chromanyl, indolinyl groups, and the like. In some embodiments, aryl groups optionally contain up to four independently selected -Z-R10 or R13 groups, where Z, R10, and R13 are as described herein.
[0079] As used herein, "heteroaryl" refers to an aromatic monocyclic ring system containing at least 1 ring heteroatom selected from oxygen (O), nitrogen (N) and sulfur (S) or a polycyclic ring system where at least one of the rings present in the ring system is aromatic and contains at least 1 ring heteroatom. A heteroaryl group, as a whole, can have, for example, from 5 to 13 ring atoms and contain 1-5 ring heteroatoms. Heteroaryl groups include monocyclic heteroaryl rings fused to one or more aromatic carbocyclic rings, non-aromatic carbocyclic rings, and non- aromatic cycloheteroalkyl rings. The heteroaryl group can be attached to the defined chemical structure at any heteroatom or carbon atom that results in a stable structure. Generally, heteroaryl rings do not contain 0-0, S-S, or S-O bonds. However, one or more N or S atoms in a heteroaryl group can be oxidized (e.g., pyridine N-oxide, thiophene S-oxide, thiophene S,S-dioxide). Examples of heteroaryl groups include, for example, the 5-membered monocyclic and 5-6 bicyclic ring systems shown below:
where T is O, S, NH, N-Z-R2, or N-Z-R8, wherein Z, R2, and R8 are as defined herein. Examples of such heteroaryl rings include pyrrolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, isothiazolyl, thiazolyl, thiadiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuryl, benzothienyl, quinolyl, 2-methylquinolyl, isoquinolyl, quinoxalyl, quinazolyl, benzotriazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzoxadiazolyl, benzoxazolyl, cinnolinyl, IH- indazolyl, 2H-indazolyl, indolizinyl, isobenzofuyl, naphthyridinyl, phthalazinyl, pteridinyl, purinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyridinyl, furopyridinyl, thienopyridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl groups, and the like. Further examples of heteroaryl groups include 4,5,6,7-tetrahydroindolyl, tetrahydroquinolinyl, benzothienopyridinyl, benzofuropyridinyl groups, and the like. In some embodiments, heteroaryl groups can be substituted with up to four substituents independently selected from -Z-R10 group and -R13 group, wherein Z, R10, and R13 are as described herein.
[0080] The compounds of the present teachings can include a "divalent group" defined herein as a linking group capable of forming a covalent bond with two other moieties. For example, compounds described herein can include a divalent C1-Io alkyl group, such as, for example, a methylene group. [0081] At various places in the present specification, substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, the term "Ci-I0 alkyl" is specifically intended to individually disclose C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C1-C10, C1-C9, Ci-C8, C1-C7, Ci-C6, CJ-C5, Ci-C4, Ci-C3, Ci-C2, C2-Ci0, C2-C9, C2-C8, C2-C7, C2-C6, C2-C5, C2-C4, C2-C3, C3-C10, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C10, C4-C9, C4-C8, C4-C7, C4-C6, C4-C5, C5-C10, C5-C9, C5-C8, C5-C7, C5-C6, C6-Ci0, C6-C9, C6-C8, C6-C7, C7-Ci0, C7-C9, C7-C8, C8-C10, C8-C9, and C9-C0 alkyl. By way of another example, the term "5-13 membered heteroaryl group" is specifically intended to individually disclose a heteroaryl group having 5, 6, 7, 8, 9, 10, 11, 12, 13, 5-13, 5-12, 5-11, 5-10, 5-9, 5-8, 5-7, 5-6, 6-13, 6-12, 6-1 1, 6-10, 6-9, 6-8, 6-7, 7- 13, 7-12, 7-11, 7-10, 7-9, 7-8, 8-13, 8-12, 8-11, 8-10, 8-9, 9-13, 9-12, 9-11, 9-10, 10- 13, 10-12, 10-11, 11-13, 11-12, or 12-13 ring atoms; and the phrase "optionally substituted with 1-4 substituents" is specifically intended to individually disclose a chemical group that can include 0, 1, 2, 3, 4, 0-4, 0-3, 0-2, 0-1, 1-4, 1-3, 1-2, 2-4, 2- 3, and 3-4 substituents.
[0082] Compounds described herein can contain an asymmetric atom (also referred as a chiral center), and some of the compounds can contain one or more asymmetric atoms or centers, which can thus give rise to optical isomers
(enantiomers) and diastereomers. The present teachings include methods for preparing such optical isomers (enantiomers) and diastereomers (geometric isomers), as well as the racemic and resolved, enantiomerically pure (+) and (-) stereoisomers, as well as other mixtures of the (+) and (-) stereoisomers and pharmaceutically acceptable salts thereof. In some embodiments, optical isomers can be obtained in enantiomerically enriched or pure form by standard procedures known to those skilled in the art, which include, for example, chiral separation, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. The present teachings also encompass methods for preparing cis and trans isomers of compounds containing alkenyl moieties (e.g., alkenes and imines). It is also understood that the present teachings encompass all methods for making possible regioisomers in pure form and mixtures thereof, which can include standard separation procedures known to those skilled in the art, for examples, column chromatography, thin-layer chromatography, simulated moving-bed chromatography, and high-performance liquid chromatography.
[0083] The compounds of the present teachings can be prepared in accordance with the procedures outlined in the scheme below, from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of the compounds described herein.
[0084] The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or C), infrared spectroscopy, spectrophotometry (e.g., UV -visible), or mass spectrometry, or by chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography.
[0085] Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 4th Ed., Wiley & Sons, 2006, the entire disclosure of which is incorporated by reference herein for all purposes. [0086] The reactions of the processes described herein can be carried out in suitable solvents which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i.e., temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected.
[0087] Scheme 1 below depicts an exemplary synthetic route for the preparation of compounds of formula I.
Scheme 1
[0088] As shown in Scheme 1, a compound of formula I, including compound iv, can be prepared from a sulfonyl chloride intermediate i. A compound of formula i can react with an amino acid or a derivative thereof to provide a compound of formula ii. The -NO2 group can be converted into an amino group, through which R2 and R3 can be incorporated to provide a compound of formula iv.
[0089] Scheme 2 below depicts an exemplary synthetic route for the preparation of the sulfonyl chloride intermediate i. Scheme 2
[0090] As shown in Scheme 2, a compound having a tricyclic core optionally substituted with R4 and R5, i.e., a compound of formula v, can be nitrated to provide a compound of formula vi, which can be sulfonated directly to provide a compound of formula i or indirectly to provide a compound of formula ix. The compound of formula ix can be further nitrated to provide the compound of formula i. Alternatively, the compound of formula v can be converted into the compound of formula i by a chlorosulfonation followed by a nitration.
[0091] The following examples illustrate various synthetic routes which can be used to prepare compounds of the invention of formula I.
Example 1: Preparation of (R)-2-(7-methoxycarbonyIamino-dibenzofuran-2- sulfonylamino)-3-methyl-butyric acid
Step 1: Preparation of 3-nitrodibenzo[b,dlfuran
[0092] The following procedures are similar to those described in Keumi et al. (1991), J. Org. Chem., 56: 4671-4677. Dibenzofuran (50 g) was mixed with 400 mL of trifluoroacetic acid (TFA). The resulting suspension was cooled in an ethanol ice bath and 11.7 mL of fuming nitric acid (HNO3, >90%) was added drop- wise over 10 minutes. The reaction mixture was allowed to warm to room temperature and stirred for two hours followed by filtration. The solid from the filtration was triturated with methanol (MeOH) and dried under reduced pressure to provide 45 g of 3-nitrodibenzo[b,d]furan in 70% yield.
Step 2: Preparation of 7-nitrodibenzorb,d]furan-2-sulfonic acid
[0093] To a round-bottom flask containing 3-nitrodibenzo[b,d]furan (21.4 g, 100 mmol) in 200 mL of chloroform (CHCl3) was slowly added chlorosulfonic acid (15.2 g, 130 mmol) at 0°C. The resulting suspension was allowed to warm to room temperature and stirred for 4 hours. After being cooled to O0C, the reaction mixture was filtered and 24.1 g of 7-nitrodibenzo [b,d]furan-2-sulfonic acid was collected from the filtrate as a white solid in 81% yield.
Step 3: Preparation of 7-nitrodibenzo[b,d]furan-2-sulfonyl chloride
[0094] 7-Nitrodibenzo[b,d]furan-2-sulfonic acid (2.93 g, 10 mmol) obtained from Step 2 was mixed with 15 mL of thionyl chloride (SOCl2) followed by slow addition of a few drops of dimethylformamide (DMF). The mixture was stirred at 80°C for 24 hours. The reaction mixture was filtered and excess SOCl2 in the filtrate was removed under reduced pressure. The crude product from the filtrate was isolated as a solid and triturated with ice water to provide 2.78 g of 7- nitrodibenzo[b,d]furan-2-sulfonyl chloride as an off-white solid in 89% yield.
Step 4: Preparation of (RΗert-butyl 3-methyl-2-(7-nitrodibenzo[b,dlfuran-2- sulfonamido'jbutanoate
[0095] 7-Nitrodibenzo[b,d]furan-2-sulfonyl chloride (570 mg, 1.83 mmol) from Step 3 and (R)-tert-buty\ 2-amino-3-methylbutanoate hydrochloride (422 mg, 2.0 mmol) were mixed with 5 mL of dichloromethane (CH2Cl2) followed by slow addition of N,N-diisopropylethylamine (520 mg, 4 mmol) at 0°C. The mixture was stirred and allowed to warm to room temperature for 4 hours. The reaction mixture was purified by column chromatography to provide (R)-valine sulfonamide as a white solid in 88% yield. Step 5: Preparation of (RVtert-butyl 2-(7-aminodibenzorb,d]furan-2-sulfonamido)-3- methylbutanoate
[0096] The nitro sulfonamide obtained in Step 4 (480 mg) was mixed with 20 mL of MeOH and 100 mg of palladium on carbon (Pd/C) (10%). The reaction was carried out in a Parr shaker at room temperature under hydrogen (50 psi) overnight. The reaction mixture was filtered through Celite® and concentrated to provide (R)-tert-butyl 2-(7-aminodibenzo[b,d]furan-2-sulfonamido)-3- methylbutanoate (430 mg) as an off-white solid in quantitative yield.
Step 6: Preparation of (RVtert-butyl 2-(7-methoxycarbonylamino-dibenzofuran-2- sulfonylamino)-3 -methyl-butyric acid
[0097] The aryl amine (0.25 mmol) from Step 5 and dimethylaminopyridine (DMAP, 37 mg, 0.3 mmol) were dissolved in 2 mL Of CH2Cl2, followed by the addition of methyl chloroformate (0.28 mmol). The mixture was stirred at room temperature overnight and purified by a silica gel column chromatography to provide (R)-tert-butyl 2-(7-methoxycarbonylamino-dibenzofuran-2-sulfonylamino)- 3-methyl-butyric acid as a white solid in 90% yield.
Step 7: Preparation of (R>2-(7-methoxycarbonylamino-dibenzofuran-2- sulfonylamino)-3-methyl-butyric acid
[0098] The sulfonamide t-butyl ester (0.2 mmol) from Step 6 was dissolved in 2 mL of TFA/CH2C12 (1 :1). The solution was stirred at room temperature for 3 hours. The solvents were removed under reduced pressure and the residue was triturated in acetonitrile (CH3CN)/water (H2O) followed by a freeze-dry process. (S)-2-(7- Methoxycarbonylamino-dibenzofuran-2-sulfonylamino)-3-methyl-butyric acid was obtained as a white solid. HRMS: calculated for [Ci9H20N2O7S - H]" 419.09185; found (ESI-FTMS, [M-H]1') 419.0916.
[0099] The sodium salt was prepared by treatment of (S)-2-(7- methoxycarbonylamino-dibenzofuran-2-sulfonylamino)-3 -methyl-butyric acid with 1.0 equivalent of sodium hydroxide (NaOH). The salt was obtained as a white solid. Example 2: Preparation of (R)-3-methyl-2-(7-(propoxycarbonylamino)dibenzo [b,d]furan-2-sulfonamido)butanoic acid
[0100] Following procedures analogous to those described in Example 1 and using propyl chloroformate, (R)-3-methyl-2-(7- (propoxycarbonylamino)dibenzo[b,d]furan-2-sulfonamido)butanoic acid was prepared from (R)-tert-butyl 2-(7-aminodibenzo[b,d]furan-2-sulfonamido)-3- methylbutanoate and obtained as a white solid. HRMS: calculated for [C21H24N2O7S - H]" 448.1304; found (ESI-FTMS, [M-H]1') 448.1313.
Example 3: Preparation of (R)-2-(7-(isopropoxycarbonylamino)dibenzo [b,d]furan-2-sulfonamido)-3-methylbutanoic acid
[0101] Following procedures analogous to those described in Example 1 and using isopropyl chloroformate, (R)-2-(7-(isopropoxycarbonylamino)dibenzo[b,d]furan-2- sulfonamido)-3-methylbutanoic acid was prepared from (R)-tert-butyl 2-(7- aminodibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoate and obtained as a white solid. HRMS: calculated for [C2iH24N2O7S - H]" 447.1226; found (ESI-FTMS, [M- H]1") 447.1216.
Example 4: Preparation of (R)-3-methyl-2-(7-(phenoxycarbonylamino)dibenzo [b,d]furan-2-suIfonamido) butanoic acid
[0102] Following procedures analogous to those described in Example 1 and using phenoxy chloroformate, (R)-3-methyl-2-(7-
(phenoxycarbonylamino)dibenzo[b,d]furan-2-sulfonamido) butanoic acid was prepared from (R)-tert-butyl 2-(7-aminodibenzo[b,d]furan-2-sulfonamido)-3- methylbutanoate and obtained as a white solid. HRMS: calculated for [C24H22N2O7S - H]" 481.1069; found (ESI-FTMS, [M-H]1") 481.1153. <
Example 5: Preparation of (R)-2-(7-(3-ethylureido)dibenzo[b,d]furan-2- sulfonamido)-3-methylbutanoic acid Step 1 : Preparation of (RVtert-butyl 2-(7-(3-ethylureido)dibenzo[b,d]furan-2- sulfonamido)-3-methylbutanoate
[0103] (R)-2-(7-Amino-dibenzofuran-2-sulfonylamino)-3-methyl-butyric acid tert- butyl ester (138 mg, 0.33 mmol) and ethylisocyanate (0.4 mmol) were mixed with 2 mL of tetrahydrofuran (THF). The mixture was irradiated with microwave at 12O0C for 20 minutes. (R)-Tert-butyl 2-(7-(3-ethylureido)dibenzo[b,d] furan-2- sulfonamido)-3-methylbutanoate was obtained as an off-white solid after column chromatography in 75% yield.
Step 2: Preparation of (R*)-2-(7-(3-ethylureido)dibenzo[b,d1 furan-2-sulfonamido)-3- methylbutanoic acid
[0104] (R)-Tert-butyl 2-(7-(3-ethylureido)dibenzo[b,d]furan-2-sulfonamido)-3- methylbutanoate (0.2 mmol) was dissolved in 4 mL OfTFAZCH2Cl2 (1:1). The solution was stirred at room temperature for 4 hours. The solvents were removed under reduced pressure and the residue was triturated with ether. (R)-2-(7-(3- Ethylureido)dibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoic acid was obtained as an off white solid after dried under high reduced pressure. 1H NMR (400 MHz, DMSOd6) δ ppm 0.81 (dd, J=I 3.90, 6.82 Hz, 6 H), 1.08 (t, 3 H), 1.88 - 1.99 (m, 1 H), 3.09 - 3.20 (m, 2 H), 3.58 (dd, J=9.60, 6.06 Hz, 1 H), 6.25 (t, J=5.56 Hz, 1 H), 7.23 (dd, J=8.59, 1.77 Hz, 1 H), 7.75 - 7.80 (m, 1 H), 7.80 - 7.84 (m, 1 H), 8.00 (d, J=9.60 Hz, 1 H), 8.07 (dd, J=5.31, 3.03 Hz, 2 H), 8.42 (dd, J=I .89, 0.63 Hz, 1 H), 8.87 (s, 1 H), and 12.50 (s, 1 H) (extra peak at 3.67); MS (ES-): 432.1.
[0105] The sodium salt was prepared by treatment of (R)-2-(7-(3- ethylureido)dibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoic acid with 1.0 equivalent of NaOH. The salt was obtained as a white solid.
Example 6: Preparation of (R)-2-{7-[3-(4-fluoro-benzyl)-ureido]-dibenzofuran- 2-sulfonylamino}-3-methyl-butyric acid
[0106] Following procedures analogous to those described in Example 5 and using 4-fluoro-benzyl isocyanate, (R)-2-{7-[3-(4-fluoro-benzyl)-ureido]-dibenzofuran-2- sulfonylamino} -3 -methyl-butyric acid was prepared as a white solid from (R)-tert- butyl 2-(7-aminodibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoate. MS (ES-): 512.1.
Example 7: Preparation of (R)-2-[7-(3-cyclopentylmethyl-ureido)- dibenzofuran-2-sulfonyIamino]-3-methyl-butyric acid
[0107] Following procedures analogous to those described in Example 5 and using cyclopentylmethyl isocyanate, (R)-2-[7-(3-cyclopentylmethyl-ureido)-dibenzofuran- 2-sulfonylamino]-3-methyl-butyric acid was prepared as an off-white solid from (R)-tert-butyl 2-(7-aminodibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoate. 1H NMR (400 MHz, DMSO-J6) δ ppm 0.81 (dd, J=14.15, 6.82 Hz, 6 H), 1.33 - 1.45 (m, 2 H), 1.50 - 1.71 (m, 4 H), 1.80 - 2.00 (m, 3 H), 3.58 (dd, J=9.47, 5.94 Hz, 1 H), 3.91 - 4.04 (m, 1 H), 6.31 (d, J=7.33 Hz, 1 H), 7.20 (dd, J=8.59, 1.77 Hz, 1 H), 7.75 - 7.87 (m, 2 H), 8.01 (d, J=9.35 Hz, 1 H), 8.04 - 8.11 (m, 2 H), 8.42 (d, J=I.52 Hz, 1 H), and 8.71 (s, 1 H) 12.50 (s, 1 H); MS (ES-) 472.1.
Example 8: Preparation of (R)-2-[7-(3-isopropylureido)-dibenzofuran -2- sulfonylamino]-3-methyl-butyric acid
[0108] Following procedures analogous to those described in Example 5 and using isopropyl isocyanate, (R)-2-[7-(3-isopropylureido)-dibenzofuran-2-sulfonylamino]- 3-methyl-butyric acid was prepared as an off-white solid from (R)-tert-butyl 2-(7- aminodibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoate. 1H NMR (400 MHz, DMSO-J6) δ ppm 0.81 (dd, J=14.15, 6.82 Hz, 6 H), 1.12 (s, 3 H), 1.13 (s, 3 H), 1.89 - 1.99 (m, 1 H), 3.58 (dd, J=9.47, 5.94 Hz, 1 H), 3.80 (dd, J=13.89, 6.57 Hz, 1 H), 6.15 (d, J=7.58 Hz, 1 H), 7.20 (dd, J=8.59, 1.77 Hz, 1 H), 7.75 - 7.85 (m, 2 H), 8.01 (d, J=9.60 Hz, 1 H), 8.05 - 8.10 (m, 2 H), 8.42 (d, J-2.02 Hz, 1 H), and 8.74 (s, 1 H) 12.50 (s, I H); MS (ES-) 446.1.
Example 9: Preparation of (R)-3-methyl-2-{7-[3-(3,4,5-trimethoxy-phenyl)- ureido]-dibenzofuran-2-sulfonylamino}-butyric acid
[0109] Following procedures analogous to those described in Example 5 and using 3 ,4, 5 -trimethoxy-pheny 1 isocyanate, (R)-3 -methy 1-2- { 7- [3 -(3 ,4,5 -trimethoxy- phenyl)-ureido]-dibenzofuran-2-sulfonylamino} -butyric acid was prepared as an off- white solid from (R)-tert-butyl 2-(7-aminodibenzo[b,d]furan-2-sulfonamido)-3- methylbutanoate. 1H NMR (400 MHz, DMSO-^6) δ ppm 0.82 (dd, J=14.15, 6.82 Hz, 6 H), 1.95 (dd, J=12.88, 6.82 Hz, 1 H), 3.56 - 3.62 (m, 1 H), 3.62 (s, 3 H), 3.77 (s, 6 H), 6.83 (s, 2 H), 7.33 (dd, J=8.46, 1.89 Hz, 1 H), 7.79 - 7.83 (m, 1 H), 7.83 - 7.88 (m, 1 H), 8.02 (d, J=9.60 Hz, 1 H), 8.09 (d, J=I .77 Hz, 1 H), 8.15 (d, J=8.34 Hz, 1 H), 8.47 (dd, J=I.77, 0.51 Hz, 1 H), 8.76 (s, 1 H), 9.06 (s, 1 H), and 12.50 (s, 1 H); MS (ES-): 570.1.
Example 10: Preparation of (R)-2-(7-(3-(3,4-difluorophenyl)ureido)dibenzo [b,d]furan-2-suIfonamido)-3-methylbutanoic acid
[0110] Following procedures analogous to those described in Example 5 and using 3,4-difluorophenyl isocyanate, (R)-2-(7-(3-(3,4- difluorophenyl)ureido)dibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoic acid was prepared as an off-white solid from (R)-tert-butyl 2-(7-aminodibenzo[b,d]furan-2- sulfonamido)-3-methylbutanoate. 1H NMR (400 MHz, DMSOd6) δ ppm 0.82 (dd, J=13.77, 6.69 Hz, 6 H), 1.89 - 2.01 (m, 1 H), 3.60 (dd, J=9.47, 5.94 Hz, 1 H), 7.14 - 7.21 (m, 1 H), 7.33 - 7.42 (m, 2 H), 7.66 - 7.74 (m, 1 H), 7.79 - 7.84 (m, 1 H), 7.84 - 7.88 (m, 1 H), 8.03 (d, J=9.60 Hz, 1 H), 8.09 (d, J=I.77 Hz, 1 H), 8.16 (d, J=8.34 Hz, 1 H), 8.48 (d, J=2.02 Hz, 1 H), 9.06 (s, 1 H), 9.22 (s, 1 H), and 12.50 (s, 1 H); MS (ES-) 516.1.
Example 11: Preparation of (R)-2-(7-(3-(4-(dimethylamino)phenyl)ureido) dibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoic acid
[01 11] Following procedures analogous to those described in Example 5 and using 4-(dimethylamino) phenyl isocyanate, (R)-2-(7-(3-(4-
(dimethylamino)phenyl)ureido)dibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoic acid was prepared as an off-white solid from (R)-tert-butyl 2-(7- aminodibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoate. 1H NMR (400 MHz, DMSO-<4) δ ppm 0.82 (dd, J=13.90, 6.82 Hz, 6 H), 1.87 - 2.01 (m, 1 H), 3.02 (s, 6 H), 3.59 (dd, J=9.47, 5.94 Hz, 1 H), 7.18 (s, 2 H), 7.34 (dd, J=8.46, 1.64 Hz, 1 H), 7.49 (d, J=8.59 Hz, 2 H), 7.77 - 7.88 (m, 2 H), 8.03 (d, J=9.60 Hz, 1 H), 8.09 - 8.19 (m, 2 H), 8.47 (d, J=I.77 Hz, 1 H), 8.97 (s, 1 H), 9.29 (s, 1 H), and 12.50 (s, 1 H); MS (ES-) 523.2.
Example 12: Preparation of (R)-3-methyl-2-(7-(3-(3-phenoxyphenyI)ureido) dibenzo[b,d]furan-2-sulfonamido)-butanoic acid
[0112] Following procedures analogous to those described in Example 5 and using 3-phenoxyphenyl isocyanate, (R)-3-methyl-2-(7-(3-(3- phenoxyphenyl)ureido)dibenzo [b,d] furan-2-sulfonamido)-butanoic acid was prepared as an off-white solid from (R)-tert-butyl 2-(7-aminodibenzo[b,d]furan-2- sulfonamido)-3-methylbutanoate. 1H NMR (400 MHz, DMSO-J6) δ ppm 0.82 (dd, J=14.02, 6.69 Hz, 6 H), 1.89 - 2.00 (m, 1 H), 3.59 (dd, J=9.60, 6.06 Hz, 1 H), 6.62 - 6.67 (m, 1 H), 7.03 - 7.08 (m, 2 H), 7.14 - 7.20 (m, 2 H), 7.27 - 7.33 (m, 3 H), 7.39 - 7.45 (m, 2 H), 7.79 - 7.83 (m, 1 H), 7.83 - 7.87 (m, 1 H), 8.02 (d, J=9.35 Hz, 1 H), 8.06 (d, J=1.77 Hz, 1 H), 8.14 (d, J=8.59 Hz, 1 H), 8.47 (d, J=1.26 Hz, 1 H), 8.94 (s, 1 H), 9.09 (s, 1 H), and 12.50 (s, 1 H); MS (ES-) 572.2.
Example 13: Preparation of (R)-3-methyl-2-(7-ureidodibenzo[b,d]furan-2- sulfonamido)butanoic acid
[01 13] Following procedures analogous to those described in Example 5, (R)-3- methyl-2-(7-ureidodibenzo[b,d]furan-2-sulfonamido)butanoic acid was prepared as an off-white solid from (R)-tert-butyl 2-(7-aminodibenzo[b,d]furan-2-sulfonamido)- 3-methylbutanoate and 4-methoxybenzyl isocyanate. 1H NMR (400 MHz, DMSO- ^6) δ ppm 0.82 (dd, J=14.02, 6.69 Hz, 6 H), 1.89 - 1.99 (m, 1 H), 3.59 (dd, J=9.47, 5.94 Hz, 1 H), 6.02 (s, 2 H), 7.25 (dd, J=8.46, 1.89 Hz, 1 H), 7.76 - 7.80 (m, 1 H), 7.80 - 7.85 (m, 1 H), 8.01 (d, J=9.35 Hz, 1 H), 8.04 - 8.11 (m, 2 H), 8.43 (d, J=2.02 Hz, 1 H), 8.97 (s, 1 H), and 12.50 (s, 1 H); MS (ES-) 404.1.
Example 14: Preparation of (R)-3-methyl-2-(7-(3-(4-
(trifluoromethoxy)phenyl)ureido)dibenzo[b,d]furan-2-sulfonamido)butanoic acid [0114] Following procedures analogous to those described in Example 5 and using 4-(trifluoromethoxy)phenyl isocyanate, (R)-3-methyl-2-(7-(3-(4- (trifluoromethoxy)phenyl)ureido)dibenzo[b,d]furan-2-sulfonamido)butanoic acid was prepared as an off-white solid from (R)-tert-butyl 2-(7-aminodibenzo[b,d]furan- 2-sulfonamido)-3-methylbutanoate. 1H NMR (400 MHz, DMSOd6) δ ppm 0.82 (dd, J-13.90, 6.57 Hz, 6 H), 1.90 - 2.00 (m, 1 H), 3.60 (dd, J=9.47, 5.94 Hz, 1 H), 7.28 - 7.38 (m, 3 H), 7.57 - 7.63 (m, 2 H), 7.79 - 7.84 (m, 1 H), 7.84 - 7.88 (m, 1 H), 8.03 (d, J=9.60 Hz, 1 H), 8.11 (d, J=I.77 Hz, 1 H), 8.16 (d, J=8.59 Hz, 1 H), 8.48 (dd, J=2.02, 0.51 Hz, 1 H), 9.03 (s, 1 H), 9.18 (s, 1 H), and 12.51 (s, 1 H); MS (ES-) 564.1.
Example 15: Preparation of (R)-2-(7-(3-(2,6-dichloropyridin-4-yl)ureido) dibenzo[b,d]furan-2-suIfonamido)-3-methylbutanoic acid
[0115] Following procedures analogous to those described in Example 5 and using 2,6-dichloropyridin-4-yl isocyanate, (R)-2-(7-(3-(2,6-dichloropyridin-4- yl)ureido)dibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoic acid was prepared as an off-white solid from (R)-tert-butyl 2-(7-aminodibenzo[b,d]furan-2-sulfonamido)- 3-methylbutanoate. 1H NMR (400 MHz, DMSO-</6) δ ppm 0.82 (dd, J=13.64, 6.82 Hz, 6 H), 1.90 - 2.00 (m, 1 H), 3.60 (dd, ./=9.47, 5.94 Hz, 1 H), 7.40 (dd, J=8.59, 1.77 Hz, 1 H), 7.60 (s, 2 H), 7.82 - 7.86 (m, 1 H), 7.86 - 7.90 (m, 1 H), 8.04 (d, J=9.60 Hz, 1 H), 8.08 (d, J=I.77 Hz, 1 H), 8.21 (d, J=8.34 Hz, 1 H), 8.50 (dd, J=IJl, 0.51 Hz, 1 H), 9.60 (s, 1 H), 9.71 (s, 1 H), and 12.50 (s, 1 H); MS (ES-) 549.1.
Example 16: Preparation of (R)-3-methyl-2-(7-(3-(2-(thiophen-2- yl)ethyl)ureido)dibenzo[b,d]furan-2-suIfonamido)butanoic acid
[0116] Following procedures analogous to those described in Example 5 and using 2-(thiophen-2-yl)ethyl isocyanate, (R)-3-methyl-2-(7-(3-(2-(thiophen-2- yl)ethyl)ureido)dibenzo[b,d]furan-2-sulfonamido)butanoic acid was prepared as an off-white solid from (R)-tert-butyl 2-(7-aminodibenzo[b,d]furan-2-sulfonamido)-3- methylbutanoate. 1H NMR (400 MHz, DMSO-^6) δ ppm 0.82 (dd, ./=13.90, 6.82 Hz, 6 H), 1.89 - 1.99 (m, 1 H), 3.00 (t, J=6.95 Hz, 2 H), 3.37 - 3.43 (m, 2 H), 3.59 (dd, J=9.47, 5.94 Hz, 1 H), 6.37 (t, J=5.81 Hz, 1 H), 6.94 (dd, J=3.41, 1.14 Hz, 1 H), 6.99 (dd, J=5.05, 3.28 Hz, 1 H), 7.23 (dd, J=8.59, 1.77 Hz, 1 H), 7.36 (dd, J=5.05, 1.26 Hz, 1 H), 7.77 - 7.81 (m, 1 H), 7.81 - 7.85 (m, 1 H), 8.01 (d, J=9.60 Hz, 1 H), 8.08 (dd, J=5.05, 3.03 Hz, 2 H), 8.43 (dd, J=I.90, 0.63 Hz, 1 H), 9.01 (s, 1 H), and 12.50 (s, I H); MS (ES-) 514.2.
Example 17: Preparation of (S)-2-(7-(3-ethylureido)dibenzo[b,d]furan-2- sulfonamido)-3-methylbutanoic acid
[0117] Following procedures analogous to those described in Example 5, (S)-2-(7- (3-ethylureido)dibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoic acid was prepared as an off-white solid from (S)-tert-butyl 2-(7-aminodibenzo[b,d]furan-2- sulfonamido)-3-methylbutanoate. 1H NMR (400 MHz, DMSO-£/6) δ ppm 0.82 (dd, J=13.90, 6.82 Hz, 6 H), 1.08 (t, J=7.20 Hz, 3 H), 1.89 - 1.99 (m, 1 H), 3.10 - 3.19 (m, 2 H), 3.58 (dd, J=9.47, 5.94 Hz, 1 H), 6.25 (t, J-5.56 Hz, 1 H), 7.23 (dd, J=8.59, 1.77 Hz, 1 H), 7.76 - 7.80 (m, 1 H), 7.80 - 7.85 (m, 1 H), 8.01 (d, J=9.60 Hz, 1 H), 8.07 (dd, J=5.05, 3.03 Hz, 2 H), 8.42 (dd, J=1.89, 0.63 Hz, 1 H), 8.88 (s, 1 H), and 12.50 (s, I H); MS (ES-) 432.1.
Example 18: Preparation of (R)-3-methyl-2-(7-(methylsulfonamido)dibenzo |b,d]furan-2-sulfonamido)bu tannic acid
Step 1 : Preparation of (Ry3-methyl-2-(7-(methylsulfonamido)dibenzo[b,d]furan-2- sulfonamido'lbutanoic acid tert-butyl ester
[0118] (R)-Tert-butyl 2-(7-aminodibenzo[b,d]furan-2-sulfonamido)-3- methylbutanoate (0.36 mmol) and DMAP (53 mg, 0.43 mmol) were mixed with 2 mL of CH2Cl2, followed by addition of methylsulfonyl chloride (0.40 mmol). The mixture was stirred at room temperature for two hours and purified with a silica gel column chromatography to provide the methylsulfonamide t-butyl ester as a white solid in 90% yield. Step 2: Preparation of (R)-3-methyl-2-(7-(methylsulfonamido)dibenzo[b,d1furan-2- sulfonamido)butanoic acid
[01 19] The above sulfonamide t-butyl ester was dissolved in 4 mL of TFA/CH2Cl2 (1 :1). The solution was stirred at room temperature for 4 hours. The solvents were removed under reduced pressure and the residue was triturated in CH3CNZH2O followed by a freeze-dry process. (R)-3-Methyl-2-(7-
(methylsulfonamido)dibenzo[b,d]furan-2-sulfonamido)butanoic acid was obtained as a white solid. 1H NMR (400 MHz, DMSO-J6) δ ppm 0.81 (dd, J=14.15, 6.82 Hz, 6 H), 1.94 (dd, J=12.88, 6.82 Hz, 1 H), 3.09 (s, 3 H), 3.59 (dd, J=9.47, 5.94 Hz, 1 H), 7.29 (dd, J=8.46, 1.89 Hz, 1 H), 7.57 (d, J=I .77 Hz, 1 H), 7.82 - 7.86 (m, 1 H), 7.87 - 7.90 (m, 1 H), 8.05 (d, J=9.60 Hz, 1 H), 8.24 (d, J=8.34 Hz, 1 H), 8.51 (dd, J=2.02, 0.51 Hz, 1 H), 10.18 (s, 1 H), and 12.50 (s, 1 H); HRMS: calculated for 2[C18H20N2O7S2 + H]+ 881.14966; found (ESI-FTMS, [2M+H]I+) 881.1488.
[0120] The sodium salt was prepared by treatment of (R)-3-methyl-2-(7- (methylsulfonamido)dibenzo[b,d]furan-2-sulfonamido)butanoic acid with 1.0 equivalent of NaOH. The salt was obtained as a white solid.
Example 19: Preparation of (S)-3-methyl-2-(7- (methylsulfonamido)dibenzo[b,d]furan-2-sulfonamido)butanoic acid
[0121] Following procedures analogous to those described in Example 18 and using the corresponding aniline analog derived from L-valine, (S)-3-methyl-2-(7-
(methylsulfonamido)dibenzo[b,d]furan-2-sulfonamido)butanoic acid was prepared as a white solid. MS (ES-) 439.1.
Example 20: Preparation of (R)-2-(7-
(chloromethylsulfonamido)dibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoic acid
[0122] Following procedures analogous to those described in Example 18 and using chloromethylsulfonyl chloride, (R)-2-(7- (chloromethylsulfonamido)dibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoic acid was prepared as a white solid in 95% yield from (R)-tert-butyl 2-(7- aminodibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoate. MS (ES-) 473.0.
Example 21: Preparation of (R)-3-methyl-2-(7-(isopropylsulfonamido) dibenzo[b,d]furan-2-sulfonamido)butanoic acid
[0123] Following procedures analogous to those described in Example 18 and using isopropylsulfonyl chloride, (R)-3-methyl-2-(7-
(isopropylsulfonamido)dibenzo[b,d]furan-2-sulfonamido)butanoic acid was prepared from (R)-tert-butyl 2-(7-aminodibenzo[b,d]furan-2-sulfonamido)-3- methylbutanoate. MS (ES-) 467.1.
Example 22 : Preparation of (R)-2-(7-(3,5-dimethylisoxazole-4- sulfonamido)dibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoic acid
[0124] Following procedures analogous to those described in Example 18 and using 3,5-dimethylisoxazol-4-yl sulfonyl chloride, (R)-2-(7-(3,5-dimethylisoxazole-4- sulfonamido)dibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoic acid was prepared as a white solid from (R)-tert-butyl 2-(7-aminodibenzo[b,d]furan-2-sulfonamido)-3- methylbutanoate. MS (ES-) 520.1.
Example 23: Preparation of (R)-3-methyl-2-(7- (phenylsulfonamido)dibenzo[b,d]furan-2-sulfonamido)butanoic acid
[0125] Following procedures analogous to those described in Example 18 and using phenyl sulfonyl chloride, (R)-3-methyl-2-(7-(phenylsulfonamido)dibenzo[b,d]furan- 2-sulfonamido)butanoic acid was prepared as a white solid from (R)-tert-butyl 2-(7- aminodibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoate. MS (ES-) 501.1.
Example 24: Preparation of (S)-2-(7-
(methoxycarbonylamino)dibenzo[b,d]thiophene-2-sulfonamido)-3- methylbutanoic acid
[0126] Following procedures analogous to those described in Example 1 and using (S)-tert-butyl 2-amino-3-methylbutanoate hydrochloride, (S)-2-(7- (methoxycarbonylamino)dibenzo[b,d]thiophene-2-sulfonamido)-3-methylbutanoic acid was prepared as a white solid from dibenzothiophene. HRMS: calculated for [Ci9H20N2O6S2 + H]+ 437.08355; found (ESI-FTMS, [M+H]1+) 437.0833.
Example 25: Preparation of (R)-2-(7-
(methoxycarbonylamino)dibenzo[b,d]thiophene-2-sulfonamido)-3- methylbutanoic acid
[0127] Following procedures analogous to those described in Example 1 and using (R)-tert-butyl 2-amino-3-methylbutanoate hydrochloride, (R)-2-(7- (methoxycarbonylamino)dibenzo[b,d]thiophene-2-sulfonamido)-3-methylbutanoic acid was prepared as a white solid from dibenzothiophene. HRMS: calculated for [C9H20N2O6S2 + H]+ 437.08355; found (ESI-FTMS, [M+H]1+) 437.0833.
Example 26: Preparation of (S)-3-methyl-2-(7- (methylsulfonamido)dibenzo[b,d] thiophene-2-sulfonamido)butanoic acid
[0128] Following procedures analogous to those described in Example 18, (S)-3- methyl-2-(7-(methylsulfonamido)dibenzo[b,d]thiophene-2-sulfonamido)butanoic acid was prepared as a white solid from (S)-tert-butyl 2-(7-aminodibenzo[b,d] thiophene-2-sulfonamido)-3-methylbutanoate. HRMS: calculated for [Ci8H20N2O6S3 + H]+ 457.05562; found (ESI-FTMS, [M+H]1+) 457.0555.
Example 27: Preparation of (R)-3-methyl-2-(7- (methylsuIfonamido)dibenzo[b,d]thiophene-2-sulfonamido)butanoic acid
[0129] Following procedures analogous to those described in Example 18, (R)-3- methyl-2-(7-(methylsulfonamido)dibenzo[b,d]thiophene-2-sulfonamido)butanoic acid was prepared and obtained as a white solid from (R)-tert-butyl 2-(7- aminodibenzo[b,d]thiophene-2-sulfonamido)-3-methylbutanoate. HRMS: calculated for [C18H20N2O6S3 + H]+ 457.05562; found (ESI-FTMS, [M+H]1+) 457.0548.
Example 28: Preparation of (S)-2-(8-
(isobutoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid Step 1 : Preparation of dibenzo[b,d]furan-3-amine
[0130] 3-Nitrodibenzo[b,d]furan obtained from nitration of dibenzofuran (Example 1) (2.13 g, 10 mmol) was mixed with 20 mL of MeOH and 0.5 g of Pd/C. The reaction was carried out using a Parr shaker at room temperature under hydrogen (50 psi) overnight. The reaction mixture was filtered through Celite®. Removal of MeOH gave 1.80 g of dibenzo[b,d]furan-3 -amine as an off-white solid in 98% yield.
Step 2: Preparation of dibenzo[b1d1furan-3-sulfonyl chloride
[0131] A mixture of dibenzo[b,d]furan-3-amine (6 g, 32.4 mmol), glacial acetic acid (AcOH, 60 mL), and concentrated hydrochloric acid (HCl, 60 mL) was added slowly to sodium nitrite (NaNO2) (2.68 g, 38.8 mmol) in 20 mL of H2O at -2O0C to give a yellow suspension. The suspension was stirred for 30 minutes, and subsequently treated with a mixture of sulfur dioxide (30 mL) in 40 mL of 50% AcOH and dihydrate of copper (I) chloride (CuCl2-2H2O, 11.5 g, 676.2 mmol) at - 23 °C. The mixture was slowly warmed to room temperature and stirred for 21 hours. Once the disappearance of the starting material was confirmed by thin layer chromatography (TLC), the reaction mixture was quenched with water and extracted with ethyl acetate (EtOAc, 3 x 50 mL). The combined organic layers were washed with a saturated solution of sodium bicarbonate and brine, dried over sodium sulfate, and concentrated to provide 4.44 g of dibenzo[b,d]furan-3-sulfonyl chloride as a white solid in 51% yield.
Step 3: Preparation of 8-nitrodibenzo[b,d]furan-3-sulfonyl chloride
[0132] Dibenzo[b,d]furan-3-sulfonyl chloride (10.64 g, 40 mmol) was dissolved in 60 mL Of CH2Cl2 and the resulting solution was stirred for 30 minutes at room temperature. After addition of 100 mL of TFA to the solution, nitric acid (HNO3, 10.6g, 168 mmol) was added dropwise. The mixture was stirred at room temperature for 6 hours and monitored by 1H NMR, and the desired product precipitated out of the reaction mixture. CH2Cl2 was removed under reduced pressuremore TFA (60 mL) was added, and the reaction mixture was filtered. The filter cake was washed with cold water to provide 10.11 g of 8- nitrodibenzo[b,d]furan-3-sulfonyl chloride as a yellow solid in 78% yield. Step 4: Preparation of (S)-tert-butyl 3-methyl-2-(8-nitrodibenzo[b,d]furan-3- sulfonamido)butanoate
[0133] L- Valine /-butyl ester (HCl salt, 14.98 g, 71.4 mmol) and di- isopropylethylamine (20 g, 24.9 rnL) were mixed in CH2Cl2 (250 mL), and 8- nitrodibenzo[b,d]furan-3-sulfonyl chloride from Step 3 (22.26 g, 71.4 mmol) was added slowly at 0°C. The reaction was allowed to warm up to room temperature for 2 hours. Water (200 mL) was added into the reaction flask and CH2Cl2 was removed under reduced pressure with continuous stirring. The desired product precipitated out as a white solid in the aqueous media after complete removal of CH2Cl2. The suspension was filtered and the filter cake was washed with water and dried to give 30.4 g of (S)-tert-butyl 3-methyl-2-(8-nitrodibenzo[b,d]furan-3- sulfonamido)butanoate in 94% yield.
Step 5: Preparation of (S)-tert-butyl 2-(8-aminodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate [0134] (S)-Tert-butyl 3-methyl-2-(8-nitrodibenzo[b,d]furan-3-sulfonamido) butanoate (6.12 g) and 0.6 g of 10% Pd/C (50% water) in MeOH (150 mL) was placed in a Parr shaker under hydrogen atmosphere (50 psi) for 6 hours. The suspension was filtered through Celite®. Concentration of the filtrate afforded 5.70 g of (S)-tert-butyl 2-(8-aminodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate as a white solid in 98% yield.
Step 6: Preparation of (S)-2-(8-(isobutoxycarbonylaniino)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoic acid tert-butyl ester
[0135] (S)-Tert-butyl 2-(8-aminodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate (0.5 mmol) from Step 5 and DMAP (0.6 mmol) was dissolved in 5 mL Of CH2Cl2, followed by slow addition of isobutyl chloroformate (0.55 mmol). The mixture was stirred at room temperature overnight, and purified by a silica gel column chromatography to provide (S)-2-(8-(isobutoxycarbonylamino)dibenzo [b,d]furan-3-sulfonamido)-3-methylbutanoic acid tert-butyl ester as a white solid in85% yield. Step 7: Preparation of (S)-2-(8-(isobutoxycarbonylamino)dibenzofb,d]furan-3- sulfonamido)-3-methylbutanoic acid
[0136] The carbamate t-butyl ester (0.4 mmol, Step 6) was dissolved in 4 mL of TFA/CH2C12 (1 :1). The solution was stirred at room temperature for 3 hours. The solvents were removed under reduced pressure and the residue was triturated in CH3CN/water followed by a freeze-dry process. (S)-2-(8-
(Isobutoxycarbonylamino)dibenzo [b,d] furan-3 -sulfonamido)-3 -methylbutanoic acid was obtained as a white solid in 98% yield. HRMS: calculated for [C22H26N2O7S + H]+ 463.15335; found (ESI-FTMS, [M+H]1+) 463.1544.
[0137] The sodium salt was prepared by treatment of (S)-2-(8-
(isobutoxycarbonylamino) dibenzo[b,d] furan-3 -sulfonamido)-3 -methylbutanoic acid with 1.0 equivalent of NaOH. The salt was obtained as a white solid.
Example 29: Preparation of (S)-2-(8-((2- chloroethoxy)carbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoic acid
[0138] Following procedures analogous to those described in Example 28, (S)-2-(8- ((2-chloroethoxy)carbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoic acid was prepared as a white solid in 100% yield from 2-chloroethyl chloroformate. HRMS: calculated for [C20H21ClN2O7S + H]+ 469.08308; found (ESI-FTMS, [M+H]1+) 469.0835.
Example 30: Preparation of (S)-2-(8-((2- bromoethoxy)carbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoic acid
[0139] Following procedures analogous to those described in Example 28 and using 2-bromoethyl chloroformate, (S)-2-(8-((2- bromoethoxy)carbonylamino)dibenzo [b,d] furan-3 -sulfonamido)-3 -methylbutanoic acid was prepared as a white solid in 90% yield. MS (ES-) 513.02. Example 31: Preparation of (S)-2-(8-
(isopropoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoic acid
[0140] Following procedures analogous to those described in Example 28 and using isopropyl chloroformate, (S)-2-(8-(isopropoxycarbonylamino)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoic acid was prepared as a white solid in 100% yield. HRMS: calculated for [C21H24N2O7S + H]+ 449.13770; found (ESI-FTMS, [M+H]1+) 449.1379.
Example 32: Preparation of (S)-2-(8-((4- fluorophenoxy)carbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoic acid
[0141] Following procedures analogous to those described in Example 28 and using 4-fluorophenyl chloroformate, (S)-2-(8-((4- fluorophenoxy)carbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid was prepared as a white solid in 90% yield. HRMS: calculated for [C24H2IFN2O7S + H]+ 501.11263; found (ESI-FTMS, [M+H]1+) 501.1125.
Example 33: Preparation of (S)-2-(8-((2- chlorophenoxy)carbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoic acid
[0142] Following procedures analogous to those described in Example 28 and using 2-chlorophenyl chloforomate, (S)-2-(8-((2- chlorophenoxy)carbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid was prepared as a white solid in 96% yield. HRMS: calculated for [C24H21ClN2O7S + NH4]+ 534.10963; found (ESI-FTMS, [M+NH4]I+) 534.1096.
Example 34: Preparation of (S)-2-(8-((but-2- ynyloxy)carbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid [0143] Following procedures analogous to those described in Example 28 and using but-2-ynyl chloroformate, (S)-2-(8-((but-2-ynyloxy) carbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid was prepared as a white solid in 100% yield. HRMS: calculated for [C22H22N2O7S + H]+ 459.12205; found (ESI-FTMS, [M+H]1+) 459.1216.
Example 35: Preparation of (S)-3-methyl-2-(8-(p- tolyloxycarbonyIamino)dibenzo[b,d]furan-3-sulfonamido)butanoic acid
[0144] Following procedures analogous to those described in Example 28 and using p-tolyl chloroformate, (S)-3-methyl-2-(8-(p- tolyloxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)butanoic acid was prepared as a white solid in 99% yield. HRMS: calculated for [C25H24N2O7S + H]+ 497.13770; found (ESI-FTMS, [M+H]1+) 497.1377.
Example 36: Preparation of (S)-3-methyI-2-(8- (phenoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)butanoic acid
[0145] Following procedures analogous to those described in Example 28 and using phenyl chloroformate, (S)-3-methyl-2-(8-
(phenoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)butanoic acid was prepared as a white solid in 93% yield. HRMS: calculated for [C24H22N2O7S + H]+ 483.12205; found (ESI-FTMS, [M+H]1+) 483.1229.
Example 37: Preparation of (S)-2-(8-
(benzyloxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methyIbutanoic acid
[0146] Following procedures analogous to those described in Example 28 and using benzyl chloroformate, (S)-2-(8-(benzyloxycarbonylamino)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoic acid was prepared as a white solid in 93% yield. HRMS: calculated for [C25H24N2O7S + H]+ 497.13770; found (ESI-FTMS, [M+H]1+) 497.1387. Example 38: Preparation of (S)-2-(8-
(hexyloxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid
[0147] Following procedures analogous to those described in Example 28 and using hexyl chloroformate, (S)-2-(8-(hexyloxycarbonylamino)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoic acid was prepared as a white solid in 97% yield. HRMS: calculated for [C24H30N2O7S + H]+ 491.18465; found (ESI-FTMS, [M+H]1+) 491.1857.
Example 39: Preparation of (S)-2-(8-((2- fluoroethoxy)carbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoic acid
[0148] Following procedures analogous to those described in Example 28 and using 2-fluoroethyl chloroformate, (S)-2-(8-((2- fluoroethoxy)carbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid was prepared as a white solid in 100% yield. HRMS: calculated for [C20H2IFN2O7S + H]+ 453.1 1263; found (ESI-FTMS, [M+H]1+) 453.1135.
Example 40: Preparation of (S)-2-(8-
(methoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid
[0149] Following procedures analogous to those described in Example 28 and using methyl chloroformate, (S)-2-(8-(methoxycarbonyl amino)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoic acid was prepared as a white solid in 95% yield. MS (ES-) 419.10.
Example 41: Preparation of (S)-2-(8-(ethoxycarbonylamino)dibenzo[b,d]furan- 3-sulfonamido)-3-methylbutanoic acid
[0150] Following procedures analogous to those described in Example 28 and using ethyl chloroformate, (S)-2-(8-(ethoxycarbonyl amino)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoic acid was prepared as a white solid in 95% yield. MS (ES-) 433.1.
Example 42: Preparation of (S)-3-methyl-2-(8- (propoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)butanoic acid
[0151] Following procedures analogous to those described in Example 28 and using propyl chloroformate, (S)-3-methyl-2-(8-
(propoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)butanoic acid was prepared as a white solid in 100% yield. HRMS: calculated for [C2iH24N2O7S + H]+ 449.13770; found (ESI-FTMS, [M+H]1+) 449.1386.
Example 43: Preparation of (S)-2-(8-(butoxycarbonylamino)dibenzo[b,d]furan- 3-sulfonamido)-3-methylbutanoic acid
[0152] Following procedures analogous to those described in Example 28 and using butyl chloroformate, (S)-2-(8-(butoxycarbonylamino)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoic acid was prepared as a white solid in 100% yield. HRMS: calculated for [C22H26N2O7S + H]+ 463.15335; found (ESI-FTMS, [M+H]1+) 463.1527.
Example 44: Preparation of (S)-2-(8-((but-3- ynyIoxy)carbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methyIbutanoic acid
[0153] Following procedures analogous to those described in Example 28 and using but-3-ynyl chloroformate, (S)-2-(8-((but-3- ynyloxy)carbonylamino)dibenzo [b,d] furan-3 -sulfonamido)-3 -methy lbutanoic acid was prepared as a white solid in 97% yield. HRMS: calculated for [C22H22N2O7S + H]+, 459.12205; found (ESI-FTMS, [M+H]l+) 459.1215.
Example 45: Preparation of (S)-2-(8-(3-(3,5-dimethylisoxazol-4- yl)ureido)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid
[0154] Following procedures analogous to those described in Examples 5 and 28 and using 3,5-dimethylisoxazol-4-yl isocyanate, (S)-2-(8-(3-(3,5-dimethylisoxazol- 4-yl)ureido)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid was prepared as a white solid. HRMS: calculated for [C23H24N4O7S + H]+ 501.14385; found (ESI- FTMS, [M+H]1+) 501.1453.
Example 46: Preparation of (S)-3-methyl-2-(8-(3-thiophen-3- ylureido)dibenzo|b,d]furan-3-sulfonamido)butanoic acid
[0155] Following procedures analogous to those described in Examples 5 and 28 and using 3-thiophen-3-yl isocynate, (S)-3-methyl-2-(8-(3-thiophen-3- ylureido)dibenzo[b,d]furan-3-sulfonamido)butanoic acid was prepared as a white solid. HRMS: calculated for [C22H21N3O6S2 + H]+ 488.09445; found (ESI-FTMS, [M+H]1+) 488.0948.
Example 47: Preparation of (S)-3-methyl-2-(8-(3-(3,4,5- trimethoxyphenyl)ureido)dibenzo[b,d]furan-3-sulfonamido)butanoic acid
[0156] Following procedures analogous to those described in Examples 5 and 28 and using 3,4,5-trimethoxyphenyl isocynate, (S)-3-methyl-2-(8-(3-(3,4,5- trimethoxyphenyl)ureido)dibenzo[b,d]furan-3-sulfonamido)butanoic acid was prepared as a white solid. HRMS: calculated for [C27H29N3O9S + H]+ 572.16973; found (ESI-FTMS, [M+H]l+) 572.17.
Example 48: Preparation of (S)-2-(8-(3-(3,4- difluorophenyl)ureido)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid
[0157] Following procedures analogous to those described in Examples 5 and 28 and using 3,4-difluorophenyl isocynate, (S)-2-(8-(3-(3,4- difluorophenyl)ureido)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid was prepared as a white solid. HRMS: calculated for [C24H21F2N3O6S + H]+ 518.11919; found (ESI-FTMS, [M+H] 1+) 518.1196. Example 49: Preparation of (S)-3-methyl-2-(8-(3-(3- phenoxyphenyl)ureido)dibenzo[b,d|furan-3-sulfonamido)butanoic acid
[0158] Following procedures analogous to those described in Examples 5 and 28 and using 3-phenoxyphenyl isocynate, (S)-3-methyl-2-(8-(3-(3- phenoxyphenyl)ureido)dibenzo[b,d]furan-3-sulfonamido)butanoic acid was prepared as a white solid. HRMS: calculated for [C30H27N3O7S + H]+ 574.16425; found (ESI- FTMS, [M+H]1+) 574.1652.
Example 50: Preparation of (S)-3-methyl-2-(8-ureidodibenzo[b,d]furan-3- sulfonamido)butanoic acid
[0159] (S)-3-Methyl-2-(8-ureidodibenzo[b,d]furan-3-sulfonamido)butanoic acid was prepared as a pale yellow solid following procedures analogous to those described in Examples 5, 13, and 28. HRMS: calculated for [Ci8Hi9N3O6S + H]+ 406.10673; found (ESI-FTMS, [M+H]1+) 406.1079.
Example 51: Preparation of (S)-2-(8-(3-(2,6-dichloropyridin-4- yl)ureido)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid
[0160] Following procedures analogous to those described in Examples 5 and 28 and using 2,6-dichloropyridin-4-yl isocynate, (S)-2-(8-(3-(2,6-dichloropyridin-4- yl)ureido)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid was prepared as a white solid. HRMS: calculated for [C23H20Cl2N4O6S + H]+ 551.05534; found (ESI-FTMS, [M+H] 1+) 551.0572.
Example 52: Preparation of (S)-2-(8-(3-(4-
(dimethylamino)phenyl)ureido)dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoic acid
[0161] Following procedures analogous to those described in Examples 5 and 28 and using 4-(dimethylamino)phenyl isocynate, (S)-2-(8-(3-(4-
(dimethylamino)phenyl)ureido)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid was prepared as a white solid. HRMS: calculated for [C26H28N4O6S + H)+ 525.18023; found (ESI-FTMS, [M+H]1+) 525.1815. Example 53: Preparation of (S)-3-methyl-2-(8-(3-(2-(thiophen-2- yl)ethyl)ureido)dibenzo[b,d]furan-3-sulfonamido)butanoic acid
[0162] Following procedures analogous to those described in Examples 5 and 28 and using 2-(thiophen-2-yl)ethyl isocynate, (S)-3-methyl-2-(8-(3-(2-(thiophen-2- yl)ethyl)ureido)dibenzo[b,d]furan-3-sulfonamido)butanoic acid was prepared as a white solid. HRMS: calculated for [C24H25N3O6S2 + H]+ 516.12575; found (ESI- FTMS, [M+H]l+) 516.1247.
Example 54: Preparation of (S)-3-methyl-2-(8-(3-(4-
(trifluoromethoxy)phenyl)ureido)dibenzo[b,d]furan-3-sulfonamido)butanoic acid
[0163] Following procedures analogous to those described in Examples 5 and 28 and using 4-(trifluoromethoxy)phenyl isocynate, (S)-3-methyl-2-(8-(3-(4- (trifluoromethoxy)phenyl)ureido)dibenzo[b,d]furan-3-sulfonamido)butanoic acid was prepared as a white solid. HRMS: calculated for [C25H22F3N3O7S + H]+ 566.12033; found (ESI-FTMS, [M+H]1+) 566.1217.
Example 55: Preparation of (S)-2-(8-(3-cyclopentylureido)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoic acid
[0164] Following procedures analogous to those described in Examples 5 and 28 and using cyclopentyl isocynate, (S)-2-(8-(3-cyclopentylureido)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoic acid was prepared as a white solid. HRMS: calculated for [C23H27N3O6S + H]+ 474.16933; found (ESI-FTMS, [M+H]1+) 474.1696.
Example 56: Preparation of (S)-2-(8-(3-(4- fluorobenzyl)ureido)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid
[0165] Following procedures analogous to those described in Examples 5 and 28 and using 4-fluorobenzyl isocyanate, (S)-2-(8-(3-(4- fluorobenzyl)ureido)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid was prepared as a white solid. HRMS: calculated for [C25H24FN3O6S + H]+ 514.14426; found (ESI-FTMS, [M+H]1+) 514.1445.
Example 57: Preparation of (S)-3-methyl-2-(8-(methylsulfonamido)- dibenzo[b,d]furan-3-sulfonamido)butanoic acid
[0166] Following procedures analogous to those described in Examples 18 and 28 and using methyl sulfonyl chloride, (S)-3-methyl-2-(8-(methylsulfonamido)- dibenzo[b,d]furan-3-sulfonamido)butanoic acid was prepared as a white solid. HRMS: calculated for [Ci8H20N2O7S2 + H]+ 441.07847; found (ESI-FTMS, [M+H]1+) 441.0784.
Example 58: Preparation of (S)-2-[8-
(methoxycarbonylamino)dibenzo[b,d]thiophene-3-sulfonamido]-3- methylbutanoic acid
Step 1 : Preparation of dibenzo[b,d]thiophene-3-sulfonyl chloride
[0167] 5-(Trifluoromethyl)-5H-dibenzo[b,d]thiophenium-3-sulfonate (200 mg) was mixed with 10 mL of thionyl chloride and a few drops of dry DMF. The mixture was stirred at 80°C for 24 hours. Excess SOCl2 was removed under reduced pressure and the residue was triturated with ice-cold water followed by filtration. 150 mg of dibenzo[b,d]thiophene-3-sulfonyl chloride was obtained as a white solid.
Step 2: Preparation of 8-nitrodibenzo[b,d]thiophene-3-sulfonyl chloride [0168] Dibenzo[b,d]thiophene-3-sulfonyl chloride (2.0 g, 7.1 mmol) was mixed with trifluoroacetic acid and the mixture was stirred at room temperature. Nitric acid (>90%, Fuming, 0.29 mL) was added drop-wise. The mixture was stirred at room temperature for 3 hours and was filtered. The solid was washed with TFA and dried in the air. 8-Nitrodibenzo[b,d]thiophene-3 -sulfonyl chloride was obtained (1.1 g) as an off-white solid. Step 3: Preparation of (S)-tert-butyl 3-methyl-2-(8-nitrodibenzo[b,d]thiophene-3- sulfonamido)butanoate
[0169] 8-Nitrodibenzo[b,d]thiophene-3-sulfonyl chloride (450 mg, 1.38 mmol) and ter/-butyl 2-amino-3-methylbutanoate hydrochloride (316 mg, 1.51 mmol) were mixed with 3 mL Of CH2Cl2 and N,N-diisopropylethylamine (392 mg, 3.0 mmol.). The mixture was stirred at room temperature for 4 hours and purified with a silica gel column chromatography to provide 450 mg of (S)-tert-butyl 3-methyl-2-(8- nitrodibenzo[b,d]thiophene-3-sulfonamido)butanoate as an off-white solid..
Step 4: Preparation of (S)-tert-butyl 2-(8-aminodibenzo[b,d1thiophene-3- sulfonamidoV3-methylbutanoate
[0170] (S)-Tert-butyl 3-methyl-2-(8-nitrodibenzo[b,d]thiophene-3- sulfonamido)butanoate (450 mg) was mixed with 20 mL of MeOH and 100 mg of Pd/C. The reaction was carried out in a Parr shaker at room temperature under 50 psi H2 overnight. The reaction mixture was filtered through Celite and the filtrate was concentrated to give 370 mg of (S)-tert-butyl 2-(8-aminodibenzo[b,d]thiophene- 3-sulfonamido)-3-methylbutanoate as an off white solid.
Step 5. Preparation of (SVtert-butyl 2-(8- (methoxycarbonylaminoMibenzo[b,d]thiophene-3-sulfonamidoV3-methylbutanoate
[0171] (S)-Tert-butyl 2-(8-aminodibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoate (109 mg, 0.25 mmol) and DMAP (37 mg, 0.3 mmol) were dissolved in CH2Cl2 (3 mL) and methyl chloroformate (28 mg, 0.28 mmol) was added. The mixture was stirred at room temperature overnight and was purified with a silica gel column chromatography to provide 115 mg of (S)-tert-butyl 2-(8- (methoxycarbonylamino)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoate as a white solid.
Step 6. Preparation of (Ss)-2-(8-(methoxycarbonylamino)dibenzo[b,d1thiophene-3- sulfonamidoV3-methylbutanoic acid
[0172] (S)-Tert-butyl 2-(8-(methoxycarbonylamino)dibenzo[b,d]thiophene-3- sulfonamido)-3-methylbutanoate (115 mg) was dissolved in a mixture Of CH2Cl2 (2 mL) and TFA (2 mL). The solution was stirred at room temperature for 3 hours. The solvents were removed under reduced pressure and the residue was triturated in CH3CN/water, followed by a freeze-dry process. 95 mg of (S)-2-(8- (methoxycarbonylamino)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid were obtained as a white solid. HRMS: calculated for [C 19H20N2O6S2 + H]+ 437.08355; found (ESI-FTMS, [M+H]1+) 437.0833.
[0173] The sodium salt was prepared by treatment of (S)-2-[8- (methoxycarbonylamino) dibenzo[b,d] thiophene-3-sulfonamido]-3-methylbutanoic acid with 1.0 equivalent of NaOH. The salt was obtained as a white solid.
Example 59: Preparation of (R)-2-(8-
(methoxycarbonylamino)dibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoic acid
[0174] Following procedures analogous to those described in Example 58 and using (R)-tert-butyl 2-(8-aminodibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoate and methyl chloroformate, (R)-2-(8-
(methoxycarbonylamino)dibenzo [b,d] thiophene-3 -sulfonamido)-3 -methylbutanoic acid was obtained as a white solid. HRMS: calculated for [C 19H20N2O6S2 + H]+ 437.08355; found (ESI-FTMS, [M+H]1+) 437.0822.
Example 60: Preparation of (S)-3-methyl-2-(8- (methylsulfonamido)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid
[0175] Following procedures analogous to those described in Examples 18 and 58 and using methyl sulfonyl chloride, (S)-3-methyl-2-(8- (methylsulfonamido)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid was obtained as a white solid. HRMS: calculated for [Ci8H20N2O6S3 + H]+ 457.05562; found (ESI-FTMS, [M+H] 1+) 457.0546. Example 61: Preparation of (R)-3-methyI-2-(8- (methyIsulfonamido)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid
[0176] Following procedures analogous to those described in Examples 18 and 58 and using (R)-tert-butyl 2-(8-aminodibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoate methyl sulfonyl chloride, (R)-3-methyl-2-(8-
(methylsulfonamido)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid was obtained as a white solid. HRMS: calculated for [Ci8H20N2O6S3 + H]+ 457.05562; found (ESI-FTMS, [M+H]1+) 457.0546.
Example 62: Preparation of (R)-2-(7-aminodibenzo[b,d]furan-2-sulfonamido)- 3-methylbutanoic acid
[0177] (R)-Tert-butyl 2-(7-aminodibenzo[b,d]furan-2-sulfonamido)-3- methylbutanoate obtained from Example 1 was dissolved in 4 mL of TFA/CH2C12 (1 :1). The solution was stirred at room temperature for 4 hours. The solvents were removed under reduced pressure and the residue was triturated in ether/hexane followed by filtration to provide (R)-2-(7-aminodibenzo[b,d]furan-2-sulfonamido)- 3-methylbutanoic acid as a beige solid in 94% yield. 1H NMR (400 MHz, DMSO- d6) δ ppm 0.81 (dd, J=13.64, 6.82 Hz, 6 H), 1.87 - 1.98 (m, 1 H), 3.56 (dd, J-9.47, 5.94 Hz, 1 H), 6.71 (dd, J=8.46, 1.89 Hz, 1 H), 6.81 (d, J=I.77 Hz, 1 H), 7.64 - 7.68 (m, 1 H), 7.68 - 7.73 (m, 1 H), 7.84 (d, J=8.34 Hz, 1 H), 7.94 (d, J=9.35 Hz, 1 H), 8.26 (dd, J=2.02, 0.51 Hz, 1 H), and 12.50 (s, 1 H); MS (ES-): 361.07.
[0178] The sodium salt was prepared by treatment of (R)-2-(7- aminodibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoic acid with 1.0 equivalent of NaOH. The salt was obtained as a white solid.
Example 63: Preparation of (S)-2-(7-aminodibenzo[b,d]furan-2-sulfonamido)- 3-methylbutanoic acid
[0179] Following procedures analogous to those described in Example 62 and starting from (S)-tert-butyl 2-(7-aminodibenzo[b,d]furan-2-sulfonamido)-3- methylbutanoate, (S)-2-(7-aminodibenzo [b,d]furan-2-sulfonamido)-3- methylbutanoic acid was obtained as a beige solid. 1H NMR (400 MHz, DMSO-t/g) δ ppm 0.81 (dd, J=13.64, 6.82 Hz, 6 H), 1.86 - 1.99 (m, 1 H), 3.56 (dd, J=9.47, 5.94 Hz, 1 H), 5.83 (s, 2 H), 6.69 (dd, J=8.46, 1.89 Hz, 1 H), 6.80 (d, J=I.77 Hz, 1 H), 7.61 - 7.67 (m, 1 H), 7.68 - 7.74 (m, 1 H), 7.83 (d, J=8.34 Hz, 1 H), 7.94 (d, J=9.35 Hz, 1 H), 8.25 (d, J=IHl Hz, 1 H), and 12.49 (s, 1 H); MS (ES-) 361.05.
Example 64: Preparation of (S)-2-(8-aminodibenzo[b,d]furan-3-sulfonamido)- 3-methylbutanoic acid
[0180] Following procedures analogous to those described in Example 62 and starting from (S)-tert-butyl 2-(8-aminodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate, (S)-2-(8-aminodibenzo [b,d]furan-3-sulfonamido)-3- methylbutanoic acid was prepared as a beige solid. HRMS: calculated for [Ci7H18N2O5S + H]+ 363.10092; found (ESI-FTMS, [M+H]1+) 363.1009.
Example 65: Preparation of (S)-2-(7-(3- cyclopentylureido)dibenzo[b,d]thiophene-3-suIfonamido)-3-methylbutanoic acid
Step 1 : Preparation of 7-nitro-5-(trifluoromethyl)-5H-dibenzo[b,dlthiophenium-3- sulfonate
[0181] 5-(Trifluoromethyl)-5H-dibenzo[b,d]thiophenium-3-sulfonate (5.0 g) was added portionwise to a mixture of 30% oleum (3.3 mL) and 90% HNO3 (1.7 mL). The mixture was stirred at room temperature overnight and then added dropwise in cold diethyl ether (250 mL). 7-Nitro-5-(trifluoromethyl)-5H- dibenzo[b,d]thiophenium-3-sulfonate precipitated out and was collected by filtration and dried under reduced pressure (5.37 g, 95 % yield).
Step 2: Preparation of 7-nitrodibenzo[b,d]thiophene-3-sulfonyl chloride
[0182] 7-Nitro-5-(trifluoromethyl)-5H-dibenzo[b,d]thiophenium-3-sulfonate (5 g) was dissolved in SOCl2 (35 mL) and a few drops of DMF were added. The mixture was heated at 80°C for 24 hours. The excess SOCl2 was removed under reduced pressure and the residue was triturated twice with CH2Cl2 to give a quantitative yield of 7-nitrodibenzo[b,d]thiophene-3-sulfonyl chloride for use in the next step without further purification. Step 3: Preparation of (S Vtert-butyl 3-methyl-2-(7-nitrodibenzo|"b,d~|thiophene-3- sulfonamido) butanoate
[0183] Following procedures analogous to those described in Example 1, Step 4, (S)-tert-buty\ 3-methyl-2-(7-nitrodibenzo[b,d]thiophene-3-sulfonamido) butanoate was obtained as a white solid in 95% yield. 1H NMR (DMSO-^6) δ ppm 0.89 (d, J= 6.6Hz, 3H), 0.90 (d, J= 6.6Hz, 3H), 1.15 (s, 9H), 2.00 (m, IH), 3.63 (d, J= 6.3Hz, IH), 7.81 (s br, IH), 7.98 (dd, J= 8.5, 1.9Hz, IH), 8.35 (dd, J= 8.5, 1.9Hz, IH), '8.56 (dd, J= 1.6, 0.6Hz, IH), 8.66 (d, J= 8.2Hz, IH), 8.67 (d, J= 8.5Hz, IH), and 9.05 (d, J=2.2Hz, IH).
Step 4: Preparation of (SVtert-butyl 2-(7-aminodibenzo[b,dlthiophene-3- sulfonamido)-3-methylbutanoate
[0184] (S)-Tert-butyl 3-methyl-2-(7-nitrodibenzo[b,d]thiophene-3- sulfonamido)butanoate was dissolved in MeOH and the resulting mixture was treated overnight with hydrogen (40 psi) in the presence of 10% Pd/C (10% w/w). The catalyst was removed by filtration and (S)-tert-butyl 2-(7- aminodibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoate was obtained in a quantitative yield after evaporation of the solvent. 1H NMR (DMSO-c/6) δ ppm 0.82 (d, J= 6.6 Hz, 3H), 0.85 (d, J= 6.6Hz, 3H), 1.07 (s, 9H), 1.92 (m, IH), 3.50 (dd, J=9.7, 6.3Hz, IH), 5.71 (s br, 2H), 6.79 (dd, J= 8.5, 1.9 Hz, IH), 7.05 (d, J=I .9Hz, IH), 7.72 (dd, J=8.5, 1.9Hz, IH), 8.01 (d, J= 9.1Hz, IH), 8.02 (d, J= 8.5Hz, IH), 8.15 (d, J= 8.2Hz, IH), and 8.21 (d, J=1.9Hz, IH).
Steps 5 and 6: Preparation of (S)-2-(7-(3-cyclopentylureido)dibenzorb,d1thiophene- 3-sulfonamido)-3-methylbutanoic acid
[0185] (S)-Tert-butyl 2-(7-aminodibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoate (250 mg, 0.57 mmol) was dissolved in 5 mL of dry CH2Cl2, cyclopentylisocyanate (1.2 eq.) was added, and the mixture was stirred for 24 hours at room temperature. The crude product was purified using a silica gel cartridge. The product was treated with 30 % TFA in CH2Cl2 for 6 hours and was purified by a preparative high pressure liquid chromatography (HPLC) to provide (S)-2-[7-(3- cyclopentyl-ureido)-dibenzothiophene-3-sulfonylamino]-3-methyl-butyric acid. (1H CDCl3) δ ppm 0.84 (d, J=6.9 Hz, 3H), 0.98 (d, J=6.9 Hz, 3H), 1.49-1.32 (m, 2H), 1.74-1.53 (m, 4H), 2.14-1.88 (m, 3H), 3.71 (m, IH), 4.10 (dt, J=13.2, 6.6 Hz, IH), 5.33 (d, J=10.1 Hz, IH), 7.29 (dd, J= 8.8, 2.2 Hz, IH), 7.83 (dd, J=8.2, 1.6 Hz, IH), 7.96 (d, J=8.8 Hz, IH), 8.03 (d, J=8.8 Hz, IH), 8.19 (d, J= 2.2 Hz, IH), and 8.24 (d, J=I .6 Hz, IH); MS (ES+) 490.1.
[0186] The sodium salt was prepared by treatment of (S)-2-[7-(3-cyclopentyl- ureido)-dibenzothiophene-3-sulfonylamino] -3 -methyl-butyric acid with 1.0 equivalent of NaOH. The salt was obtained as a white solid.
Example 66: Preparation of (S)-3-methyl-2-(7-(3-(2-(thiophen-2- yI)ethyl)ureido)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid
[0187] (S)-3-Methyl-2-(7-(3-(2-(thiophen-2-yl)ethyl)ureido) dibenzo[b,d]thiophene- 3-sulfonamido)butanoic acid was prepared following procedures analogous to those described in Example 65 and using 2-(thiophen-2-yl)ethyl isocyanate. (1H DMSO 353K) δ ppm 0.86 (d, J= 6.9 Hz, 3H), 0.88 (d, J=6.9 Hz, 3H), 1.99 (m, IH), 3.04 (t, J=6.6 Hz, 2H), 3.45 (dt, J=6.6, 6.0 Hz, 2H), 3.63 (d, J=6.0 Hz, IH), 6.22 (t, J=6.0 Hz, IH), 6.93 (m, IH), 6.98 (dd, J=5.0, 3.5 Hz, IH), 7.31 (dd, J=5.0, 1.3 Hz, IH), 7.47 (dd,J=8.8, 1.9 Hz, IH), 7.84 (dd, J=8.5, 1.9 Hz, IH), 8.19 (d, J=2.2 Hz, IH), 8.23 (d, J=8.8 Hz, IH), 8.30 (d, J=8.5 Hz, IH), 8.34 (d, J=I.6 Hz, IH), and 8.67 (s br, IH); MS (ES+) 532.1.
Example 67: Preparation of (S)-2-(7-(3-(4- fluorophenyl)ureido)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid
[0188] (S)-2-(7-(3-(4-Fluorophenyl)ureido)dibenzo[b,d]thiophene-3-sulfonamido)- 3-methylbutanoic acid was prepared following procedures analogous to those described in Example 65 and using 4-fluorophenyl isocyanate. 1H NMR (DMSO- d6) δ ppm 0.80 (d, J=6.9 Hz, 3H), 0.84 (d, J=6.6 Hz, 3H), 1.95 (m, IH), 3.60 (dd, J=9.4, 6.0 Hz, IH), 7.14 (dd, J=8.8, 8.8 Hz, 2H), 7.56-7.45 (m, 3H), 7.83 (dd, J=8.5, 1.6 Hz, IH), 8.01 (d br, J=9.4 Hz, IH), 8.27 (d, J=I.9 Hz, IH), 8.33 (d, J=8.5 Hz, IH), 8.37 (d, J=7.9 Hz, IH), 8.38 (d, J=2.2 Hz, IH), 8.86 (s br, IH), 9.07 (s, IH), and 12.48 (s br, IH); MS (ES+) 516.1.
Example 68: Preparation of (S)-3-methyl-2-(7-(3- phenethylureido)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid
[0189] (S)-3-Methyl-2-(7-(3-phenethylureido)dibenzo[b,d] thiophene-3- sulfonamido) butanoic acid was prepared following procedures analogous to those described in Example 65 and using 3-phenethyl isocyanate. 1H NMR (CDCl3) δ ppm 0.84 (d, J= 6.9 Hz, 3H), 0.98 (d, J= 6.9 Hz, 3H), 2.06 (m, IH), 2.85 (t, J- 6.9 Hz, 2H), 3.5 (t, J=6.9 Hz, 2H), 3.72 (m, IH), 5.32 (d, J=9.7 Hz, IH), 7.33-7.14 (m, 6H), 7.83 (dd, J=8.5, 1.9 Hz, IH), 7.96 (d, J=8.5 Hz, IH), 8.04 (d, J=8.2 Hz, IH), 8.19 (d, J=1.9 Hz, IH), and 8.25 (d, J=1.6 Hz, IH); MS (ES+) 526.1.
Example 69: Preparation of (S)-2-(7-(3-benzylureido)dibenzo[b,d]thiophene-3- sulfonamido)-3-methylbutanoic acid
[0190] (S)-2-(7-(3-Benzylureido)dibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoic acid was prepared following procedures analogous to those described in Example 65 and using 3-benzyl isocyanate. 1H NMR (DMSO-J6) δ ppm 0.80 (d, J=6.9 Hz, 3H), 0.84 (d, J=6.9 Hz, 3H), 1.95 (m, IH), 3.59 (m, IH), 4.34 (d, J=5.6 Hz, 2H), 6.79 (7 br, J=5.7 Hz, IH), 7.22-7.37 (m, 5H), 7.46 (dd, J=8.7 2.0 Hz, IH), 7.81 (dd, J=8.5 2.1 Hz, IH), 8.0 (d br, J=9.5 Hz, IH), 8.25 (d, J=I .8 Hz IH), 8.27 (d, J=8.2 Hz, IH), 8.34 (d, J=8.1 Hz, IH), 8.35 (s, IH), 8.96 (s, IH), and 12.49 (s br, IH); MS (ES+) 512.1.
Example 70: Preparation of (S)-2-(7-(3-(4-Fluorobenzyl)ureido)dibenzo [b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid
[0191] (S)-2-(7-(3-(4-Fluorobenzyl)ureido)dibenzo[b,d]thiophene-3-sulfonamido)- 3 -methylbutanoic acid was prepared following procedures analogous to those described in Example 65 and using 4-fluorobenzyl isocyanate. 1H NMR (DMSO-J6) δ ppm 0.80 (d, J=6.9 Hz, 3H), 0.84 (d, J=6.9 Hz, 3H), 1.95 (m, IH), 3.53 (m, IH), 4.31 (d, J=5.9 Hz, 2H), 6.84 (m, IH), 7.16 (dd, J=9.1 9.1 Hz, 2H), 7.37 (dd, J=9.1 6.5 Hz, 2H), 7.45 (d br, J=9.1 Hz, IH), 7.80 (dd, J=8.9 2.0 Hz, IH), 7.95 (s br, IH), 8.24 (d, J=2.0 Hz, IH), 8.26 (d, J=9.2 Hz, IH), 8.34 (d, J=8.3 Hz , IH), 8.35 (s br, IH), 9.00 (s br, IH), and 12. 51 (s br, IH); MS (ES+) 530.1.
Example 71: Preparation of (S)-3-methyl-2-(7-(3-p- tolylureido)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid
[0192] (S)-3-Methyl-2-(7-(3-p-tolylureido)dibenzo[b,d]thiophene-3- sulfonamido)butanoic acid was prepared following procedures analogous to those described in Example 65 and using 3-p-tolylisocyanate. 1H NMR (DMSO-J6) δ ppm 0.81 (d, J=6.9 Hz, 3H), 0.85 (d, J=6.9 Hz, 3H), 1.95 (m, IH), 2.27 (s, 3H), 3.61 (dd, J=9.5 6.1 Hz, IH), 7.11 (d, J=8.9 Hz, 2H), 7.38 (d, J=8.9 Hz, 2H), 7.53 (dd, J=8.3 1.9 Hz, IH), 7.83 (dd, J=8.6 1.6 Hz, IH), 8.05 (d, J=9.6 Hz, IH), 8.28 (d, J=I.9 Hz, IH), 8.33 (d, J=8.4 Hz, IH), 8.38 (d, J=8.2 Hz, IH), 8.39 (d, J=I.9 Hz, IH), 8.69 (s br, IH), 9.00 (s br, IH), and 12.51 (s br, IH); MS (ES+) 512.2.
Example 72: Preparation of (S)-3-methyl-2-(7-(3-(3,4,5- trimethoxyphenyl)ureido)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid
[0193] (S)-3-Methyl-2-(7-(3-(3,4,5- trimethoxyphenyl)ureido)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid was prepared following procedures analogous to those described in Example 65 and using 3,4,5-trimethoxyphenylisocyanate. 1H NMR (DMSO-J6) δ ppm 0.81 (d, J=6.9 Hz, 3H), 0.85 (d, J=6.9 Hz, 3H), 1.95 (m, IH), 3.61 (dd, J=9.1 6.0 Hz, IH), 3.63 (s, 3H), 3.78 (s, 6H), 6.84 (s, 2H), 7.52 (dd, J=8.1 1.5 Hz, IH), 7.84 (dd, J=8.6 1.5 Hz, IH), 8.05 (d, J=9.6 Hz, IH), 8.41-8.30 (m, 4H), 8.75 (s br, IH), 8.99 (s br, IH), and 12.51 (s br, IH); MS (ES+) 588.2.
Example 73: Preparation of (S)-2-(7-(3-ethylureido)dibenzo[b,d]thiophene-3- sulfonamido)-3-methylbutanoic acid
[0194] (S)-2-(7-(3-Ethylureido)dibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoic acid was prepared following procedures analogous to those described in Example 65 and using ethylisocyanate. 1H NMR (DMSO-J6) δ ppm 0.81 (d, J=6.9 Hz, 3H), 0.84 (d, J=6.9 Hz, 3H), 1.09 (t, J=5.6 Hz, 3H), 1.95 (m, IH), 3.15 (dq, J=7.0 5.6 Hz, 2H), 3.58 (m, IH), 6.27 (t br, J=5.5 Hz, IH), 7.45 (dd, J=8.6 2.0 Hz, IH), 7.81 (dd, J=8.5 1.8 Hz, IH), 8.00 (d br, J=9.0 Hz, IH), 8.23 (d, J=I.8 Hz, IH), 8.26 (d, J=8.3 Hz, IH), 8.34 (d, J=8.3 Hz, IH), 8.36 (d, J=I.8 Hz, IH), 8.82 (s br, IH), and 12.51 (s br, IH); MS (ES+) 450.1.
Example 74: Preparation of (S)-2-(7-(3-(3,4- difluorophenyl)ureido)dibenzo[b,d]thiophene-3-suIfonamido)-3-methylbutanoic acid
[0195] (S)-2-(7-(3-(3,4-Difluorophenyl)ureido)dibenzo[b,d]thiophene-3- sulfonamido)-3-methylbutanoic acid was prepared following procedures analogous to those described in Example 65 and using 3,4-difluorophenylisocyanate. 1H NMR (DMSO-^6) δ ppm 0.81 (d, J=6.9 Hz, 3H), 0.85 (d, J=6.9 Hz, 3H), 1.96 (m, IH), 3.6 (dd, J=9.4 6.3 Hz, IH), 7.17 (m, IH), 7.37 (dt, J=10.1 9.2 Hz, IH), 7.54 (d br, J=8.3 Hz, IH), 7.70 (ddd, J=13.8 7.4 2.8 Hz, IH), 7.84 (dd, J=8.7 1.4 Hz, IH), 8.04 (s br, IH), 8.27 (s br, IH), 8.41-8.31 (m, 3H), 9.04 (s br, IH), 9.15 (s br, IH), and 12.51 (s br, IH); MS (ES+) 534.1.
Example 75: Preparation of (S)-3-methyl-2-(7-(3-(4-
(trifluoromethyl)phenyl)ureido)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid
[0196] (S)-3-Methyl-2-(7-(3-(4- (trifluoromethyl)phenyl)ureido)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid was prepared following procedures analogous to those described in Example 65 and using 4-(trifiuoromethyl)phenylisocyanate. 1H NMR (DMSOd6) δ ppm 0.81 (d, J=6.9 Hz, 3H), 0.85 (d, J=6.9 Hz, 3H), 1.96 (m, IH), 3.61 (dd, J=9.7 6.1 Hz, IH), 7.57 (dd, J=8.8 1.9 Hz, IH), 7.66 (d, J=9.2 Hz, 2H), 7.71 (d, J=9.2 Hz, 2H), 7.84 (dd, J=8.4 1.5 Hz, IH), 8.05 (d br, J=9.2 Hz, IH), 8.29 (d, J=I.8 Hz, IH), 1.36 (d, J=8.5 Hz, IH), 8.40 (d, J=8.0 Hz, IH), 8.40 (d, J=I .8 Hz, IH), 9.20 (s br, IH), 9.25 (s br, IH), and 12.51 (s br, IH); MS (ES+) 566.1. Example 76: Preparation of (S)-2-(7-(3-(2,3-dihydrobenzo[b][l,4]dioxin-6- yl)ureido)dibenzo[b,d]thiophene-3-sulfonamido)-3-methyIbutanoic acid
[0197] (S)-2-(7-(3-(2,3-Dihydrobenzo[b] [ 1 ,4]dioxin-6- yl)ureido)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid was prepared following procedures analogous to those described in Example 65 and using 2,3-dihydrobenzo[b][l,4]dioxin-6-yl isocyanate. 1H NMR (DMSO-J6) δ ppm 0.81 (d, J=6.9 Hz, 3H), 0.85 (d, J=6.9 Hz, 3H), 1.96 (m, IH), 3.61 (dd, J=9.5 5.9 Hz, IH), 4.26-4.17 (m, 4H), 6.78 (d, J=8.6 Hz, IH), 6.84 (dd, J=8.6 2.3 Hz, IH), 7.12 (d, J=2.3 Hz, IH), 7.51 (dd, J=8.8 2.0 Hz, IH), 7.83 (dd, J=8.4 1.6 Hz, IH), 8.04 (d br, J=9.7 Hz, IH), 8.27 (d, J=I.8 Hz, IH), 8.32 (d, J=8.6 Hz, IH), 8.37 (d, J=7.9 Hz, IH), 8.38 (d, J=2.0 Hz, IH), 8.61 (s br, IH), 8.96 (s br, IH), and 12.50 (s br, IH); MS (ES+) 556.1.
Example 77: Preparation of (S)-3-methyl-2-(7-(3- phenylureido)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid
[0198] (S)-3-Methyl-2-(7-(3-phenylureido)dibenzo[b,d] thiophene-3- sulfonamido)butanoic acid was prepared following procedures analogous to those described in Example 65 and using phenylisocyanate. 1H NMR (DMSO-J6) δ ppm 0.81 (d, J=6.9 Hz, 3H), 0.84 (d, J=6.9 Hz, 3H), 1.96 (m, IH), 3.60 (dd, J=9.6 6.4 Hz, IH), 7.00 (dd, J=8.0 8.0 Hz, IH), 7.31 (dd, J=8.0 8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.54 (m, IH), 7.83 (dd, J=8.5 1.6 Hz, IH), 8.01 (d br, J=8.5 Hz, IH), 8.28 (d, J=I.8 Hz, IH), 8.33 (d, J=8.7 Hz, IH), 8.38 (d, J=5.3 Hz, IH), 8.39 (d, J=I .2 Hz, IH), 8.82 (s br, IH), 9.07 (s br, IH), and 12.50 (s br, IH); MS (ES+) 498.1.
Example 78: Preparation of (S)-2-(7-(3-(4-
(dimethyIamino)phenyl)ureido)dibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoic acid
[0199] (S)-2-(7-(3-(4-(Dimethylamino)phenyl)ureido)dibenzo[b,d]thiophene-3- sulfonamido)-3 -methylbutanoic acid was prepared following procedures analogous to those described in Example 65 and using 4-(dimethylamino)phenylisocyanate. 1H NMR (DMSO-J6) δ ppm 0.81 (d, J=6.9 Hz, 3H), 0.84 (d, J=6.9 Hz, 3H), 1.96 (m, IH), 2.96 (s, 6H), 3.61 (dd, J=9.7 5.7 Hz, IH), 6.97 (s br, 2H), 7.40 (d br, J=8.4 Hz, 2H), 7:53 (dd, J=8.9 1.9 Hz, IH), 7.83 (dd, J=8.3 1.7 Hz, IH), 8.05 (d, J=I 0.0 Hz, IH), 8.28 (d, J=I .8 Hz, IH), 8.33 (d, J=8.7 Hz , IH), 8.37 (d, J=5.1 Hz, IH), 8.39 (d, J=I.3 Hz, IH), 8.66 (s br, IH), 9.01 (s br, IH), and 12.54 (s br, IH); MS (ES+) 5 541.2.
Example 79: Preparation of (S)-3-methyl-2-(7-(3-pyridin-4- ylureido)dibenzo[b,d]thiophene-3-suIfonamido)butanoic acid
[0200] (S)-3-Methyl-2-(7-(3-pyridin-4-ylureido)dibenzo[b,d]thiophene-3- sulfonamido)butanoic acid was prepared following procedures analogous to those 10 described in Example 65 and using pyridin-4-yl isocyanate. 1H NMR (DMSO-cfc) δ ppm 0.81 (d, J=6.9 Hz, 3H), 0.85 (d, J=6.9 Hz, 3H), 1.96 (m, IH), 3.63 (dd, J=9.5 6.1 Hz, IH), 7.63 (dd, J=8.7 2.0 Hz, IH), 7.86 (dd, J=8.5 1.7 Hz, IH), 7.98 (d, J=7.5 Hz, 2H), 8.08 (d, J=9.4 Hz, IH), 8.34 (d, J=2.0 Hz, IH), 8.43 (m, 3H), 8.64 (d. J=7.5 Hz, 2H), 10.14 (s br, IH), 10.90 (s br, IH), and 12.52 (s br, IH); MS (ES+) 499.0.
15 Example 80: Preparation of (S)-2-(7-(3-(3,5-dimethylisoxazol-4- / yl)ureido)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid
[0201] (S)-2-(7-(3-(3,5-Dimethylisoxazol-4-yl)ureido)dibenzo[b,d]thiophene-3- sulfonamido)-3-methylbutanoic acid was prepared following procedures analogous to those described in Example 65 and using 3,5-dimethylisoxazol-4-yl isocyanate. 20 (1H-DMSO 353K) δ ppm 0.86 (d, J=6.9 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H), 2.00 (m, IH), 2.17 (s, 3H), 2.33 (s, 3H), 3.61 (d, J=5.7 Hz, IH), 3.68 (s br, IH), 7.52 (dd, J=8.8 1.9 Hz, IH), 7.86 (dd, J=8.3 1.6 Hz, IH), 7.90 (s br, IH), 8.20 (d, J=I .7 Hz, IH), 8.25 (d, J=8.6 Hz, IH), 8.32 (d, J=8.4 Hz, IH), 8.36 (d, J=I.5 Hz, IH), and 9.07 (s br, IH); MS (ES+) 517.0.
25 Example 81 : Preparation of (S)-2-(7-
(methoxycarbonylamino)dibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoic acid
[0202] (S)-2-(7-(Methoxycarbonylamino)dibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoic acid was prepared following procedures analogous to those described in Examples 1 and 65 and using methyl chloroformate. 1H NMR (DMSO- d6) δ ppm 0.80 (d, J= 6.9 Hz, 3H), 0.83 (d, J=6.6 Hz, 3H), 1.95 (m, IH), 3.61 (m, IH), 3.72 (s, 3H), 7.81 (d, J=8.8 Hz, IH), 7.91 (dd, J=8.5, 1.6 Hz, IH), 8.10 (m, IH), 8.42 (d, J=8.8 Hz, IH), 8.50 (d, J=8.5 Hz, IH), 8.52 (d, J=I.3 Hz, IH), 9.46 (s, IH), and 12.45 (s br, IH); MS (ES+) 437.1.
Example 82: Preparation of (S)-2-(7-
(ethoxycarbonylamino)dibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoic acid
[0203] (S)-2-(7-(Ethoxycarbonylamino)dibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoic acid was prepared following procedures analogous to those described in Examples 1 and 65 and using ethyl chloroformate. 1H NMR (DMSO- d6) δ ppm 0.80 (d, J= 6.6 Hz, 3H), 0.83 (d, J=6.6 Hz, 3H), 1.28 (t, J=7.2 Hz, 3H), 1.95 (m, IH), 3.56 (m, IH), 4.18 (q, J=7.2 Hz, 2H), 7.58 (dd, J=8.8, 1.9 Hz, IH), 7.83 (dd, J=8.8, 1.6 Hz, IH), 7.99 (s br, IH), 8.22 (d, J=I .9 Hz, IH), 8.34 (d, J=8.8, Hz, IH), 8.37 (d, J=7.9 Hz, IH), 8.38 (d, J=2.2 Hz, IH), 10.00 (s, IH), and 12.49 (s br, IH); MS (ES+) 450.9.
Example 83: Preparation of (S)-2-(7-
(isobutoxycarbonylammo)dibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoic acid
[0204] (S)-2-(7-(Isobutoxycarbonylamino)dibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoic acid was prepared following procedures analogous to those described in Examples 1 and 65 and using isobutyl chloroformate. 1H NMR (DMSO-J6) δ ppm 0.80 (d, J=6.9 Hz, 3H), 0.83 (d, J=6.9 Hz, 3H), 0.96 (d, J=6.6Hz, 6H), 1.94 (m, 2H), 3.59 (m, IH), 3.93 (d, J=6.6 Hz, 2H), 7.58 (dd, J=8.5, 1.9 Hz, IH), 7.83 (dd, J=8.5, 1.6 Hz, IH), 8.03 (d br, J=8.5 Hz, IH), 8.23 (d, =1.9 Hz, IH), 8.34 (d, J=8.5 Hz, IH), 8.38 (d, J=8.5 Hz, IH), 8.39 (d, J=I.6 Hz, IH), 10.00 (s, IH), and 12.49 (s br, IH); MS (ES+) 479.0. Example 84: Preparation of (S)-2-(6-chloro-7- (methoxycarbonylamino)dibenzo[b,d]thiophene-3-suIfonamido)-3- methylbutanoic acid
[0205] (S)-2-(6-Chloro-7-(methoxycarbonylamino)dibenzo[b,d]thiophene-3- sulfonamido)-3-methylbutanoic acid was prepared following procedures analogous to those described in Examples 1 and 65. 1H NMR (DMSO-J6) δ ppm 0.80 (d, J= 6.9 Hz, 3H), 0.83 (d, J=6.6 Hz, 3H), 1.95 (m, IH), 3.61 (m, IH), 3.72 (s, 3H), 7.81 (d, J=8.8 Hz, IH), 7.91 (dd, J=8.5, 1.6 Hz, IH), 8.10 (m, IH), 8.42 (d, J=8.8 Hz, IH), 8.50 (d, J=8.5 Hz, IH), 8.52 (d, J=I.3 Hz, IH), 9.46 (s, IH), and 12.45 (s br, IH); MS (ES+) 471.0.
Example 85: Preparation of (S)-2-(7-
(isopropoxycarbonylamino)dibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoic acid
[0206] (S)-2-(7-(Isopropoxycarbonylamino)dibenzo[b,d]thiophene-3-sulfonamido)- 3-methylbutanoic acid was prepared following procedures analogous to those described in Examples 1 and 65 and using isopropyl chloro formate. 1H NMR (DMSO-J6) δ ppm 0.81 (d, J=6.9 Hz, 3H), 0.84 (d, J=6.9 Hz, 3H), 1.30 (d, J=6.2 Hz, 6H), 1.95 (m, IH), 3.60 (dd, J=9.5 6.0 Hz, IH), 4.95 (dq, J=6.2 6.2 Hz, IH), 7.58 (dd, J=8.7 1.9 Hz, IH), 7.83 (dd, J=8.3 1.6 Hz, IH), 8.05 (d, J=9.6 Hz, IH), 8.23 (d, J=I.8 Hz, IH), 8.33 (d, J=8.8 Hz, IH), 8.38 (d, J=7.8 Hz, IH), 8.39 (d, J=I.8 Hz, IH), 9.96 (s, IH), and 12.50 (s br, IH); MS (ES+) 465.1.
Example 86: Preparation of (S)-3-methyl-2-(7-(p- tolyloxycarbonylamino)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid
[0207] (S)-3-Methyl-2-(7-(p-tolyloxycarbonylamino)dibenzo[b,d]thiophene-3- sulfonamido)butanoic acid was prepared following procedures analogous to those described in Examples 1 and 65 and using p-tolyl chloroformate. 1H NMR (DMSO- J6) δ ppm 0.81 (d, J=6.9 Hz, 3H), 0.84 (d, J=6.9 Hz, 3H), 1.96 (m, IH), 2.33 (s, 3H), 3.57 (m, IH), 7.14 (d, J=8.7 Hz, 2H), 7.25 (d, J=8.7 Hz, 2H), 7.65 (dd, J=9.1 2.5 Hz, IH), 7.85 (dd, J=8.7 1.7 Hz, IH), 8.04 (s br, IH), 8.25 (d, J=I.9 Hz, IH), 8.41 (m, 3H), 10. 57 (s br, IH), and 12.52 (s br, (IH); MS (ES+) 513.1.
Example 87: Preparation of (S)-2-(7-((4- fluorophenoxy)carbonylamino)dibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoic acid
[0208] (S)-2-(7-((4-Fluorophenoxy)carbonylamino)dibenzo[b,d]thiophene-3- sulfonamido)-3-methylbutanoic acid was prepared following procedures analogous to those described in Examples 1 and 65 and using 4-fluorophenyl chloroformate. 1H NMR (DMSO-J6) δ ppm 0.81 (d, J=6.9 Hz, 3H), 0.84 (d, J=6.9 Hz, 3H), 1.95 (m, IH), 3.6 (m, IH), 7.37-7.23 (m, 4H), 7.65 (dd, J=8.7 1.8 Hz, IH), 7.85 (dd, J=8.5 1.6 Hz, IH), 8.05 (d br, J=9.5 Hz, IH), 8.25 (d, J=I .9 Hz, IH), 8.41 (m, 3H), 10.63 (s br, IH), and 12.51 (s br, IH); MS (ES+) 517.1.
Example 88: Preparation of (S)-3-methyl-2-(7- (phenoxycarbonylamino)dibenzo|b,d]thiophene-3-sulfonamido)butanoic acid
[0209] (S)-3-Methyl-2-(7-(phenoxycarbonylamino)dibenzo[b,d]thiophene-3- sulfonamido)butanoic acid was prepared following procedures analogous to those described in Examples 1 and 65 and using phenyl chloroformate. 1H NMR (DMSO- d6) δ ppm 0.81 (d, J=6.9 Hz, 3H), 0.85 (d, J=6.9 Hz, 3H), 1.96 (m, IH), 3.58 (m, IH), 7.28 (d, J=8.6 Hz, 2H), 7.29 (dd, J=8.6 8.6 Hz, IH), 7.46 (dd, J=8.6 8.6 Hz, 2H), 7.66 (dd, J=8.8 2.0 Hz, IH), 7.85 (dd, J=8.5 1.5 Hz, IH), 8.02 (s br, IH), 8.26 (d, J=I.8 Hz, IH), 8.41 (m, 3H), 10.62 (s br, IH), and 12.48 (s br, IH); MS (ES+) 499.0.
Example 89: Preparation of (S)-2-(7-((but-3- ynyloxy)carbonylamino)dibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoic acid
[0210] (S)-2-(7-((But-3 -ynyloxy)carbonylamino)dibenzo [b,d] thiophene-3 - sulfonamido)-3 -methylbutanoic acid was prepared following procedures analogous to those described in Examples 1 and 65 and using but-3-ynyl chloroformate. 1H NMR (DMSO-c/e) δ ppm 0.80 (d, J=6.9 Hz, 3H), 0.84 (d, J=6.9 Hz, 3H), 1.95 (m, IH), 2.60 (dt, J=6.4 2.6 Hz, 2H), 2.91 (t, J= 2.6 Hz, IH), 3.60 (dd, J=9.1 5.9 Hz, IH), 4.22 (t, J=6.4 Hz, 2H), 7.60 (dd, J=8.7 1.7 Hz, IH), 7.84 (dd, J=8.5 1.6 Hz, IH), 8.05 (d br, J=9.4 Hz, IH), 8.24 (d, J=I .7 Hz, IH), 8.35 (d, J=8.8 Hz, IH), 8.39 (d, J=8.0 Hz, IH), 8.4 (d, J=I.9 Hz, IH), 10.14 (s br, IH), and 12.51 (s br, IH); MS (ES+) 475.1.
Example 90: Preparation of (S)-3-methyl-2-(7-((2- (methylsulfonyl)ethoxy)carbonylamino)dibenzo[b,d]thiophene-3- sulfonamido)butanoic acid
[0211] (S)-3-Methyl-2-(7-((2-(methylsulfonyl)ethoxy)carbonylamino)dibenzo[b,d] thiophene-3-sulfonamido)butanoic acid was prepared following procedures analogous to those described in Examples 1 and 65 and using 2- (methylsulfonyl)ethyl chloroformate. 1H NMR (DMSO-J6) δ ppm 0.80 (d, J=6.9 Hz, 3H), 0.84 (d, J=6.9 Hz, 3H), 1.95 (m, IH), 3.10 (s, 3H), 3.58 (m, 3H), 4.51 (dd, J=6.01 6.01 Hz, 2H), 7.60 (dd, J=8.4 1.9 Hz, IH), 7.84 (dd, J= 8.6 1.9 Hz, IH), 8.01 (d br, J= 9.1 Hz, IH), 8.24 (d, J=1.8 Hz, IH), 8.42-8.34 (m, 3H), 10.16 (s br, IH), and 12.52 (s br, IH); MS (ES+) 529.1.
Example 91: Preparation of (S)-2-(7-
(benzyloxycarbonylamino)dibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoic acid
[0212] (S)-2-(7-(Benzyloxycarbonylamino)dibenzo[b,d]thiophene-3-sulfonamido)- 3-methylbutanoic acid was prepared following procedures analogous to those described in Examples 1 and 65 and using benzyl chloroformate. 1H NMR (DMSO- d6) δ ppm 0.81 (d, J=6.9 Hz, 3H), 0.84 (d, J=6.9 Hz, 3H), 1.95 (m, IH), 3.60 (dd, J=9.5 5.9 Hz, IH), 5.21 (s, 2H), 7.49-7.33 (m, 5H), 7.58 (dd, J=8.8 2.0 Hz, IH), 7.84 (dd, J=8.5 1.6 Hz, IH), 8.06 (d, J=9.3 Hz, IH), 8.24 (d, J=I.7 Hz, IH), 8.35 (d,
J=8.6 Hz, IH), 8.39 (d, J=8.0 Hz, IH), 8.39 (d, J=1.9 Hz, IH), 10.17 (s br, IH), and 12.52 (s br, IH); MS (ES+) 513.1. Example 92: Preparation of (R)-2-{7-[4-(2-hydroxy-ethyl)-[l,2,3]triazol-l-yl]- dibenzofuran-2-sulfonylamino}-3-methyl-butyric acid
Step 1 : Preparation of (RV2-(7-azido-dibenzofuran-2-sulfonylamino)-3-methyl- butyric acid methyl ester [0213] A suspension of (R)-2-(7-amino-dibenzofuran-2-sulfonylamino)-3-methyl- butyric acid methyl ester (1.83 g, 5 mmol) in 18% HCl (30 mL) was cooled with an ice-water batch and an aqueous NaNO2 solution (1.0 M, 7.5 mL) was added. After 20 minutes of stirring, an aqueous sodium azide solution (1.0 M, 10 mL) was added and the resulting mixture was stirred at ambient temperature for 2 hours. The reaction was neutralized with a NaOH solution to pH ~ 6. The precipitate was collected through filtration to give 1.9 g of 2-(7-azido-dibenzofuran-2- sulfonylamino)-3-methyl-butyric acid methyl ester. 1H NMR (400 MHz, DMSO-^6) δ ppm 0.81 (d, 6 H), 1.89 (d, 1 H), 3.26 (d, 3 H), 3.65 (d, 1 H), 7.24 (dd, J=8.34, 2.02 Hz, 1 H), 7.61 (d, J=2.02 Hz, 1 H), 7.86 - 7.90 (m, 2 H), 8.35 (d, J=8.34 Hz, 1 H), and 8.57 (d, J=1.52 Hz, 1 H).
Step 2: Preparation of (R)-2-{7-[4-(2-hvdroxy-ethyl)-[l,2Jltriazol-l-vn- dibenzofuran-2-sulfonylamino}-3-methyl-butyric acid methyl ester
[0214] To a suspension of 2-(7-azido-dibenzofuran-2-sulfonylamino)-3 -methyl- butyric acid methyl ester (200 mg, 0.5 mmol) in dimethylsulfoxide and water (2 mL, 1 :1) was added but-3-yn-l-ol (1.5 mmol), copper (II) sulfate (25 mg), and sodium L- ascorbate (250 mg). The reaction mixture was stirred at room temperature overnight, diluted with water, acidified to pH ~ 3 with 1 N HCl, and filtered to give 195 mg of (R)-2- { 7-[4-(2-hydroxy-ethyl)-[ 1 ,2,3]triazol- 1 -yl] -dibenzofuran-2- sulfonylamino}-3-methyl-butyric acid methyl ester. 1H NMR (400 MHz, DMSO- d6) δ ppm 0.84 (t, J=7.07 Hz, 6 H), 1.89 - 2.01 (m, 1 H), 2.93 (t, J=6.69 Hz, 2 H), 3.28 (s, 3 H), 3.70 (d, J=6.57 Hz, 1 H), 3.78 (t, 2 H), 7.89 - 8.06 (m, 3 H), 8.32 (d, 1 H), 8.48 (d, J=8.34 Hz, 1 H), and 8.66 (s, 1 H). Step 3: Preparation of (RV2-(7-r4-(2-hvdroxy-ethylVπ.2.31triazol-l-yll- dibenzofuran-2-sulfonylamino}-3-methyl-butyric acid
[0215] (R)-2-{7-[4-(2-Hydroxy-ethyl)-[l,2,3]triazol-l-yl]-dibenzofuran-2- sulfonylamino} -3 -methyl-butyric acid methyl ester from the previous step (195 mg) was suspended in water (4 mL) and THF (1 mL) and lithium hydroxide (230 mg, 10 mmol) was added. The resulting mixture was stirred at room temperature overnight, and acidified with HCl to pH ~ 4, and filtered to give 161 mg of (R)-2-{7- [4-(2-hydroxy-ethyl)-[l,2,3]triazol-l-yl]-dibenzofuran-2-sulfonylamino}-3-methyl- butyric acid. 1H NMR (400 MHz, DMSCW6) δ ppm 0.82 (dd, J=I 5.92, 6.57 Hz, 6 H), 1.87 - 2.02 (m, 1 H), 2.90 (t, 2 H), 3.74 (t, 2 H), 4.82 (d, 1 H), 7.96 (d, 2 H), 8.06 (s, 1 H), 8.36 (d, J=I .77 Hz, 1 H), 8.52 (d, J=8.34 Hz, 1 H), 8.66 - 8.69 (m, 1 H), and 8.75 (s, 1 H). MS (ES-): 457.1.
Example 93: Preparation of (R)-2-[7-(4-isobutyl-[l,2,3]triazol-l-yl)- dibenzofuran-2-sulfonylamino]-3-methyl-butyric acid
[0216] Following procedures analogous to those described in Example 92, (R)-2-[7- (4-isobutyl-[l,2,3]triazol-l-yl)-dibenzofuran-2-sulfonylamino]-3-methyl-butyric acid was prepared as an off-white solid. 1H NMR (400 MHz, DMSO-^6) δ ppm 0.79 - 1.01 (m, 12 H), 1.24 (d, 2 H), 1.91 - 2.08 (m, 1 H), 2.35 - 2.40 (m, 1 H), 3.70 (d, 1 H), 7.89 - 7.93 (m, 1 H), 7.99 (dd, J=8.59, 2.02 Hz, 1 H), 8.04 (dd, J=8.46, 1.89 Hz, 1 H), 8.32 (d, J=I.77 Hz, 1 H), 8.46 (d, J=8.59 Hz, 1 H), and 8.62 (s, 1 H); MS (ES-) 469.2.
Example 94: Preparation of (R)-2-[7-(4-hydroxymethyl-[l,2,3]triazol-l-yl)- dibenzofuran-2-sulfonylamino]-3-methyl-butyric acid
[0217] Following procedures analogous to those described in Example 92, (R)-2-[7- (4-hydroxymethyl-[l,2,3]triazol-l-yl)-dibenzofuran-2-sulfonylamino]-3-methyl- butyric acid was prepared as an off-white solid. 1H NMR (400 MHz, DMSO-J6) δ ppm 0.84 (dd, 6 H), 1.87 - 2.03 (m, 1 H), 3.54 - 3.68 (m, 1 H), 4.65 (d, J=5.56 Hz, 2 H), 7.92 - 8.00 (m, 1 H), 8.07 (dd, J=8.34, 2.02 Hz, 1 H), 8.12 (d, J=9.35 Hz, 1 H), 8.39 (d, J=2.02 Hz, 1 H), 8.53 (d, J=8.34 Hz, 1 H), 8.66 - 8.70 (m, 1 H), and 8.86 (s, I H); MS (ES-) 443.1. Example 95: Preparation of (R)-2-[7-(4-Cyclohexyl-[l,2,3]triazol-l-yl)- dibenzofuran-2-sulfonylamino]-3-methyl-butyric acid
[0218] Following procedures analogous to those described in Example 92, (R)-2-[7- (4-cyclohexyl-[l,2,3]triazol-l-yl)-dibenzoruran-2-sulfonylamino]-3-methyl-butyric acid was prepared as an off-white solid. 1H NMR (400 MHz, MeOD) δ ppm 1.84 (dd, ./=15.41, 6.82 Hz, 6 H), 2.22 - 3.14 (m, 12 H), 4.62 (d, 1 H), 8.93 - 9.02 (m, 2 H), 9.06 (dd, J=8.46, 1.89 Hz, 1 H), 9.37 (d, J=2.02 Hz, 1 H), 9.54 (d, J=8.34 Hz, 1 H), 9.69 (d, J=I.26 Hz, 1 H), and 9.75 (s, 1 H); MS (ES-) 495.2.
Example 96: Preparation of (R)-l-[8-(l-carboxy-2-methyl-propylsulfamoyl)- dibenzofuran-3-yl]-lH-[l,2,3]triazole-4-carboxylic acid
[0219] Following procedures analogous to those described in Example 92, (R)- 1 -[8- (l-carboxy-2-methyl-propylsulfamoyl)-dibenzofuran-3-yl]-lH-[l,2,3]triazole-4- carboxylic acid was prepared as an off-white solid. 1H NMR (400 MHz, DMSO-^6) δ ppm 0.83 (s, 6 H), 1.85 - 2.06 (m, 1 H), 3.60 - 3.71 (m, 1 H), 7.88 - 8.05 (m, 2 H), 8.15 (s, 1 H), 8.49 (s, 1 H), 8.52 - 8.60 (m, 1 H), 8.71 (s, 1 H), and 9.57 (s, 1 H); MS (ES-) 457.1.
Example 97: Preparation of (R)-3-methyl-2-[7-(4-phenyl-[l,2,3]triazol-l-yl)- dibenzofuran-2-sulfonylamino]-butyric acid
[0220] Following procedures analogous to those described in Example 92, (R)-3- methyl-2-[7-(4-phenyl-[l,2,3]triazol-l-yl)-dibenzofuran-2-sulfonylamino]-butyric acid was prepared as an off-white solid. 1H NMR (400 MHz, DMSO-^6) δ ppm 0.77 - 0.91 (m, 6 H), 1.85 - 2.05 (m, 1 H), 3.64 (dd, J=9.47, 5.94 Hz, 1 H), 7.37 - 7.45 (m, 1 H), 7.54 (t, J=7.58 Hz, 1 H), 7.93 - 8.02 (m, 3 H), 8.09 - 8.17 (m, 2 H), 8.44 (d, J=I .77 Hz, 1 H), 8.59 (d, J=8.59 Hz, 1 H), 8.71 (d, J=I.52 Hz, 1 H), and 9.47 (s, I H); MS (ES-) 489.1. Example 98: Preparation of (R)-2-[7-(4-dimethylaminomethyl-[l,2,3]triazol-l- yl)-dibenzofuran-2-sulfonylamino]-3-methyl-butyric acid
[0221] Following procedures analogous to those described in Example 92, (R)-2-[7- (4-dimethylaminomethyl-[l,2,3]triazol-l-yl)-dibenzofuran-2-sulfonylamino]-3- methyl-butyric acid was prepared as an off-white solid. 1H NMR (400 MHz, DMSO-J6) δ ppm 0.82 (dd, 6 H), 1.89 - 2.04 (m, 1 H), 2.78 - 2.87 (m, 8 H), 3.63 (dd, J=9.60, 6.06 Hz, 1 H), 7.94 - 8.03 (m, 1 H), 8.07 (dd, J=8.46, 1.89 Hz, 1 H), 8.15 (d, J=9.60 Hz, 1 H), 8.42 (d, J=I .77 Hz, 1 H), 8.59 (d, J=8.34 Hz, 1 H), 8.72 (d, J=I .77 Hz, 1 H), and 9.13 (s, 1 H); MS (ES-) 470.2.
Example 99: Preparation of (S)-3-methyl-2-(8-(2-oxooxazolidin-3- yl)dibenzo[b,d]furan-3-suIfonamido)butanoic acid
Step 1 : Preparation of (S Vtert-butyl 2-(8-((2- bromoethoxy)carbonylamino)dibenzo[b,dlfuran-3-sulfonamido)-3-methylbutanoate
[0222] (S)-Tert-butyl 2-(8-aminodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate (1.105 g, 2.64 mmol) and DMAP (0.387 g, 3.17 mmol) were dissolved in 30 mL Of CH2Cl2, followed by addition of 2-bromoethyl chloroformate (0.55 g, 2.9 mmol). The mixture was stirred at room temperature overnight, concentrated, and purified with a silica gel column chromatography to give (S)-tert- butyl 2-(8-((2-bromoethoxy)carbonylamino) dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate as a grey solid in 95% yield.
Step 2: Preparation of (S Wer/-butyl 3-methyl-2-(8-(2-oxooxazolidin-3- yl)dibenzo[b,d]furan-3-sulfonamido)butanoate
[0223] (S)-Tert-butyl 2-(8-((2-bromoethoxy)carbonylamino) dibenzo[b,d]furan-3- sulfonamido)-3 -methylbutanoate from Step 1 (1.36 g, 2.4 mmol) in 10 mL of DMF was mixed with potassium carbonate (1 g, 0.72 mol). The reaction mixture was stirred for 18 hours and purified with a preparative HPLC to provide (S)-tert-buty\ 3-methyl-2-(8-(2-oxooxazolidin-3-yl)dibenzo [b,d]furan-3-sulfonamido)butanoate as a pale yellow solid in 92% yield. Step 3: Preparation of (S)-3-methyl-2-(8-(2-oxooxazolidin-3-yl)dibenzo[b,d] furan-3 - sulfonamido)butanoic acid
[0224] The sulfonamide t-butyl ester (1.03 g, 2.1 mmol) from Step 2 was mixed with 20 mL of TFA/CH2C12 (1:1) and stirred at room temperature for 4 hours. The solvents were removed under reduced pressure and the residue was triturated in CH3CN/H2O followed by a freeze-dry process. (S)-3-Methyl-2-(8-(2- oxooxazolidin-3-yl)dibenzo[b,d]furan-3-sulfonamido)butanoic acid was obtained as a pale yellow solid in 99% yield. HRMS: calculated for [C20H20N2O7S + H]+ 433.10640; found (ESI-FTMS, [M+H]1+) 433.10635.
Example 100: Preparation of (S)-2-(8-(diethylamino)dibenzo[b,d]furan-3- sulfonamido)3-methylbutanoic acid
Step 1 : Preparation of (SVtert-butyl 2-(8-(diethylamino)dibenzo[b,d1furan-3- sulfonamido)3-methylbutanoate and (S)-tert-butyl 2-(8- (ethylamino)dibenzo [b,d] furan-3 -sulfonamido)3 -methylbutanoate [0225] (S)-Tert-butyl 3-methyl-2-(8-nitrodibenzo[b,d]furan-3- sulfonamido)butanoate (560 mg) and 200 mg of Pd/C (10%) were mixed with 150 mL of MeOH and 2 mL Of CH3CN. The reaction was carried out in a Pan- shaker at room temperature under hydrogen (50 psi) overnight. The reaction mixture was filtered through Celite®. Separation of the reaction mixture gave 292 mg of (S)-tert-butyl 2-(8-(diethylamino)dibenzo[b,d]furan-3-sulfonamido)3- methylbutanoate and 235 mg of (S)-tert-butyl 2-(8-(ethylamino)dibenzo[b,d]furan-3- sulfonamido)3 -methylbutanoate, both as yellow solids.
Step 2: Preparation of (SV2-(8-(diethylamino)dibenzo[b,d]furan-3-sulfonamido)3- methylbutanoic acid [0226] The sulfonamide t-butyl ester of the diethylated compound (126 mg) from Step 1 was mixed in 2 mL of TFA/CH2CI2 (1 :1) and stirred at room temperature for 4 hours. The solvents were removed under reduced pressure and the residue was triturated with CH3CN/H2O followed by a freeze-dry process. (S)-2-(8- (Diethylamino)dibenzo [b,d] furan-3 -sulfonamido)3 -methylbutanoic acid was obtained as a white solid in 95% yield. HRMS: calculated for [C2iH26N2O5S + H]+ 419.16352; found (ESI-FTMS, [M+H]l+) 419.16354.
Example 101: Preparation of (S)-2-(8-(ethylamino)dibenzo[b,d]furan-3- sulfonamido)3-methylbutanoic acid
[0227] (S)-Tert-butyl 2-(8-(ethylamino)dibenzo[b,d]furan-3-sulfonamido)3- methylbutanoate (Example 100, Step 1, 58 mg) was treated analogously as the diethylated t-butyl ester in Step 2 of Example 100. (S)-2-(8-
(Ethylamino)dibenzo[b,d]furan-3-sulfonamido)3-methylbutanoic acid (50.6 mg) was obtained as a white solid in quantitative yield. HRMS: calculated for [C19H22N2O5S + H]+ 391.13222; found (ESI-FTMS, [M+H]1+) 391.13198.
Example 102: Preparation of (S)-2-(8-
(ethyl(methoxycarbonyl)amino)dibenzo[b,d]furan-3-sulfonamido)3- methylbutanoic acid
Step 1 : Preparation of f SVtert-butyl 2-(8- (ethyl(methoxycarbonyl')amino')dibenzo[b,d1furan-3-sulfonamido')3-methylbutanoate
[0228] (S)-Tert-butyl 2-(8-(ethylamino)dibenzo[b,d]furan-3-sulfonamido)3- methylbutanoate from (Example 100, Step 1, 122 mg, 0.27 mmol) and DMAP (40 mg, 0.33 mmol) were dissolved in 3 mL OfCH2Cl2, followed by addition of methyl chloroformate (31 mg, 0.33 mmol). The mixture was stirred at room temperature overnight, concentrated, and purified with a silica gel column chromatography to provide (S)-tert-butyl 2-(8- (ethyl(methoxycarbonyl)amino)dibenzo [b,d]furan-3-sulfonamido)3- methylbutanoate as a white solid in 95% yield.
Step 2: Preparation of (S)-2-(8-(ethyl(methoxycarbonyl)amino)dibenzo[b,d]furan-3- sulfonamido*)3-methylbutanoic acid
[0229] The sulfonamide t-butyl ester (100 mg) from Step 1 was mixed with 1 mL of TFA/ CH2Cl2 (1 :1) and stirred at room temperature for 4 hours. The solvents were removed under reduced pressure and the residue was triturated in CH3CN/H2O followed by a freeze-dry process to provide 96 mg of (S)-2-(8- (ethyl(methoxycarbonyl)amino)dibenzo[b,d]furan-3-sulfonamido)3-methylbutanoic acid as a white solid in quantitative yield. HRMS: calculated for [C2[H24N2O7S + H]+ 449.13770; found (ESI-FTMS, [M+H]1+) 449.1379.
Example 103: Preparation of (S)-3-methyI-2-(8-morpholinodibenzo[b,d]furan- 3-sulfonamido)butanoic acid
Step 1 : Preparation of 8-bromodibenzo[b,d]furan-3-sulfonyl chloride
[0230] Dibenzo[b,d]furan-3-sulfonyl chloride (5.3 g) was mixed with AcOH (glacial, 120 niL) and bromine (10 eq., 10 mL). The mixture was stirred at 7O0C for 4 hours. The excess bromine was removed by bubbling nitrogen through the reaction mixture. The reaction mixture was cooled to room temperature and filtered to provide 5.4 g of 8-bromodibenzo[b,d] furan-3-sulfonyl chloride as a light brown solid.
Step 2: Preparation of (S)-tert-butyl 2-(*8-bromodibenzo[b,d]furan-3-surfonamido)-3- methylbutanoate [0231] 8-Bromodibenzo[b,d]furan-3-sulfonyl chloride (3.46 g, 10 mmol) and (S)- tert-butyl 2-amino-3-methylbutanoate hydrochloride (2.3 g, 1.1 eq.) were mixed with 30 mL Of CH2Cl2, to which N,N-diisopropylethylamine (3.84 mL, 2.2 eq.) was added. The mixture was stirred at room temperature for 5 hours and purified with a column chromatography to give 4.7 g of (S)-tert-butyl 2-(8- bromodibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate as a white solid.
Step 3: Preparation of (S)-tert-butyl 3-methyl-2-(8-morpholinodibenzo[b,d]furan-3- sulfonamido^butanoate
[0232] (S)-Tert-butyl 2-(8-bromodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate (240 mg, 0.5 mmol), 2-(dicyclohexylphosphino)biphenyl (120 mg), morpholine (104 mg, 2.4 eq.), tripotassium phosphate (K3PO4, 320 mg), and tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3, 30 mg) were mixed with 4 mL of dioxane. The mixture was deoxygenated with nitrogen gas and stirred at 90°C overnight. The reaction mixture was mixed with brine and extracted with EtOAc. Removal of solvent gave a crude product, which was purified by a column chromatography to give 16 mg of (S)-tert-butyl 3-methyl-2-(8- morpholinodibenzo[b,d]furan-3-sulfonamido)butanoate as a white solid.
Step 4: Preparation of (S)-2-(8-(6-methoxypyridin-3-yl)dibenzo[b,d1furan-3- sulfonamido)-3-methylbutanoic acid [0233] (S)-Tert-butyl 2-(8-(6-methoxypyridin-3-yl)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoate (16 mg) was dissolved in 2 mL of TF A/C H2Cl2 (1 :1). The solution was stirred at room temperature for 3 hours and concentrated under reduced pressure and the residue was triturated with CH3CN/H2O followed by a freeze-dry process to give 11 mg of (S)-3-methyl-2-(8- moφholinodibenzo[b,d]furan-3-sulfonamido)butanoic acid as a white solid. HRMS: calculated for [C2iH24N2O6S + H]+ 433.14278; found (ESI-FTMS, [M+H]1+) 433.1425.
Example 104: Preparation of (S)-3-methyl-2-(8-(3-(trifluoromethyl)-lH- pyrazol-l-yl)dibenzo[b,d]furan-3-sulfonamido)butanoic acid
Step 1 : Preparation of (SWert-butyl 3-methyl-2-(8-(3-(trifluoromethvO-lH-pyrazol- l-yDdibenzo[b,d1furan-3-ylsulfonamido)butanoate
[0234] (S)-Tert-butyl 2-(8-bromodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate from (Example 103, Step 2, 485 mg, 1 mmol), 3- (trifluoromethyl)pyrazole (274 mg, 2 mmol), /røm'-N,N'-dimethyl-l,2- cyclohexanediamine (29 mg, 0.2 mmol), copper (I) iodide (CuI, 10 mg, 0.05 mmol), and K3PO4 (450 mg, 21 mmol) were mixed in 2 mL of toluene. The mixture was irradiated with microwave at 13O0C for 3 hours. The reaction mixture was purified by a preparative ΗPLC to give 313 mg of (S)-/erf-butyl 3-methyl-2-(8-(3- (trifluoromethyl)-l/7-pyrazol-l-yl)dibenzo[b,d]furan-3-ylsulfonamido)butanoate as a white solid in 58% yield.
Step 2: Preparation of fSV3-methyl-2-(8-(3-(trifluoromethvO-lH-pyrazol-l- vDdibenzo [b.d] furan-3 -sulfonamido)butanoic acid
[0235] The sulfonamide t-butyl ester from Step 1 (100 mg) was mixed in 1 mL of TFA/ CH2Cl2 (1 :1) and stirred at room temperature for 4 hours. The solvents were removed under reduced pressure and the residue was triturated in CH3CN/H2O followed by a freeze-dry process to give 96 mg of (S)-3-methyl-2-(8-(3- (trifluoromethyl)-l//-pyrazol-l-yl)dibenzo[b,d]furan-3-sulfonamido)butanoic acid as a white solid in quantitative yield. HRMS: calculated for [C2IHi8F3N3O5S + H]+ 482.09920; found (ESI-FTMS, [M+H]1+) 482.09983.
Example 105: Preparation of (S)-2-(8-(l//-pyrazol-l-yl)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoic acid
Step 1 : Preparation of CS Wer/-butyl 2-(8-(lH-pyrazol-l-yl)dibenzorb.dlfuran-3- sulfonamido)-3-methylbutanoate [0236] (S)-Tert-butyl 2-(8-bromodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate (200 mg, 0.4 mmol), pyrazole (56 mg, 0.8 mmol), trans-N,W- dimethyl-l,2-cyclohexanediamine (12 mg, 0.08 mmol), CuI (4 mg, 0.02 mmol), and K3PO4 (185 mg, 0.87 mmol) were mixed in 2 mL of toluene. The mixture was irradiated with microwave at 13O0C for 3 hours. The reaction mixture was purified by a preparative HPLC to give 40 mg of (S)-tert-butyl 2-(8-(l//-pyrazol-l- yl)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate as a white solid in 20% yield.
Step 2: Preparation of (SV2-(8-(lH-pyrazol-l-vOdibenzo[b,dlfuran-3-sulfonamido)- 3-methylbutanoic acid [0237] The sulfonamide t-butyl ester (27 mg) from Step 1 was mixed in 0.5 mL of TFA/ CH2Cl2 (1 :1) and stirred at room temperature for 4 hours. The solvents were removed under reduced pressure and the residue was triturated in CH3CN/H2O followed by a freeze-dry process to give 23 mg of (S)-2-(8-(lH-pyrazol-l- yl)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid as a white solid in ' quantitative yield. ΗRMS: calculated for [C20Hi9N3O5S + H]+ 414.11182; found (ESI-FTMS, [M+H]1+) 414.11215. Example 106: Preparation of (S)-3-methyl-2-(8-(piperazin-l- yl)dibenzo[b,d]furan-3-sulfonamido)butanoic acid
Step 1 : Preparation of (SWert-butyl 4-(7-(N-(l-fert4?utoxy-3-methyl-l-oxotuban-2- yl) sulfamoyl)dibenzo[b,d]furan-2-yl)piperazine-l-carboxylate [0238] (S)-Tert'-butyl 2-(8-bromodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate (320 mg, 0.66 mol), /er/-butyl 1 -piperazinecarboxylate (247 mg, 1.32 mmol), Pd2(dba)3 (14 mg, 0.01 mmol), tri(o-tolyl) phosphine (8 mg, 0.04 mmol), and sodium /ert-butoxide (140 mg, 1.45 mmol) were mixed in 2 mL of toluene and stirred at 11O0C for 18 hours. The reaction mixture was purified by a preparative HPLC to give 54 mg of (S)-/er?-butyl 4-(7-(/V-(l-/er/-butoxy-3-methyl- l-oxotuban-2-yl) sulfamoyl)dibenzo[b,d]furan-2-yl)piperazine-l-carboxylate as a white solid in 14% yield.
Step 2: Preparation of (SV3-methyl-2-('8-(piperazin-l-yl)dibenzorb,d1furan-3- sulfonamido)butanoic acid [0239] The sulfonamide t-butyl ester (50 mg) from Step 1 was mixed in 0.5 mL of TFA/CH2C12 (1 : 1) and stirred at room temperature for 4 hours. The solvents were removed under reduced pressure and the residue was triturated in CH3CNZH2O followed by a freeze-dry process to give 36 mg of (S)-3-methyl-2-(8-(piperazin-l- yl)dibenzo[b,d]furan-3-sulfonamido)butanoic acid_as a white solid in quantitative yield. MS (LCMS-ESI) 432.3.
Example 107: Preparation of (S)-2-(8-(lH-imidazol-l-yl)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoic acid
Step 1 : Preparation of (S)-tert-butyl 2-(8-(lH-imidazol-l-yl)dibenzo[b,d]furan-3- sulfonamido)-3 -methy lbutanoate [0240] (S)-Tert-butyl 2-(8-aminodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate (418 mg, 1 mmol) in MeOH (10 mL) was treated with 40% aqueous glyoxal (160 mg, 1.1 mmol) for 16 hours at room temperature. Ammonium chloride (106 mg, 2 mmol) was added followed by 37% aqueous formaldehyde (162 mg, 2 mmol). The mixture was diluted with 20 mL of MeOH and the resulting mixture was heated to reflux for 1 hour. Phosphoric acid (1 mL) was added drop- wise and the mixture was heated to reflux for additional 4-8 hours. The reaction mixture was mixed with water and was neutralized with aqueous NaOH to pH 9. The mixture was extracted with CH2Cl2. The combined organic layers were concentrated to give a crude product which was purified by a column chromatography to give 160 mg of (S)-tert-butyl 2-(8-(lH-imidazol-l- yl)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate as a pale brown oil.
Step 2: Preparation of (SV2-(8-(lH-imidazol-l-vπdibenzorb,dlfuran-3- sulfonamidoVS-methylbutanoic acid [0241] The sulfonamide t-butyl ester (0.2 mmol) from Step 1 was dissolved in 2 mL of TFA/CH2C12 (1 :1). The solution was stirred at room temperature for 3 hours and concentrated under reduced pressure and the residue was triturated with CH3CN/H2O followed by a freeze-dry process. (S)-2-(8-(lH-Imidazol-l- yl)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid was obtained as a white solid in 95% yield. HRMS: calculated for [C20Hi9N3O5S + H]+ 414.11182; found (ESI-FTMS, [M+H]1+) 414.11231.
Example 108: Preparation of (S)-2-(8-(4,5-dimethyl-lH-imidazoI-l- yl)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid
[0242] Following procedures analogous to those described in Example 107, (S)-2- (8-(4,5-dimethyl-lH-imidazol-l-yl)dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoic acid was prepared as an off-white solid. HRMS: calculated for [C22H23N3O5S + H]+ 442.14312; found (ESI-FTMS, [M+H]) 442.1443.
Example 109: Preparation of (R)-3-methyl-2-(7-(4-((trimethyIsilyl)methyl)-lH- l,2,3-triazol-l-yI)dibenzo[b,d]furan-2-sulfonamido)butanoic acid
[0243] Following procedures analogous to those described in Example 92 and using trimethyl(prop-2-ynyl)silane, (R)-3-methyl-2-(7-(4-((trimethylsilyl)methyl)-lH- l,2,3-triazol-l-yl)dibenzo[b,d]furan-2-sulfonamido)butanoic acid was obtained as an off-white solid. 1H NMR (400 MHz, DMSO-</6) δ ppm 8.60 (d, J=I .26 Hz, 1 H), 8.49 (s, 1 H), 8.44 (d, J=8.08 Hz, 1 H), 8.29 (d, J=2.27 Hz, 1 H), 8.05 (d, J=9.60 Hz, 1 H), 7.98 (dd, J-8.46, 1.89 Hz, 1 H), 7.85 - 7.93 (m, 2 H), 3.52 - 3.58 (m, 1 H), 1.83 - 1.94 (m, 1 H), 0.75 (dd, 6 H), and -0.01 - 0.01 (m, 9 H); MS (LCMS-ESI, M+H) 501.24.
Example 110: Preparation of (S)-2-(8-(4-cyclohexyl-lH-l,2,3-triazol-l- yl)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid
Step 1 : Preparation of (S)-methyl 3-methyl-2-(8-nitrc>dibenzo[b,d]furan-3- sulfonamido)butanoate
[0244] L-Valine methyl ester (HCl salt, 6.44 g, 35.7 mmol) and di- isopropylethylamine (8.6 g, 10 mL) were mixed in CH2Cl2 (100 mL) and 8- nitrodibenzo[b,d]furan-3-sulfonyl chloride (Example 28) (9.57 g, 35.7 mmol) was added portion-wise at 0°C. The reaction was allowed to warm up to room temperature for 2 hours. Water (200 mL) was added and CH2Cl2 was removed under reduced pressure. The resulting suspension was filtered and the filter cake was washed with water and dried to give 14.0 g of (S)-methyl 3-methyl-2-(8- nitrodibenzo[b,d]furan-3-sulfonamido)butanoate in 97% yield.
Step 2: Preparation of (S)-methyl 2-(8-aminodibenzo[b,d1furan-3-sulfonamido)-3- methylbutanoate
[0245] (S)-Methyl 3-methyl-2-(8-nitrodibenzo[b,d]furan-3-sulfonamido)butanoate from Step 1 (14 g) and 0.5 g of 10% Pd/C (50% water) in MeOH (150 mL) was agitated in a Parr shaker under hydrogen (50 psi) for 16 hours. The suspension was filtered through Celite . Concentration of the filtrate afforded 13.5 g of (S)-methyl 2-(8-aminodibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate as a white solid in 99% yield.
Step 3: Preparation of (S)-methyl 2-(8-azidodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate
[0246] A suspension of (S)-methyl 2-(8-aminodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate (3.62 g, 10 mmol) from Step 2 in 18% HCl (60 mL) was cooled with an ice-water batch and an aqueous sodium nitrite solution (1.0 M, 16 mL) was added. The resulting reaction was stirred for 20 min, to which sodium azide solution (1.0 M, 20 niL) was added. The resulting mixture was stirred at ambient temperature for 3 hours, neutralized with sodium hydroxide solution to pH ~ 6, and filtered to give (S)-methyl 2-(8-azidodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate (3.0 g).
Step 4: Preparation of (SVmethyl 2-(8-(4-cvclohexyl-lH-1.2.3-triazol-l- vOdibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate
[0247] To a suspension of (S)-methyl 2-(8-azidodibenzo[b,d]furan-3-sulfonamido)- 3-methylbutanoate (200 mg, 0.5 mmol) from Step 3 in DMSO (1 mL) and water (1 mL) was added ethynylcyclohexane (0.5 mmol), copper sulfate (25 mg), and sodium L-ascorbate (250 mg). The reaction mixture was stirred at room temperature overnight, diluted with water, acidified to pH ~ 2 with 1 N HCl, and filtered to give (S)-methyl 2-(8-(4-cyclohexyl- 1 H- 1 ,2,3-triazol- 1 -yl)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoate (225 mg).
Step 5: Preparation of (SV2-f8-(4-cvclohexyl-lH-1.2.3-triazol-l- vDdibenzo[b,d]furan-3-sulfonamido>3-methylbutanoic acid
[0248] (S)-Methyl 2-(8-(4-cyclohexyl- IH-1 ,2,3-triazol- l-yl)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoate (225 mg) from Step 4 was suspended in water (4 mL) and THF (1 mL). To the mixture was added lithium hydroxide (230 mg, 10 mmol). The reaction mixture was stirred at room temperature overnight and acidified with hydrochloric acid to pH ~ 2. The precipitate was collected through filtration to give (S)-2-(8-(4-cyclohexyl-lH-l,2,3-triazol-l-yl)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoic acid (180 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-J6) δ ppm 8.83 (d, J=2.53 Hz, 1 H), 8.64 (s, 1 H), 8.42 (d, J=8.34 Hz, 1 H), 8.10 - 8.16 (m, 2 H), 8.01 (d, J=9.09 Hz, 1 H), 7.84 - 7.90 (m, 1 H), 3.58 - 3.67 (m, 1 H), 2.01 - 2.13 (m, 3 H), 1.89 - 2.02 (m, 1 H), 1.20 - 1.86 (m, 8 H), and 0.83 (dd, 6 H); MS (LCMS-ESI, M+H) 497.40.
- I l l - Example 111: Preparation of (S)-2-(8-(4-(2-hydroxyethyI)-lH-l,2,3-triazol-l- yl)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid
[0249] Following procedures analogous to those described in Example 110 and using but-3-yn-l-ol in place of ethynylcyclohexane, (S)-2-(8-(4-(2-hydroxyethyl)- lH-l,2,3-triazol-l-yl)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid was obtained as an off-white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 8.83 (d, J=I .77 Hz, 1 H), 8.65 (s, 1 H), 8.43 (d, J=8.08 Hz, 1 H), 8.08 - 8.16 (m, 2 H), 8.01 (d, J=9.35 Hz, 1 H), 7.87 (dd, J=8.08, 1.52 Hz, 1 H), 3.74 (t, 2 H), 3.45 - 3.57 (m, 1 H), 2.90 (t, J=6.82 Hz, 2 H), 1.89 - 2.03 (m, 1 H), and 0.82 (dd, J=I 9.96, 6.82 Hz, 6 H); MS (LCMS-ESI, M+H) 459.30.
Example 112: Preparation of (S)-2-(8-(4-((dimethylamino)methyl)-lH-l,2,3- triazoI-l-yl)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid
[0250] Following procedures analogous to those described in Example 110 and using N,N-dimethylprop-2-yn- 1 -amine, (S)-2-(8-(4-((dimethylamino)methyl)- 1 H- 1 ,2,3-triazol-l-yl)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid was obtained as an off-white solid. 1H NMR (400 MHz, MeOD) δ ppm 9.06 (s, 1 H), 8.87 (d, J=2.27 Hz, 1 H), 8.53 (d, J=8.08 Hz, 1 H), 8.39 (s, 1 H), 8.28 - 8.34 (m, 1 H), 8.14 (d, J=8.84 Hz, 2 H), 4.92 - 5.18 (m, 6 H), 3.67 - 3.73 (m, 1 H), 3.16 - 3.26 (m, 2 H), and 1.16 (dd, 6 H); MS (LCMS-ESI, M+H) 472.20.
Example 113: Preparation of (S)-3-methyl-2-(8-(4-phenyl-lH-l,2,3-triazoI-l- yl)dibenzo[b,d]furan-3-sulfonamido)butanoic acid
[0251] Following procedures analogous to those described in Example 110 and using ethynylbenzene, (S)-3-methyl-2-(8-(4-phenyl- 1 H- 1 ,2,3-triazol- 1 - yl)dibenzo[b,d]furan-3-sulfonamido)butanoic acid was obtained as an off-white solid. 1H NMR (400 MHz, DMSO-J6) δ ppm 9.39 (s, 1 H), 8.90 (d, J=2.27 Hz,
1 H), 8.44 (d, J=8.08 Hz, 1 H), 8.19 (dd, J=8.84, 2.27 Hz, 1 H), 8.13 - 8.17 (m, 1 H), 8.07 (d, J=9.09 Hz, 1 H), 7.94 - 8.02 (m, 2 H), 7.88 (dd, J=8.21, 1.39 Hz, 1 H), 7.53 (t, J=7.58 Hz, 2 H), 7.37 - 7.45 (m, 1 H), 3.42 - 3.54 (m, 1 H), 1.91 - 2.03 (m, 1 H), and 0.83 (dd, J=22.86, 6.69 Hz, 6 H); MS (LCMS-ESI, M+H) 491.30. Example 114: Preparation of (S)-2-(8-(4-isobutyl-lH-l,2,3-triazol-l- yl)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid
[0252] Following procedures analogous to those described in Example 1 10 and using 4-methylpent- 1 -yne, (S)-2-(8-(4-isobutyl- 1 H- 1 ,2,3-triazol- 1 - yl)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid was obtained as an off- white solid. 1H NMR (400 MHz, DMSO-J6) δ ppm 8.71 (s, 1 H), 8.57 (s, 1 H), 8.40 (d, 1 H), 8.06 - 8.18 (m, 2 H), 8.00 (d, 1 H), 7.88 (d, 1 H), 1.84 - 2.13 (m, 1 H), 1.21 (d, 2 H), 0.97 (d, 6 H), and 0.66 - 0.91 (m, 6 H); MS (LCMS-ESI, M+H) 471.40.
Example 115: Preparation of (S)-3-methyl-2-(7-(4-(l-methyl-lH-pyrroI-2-yl)- lH-l,2,3-triazol-l-yl)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid
Step 1 : Preparation of (S)-methyl 3-methyl-2-(7-nitrodibenzo(~b,d]thiophene-3- sulfonamido)butanoate
[0253] 7-Nitrodibenzo[b,d]thiophene-3-sulfonyl chloride (Example 65, Step 2, 599 mg, 1.83 mmol) and (S)-methyl 2-amino-3-methylbutanoate hydrochloride (335 mg, 2.0 mmol) were mixed with 5 mL CH2Cl2, followed by slow addition of N,N-diisopropylethylamine (520 mg, 4 mmol) at 0°C. The mixture was allowed to warm to room temperature for 4 hours and purified with a column chromatography to provide (S)-methyl 3-methyl-2-(7-nitrodibenzo[b,d]thiophene-3- sulfonamido)butanoate as a white solid in 80% yield.
Step 2: Preparation of (S)-methyl 2-(7-aminodibenzo[b,d]thiophene-3-sulfonamido)- 3-methylbutanoate
[0254] (S)-Methyl 3-methyl-2-(7-nitrodibenzo[b,d]thiophene-3- sulfonamido)butanoate was mixed with MeOH and treated with hydrogen (40 psi) overnight in the presence of 10% Pd/C (10% w/w). The catalyst was filtered off and (S)-methyl 2-(7-aminodibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoate was obtained in quantitative yield after removal of the solvent. Step 3: Preparation of (S)-methyl 2-(7-azidodibenzo[b,d"|thiophene-3-sulfonamidoy 3-methylbutanoate
[0255] A suspension of (S)-methyl 2-(7-aminodibenzo[b,d]thiophene-3- sulfonamido)-3-methylbutanoate (3.93 g, 10 mmol) from Step 2 in 18% HCl (60 mL) was cooled with an ice-water bath and an aqueous sodium nitrite solution (1.0 M, 16 mL) was added. The resulting solution was stirred for 20 min, to which an aqueous sodium azide solution (1.0 M, 20 mL) was added. The reaction mixture was stirred at ambient temperature for 3 hours, neutralized with sodium hydroxide solution to pH ~ 6, and filtered to give (S)-methyl 2-(7-azidodibenzo[b,d]thiophene- 3-sulfonamido)-3-methylbutanoate as an off-white solid.
Step 4: Preparation of (SVmethyl 3-methyl-2-(7-(4-π-methyl-lH-pyrrol-2-vO-lH- L∑J-triazol-l-vDdibenzorKdithiophene-S-sulfonamido^utanoate
[0256] To a suspension of (S)-methyl 2-(7-azidodibenzo[b,d]thiophene-3- sulfonamido)-3-methylbutanoate (209 mg, 0.5 mmol) from Step 3 in DMSO (1 mL) and water (1 mL) was added 2-ethynyl-l -methyl- lH-pyrrole (0.5 mmol), copper sulfate (25 mg), and sodium L-ascorbate (250 mg). The reaction mixture was stirred at room temperature overnight, diluted with water, acidified with 1 N HCl, and filtered to give (S)-methyl 3-methyl-2-(7-(4-(l-methyl-lH-pyrrol-2-yl)-lH-l,2,3- triazol-l-yl)dibenzo[b,d]thiophene-3-sulfonamido)butanoate as off-white solid in 60% yield.
Step 5: Preparation of (SV3-methyl-2-(7-(4-(l-methyl-lH-pyrrol-2-vn-lH-1.2.3- triazol-l-yl)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid
[0257] (S)-Methyl 3-methyl-2-(7-(4-( 1 -methyl- 1 H-pyrrol-2-yl)- 1 H- 1 ,2,3-triazol- 1 - yl)dibenzo[b,d]thiophene-3-sulfonamido)butanoate (225 mg) from Step 4 was suspended in water (4 mL) and THF (1 mL) and lithium hydroxide (230 mg, 10 mmol) was added. The resulting mixture was stirred at room temperature overnight, acidified with hydrochloric acid to pH ~ 4, and filtered to give (S)-3- methyl-2-(7-(4-( 1 -methyl- 1 H-pyrrol-2-yl)- 1 H- 1 ,2,3-triazol- 1 - yl)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid as an off-white solid in 90% yield. MS (ES+) 510.24. [0258] The sodium salt was prepared by treatment of (S)-3-methyl-2-(7-(4-(l- methyl- 1 H-pyrrol-2-yl)- IH-1 ,2,3-triazol- 1 -yl)dibenzo[b,d]thiophene-3- sulfonamido)butanoic acid with 1.0 equivalent of NaOH. The salt was obtained as a white solid.
Example 116: Preparation of (S)-3-methyl-2-(7-(4-phenyl-lH-l,2,3-triazoI-l- yl)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid
[0259] Following procedures analogous to those described in Example 115 and using ethynylbenzene, (S)-3-methyl-2-(7-(4-phenyl- 1 H- 1 ,2,3-triazol- 1 - yl)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid was obtained. MS (ES+) 507.10.
Example 117: Preparation of (S)-2-(7-(4-cyclohexyl-lH-l,2,3-triazol-l- yI)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid
[0260] Following procedures analogous to those described in Example 115 and using ethynylcyclohexane, (S)-2-(7-(4-cyclohexyl- 1 H- 1 ,2,3-triazol- 1 - yl)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid was prepared. 1H NMR (300 MHz, DMSO-J6) δ ppm 8.56 - 8.77 (m, 4 H), 8.52 (d, J=I .5 Hz, 1 H), 8.12 (dd, J=8.8, 2.1 Hz, 1 H), 7.91 (dd, J=8.4, 1.3 Hz, 1 H), 3.58 (d, J=5.0 Hz, 1 H), 2.65 - 2.91 (m, 1 H), 1.87 - 2.18 (m, 3 H), 1.65 - 1.87 (m, 3 H), 1.23 - 1.56 (m, 5 H), 0.85 (d, J=6.7 Hz, 3 H), and 0.81 (d, J=6.7 Hz, 3 H); MS (ES+) 513.16.
Example 118: Preparation of (S)-2-(7-(4-(methoxymethyI)-lH-l,2,3-triazol-l- yl)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid
[0261] Following procedures analogous to those described in Example 1 15 and using 3-methoxyprop-l-yne, (S)-2-(7-(4-(methoxymethyl)-lH-l,2,3-triazol-l- yl)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid was prepared. 1H NMR (300 MHz, DMSO-Jn) δ ppm 8.94 (s, 1 H), 8.74 (d, J=I .8 Hz, 1 H), 8.68 (d, J=8.8 Hz, 1 H), 8.62 (d, J=8.2 Hz, 1 H), 8.14 (dd, J=8.5, 2.1 Hz, 2 H), 7.92 (dd, J=8.5, 1.8 Hz, 1 H), 4.60 (s, 2 H), 3.63 (s, 1 H), 3.36 (s, 3 H), 1.79 - 2.11 (m, 1 H), 0.85 (d, J=6.7 Hz, 3 H), and 0.81 (d, J=6.7 Hz, 3 H); MS (ES+) 475.12. Example 119: Preparation of (S)-2-(7-(4-tert-butyl-lH-l,2,3-triazol-l- yl)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid
[0262] Following procedures analogous to those described in Example 115 and using 3,3-dimethylbut-l-yne, (S)-2-(7-(4-tert-butyl-lH-l,2,3-triazol-l- yl)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid was prepared. 1H NMR (300 MHz, DMSO-J6) δ ppm 8.73 (s, 1 H), 8.70 (d, J=I .8 Hz, 1 H), 8.66 (d, J=8.5 Hz, 1 H), 8.60 (d, J=8.2 Hz, 1 H), 8.52 (d, J=I .2 Hz, 1 H), 8.13 (dd, J=8.8, 2.1 Hz, 1 H), 7.92 (dd, J=8.4, 1.6 Hz, 1 H), 3.62 (d, J=5.3 Hz, 1 H), 1.83 - 2.09 (m, 1 H), 1.39 (s, 9 H), 0.85 (d, J=7.0 Hz, 3 H), and 0.81 (d, J=7.0 Hz, 3 H); MS (ES+) 487.17.
Example 120: Preparation of (S)-2-(7-(4-((dimethylamino)methyl)-lH-l,2,3- triazol-l-yl)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid
[0263] Following procedures analogous to those described in Example 1 15 and using N,N-dimethylprop-2-yn- 1 -amine, (S)-2-(7-(4-((dimethylamino)methyl)- 1 H- l,2,3-triazol-l-yl)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid was prepared. 1H NMR (300 MHz, MeOD) δ ppm 8.53 - 8.64 (m, 3 H), 8.46 - 8.52 (m, 2 H), 8.09 (d, J=8.8 Hz, 1 H), 8.01 (dd, J=8.5, 1.5 Hz, 1 H), 4.61 (s, 2 H), 3.77 (d, J=5.9 Hz, 1 H), 3.02 (s, 6 H), 2.01 - 2.18 (m, 1 H), 0.99 (d, J=6.7 Hz, 3 H), and 0.93 (d, J=6.7 Hz, 3 H); MS (ES+) 488.18.
Example 121: Preparation of (S)-2-(7-(4-(hydroxymethyl)-lH-l,2,3-triazol-l- yl)dibenzo[b,d]thiophcne-3-sulfonamido)-3-methylbutanoic acid
[0264] Following procedures analogous to those described in Example 115 and using prop-2-yn- 1 -ol, 2-(7-(4-(hydroxym ethyl)- 1 H- 1 ,2,3-triazol- 1 - yl)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid was prepared. 1H NMR (300 MHz, DMSO-J6) δ ppm 12.53 (br. s., 1 H), 8.81 (s, 2 H), 8.73 (d, J=2.1 Hz, 1 H), 8.67 (d, J=8.5 Hz, 1 H), 8.61 (d, J=8.5 Hz, 1 H), 8.53 (d, J=I .5 Hz, 1 H), 8.14 (dd, J=8.5, 2.1 Hz, 1 H), 8.10 (br. s., 1 H), 7.92 (dd, J=8.2, 1.8 Hz, 1 H), 4.66 (d, J=5.0 Hz, 2 H), 3.56 - 3.71 (m, J=7.3, 5.9 Hz, 1 H), 1.85 - 2.06 (m, 1 H), 0.85 (d, J=6.7 Hz, 3 H), and 0.82 (d, J=6.7 Hz, 3 H); MS (ES+) 461.12. Example 122: Preparation of (S)-2-(7-(4-(methoxycarbonyI)-lH-l,2,3-triazol-l- yl)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid
[0265] Following procedures analogous to those described in Example 115 and using methyl propiolate, (S)-2-(7-(4-(methoxycarbonyl)-lH-l,2,3-triazol-l- yl)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid was prepared. 1H NMR (300 MHz, DMSO-J6) δ ppm 2.53 (br. s., 1 H), 9.63 (s, 1 H), 8.82 (d, J=2,l Hz, 1 H), 8.71 (d, J=8.8 Hz, 1 H), 8.64 (d, J=8.2 Hz, 1 H), 8.55 (d, J=I .5 Hz, 1 H), 8.21 (dd, J=8.7, 2.2 Hz, 1 H), 8.16 (d, J=9.4 Hz, 1 H), 7.93 (dd, J=8.5, 1.8 Hz, 1 H), 3.93 (s, 3 H), 3.64 (dd, 3=92, 5.7 Hz, 1 H), 1.88 - 2.06 (m, 1 H), 0.85 (d, J=6.7 Hz, 3 H), and 0.82 (d, J=6.7 Hz, 3 H); MS (ES+) 489.13.
Example 123: Preparation of (S)-l-(7-(N-(l-carboxy-2- methylpropyl)sulfamoyl)dibenzo[b,d]thiophen-3-yl)-lH-l,2,3-triazoIe-4- carboxylic acid
[0266] (S)- 1-(7-(N-(I -carboxy^-methylpropy^sulfamoy^dibenzofbjdJthiophen-S- yl)-lH-l,2,3-triazole-4-carboxylic acid was isolated as a byproduct in Example 122. MS (ES+) 475.12.
Example 124: Preparation of (S)-2-(7-(4-cyano-lH-l,2,3-triazol-l- yl)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid
[0267] Following procedures analogous to those described in Example 115 and using propiolonitrile, (S)-2-(7-(4-cyano-lH-l,2,3-triazol-l- yl)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid was prepared. 1H NMR (300 MHz, DMSO-J6) δ ppm 2.53 (br. s., 1 H), 9.85 (s, 1 H), 8.78 (d, 3=2.1 Hz, 1 H), 8.75 (d, J=8.5 Hz, 1 H), 8.65 (d, J=8.5 Hz, 1 H), 8.57 (d, J=I .2 Hz, 1 H), 8.16 (br. s., 1 H), 8.13 (dd, J=8.5, 2.1 Hz, 1 H), 7.94 (dd, J=8.2, 1.8 Hz, 1 H), 3.64 (dd, J=8.7, 5.4 Hz, 1 H), 1.87 - 2.06 (m, 1 H), 0.85 (d, J=7.0 Hz, 3 H), and 0.81 (d, J=7.0 Hz, 3 H); MS (ES+) 456.07. Example 125: Preparation of (S)-2-(7-(4-isopropyl-lH-l,2,3-triazol-l- yl)dibenzo[b,d]thiophene-3-sulfonamido)-3-mcthylbutanoic acid
[0268] Following procedures analogous to those described in Example 115 and using propiolonitrile, (S)-2-(7-(4-isopropyl-lH-l,2,3-triazol-l- yl)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid was prepared.
1H NMR (300 MHz, DMSO-J6) δ ppm 12.52 (br. s., 1 H), 8.46 - 8.79 (m, 5 H), 8.02 - 8.26 (m, 2 H), 7.92 (dd, J=8.5, 1.5 Hz, 1 H), 3.63 (dd, J=9.2, 5.7 Hz, 1 H), 2.97 - 3.19 (m, 1 H), 1.82 - 2.08 (m, 1 H), 1.34 (d, J=7.0 Hz, 6 H), 0.85 (d, J=6.7 Hz, 3 H), and 0.82 (d, J=6.7 Hz, 3 H); MS (ES+) 473.02.
Example 126: Preparation of (S)-2-(7-(4-carbamoyl-lH-l,2,3-triazol-l- yl)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid
[0269] Following procedures analogous to those described in Example 115 and using propiolamide, (S)-2-(7-(4-carbamoyl-lH-l,2,3-triazol-l- yl)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid was prepared. 1H NMR (300 MHz, DMSO-J6) δ ppm 12.52 (br. s., 1 H), 9.37 (s, 1 H), 8.79 (d, J=2.1 Hz, 1 H), 8.70 (d, J=8.8 Hz, 1 H), 8.63 (d, J=8.5 Hz, 1 H), 8.55 (d, J=I.2 Hz, 1 H), 8.19 (dd, J=8.5, 1.8 Hz, 1 H), 8.15 (d, J=9.4 Hz, 1 H), 7.98 - 8.07 (m, 1 H), 7.93 (dd, J=8.5, 1.5 Hz, 1 H), 7.62 (br. s., 1 H), 3.64 (dd, J=9.5, 5.7 Hz, 1 H), 1.85 - 2.06 (m, 1 H), 0.85 (d, J=6.7 Hz, 3 H), and 0.82 (d, J=6.7 Hz, 3 H); MS (ES+) 474.00.
Example 127: Preparation of (S)-2-(7-(4-(furan-2-yl)-lH-l,2,3-triazol-l- yl)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid
[0270] Following procedures analogous to those described in Example 115 and using 2-ethynylfuran, (S)-2-(7-(4-(furan-2-yl)- IH-1, 2,3-triazol-l- yl)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid was prepared. MS (ES+) 497.07. Example 128: Preparation of (R)-2-(7-(4H-l,2,4-triazol-4-yl)dibenzo[b,d]furan- 2-sulfonamido)-3-methylbutanoic acid
Step 1 : Preparation of (R)-methyl 3-methyl-2-(7-nitrodibenzo[b,d]furan-2- sulfonamido'lbutanoate [0271] 7-Nitrodibenzo[b,d]furan-2-sulfonyl chloride (Example 1, Step 3, 570 mg, 1.83 mmol) and (R)-methyl 2-amino-3-methylbutanoate hydrochloride (2.0 mmol) were mixed with 5 mL Of CH2Cl2 followed by slow addition of N5N- diisopropylethylamine (520 mg, 4 mmol) at O0C. The mixture was allowed to warm to room temperature for 4 hours and purified with a silica gel column chromatography to provide (R)-methyl 3-methyl-2-(7-nitrodibenzo[b,d]furan-2- sulfonamido)butanoate as a white solid in 80% yield.
Step 2: Preparation of (R)-methyl 2-(7-aminodibenzo[b,d]furan-2-sulfonamido)-3- methylbutanoate
[0272] (R)-Methyl 3-methyl-2-(7-nitrodibenzo[b,d]furan-2-sulfonamido)butanoate obtained in Step 1 (820 mg) was mixed with 20 mL of MeOH and 100 mg of palladium on carbon (Pd/C) (10%). The reaction was carried out in a Parr shaker at room temperature under hydrogen (50 psi) overnight. The reaction mixture was filtered through Celite® and MeOH was removed to provide (R)-methyl 2-(7- aminodibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoate (790 mg) as an off- white solid in quantitative yield.
Step 3: Preparation of (RVmethyl 2-(7-(4H-l,2,4-triazol-4-vDdibenzorb,d1furan-2- sulfonamidoV3-methylbutanoate
[0273] (R)-Methyl 2-(7-aminodibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoate (100 mg, 0.25 mmol) from Step 2 and N,N-dimethylformamide azine hydrochloride (55 mg, 0.25 mmol) were mixed with toluene (5 mL) and was heated under reflux for 24 hours. The toluene was removed under reduced pressure and the residue was purified by a HPLC to give (R)-methyl 2-(7-(4H-l,2,4-triazol-4- yl)dibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoate as a pale yellow solid. Step 4: Preparation of (RV2-(7-(4H-1.2.4-triazol-4-vπdibenzorb.d1furan-2- sulfonamidoV3-methylbutanoic acid
[0274] (R)-Methyl 2-(7-(4H-l,2,4-triazol-4-yl)dibenzo[b,d]furan-2-sulfonamido)-3- methylbutanoate from Step 3 was dissolved in methano I/water (1 :1), to which was added with lithium hydroxide (3.0 eq.). The resulting mixture was stirred at room temperature for 16 hours, diluted with water, acidified with 1 N HCl to pH ~ 3, and filtered to provide a crude product, which was purified with a HPLC to give (R)-2- (7-(4H-l,2,4-triazol-4-yl)dibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoic acid (20 mg) as an off-white solid. 1H NMR (400 MHz, MeOD) δ ppm 9.35 (s, 2 H), 8.84 (d, J=I.77 Hz, 1 H), 8.53 (d, J=8.34 Hz, 1 H), 8.23 - 8.29 (m, 2 H), 8.00 (d, J=8.84 Hz, 1 H), 7.95 (dd, J=8.34, 2.02 Hz, 1 H), 3.94 (dd, 1 H), 2.21 - 2.35 (m, 1 H), and 1.18 (dd, 6 H); MS (LCMS-ESI, M+H) 414.96.
Example 129: Preparation of (R)-3-methyI-2-(7-(2-oxooxazolidin-3- yl)dibenzo[b,d]furan-2-sulfonamido)butanoic acid
Step 1 : Preparation of (R)-methyl 2-(7-((2- bromoethoxy)carbonylamino)dibenzo [b,d] furan-2-sulfonamido)-3 -methylbutanoate
[0275] To a round-bottom flask was added with (R)-methyl 2-(7- aminodibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoate (Example 128, Step 2, 156 mg), dichloromethane (5 mL), 2-bromoethyl carbonochloridate (1.2 eq.), and DMAP (2.0 eq.). The reaction mixture was stirred at room temperature for 2 hours, diluted with water, and acidified with 1 N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with 0.5 N hydrochloric acid and brine, dried over sodium sulfate, and concentrated to provide (R)-methyl 2-(7-((2- bromoethoxy)carbonylamino)dibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoate (198 mg) as a white solid.
Step 2: Preparation of (R)-methyl 3-methyl-2-(7-(2-oxooxazolidin-3- yl)dibenzo[b,d]furan-2-sulfonamido)butanoate
[0276] (R)-Methyl 2-(7-((2-bromoethoxy)carbonylamino)dibenzo[b,d]furan-2- sulfonamido)-3-methylbutanoate (198 mg) from Step 1 was dissolved in DMF (2 mL). Cesium carbonate (2.0 eq.) was added and the reaction mixture was heated to 6O0C for 4 hours, cooled to room temperature, and diluted with water. The precipitate was filtered to provide (R)-methyl 3-methyl-2-(7-(2-oxooxazolidin-3- yl)dibenzo[b,d]furan-2-sulfonamido)butanoate (165 mg) as a white solid.
Step 3: Preparation of (R)-3-methyl-2-(7-(2-oxooxazolidin-3-y0dibenzo[b,d1furan- 2-sulfonamido)butanoic acid
[0277] (R)-Methyl 3-methyl-2-(7-(2-oxooxazolidin-3-yl)dibenzo[b,d]furan-2- sulfonamido)butanoate (165 mg) from Step 2 was dissolved in THF (2 mL). To the solution was added water (2 mL) and lithium hydroxide (3.0 eq.). The mixture was stirred at room temperature overnight, diluted with water, acidified with 2N hydrochloric acid to pH ~4, and filtered to provide a crude product, which was purified with a HPLC to give (R)-3-methyl-2-(7-(2-oxooxazolidin-3- yl)dibenzo[b,d]furan-2-sulfonamido)butanoic acid (143 mg) as an off-white solid. 1H NMR (400 MHz, MeOD) δ ppm 8.72 (d, J=I .52 Hz, 1 H), 8.33 (d, J=8.59 Hz, 1 H), 8.25 (d, J=I .77 Hz, 1 H), 8.17 (dd, J=8.59, 2.02 Hz, 1 H), 7.91 (d, J=8.59 Hz, 1 H), 7.84 (dd, J=8.59, 2.02 Hz, 1 H), 4.77 (dd, 2 H), 4.45 (dd, 2 H), 3.87 (d, 1 H), 2.20 - 2.32 (m, 1 H), and 1.16 (dd, 6 H); MS (LCMS-ESI, M+H) 433.21.
Example 130: Preparation of (S,E)-2-(8-
((dimethylamino)methyleneamino)dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoic acid
[0278] (S,E)-2-(8-((Dimethylamino)methyleneamino)dibenzo[b,d]furan-3- sulfonamido)-3 -methylbutanoic acid was obtained as a by-product from the last step of the scale-up preparation of Example 99. 1H NMR (400 MHz, DMSOd6) δ ppm 8.67 (s, 1 H), 8.30 (d, J=8.34 Hz, 1 H), 8.22 (d, J=2.53 Hz, 1 H), 8.11 - 8.17 (m, 1 H), 7.85 - 7.93 (m, 2 H), 7.64 (dd, J=8.84, 2.53 Hz, 1 H), 3.61 (t, J=6.06 Hz, 1 H), 3.40 (s, 3 H), 3.26 (s, 3 H), 1.87 - 2.07 (m, 1 H), and 0.82 (dd, J=I 5.41, 6.82 Hz, 6 H); MS (LCMS-ESI, M+H) 417.91.
Example 131: Preparation of (S)-2-(8-((3- chloropropoxy)carbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoic acid [0279] Following procedures analogous to those described in Example 28 and using chloropropyl chloroformate, (S)-2-(8-((3- chloropropoxy)carbonylamino)dibenzo [b,d] furan-3 -sulfonamido)-3 -methylbutanoic acid was obtained as a white solid. HRMS calculated for [C21H23ClN2O7S + H]+ 483.09873; found (ESI-FTMS, [M+H]l+) 483.10066.
Example 132: Preparation of (R)-2-(7-(2,5-dimethyl-lH-pyrrol-l- yl)dibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoic acid
Step 1 : Preparation of (RVmethyl 2-(7-(2,5-dimethyl-lH-pyrrol-l- vπdibenzo[b,dlfuran-2-sulfonamido)-3-methylbutanoate [0280] (R)-Methyl 2-(7-aminodibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoate (Example 128, Step 2, 200 mg, 0.83 mmol), hexane-2,5-dione (61 mg, 0.53 mmol), and 4-methylbenzenesulfonic acid (10 mg) were mixed with 3 mL of methanol. The mixture was irradiated with microwave at 12O0C for 30 minutes, concentrated, and purified with a column chromatography to provide (R)-methyl 2-(7-(2,5-dimethyl- lH-pyrrol-l-yl)dibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoate as a white solid in 35% yield.
Step 2: Preparation of rRV2-(7-(2.5-dimethyl-lH-Dyrrol-l-vndibenzorb.d1furan-2- sulfonamido)-3-methylbutanoic acid
[0281] 2-(7-(2,5-Dimethyl-lH-pyrrol-l-yl)dibenzo[b,d]furan-2-sulfonamido)-3- methylbutanoate (84 mg) from Step 1 was dissolved in 2 mL of THF/H2O (1 : 1), followed by the addition of LiOH (200 mg). The resulting suspension was stirred at room temperature for 3 days and the crude product was purified to provide (R)-2-(7- (2,5-dimethyl-lH-pyrrol-l-yl)dibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoic acid (78 mg) as a pale yellow solid in 97% yield. 1H NMR (400 MHz, MeOD) δ ppm 1.14 (d, J= 6.82 Hz, 3 H), 1.20 (d, J= 6.82 Hz, 3 H), 3.94 - 3.98 (m, 7 H), 6.07 (s, 2 H), 7.50 (dd, J= 8.21, 1.64 Hz, 1 H), 7.76 (d, J= 1.52 Hz, 1 H), 7.98 (d, J= 8.84 Hz, 1 H), 8.25 (dd, J= 8.84, 2.02 Hz, 1 H), 8.42 - 8.47 (m, 1 H), and 8.84 (d, J = 2.02 Hz, 1 H); HRMS calculated for [C23H24N2O5S + H]+ 441.14787; found (ESI- FTMS, [M + H]+) 441.14757. Example 133: Preparation of (R)-2-(8-bromo-7-
(methoxycarbonylamino)dibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoic acid
Step 1 : Preparation of 8-bromo-7-nitrodibenzo[b,dlfuran-2-sulfonyl chloride [0282] In a round-bottom flask was added dibenzofuran (15 g) and acetic acid (90 niL). Bromine (6.1 mL) was added via a drop funnel and the mixture was heated overnight at 550C. After the reaction mixture was cooled to O0C, the precipitate was filtered and dried in air to give 2-bromodibenzofuran (11.3 g).
[0283] 2-Bromodibenzofuran (11.3 g) was suspended in dichloromethane (100 mL), to which was added chlorosulfonic acid (4.0 mL, 1.2 eq.) slowly. The mixture was stirred at room temperature for 4 hours and the resulting precipitate was collected through filtration. The solid was added to thionyl chloride (70 mL) followed by DMF (2 drops). The resulting mixture was stirred at 8O0C overnight and concentrated, and the solid was filtered and washed with iced water to give 8- bromodibenzo[b,d]furan-2-sulfonyl chloride (4.23 g).
[0284] 8-Bromodibenzo[b,d]furan-2-sulfonyl chloride (1.0 g) was dissolved in TFA (25 mL), fuming nitric acid (355 μL in 5 mL of TFA) was added and the resulting mixture was stirred at room temperature overnight. The resulting precipitate was filtered to give 8-bromo-7-nitrodibenzo[b,d]furan-2-sulfonyl chloride (0.65 g).
Step 2: Preparation of (R)-methyl 2-(7-amino-8-bromodibenzo[b,d]furan-2- sulfonamido)-3-methylbutanoate
[0285] 8-Bromo-7-nitrodibenzo[b,d]furan-2-sulfonyl chloride (1.0 g) from Step 1 was dissolved in dichloromethane (10 mL). D-Valine methyl ester hydrochloride (1.1 eq.) and Hunig's base (N,N-diisopropylethylamine, 2.5 eq.) were added. The reaction mixture was stirred at room temperature overnight and extracted with ethyl acetate. The combined organic layers were washed with saturated ammonium chloride solution and brine, dried over sodium sulfate, and concentrated to give the corresponding sulfonamide product (1.19 g). [0286] The sulfonamide product (1.19 g) was dissolved in ethyl acetate (8 niL), to which tin (II) chloride (2.3 g, 10 eq.) was added. The mixture was stirred at 5O0C overnight and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to give (R)-methyl 2-(7-amino-8-bromodibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoate (0.8 g).
Step 3: Preparation of (R)-methyl 2-(8-bromo-7- (methoxycarbonylaminoMibenzo [b.dl furan-2-sulfonamido)-3 -methylbutanoate
[0287] (R)-Methyl 2-(7-amino-8-bromodibenzo[b,d]furan-2-sulfonamido)-3- methylbutanoate (200 mg, 0.44 mmol) and DMAP (65 mg, 0.53 mmol) were dissolved in CH2Cl2 (2 mL) and methyl chloroformate (50 mg, 0.53 mmol) was added. The mixture was stirred at room temperature overnight and concentrated. The residue was purified by a column chromatography purification to prvovide (R)- methyl 2-(8-bromo-7-(methoxycarbonylamino)dibenzo[b,d]furan-2-sulfonamido)-3- methylbutanoate as a white solid in 39% yield.
Step 4: Preparation of (R)-2-(8-bromo-7-
(methoxycarbonylamino')dibenzorb,d]furan-2-sulfonamidoV3-methylbutanoic acid
[0288] 2-(8-Bromo-7-(methoxycarbonylamino)dibenzo[b,d]furan-2-sulfonamido)-3- methylbutanoate (88 mg) was dissolved in 1:1 mixture of hydrochloric acid and acetic acid (2 mL). The mixture was heated at 1150C for 4 hours. A preparative HPLC purification afforded (R)-2-(8-bromo-7-
(methoxycarbonylamino)dibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoic acid (36.8 mg) as a pale yellow solid in 43% yield. 1H NMR (400 MHz, MeOD) δ ppm 1.13 (d, J= 6.82 Hz, 3 H), 1.20 (d, J= 6.82 Hz, 3 H), 2.25 - 2.33 (m, 1 H), 3.97 (d, J = 5.56 Hz, 1 H), 4.04 (s, 3 H), 7.89 (dd, J= 8.84, 0.51 Hz, 1 H), 8.18 (dd, J= 8.72, 1.89 Hz, 1 H), 8.38 (s, 1 H), 8.46 (s, 1 H), and 8.69 (dd, J= 2.02, 0.51 Hz, 1 H); HRMS calculated for [Ci9H19BrN2O7S + H]+ 499.01691; found (ESI-FTMS, [M+H]1+) 499.01655.
Example 134: Preparation of (S)-2-(8-bromo-7-
(methoxycarbonylamino)dibenzo[b,d]furan-2-sulfonamido)-3-mcthylbutanoic acid Step 1 : Preparation of (S)-methyl 2-(7-amino-8-bromodibenzo[b,d1furan-2- sulfonamido)- 3 -methylbutanoate
[0289] 8-Bromo-7-nitrodibenzo[b,d]furan-2-sulfonyl chloride (Example 133, Step 1, 500 mg) was dissolved in dichloromethane (5 mL) and L-valine methyl ester hydrochloride (1.1 eq.) and Hunig's base (2.5 eq.) were added. The reaction mixture was stirred at room temperature overnight and extracted with ethyl acetate. The combined organic layers were washed with saturated ammonium chloride solution and brine, dried over sodium sulfate, and concentrated to give the corresponding sulfonamide product (690 mg).
[0290] The sulfonamide product (690 mg) was dissolved into ethyl acetate (8 mL) and tin (II) chloride (1.12 g, 10 eq.) was added. The mixture was stirred at 5O0C overnight and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to give (S)-methyl 2- (7-amino-8-bromodibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoate (350 mg).
Step 2: Preparation of (S)-methyl 2-(8-bromo-7-
(methoxycarbonylamino)dibenzo[b,d]furan-2-sulfonamidoV3-methylbutanoate
[0291] (S)-Methyl 2-(7-amino-8-bromodibenzo[b,d]furan-2-sulfonamido)-3- methylbutanoate (200 mg, 0.44 mmol) from Step 1 and DMAP (65 mg, 0.53 mmol) were dissolved in CH2Cl2 (2 mL) and methyl chloroformate (50 mg, 0.53 mmol) was added. The mixture was stirred at room temperature overnight and concentrated. The residue was purified by a column chromatography to provide (S)-methyl 2-(8- bromo-7-(methoxycarbonylamino)dibenzo[b,d]furan-2-sulfonamido)-3- methylbutanoate as a white solid in 45% yield.
Step 2: Preparation of (S)-2-(8-bromo-7-(rnethoxycarbonylamino)dibenzo[b,d1furan- 2-sulfonamido)-3 -methyl butanoic acid
[0292] (S)-Methyl 2-(8-bromo-7-(methoxycarbonylamino)dibenzo[b,d]furan-2- sulfonamido)-3-methylbutanoate (78 mg) was dissolved in 1 : 1 mixture of hydrochloric acid and acetic acid (2 mL) and the mixture was heated at 1150C for 4 hours. A preparative HPLC purification afforded (S)-2-(8-bromo-7- (methoxycarbonylamino)dibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoic acid (30 mg) as a pale yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.14 (d, J= 6.82 Hz, 3 H), 1.21 (d, J= 6.82 Hz, 3 H), 2.24 - 2.34 (m, 1 H), 3.98 (d, J= 5.56 Hz, 1 H), 4.04 (s, 3 H), 7.86 - 7.90 (m, 1 H), 8.18 (dd, J= 8.59, 2.02 Hz, 1 H), 8.36 (s, 1 H), 8.43 (s, 1 H), and 8.68 (dd, J= 2.02, 0.51 Hz, 1 H); HRMS calculated for [C9Hi9BrN2O7S + H]+ 499.01691; found (ESI-FTMS, [M+H]+) 499.01737.
Example 135: Preparation of (R)-3-methyl-2-(7-(4-(trifluoromethyl)thiazol-2- ylamino)dibenzo[b,d]furan-2-sulfonamido)butanoic acid
Step 1 : Preparation of (R)-methyl 2-(7-iododibenzorb,d]furan-2-sulfonamido)-3- methylbutanoate [0293] (R)-Methyl 2-(7-aminodibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoate (Example 128, Step 2, 2165 mg, 5.75 mmol) was mixed with hydrochloric acid (18%, 12 mL). The solution was cooled to O0C and an aqueous solution of sodium nitrite (1.0 M, 9 mL) was slowly added. The reaction mixture was stirred for 20 minutes and a solution of sodium iodide (948 mg, 6.32 mmol) in 3 mL of water was added slowly. The resulting mixture was stirred for 20 minutes, diluted with water, and filtered to give (R)-methyl 2-(7-iododibenzo[b,d]furan-2-sulfonamido)-3- methylbutanoate as a dark brown solid in 71% yield.
Step 2: Preparation of (RVmethyl 3-methyl-2-(7-(4-(trifluoromethyl)thiazol-2- ylamino)dibenzo[b1dlfuran-2-sulfonamido')butanoate [0294] (R)-Methyl 2-(7-iododibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoate (145 mg, 0.3 mmol) from Step 1, 3-(trifluoromethyl)pyrazole (121 mg, 0.9 mmol), /rørts-N,N'-dimethyl-l,2-cyclohexanediamine (8.5 mg, 0.2 mmol), CuI (3 mg, 0.05 mmol), and K3PO4 (133 mg, 2.1 mmol) were mixed in 2 mL of toluene. The mixture was irradiated under microwave at 13O0C for 3 hours and purified with a preparative HPLC to give 35 mg of (R)-methyl 3-methyl-2-(7-(4-
(trifluoromethyl)thiazol-2-ylamino)dibenzo[b,d]furan-2-sulfonamido)butanoate in 22% yield. Step 3: Preparation of (RV3-methyl-2-(7-(4-(trifluoromethyl)thiazol-2- ylamino)dibenzo[b1d1ruran-2-sulfonamido')butanoic acid
[0295] (R)-Methyl 3-methyl-2-(7-(4-(trifluoromethyl)thiazol-2- ylamino)dibenzo[b,d]furan-2-sulfonamido)butanoate from step 2 (35 mg, 0.06 mmol) was dissolved in THF/MeOH/water (1 :1 :1, 2 mL) and 5 equivalents of lithium hydroxide was added. The reaction mixture was stirred overnight, diluted with water, acidified to pH between 4 and 5, and filtered to yield (R)-3-methyl-2-(7- (4-(trifluoromethyl)thiazol-2-ylamino)dibenzo[b,d]furan-2-sulfonamido)butanoic acid as a white solid in 46% yield. 1H NMR (400 MHz, MeOD) δ ppm 0.91 (d, J=6.82 Hz, 3 H), 0.98 (d, J-6.82 Hz, 3 H), 2.00 - 2.11 (m, 1 H), 3.71 (d, J=5.31 Hz, 1 H), 7.35 (s, 1 H), 7.42 (dd, J=8.46, 1.39 Hz, 2 H), 7.66 (d, J-8.84 Hz, 2 H), 7.91 (dd, J=8.72, 1.39 Hz, 2 H), 7.96 - 8.01 (m, 1 H), 8.29 - 8.32 (m, J=1.26 Hz, 1 H), and 8.42 - 8.45 (m, 1 H); HRMS calculated for [C2IH18F3N3O5S2 + H]+ 514.07127; found (ESI-FTMS, [M+H]1+) 514.07107.
Example 136: Preparation of (S)-3-methyl-2-(8-(3-(4-nitrophenyl)-lH-pyrazol- l-yl)dibenzo[b,d]furan-3-sulfonamido)butanoic acid
[0296] Following procedures analogous to those described in Example 135 and using 3-(4-nitrophenyl)-lH-pyrazole, (S)-3-methyl-2-(8-(3-(4-nitrophenyl)-l H- pyrazol-l-yl)dibenzo[b,d]furan-3-sulfonamido)butanoic acid was obtained as a white solid. 1H NMR (400 MHz, MeOD) δ ppm 0.92 (d, J=2.78 Hz, 3 H), 0.94
(d, J=2.78 Hz, 3 H), 1.99 - 2.06 (m, 1 H), 3.76 (d, J=6.32 Hz, 1 H), 7.09 (d, J=2.78 Hz, 1 H), 7.81 (d, J=0.51 Hz, 1 H), 7.83 (s, 1 H), 7.89 (dd, J=8.21, 1.64 Hz, 1 H), 8.10 - 8.15 (m, 2 H), 8.18 - 8.22 (m, 2 H), 8.29 (dd, J=8.08, 0.51 Hz, 1 H), 8.31 - 8.35 (m, 2 H), 8.41 (d, J=2.53 Hz, 1 H), and 8.61 - 8.63 (m, 1 H).
Example 137: Preparation of (R)-2-(7-(lH-pyrroI-l-yl)dibenzo[b,d]furan-2- sulfonamido)-3-methylbutanoic acid
Step 1 : Preparation of (RVmethyl 2-(7-(lH-pyrrol-l-vndibenzorb,dlfuran-2- sulfonamido)-3-methylbutanoate [0297] (S)-Methyl 2-(7-amino-8-bromodibenzo[b,d]furan-2-sulfonamido)-3- methylbutanoate (Example 134, Step 1, 100 mg, 0.27 mmol) and 2,5- dimethoxytetrahydrofuran (43 mg, 0.33 mmol) were mixed with 2 mL of AcOH. The mixture was stirred at 7O0C for one hour, concentrated, and purified by a preparative HPLC to provide (R)-methyl 2-(7-(lH-pyrrol-l-yl)dibenzo[b,d]furan-2- sulfonamido)-3-methylbutanoate as a white solid in 43% yield.
Step 2: Preparation of (RV2-(7-dH-pyrrol-l-yl)dibenzo[b,d1furan-2-sulfonamidoV 3-methylbutanoic acid
[0298] (R)-Methyl 2-(7-(lH-pyrrol-l-yl)dibenzo[b,d]furan-2-sulfonamido)-3- methylbutanoate (43 mg) was dissolved in 2 mL of THF, aqueous LiOH (200 mg in 2 mL of water) was added, and the resulting suspension was stirred at room temperature for 3 days. Acidic aqueous workup afforded (R)-2-(7-(lH-pyrrol-l- yl)dibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoic acid (28.4 mg) as a pale yellow solid in 68% yield. 1H NMR (400 MHz, MeOD) δ ppm 0.92 (d, J=6.82 Hz, 3 H), 0.98 (d, J=6.82 Hz, 3 H), 2.01 - 2.09 (m, 1 H), 3.73 (d, J=5.81 Hz, 1 H), 6.33 - 6.36 (m, 2 H), 7.29 - 7.31 (m, 2 H), 7.59 (dd, J=8.46, 1.89 Hz, 1 H), 7.71 (dd, J=8.84, 0.51 Hz, 1 H), 7.78 (d, J=I.52 Hz, 1 H), 7.98 (dd, J=8.72, 1.89 Hz, 1 H), 8.15 (d, J=8.34 Hz, 1 H), and 8.53 (dd, J=I.89, 0.63 Hz, 1 H); HRMS: calculated for [C2IH20N2O5S + H]+ 413.11657; found (ESI-FTMS, [M+H]l+) 413.11639.
Examples 138: Preparation of (S)-2-(7-aminodibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoic acid
Step 1 : Preparation of 8-bromodibenzo[b,d1furan-3-sulfonyl chloride
[0299] Dibenzo[b,d]furan-3-sulfonyl chloride (Example 28, Step 2, 5.3 g, 20 mmol) was mixed with AcOH (glacial, 120 mL) and bromine (10 mL, 10 eq.). The mixture was stirred at 7O0C for 4 hours and was filtered after the excess bromine was removed to provide 5.4 g of 8-bromodibenzo[b,d]furan-3-sulfonyl chloride as a light brown solid. Step 2: Preparation of (S)-methyl 2-(8-bromodibenzo[b,d]furan-3-sulfonamidoy3- methylbutanoate
[0300] 8-Bromodibenzo[b,d]furan-3-sulfonyl chloride (3.46 g, 10 mmol) and (S)- methyl 2-amino-3-methylbutanoate hydrochloride (1.1 eq.) were mixed with CH2Cl2 (30 mL) and N,N-diisopropylethylamine (3.84 mL, 2.2 eq) was added. The mixture was stirred at room temperature for 5 hours and purified by a column chromatography to give (S)-methyl 2-(8-bromodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate (4.7 g) as a white solid.
Step 3: Preparation of (SVmethyl 2-(8-bromo-7-nitrodibenzo[b,d]furan-3- sulfonamido)- 3 -methylbutanoate
[0301] 2-(8-Bromodibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate (3.14 g, 7.1 mmol) and HNO3 (1.0 g, 14.2 mmol, 90%) were mixed with TFA (6 mL) and CH2Cl2 (1 mL). The mixture was stirred at room temperature for 5 hours, concentrated, and purified with a silica gel column chromatography to provide (S)- methyl 2-(8-bromo-7-nitrodibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate as a white solid in 71% yield.
Step 4: Preparation of (S)-methyl 2-(7-aminodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate
[0302] (S)-Methyl 2-(8-bromo-7-nitrodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate (11.56 g, 23.8 mmol) was mixed with 200 mL of MeOH and
700 mg of Pd/C. The reaction was carried out in a Parr shaker at room temperature under H2 (50 psi) overnight. The reaction mixture was filtered through Celite and the filtrate concentrated to provide 8.92 g of (S)-methyl 2-(7- aminodibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate as a grey solid.
Step 5: Preparation of (S)-2-(7-aminodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoic acid
[0303] (S)-Methyl 2-(7-aminodibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate (87 mg) was dissolved in 2 mL of THF and a LiOH solution (1 mL, 0.9 M, in MeOH/H2O (1 :1)) was added. The resulting suspension was stirred at room temperature for 4 days and THF was removed under reduced pressure. The remaining aqueous solution was acidified to pH ~1 and filtered to give (S)-2-(7- aminodibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid as a pale yellow solid in 90% yield. HRMS: calculated for [Ci7Hi8N2O5S + H]+ 363.10092; found (ESI-FTMS, [M+H]1+) 363.10145.
Examples 139: Preparation of (S)-2-(7-(lH-pyrrol-l-yl)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoic acid
Step 1 : Preparation of (S)-methyl 2-(7-(lH-pyrrol-l-yl)dibenzo[b,dlfuran-3- sulfonamido)-3 -methylbutanoate [0304] (S)-Methyl 2-(7-aminodibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate (Example 138, Step 4, 139 mg, 0.37 mmol) and 2,5-dimethoxytetrahydrofuran (74 mg, 0.3 mmol) were mixed with AcOH (2 mL). The mixture was stirred at 7O0C for 1 hour, concentrated, and purified by a preparative HPLC to provide (S)- methyl 2-(7-(lH-pyrrol-l-yl)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate as a white solid in 54% yield.
Step 2: Preparation of (S)-2-(7-(lH-pyrrol-l-yl)dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoic acid
[0305] (S)-Methyl 2-(7-(lH-pyrrol-l-yl)dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate (85 mg) was dissolved in 2 mL of THF and a LiOH solution (1 mL, 0.9 M, in MeOH/H2O (1 : 1)) was added. The resulting suspension was stirred at room temperature for 4 days and THF was removed under reduced pressure. The remaining aqueous solution was acidified to pH ~1 and filtered to give (S)-2-(7-(lH- pyrrol-l-yl)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid as a pale yellow solid in 97% yield. MS (LC-ESIMS) 413.2.
Examples 140: Preparation of (S)-2-(7-(2,5-dimethyl-lH-pyrrol-l- yl)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid Step 1 : Preparation of (SVmethyl 2-(7-(2,5-dimethyl-lH-pyrrol-l- yl)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate
[0306] (S)-Methyl 2-(7-aminodibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate (Example 138, Step 4, 310 mg, 0.83 mmol), acetonyl acetone (943 mg, 8.3 mmol), and bismuth(III) nitrate pentahydrate (62 mg) were mixed with 20 mL OfCH2Cl2. The mixture was stirred at room temperature for 20 hours, concentrated, and purified by a column chromatography to provide (S)-methyl 2-(7-(2,5-dimethyl-lH-pyrrol-l- yl)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate as a white solid in 35% yield.
Step 2: Preparation of rSV2-(7-f2,5-dimethyl-lH-pyrrol-l-yl)dibenzo[b,dlfuran-3- sulfonamidoV3-methylbutanoic acid
[0307] (S)-Methyl 2-(7-(2,5-dimethyl-lH-pyrrol-l-yl)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoate (91 mg) was dissolved in 2 mL of THF and a LiOH solution (1 mL, 0.9 M, in MeOH/H2O (1 :1)) was added. The resulting suspension was stirred at room temperature for 3 days and THF was removed under reduced pressure. The remaining aqueous solution was acidified to pH ~1 and filtered to give (S)-2-(7-(2,5-dimethyl-lH-pyrrol-l-yl)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoic acid as a white solid in 97% yield. HRMS: calculated for [C23H24N2O5S + H]+ 441.14787; found (ESI-FTMS, [M+H]1+) 441.14906.
Examples 141: Preparation of (S)-3-methyl-2-(7-(2-oxooxazolidin-3- yl)dibenzo[b,d]furan-3-sulfonamido)butanoic acid
Step 1 : Preparation of (SVmethyl 2-(7-(Y2- bromoethoxy)carbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate [0308] (S)-Methyl 2-(7-aminodibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate (Example 138, Step 4, 226 mg, 0.6 mmol) and DMAP (100 mg, 0.72 mmol) were dissolved in 5 mL Of CH2Cl2, followed by the addition of methyl chloroformate (169 mg, 0.9 mmol). The mixture was stirred at room temperature overnight, concentrated, and purified by a column chromatography to provide (S)-methyl 2-(7- ((2-bromoethoxy)carbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate as a white solid in 91% yield.
Step 2: Preparation of (S)-methyl 3-methyl-2-(7-(2-oxooxazolidin-3- yl)dibenzo[b,d1 furan-3 -sulfonamido)butanoate [0309] To a solution of (S)-methyl 2-(7-((2- bromoethoxy)carbonylamino)dibenzo [b,d] furan-3 -sulfonamido)-3 -methylbutanoate (270 mg) in 6 mL of DMF was added 160 mg OfK2CO3. The mixture was stirred at room temperature for 6 hours and purified by a preparative HPLC to provide (S)- methyl 3 -methyl-2-(7-(2-oxooxazolidin-3 -yl)dibenzo [b,d] furan-3 - sulfonamido)butanoate as a white solid in 50% yield.
Step 3: Preparation of (S)-3-methyl-2-(7-(2-oxooxazolidin-3-yl)dibenzorb,d]furan-3- sulfonamido)butanoic acid
[0310] (S)-Methyl 3-methyl-2-(7-(2-oxooxazolidin-3-yl)dibenzo[b,d]furan-3- sulfonamido)butanoate (109 mg) was mixed with a solution of 5 mL of AcOH, 4 mL of 37% HCl, and 1 mL of H2O. The mixture was stirred at 6O0C for 20 hours and purified by a preparative HPLC to provide (S)-3-methyl-2-(7-(2-oxooxazolidin-3- yl)dibenzo[b,d] furan-3 -sulfonamido)butanoic acid as a white solid in 40% yield. HRMS: calculated for [C20H20N2O7S + H]+ 433.10640; found (ESI-FTMS, [M+H]1+) 433.10635.
Examples 142: Preparation of (S)-2-(7-(2-chloroethylamino)dibenzo[b,d]furan- 3-sulfonamido)-3-methylbutanoic acid
[0311] This compound was isolated as a by-product in Step 3 of Example 141 as an off-white solid in 10% yield. HRMS: calculated for [Ci9H2iClN2O5S + H]+ 425.09325; found (ESI-FTMS, [M+H]1+) 425.09269.
Examples 143: Preparation of (S)-2-(7-(N-(2- hydroxyethyl)acetamido)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid [0312] (S)-2-7-(N-2-Hydroxyethyl acetamido)dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoic acid was isolated as a by-product in Step 3 of Example 141 as an off-white solid in 10% yield. HRMS: calculated for [C2iH24N2O7S + H]+ 449.13770; found (ESI-FTMS, [M+H]1+) 449.1384.
Examples 144: Preparation of (S)-3-methyl-2-(7-(3-(trifluoromethyl)-lH- pyrazol-l-yI)dibenzo[b,d]furan-3-sulfonamido)butanoic acid
Step 1 : Preparation of (S Vmethyl 2-(7-iododibenzorb,d]furan-3-sulfonamido)-3- methylbutanoate
[0313] To a mixture of (S)-methyl 2-(7-aminodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate (Example 138, Step 4, 3.72 g, 9.9 mmol), 3.5 mL of HCl, 12 mL of H2O and 50 mL of AcOH at O0C was slowly added a NaNO2 solution (2 M, 7.5 mL) followed by NaI (11.87 g, 80 mmol). The mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was filtered and the solid was washed with water and further purified by a column chromatography to provide 3.94 g of (S)-methyl 2-(7-iododibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate as a grey solid.
Step 2: Preparation of (SVmethyl 3-methyl-2-(7-(3-(trifluoromethyl)-lH-pyrazol-l- y0dibenzo[b,d]furan-3-sulfonamido)butanoate
[0314] (S)-Methyl 2-(7-iododibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate (145 mg, 0.3 mmol), 3-(trifluoromethyl)pyrazole (121 mg, 0.9 mmol), (rans-~N,W- dimethyl-l,2-cyclohexanediamine (8.5 mg, 0.2 mmol), CuI (3 mg, 0.05 mmol) and K3PO4 (133 mg, 2.1 mmol) were mixed with 2 mL of toluene. The mixture was irradiated with microwave at 13O0C for 3 hours and purified by a preparative HPLC to give 98 mg of (S)-methyl 3-methyl-2-(7-(3-(trifluoromethyl)-lH-pyrazol-l- yl)dibenzo[b,d]furan-3-sulfonamido)butanoate as a white solid in 66% yield.
Step 3: Preparation of (SV3-methyl-2-(7-(3-(trifluoromethylVlH-pyrazol-l- vDdibenzo [b,d] furan-3 -sulfonamido)butanoic acid
[0315] (S)-Methyl 3-methyl-2-(7-(3-(trifluoromethyl)-lH-pyrazol-l- yl)dibenzo[b,d]furan-3-sulfonamido)butanoate (90 mg) was dissolved in 2 mL of THF and a LiOH solution (1 mL, 0.9 M, in MeOH/H2O (1 : 1)) was added. The resulting suspension was stirred at room temperature for 3 days and THF was removed under reduced pressure. The remaining aqueous solution was acidified to pH ~2 and filtered to give (S)-3-methyl-2-(7-(3-(trifluoromethyl)-lH-pyrazol-l- yl)dibenzo[b,d]furan-3-sulfonamido)butanoic acid as a white solid in 97% yield. HRMS: calculated for [C2IHi8F3N3O5S + H]+ 482.09920; found (ESI-FTMS, [M+H]1+) 482.09985.
Examples 145: Preparation of (S)-2-(8-bromo-7-nitrodibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoic acid
[0316] (S)-Methyl 2-(8-bromo-7-nitrodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate (Example 138, Step 3, 187 mg) was dissolved in 4 mL of THF and a LiOH solution (1 mL, 0.9 M, in MeOH/H2O (1 :1)) was added. The resulting suspension was stirred at room temperature for 4 days and THF was removed under reduced pressure. The remaining aqueous solution was acidified to pH ~1 and filtered to give (S)-2-(8-bromo-7-nitrodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoic acid as a pale yellow solid in 70% yield. HRMS: calculated for [Ci7Hi5BrN2O7S + H]+ 470.98561; found (ESI-FTMS, [M+H]1+) 470.98719.
Examples 146: Preparation of (S)-3-methyI-2-(7-nitrodibenzo[b,d]furan-3- sulfonamido)butanoic acid
[0317] (S)-Methyl 3-methyl-2-(7-nitrodibenzo[b,d]furan-3-sulfonamido)butanoate (a by-product in the Step 4 of Example 138, 30 mg) was dissolved in 1 mL of THF and a LiOH solution (1 mL, 0.9 M, in MeOH/H2O (1 :1)) was added. The resulting suspension was stirred at room temperature for 4 days and THF was removed under reduced pressure. The remaining aqueous solution was acidified to pH ~1 and filtered to give (S)-3-methyl-2-(7-nitrodibenzo[b,d]furan-3-sulfonamido)butanoic acid as a pale yellow solid in 69% yield. HRMS: calculated for [C]7Hi6N2O7S + H]+ 393.07510; found (ESI-FTMS, [M+H]1+) 393.07643. Examples 147: Preparation of (S)-2-(7-amino-8-bromodibenzo[b,d]furan-3- sulfonamido)-3-methyIbutanoic acid
Step 1 : Preparation of (S)-methyl 2-(7-amino-8-bromodibenzofb,dlfuran-3- sulfonamidoV3 -methyl butanoate [0318] (S)-Methyl 2-(8-bromo-7-nitrodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate (Example 138, Step 3, 1.75 g, 3.6 mmol) and tin (II) chloride (2.73 mg, 14.4 mmol) were mixed with 20 mL of EtOAc. The mixture was stirred at 600C overnight, concentrated, and purified by a column chromatography to provide (S)-methyl 2-(7-amino-8-bromodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate as a white solid in 60% yield.
Step 2: Preparation of (S)-2-(7-amino-8-bromodibenzo[b,dlfuran-3-sulfonamido)-3- methylbutanoic acid
[0319] (S)-Methyl 2-(7-amino-8-bromodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate (45 mg) from Step 1 was dissolved in 1 mL of THF and a LiOH solution (1 mL, 0.9 M, in MeOH/H2O (1 :1)) was added. The resulting suspension was stirred at room temperature for 4 days and THF was removed under reduced pressure. The remaining aqueous solution was acidified to pH ~1 and filtered to give (S)-2-(7-amino-8-bromodibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid as a white solid in 95% yield. MS (LC-ESIMS, [M+H]1+) 441.1.
Examples 148: Preparation of (R)-3-methyl-2-(7-nitrodibenzo[b,d]furan-3- sulfonamido)butanoic acid
Step 1 : Preparation of (RVmethyl 3-methyl-2-(7-nitrodibenzorb,dlfuran-3- sulfonamido)butanoate
[0320] 7-Nitrodibenzo[b,d]furan-3-sulfonyl chloride (a by-product in Step 3 of Example 28, 0.63 g, 2;02 mmol) and (R)-methyl 2-amino-3-methylbutanoate hydrochloride (346 mg, 1.02 mmol) were mixed with 30 mL Of CH2Cl2 and N,N- diisopropylethylamine (0.71 mL, 4.04 mmol) was added. The mixture was stirred at room temperature for 5 hours and was purified by a column chromatography to provide 0.69 g of (R)-m ethyl 3-methyl-2-(7-nitrodibenzo[b,d]furan-3- sulfonamido)butanoate as a white solid in 85% yield.
Step 2: Preparation of (RV3-methyl-2-(7-nitrodibenzo[b,dlfuran-3- sulfonamido)butanoic acid
[0321] (R)-Methyl 3-methyl-2-(7-nitrodibenzo[b,d]furan-3-sulfonamido)butanoate (114 mg) was dissolved in 4 mL of THF and a LiOH solution (1 mL, 0.9 M, in MeOH/H2O (1 :1)) was added. The resulting suspension was stirred at room temperature for 4 days and THF was removed under reduced pressure. The remaining aqueous solution was acidified to pH ~1 and filtered to give (R)-3- methyl-2-(7-nitrodibenzo[b,d]furan-3-sulfonamido)butanoic acid as a white solid in 95% yield. HRMS: calculated for [CnHi6N2O7S + H]+ 393.07510; found (ESI- FTMS, [M+H]1+) 393.07453.
Examples 149: Preparation of (R)-2-(7-
(methoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid
Step 1 : Preparation of (R)-methyl 2-(7-aminodibenzofb,d1furan-3-sulfonamido)-3- methylbutanoate
[0322] (R)-Methyl 3 -methyl-2-(7-nitrodibenzo [b,d] furan-3 -sulfonamido)butanoate (Example 148, Step 1, 405 mg) and 100 mg of Pd/C (10%) were mixed with 50 mL of MeOH. The reaction was carried out in a Parr shaker at room temperature under H2 (50psi) overnight. The reaction mixture was filtered through Celite and the filtrate concentrated to give 333 mg of (R)-methyl 2-(7-aminodibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoate as yellow solid in 90% yield.
Step 2: Preparation of (R)-methyl 2-(7-dnethoxycarbonylamino*)dibenzorb,d1furan- 3-sulfonamido)-3-methylbutanoate
[0323] (R)-Methyl 2-(7-aminodibenzo[b,d] furan-3 -sulfonamido)-3-methylbutanoate (51 mg, 0.13mol) and DMAP (20 mg, 0.16 mmol) were dissolved in 3 mL of CH2Cl2 and methyl chloroformate (15 mg, 0.16 mmol) was added. The mixture was stirred at room temperature overnight, concentrated, and purified by a silica gel column chromatography to provide (R)-methyl 2-(7-
(methoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate as a white solid in 71% yield.
Step 3: Preparation of (R)-2-(7-(methoxycarbonylamino)dibenzo[b,dlfuran-3- sulfbnamido)- 3 -methylbutanoic acid
[0324] (R)-Methyl 2-(7-(methoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)- 3-methylbutanoate (40 mg) was mixed with 3 mL of AcOH and 6 mL of 37% HCl. The resulting suspension was stirred at room temperature for 18 hours, concentrated, and purified by a preparative HPLC to provide (R)-2-(7- (methoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3 -methylbutanoic acid as a white solid in 74% yield. HRMS: calculated for [C9H20N2O7S + H]+ 421.10640; found (ESI-FTMS, [M+H]1+) 421.10674.
Examples 150: Preparation of (R)-2-(7-(3-(3,4- difluorophenyl)ureido)dibenzo[b,d]furan-3-suIfonamido)-3-methylbutanoic acid
Step 1 : Preparation of (R)-methyl 2-(7-(3-(3,4- difluorophenvOureido)dibenzo[b,d1furan-3-sulfonamidoV3-rnethylbutanoate
[0325] (R)-Methyl 2-(7-aminodibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate (Example 148, Step 1, 43 mg, 0.11 mmol) and 3-ethienyl isocyanate (21 mg, 0.14 mmol) were mixed with 2 mL of THF. The mixture was irradiated with microwave at 120°C for 20 minutes, concentrated, and purified by a silica gel column chromatography to provide (R)-methyl 2-(7-(3-(3,4- difluorophenyl)ureido)dibenzo [b,d] furan-3-sulfonamido)-3 -methy lbutanoate as a white solid in 72% yield.
Step 2: Preparation of (R>2-(7-(3-(3.4-difluorophenvOureido*)dibenzorb.d1furan-3- sulfonamido>3-methylbutanoic acid
[0326] (R)-Methyl 2-(7-(3-(3,4-difluorophenyl)ureido)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoate (40 mg) was dissolved in 1 mL of THF and a LiOH solution (1 mL, 0.9 M, in MeOH/H2O (1 :1)) was added. The resulting suspension was stirred at room temperature for 4 days and THF was removed under reduced pressure. The remaining aqueous solution was acidified to pH ~1 and filtered to give (R)-2-(7-(3-(3,4-difluorophenyl)ureido)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoic acid as a white solid in 95% yield. HRMS: calculated for [C24H21F2N3O6S + H]+ 518.11919; found (ESI-FTMS, [M+H]1+) 518.11967.
Examples 151: Preparation of (S)-I-(I-
(methoxycarbonylamino)dibenzo[b,d]furan-3-suIfonamido)-3-rneth\ibutanoic acid
Step 1 : Preparation of (S)-tert-butyl 3-methyl-2-(7-nitrodibenzorb,d1furan-3- sulfonamido)butanoate
[0327] 7-Nitrodibenzo[b,d]furan-3-sulfonyl chloride (a by-product isolated in Step 3 of Example 28, 0.63 g, 2.02 mmol) and (S)-terZ-butyl 2-amino-3-methylbutanoate hydrochloride (346 mg, 1.02 mmol) were mixed with 30 mL of CH2Cl2 and N5N- diisopropylethylamine (0.71 mL, 4.04 mmol) was added. The mixture was stirred at room temperature for 5 hours and purified by a silica gel column chromatography to provide 0.69 g of (S)-tert -butyl 3-methyl-2-(7-nitrodibenzo[b,d]furan-3- sulfonamido)butanoate as a white solid in 85% yield.
Step 2: Preparation of (SVtert-butyl 2-(7-aminodibenzo[b,d1furan-3-sulfonamido)-3- methylbutanoate
[0328] (S)-Tert-butyl 3-methyl-2-(7-nitrodibenzo[b,d]furan-3- sulfonamido)butanoate (420 mg) and 200 mg of Pd/C (10%) were mixed with 150 mL of MeOH. The reaction was carried out in a Parr shaker at room temperature under H2 (50 psi) overnight. The reaction mixture was filtered through Celite and the filtrate concentrated to give 325 mg of (S)-tert-butyl 2-(7- aminodibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate as yellow solid in 100% yield. Step 3: Preparation of (SVtert-butyl 2-(7-
(methoxycarbonylamino'ldibenzo [b.dl furan-3 -sulfonamido)-3 -methylbutanoate
[0329] (S)-Tert-butyl 2-(7-aminodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate (370 mg, 0.88 mol) and DMAP (0.13g, 1.06 mmol) were dissolved in 14 mL Of CH2Cl2 and methyl chloroformate (100 mg, 1.06 mmol) was added. The mixture was stirred at room temperature overnight, concentrated, and purified by a silica gel column chromatography to provide (S)-tert-butyl 2-(7- (methoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate as a white solid in 93% yield.
Step 4: Preparation of (S)-2-(7-(methoxycarbonylaminoN)dibenzo[b,dl furan-3 - sulfonamido)-3-methylbutanoic acid
[0330] (S)-Tert-butyl 2-(7-(methoxycarbonylamino)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoate (335 mg) was mixed with 6 mL Of TFAZCH2Cl2 (1 :1) and stirred at room temperature for 4 hours. The solvents were removed under reduced pressure and the residue was triturated in MeCN/water followed by a freeze-dry process to provide (S)-2-(7-(methoxycarbonylamino)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoic acid as a white solid in 96% yield. HRMS: calculated for [C19H20N2O7S + H]+ 421.10640; found (ESI-FTMS, [M+H]1+) 421.1064.
Examples 152: Preparation of (S)-2-(7-((2- fluoroethoxy)carbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoic acid
[0331] (S)-2-(7-((2-Fluoroethoxy)carbonylamino)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoic acid was prepared following procedures analogous to those described in Example 151 and using 2-fluoroethyl carbonochloridate. HRMS: calculated for [C20H21FN2O7S + H]+ 453.11263; found (ESI-FTMS, [M+H]1+) 453.11285. Examples 153: Preparation of (S)-2-(7-((but-2- ynyloxy)carbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid
[0332] (S)-2-(7-((But-2-ynyloxy)carbonylamino)dibenzo[b,d]furan-3-sulfonamido)- 3-methylbutanoic acid was prepared following procedures analogous to those described in Example 151 and using but-2-ynyl carbonochloridate. HRMS: calculated for [C22H22N2O7S + H]+ 459.12205; found (ESI-FTMS, [M+H]1+) 459.12354.
Examples 154: Preparation of (S)-2-(7-((4- fluorophenoxy)carbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoic acid
[0333] (S)-2-(7-((4-Fluorophenoxy)carbonylamino)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoic acid was prepared following procedures analogous to those described in Example 151 and using but-2-ynyl carbonochloridate. HRMS: calculated for [C24H2]FN2O7S + H]+ 501.11263; found (ESI-FTMS, [M+H]1+) 501.11483.
Examples 155: Preparation of (S)-3-methyl-2-(7-(3-thiophen-3- ylureido)dibenzo[b,d]furan-3-sulfonamido)butanoic acid
Step 1 : Preparation of (S Vtert-butyl 3-methyl-2-(7-(3-thiophen-3- ylureido)diben2o[b,d]furan-3-sulfonamido')butanoate
[0334] (S)-Tert-butyl 2-(7-aminodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate (Example 151, Step 2, 60 mg, 0.14 mmol) and 3- isocyanatothiophene (18 mg, 0.17 mmol) were mixed with 2 mL of THF. The mixture was irradiated with microwave at 12O0C for 20 minutes, concentrated, and purified by a silica gel column chromatography to provide (S)-tert-butyl 3-methyl-2- (7-(3-thiophen-3-ylureido)dibenzo[b,d]furan-3-sulfonamido)butanoate as a white solid in 38% yield. Step 2: Preparation of (S)-3-methyl-2-(7-(3-thiophen-3-ylureido)dibenzo[b,d1furan- 3-sulfonamido')butanoic acid
[0335] (S)-Tert-butyl 3-methyl-2-(7-(3-thiophen-3-ylureido)dibenzo[b,d]furan-3- sulfonamido)butanoate (36 mg) was mixed in 1 mL of TFAZCH2Cl2 (1 : 1). The resulting mixture was stirred at room temperature for 4 hours, concentrated under reduced pressure, and the residue was triturated in MeCN/water followed by a freeze-dry process to provide (S)-3-methyl-2-(7-(3-thiophen-3- ylureido)dibenzo[b,d]furan-3-sulfonamido)butanoic acid as a white solid in 90% yield. HRMS: calculated for [C22H2IN3O6S2 + H]+ 488.09445; found (ESI-FTMS, [M+H]1+) 488.09462.
Examples 156: Preparation of (S)-3-methyl-2-(7-(3-(2-(thiophen-2- yl)ethyl)ureido)dibenzo[b,d]furan-3-suIfonamido)butanoic acid
[0336] (S)-3-Methyl-2-(7-(3-(2-(thiophen-2-yl)ethyl)ureido)dibenzo[b,d]furan-3- sulfonamido)butanoic acid was prepared following procedures analogous to those described in Example 155 and using 2-(2-isocyanatoethyl)thiophene. HRMS: calculated for [C24H25N3O6S2 + H]+ 516.12575; found (ESI-FTMS, [M+H]l+) 516.12506.
Examples 157: Preparation of (S)-3-methyl-2-(7-ureidodibenzo[b,d]furan-3- sulfonamido)butanoic acid
[0337] (S)-3-Methyl-2-(7-ureidodibenzo[b,d]furan-3-sulfonamido)butanoic acid was prepared following procedures analogous to those described in Example 155 and using l-(isocyanatomethyl)-4-methoxybenzene. HRMS: calculated for [C18Hi9N3O6S + H]+ 406.10673; found (ESI-FTMS, [M+H]1+) 406.10682.
Examples 158: Preparation of (S)-2-(7-(3-(3,4- difluorophenyl)ureido)dibenzo[b,d]furan-3-sulfonamido)-3-methyIbutanoic acid
[0338] (S)-2-(7-(3-(3,4-Difluorophenyl)ureido)dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoic acid was prepared following procedures analogous to those described in Example 155 and using l,2-difluoro-4-isocyanatobenzene. HRMS: calculated for [C24H2IF2N3O6S + H]+ 518.11919; found (ESI-FTMS, [M+H]1+), 518.11942.
Examples 159: Preparation of (S)-2-(7-(ethylamino)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoic acid
Step 1 : Preparation of (SVmethyl 2-(7-(ethylamino)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoate
[0339] (S)-Methyl 2-(8-bromo-7-nitrodibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate (Example 138, Step 3, 550 mg) and 1 g of Pd/C (10%) were mixed with 150 mL of MeOH and 2 mL of MeCN. The reaction was carried out in a Parr shaker at room temperature under H2 (50 psi) overnight. The reaction mixture was filtered through Celite® and the filtrate concentrated to provide 330 mg of (S)- methyl 2-(7-(ethylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoate as a yellow solid in 72% yield.
Step 2: Preparation of (S)-2-(7-(ethylamino)dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoic acid
[0340] (S)-Methyl 2-(7-(ethylamino)dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate (140 mg) was dissolved in 2 mL of THF and a LiOH solution (1 mL, 0.9 M, in MeOH/H2O (1 : 1)) was added. The resulting suspension was stirred at room temperature for 4 days and THF was removed under reduced pressure. The remaining aqueous solution was acidified to pH ~1 and filtered to give (S)-2-(7-(ethylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid as a pale yellow solid in 95% yield. HRMS: calculated for [Ci9H22N2O5S + H]+ 391.13222; found (ESI-FTMS, [M+H]1+) 391.13253.
Examples 160: Preparation of (S)-2-(7- (ethyl(methoxycarbonyl)amino)dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoic acid
Step 1 : Preparation of (SVmethyl 2-(7-
(ethyl(methoxycarbonvOamino)dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoate [0341] (S)-Methyl 2-(7-(ethylamino)dibenzo[b,d] furan-3 -sulfonamido)-3- methylbutanoate (Example 159, Step 1, 31 mg, 0.08 mol) and DMAP (12 mg, 0.09 mmol) were dissolved in 1 mL Of CH2Cl2 and methyl chloroformate (8.7 mg, 0.09 mmol) was added. The mixture was stirred at room temperature overnight, concentrated, and purified by a silica gel column chromatography to provide (S)- methyl 2-(7-(ethyl(methoxycarbonyl)amino)dibenzo [b,d] furan-3 -sulfonamido)-3 - methylbutanoate as a white solid in 90% yield.
Step 2: Preparation of (S)-2-(7-(ethyl(methoxycarbonvDamino)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoic acid [0342] (S)-Methyl 2-(7-(ethyl(methoxycarbonyl)amino)dibenzo[b,d]furan-3- sulfonamido)-3 -methylbutanoate (14 mg) was dissolved in 0.5 mL of THF and a LiOH solution (1 mL, 0.9 M, in MeOH/H2O (1 :1)) was added. The resulting suspension was stirred at room temperature for 3 days and THF was removed under reduced pressure. The remaining aqueous solution was acidified to pH ~2 and filtered to give (S)-2-(7-(ethyl(methoxycarbonyl)amino)dibenzo[b,d]furan-3- sulfonamido)-3-methylbutanoic acid as a white solid in 95% yield. HRMS: calculated for [C2iH24N2O7S + H]+ 449.13770; found (ESI-FTMS, [M+H]1+) 449.13776.
Examples 161: Preparation of (S)-2-(7-(ethyl(methyl)amino)dibenzo[b,d]furan- 3-sulfonamido)-3-methylbutanoic acid
Step 1 : Preparation of (S)-methyl 2-(7-(ethyl(methyl)amino>)dibenzo[b,d] furan-3 - sulfonamido)-3-methylbutanoate
[0343] HCHO (32 mg, 37%, 0.4 mmol) and H2SO4 (5μL, 3M) were cooled to - 1O0C and a mixture (S)-methyl 2-(7-(ethylamino)dibenzo[b,d]furan-3-sulfonamido)- 3-methylbutanoate (Example 159, Step 1, 54 mg, 0.13 mmol) and NaBH4 (18 mg, 0.47 mmol) in 1 mL of THF was added slowly. The mixture was stirred at -1O0C for 1 hour, slowly warmed up to room temperature, concentrated, and purified by a silica gel column chromatography to provide (S)-methyl 2-(7- (ethyl(methyl)amino)dibenzo [b,d] furan-3 -sulfonamido)-3 -methylbutanoate as a white solid in 96% yield. Step 2: Preparation of (S)-2-(7-(ethyl(methyr)amino)dibenzo[b,d1 furan-3 - sulfonamido)-3-methylbutanoic acid
[0344] (S)-Methyl 2-(7-(ethyl(methyl)amino)dibenzo [b,d] furan-3 -sulfonamido)-3 - methylbutanoate (42 mg) was dissolved in 1 niL of THF and a LiOH solution (1 niL, 0.9 M, in MeOH/H2O (1:1)) was added. The resulting suspension was stirred at room temperature for 4 days and THF was removed under reduced pressure. The remaining aqueous solution was acidified to pH ~1 and filtered to give (S)-2-(7- (ethyl(methyl)amino)dibenzo[b,d] furan-3 -sulfonamido)-3-methylbutanoic acid as a white solid in 95% yield. HRMS: calculated for [C20H24N2O5S + H]+ 405.14787; found (ESI-FTMS, [M+H]1+) 405.1465.
Examples 162: Preparation of (S)-3-methyl-2-(8-(4-methylpiperazin-l- yl)dibenzo[b,d]furan-3-sulfonamido)butanoic acid
[0345] Following procedures analogous to those described in Example 104 and using 1-methylpiperazine, (S)-3-methyl-2-(8-(4-methylpiperazin-l- yl)dibenzo[b,d]furan-3-sulfonamido)butanoic acid was obtained as a white solid. HRMS: calculated for [C22H27N3O5S + H]+ 446.17442; found (ESI-FTMS, [M+H]1+) 446.17469.
Examples 163: Preparation of (S)-2-(8-(lH-l,2,4-triazol-l-yl)dibenzo[b,d]furan- 3-sulfonamido)-3-methylbutanoic acid
[0346] Following procedures analogous to those described in Example 104 and using 1 H- 1 ,2,4-triazole, (S)-2-(8-( 1 H- 1 ,2,4-triazol- 1 -yl)dibenzo [b,d] furan-3 - sulfonamido)-3-methylbutanoic acid was obtained as a white solid. HRMS: calculated for [Ci9Hi8N4O5S + H]+ 415.10707; found (ESI-FTMS, [M+H]1+) 415.10704.
Examples 164: Preparation of (S)-2-(8-(4,4-difluoropiperidin-l- yl)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid
[0347] Following procedures analogous to those described in Example 104 and using 4,4-difluoropiperidine, (S)-2-(8-(4,4-difluoropiperidin-l-yl)dibenzo[b,d]furan- 3-sulfonamido)-3-methylbutanoic acid was obtained as a white solid. HRMS: calculated for [C22H24F2N2O5S + H]+ 467.14467; found (ESI-FTMS, [M+H]l+) 467.14493.
Examples 165: Preparation of (S)-3-methyl-2-(8-(4-methyl-lH-imidazol-l- yl)dibenzo[b,d]furan-3-sulfonamido)butanoic acid
[0348] Following procedures analogous to those described in Example 104 and using 4-methyl- 1 H-imidazole, (S)-3-methyl-2-(8-(4-methyl- 1 H-imidazol- 1 - yl)dibenzo[b,d]furan-3-sulfonamido)butanoic acid was obtained as a white solid. HRMS: calculated for [C2iH2iN3O5S + H]+ 428.12747; found (ESI-FTMS, [M+H]1+) 428.12781.
Examples 166: Preparation of (S)-3-methyl-2-(8-(2,2,2- trifluoroethylsulfonamido)dibenzo[b,d]furan-3-sulfonamido)butanoic acid
[0349] Following procedures analogous to those described in Example 18 and using 2,2,2-trifluoroethanesulfonyl chloride, (S)-3-methyl-2-(8-(2,2,2- trifluoroethylsulfonamido)dibenzo[b,d]furan-3-sulfonamido)butanoic acid was obtained as a white solid. HRMS: calculated for [C9Hi9F3N2O7S2 + H]+ 509.06585; found (ESI-FTMS, [M+H]1+) 509.06656.
Examples 167: Preparation of (S)-2-(8-(4-fluoro-N-(4- fluorophenylsulfonyl)phenylsulfonamido)dibenzo[b,d]furan-3-sulfonamido)-3- methylbutanoic acid
[0350] Following procedures analogous to those described in Example 18 and using 4-fluorobenzene-l-sulfonyl chloride, (S)-2-(8-(4-fluoro-N-(4- fluorophenylsulfonyl)phenylsulfonamido)dibenzo-[b,d]furan-3-sulfonamido)-3- methylbutanoic acid was obtained as a white solid. HRMS: calculated for [C29H24F2N2O9S3 + H]+ 679.06848; found (ESI-FTMS, [M+H]1+) 679.06859.
Examples 168: Preparation of (S)-2-(8-(4,5-dichlorothiophene-2- sulfonamido)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid
[0351] Following procedures analogous to those described in Example 18 and using 4,5-dichlorothiophene-2-sulfonyl chloride, (S)-2-(8-(4,5-dichlorothiophene-2- sulfonamido)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid was obtained as a white solid. HRMS: calculated for [C2 IH18Cl2N2O7S3 + H]+ 576.97259; found (ESI-FTMS, [M+H]1+) 576.97504.
Example 169: Preparation of (R)-2-(7-(5-methoxy-2H-tetrazol-2- yl)dibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoic acid
Step 1 : Preparation of (RVmethyl 3-methyl-2-(7-(5-tosyl-2H-tetrazol-2- yl)dibenzo[b,d]furan-2-sulfonamido)butanoate
[0352] To a suspension of (R)-2-(7-azido-dibenzofuran-2-sulfonylamino)-3-methyl- butyric acid methyl ester (Example 92, Step 1 , 60 mg) was added 4- methylbenzenesulfonyl cyanide (165 mg). The reaction mixture was stirred at 8O0C overnight, cooled to room temperature, and water was added. The resulting mixture was acidified with 1 N HCl to pH ~ 2 and filtered to give (R)-methyl 3-methyl-2-(7- (5-tosyl-2H-tetrazol-2-yl)dibenzo[b,d]furan-2-sulfonamido)butanoate as a pale yellow compound.
Step 2: Preparation of (R)-2-(7-(5-methoxy-2H-tetrazol-2-yl)dibenzo[b,d]furan-2- sulfonamido)-3-methylbutanoic acid and (R)-2-(7-("5-hydroxy-2H-tetrazol-2- yQdibenzo [b,d] furan-2-sulfonamido)-3 -methylbutanoic acid
[0353] (R)-Methyl 3-methyl-2-(7-(5-tosyl-2H-tetrazol-2-yl)dibenzo[b,d]furan-2- sulfonamido)butanoate from Step 1 was dissolved in methanol/water (1 :1) and lithium hydroxide was added. The reaction solution was stirred at room temperature for 16 hours, diluted with water, acidified to pH ~ 2 with 1 N HCl, and filtered. The crude product was purified with a HPLC to give (R)-2-(7-(5-methoxy-2H-tetrazol-2- yl)dibenzo[b,d]furan-2-sulfonamido)-3-methylbutanoic acid (3 mg) as an off-white solid and (R)-2-(7-(5 -hydroxy-2H-tetrazol-2-yl)dibenzo [b,d] furan-2-sulfonamido)- 3 -methylbutanoic acid (1 mg).
[0354] (R)-2-(7-(5-methoxy-2H-tetrazol-2-yl)dibenzo[b,d]furan-2-sulfonamido)-3- methylbutanoic acid. 1H NMR (400 MHz, DMSO-c/6) δ ppm 8.71 (s, 1 H), 8.58 (d, J=8.34 Hz, 1 H), 8.39 (d, J=9.35 Hz, 1 H), 8.21 (d, J=I.77 Hz, 1 H), 7.97 - 8.00 (m, 1 H), 7.83 (dd, J=8.34, 2.02 Hz, 1 H), 4.28 (s, 3 H), 3.67 (dd, J=9.47, 6.95 Hz, 1 H), 1.86 - 1.96 (m, 1 H), and 0.81 (dd, J=I 1.37, 6.82 Hz, 6 H); MS (LCMS-ESI, M+H) 446.30.
Example 170: Preparation of (R)-2-(7-(5-hydroxy-2H-tetrazol-2- yl)dibenzo|b,d|furan-2-sulfonamido)-3-methylbutanoic acid
[0355] (R)-2-(7-(5-Hydroxy-2H-tetrazol-2-yl)dibenzo[b,d]furan-2-sulfonamido)-3- methylbutanoic acid was isolated as a by-product in Example 169 as an off-white solid. 1H NMR (400 MHz, MeOD) δ ppm 8.82 (d, J=I .26 Hz, 1 H), 8.46 - 8.54 (m, 2 H), 8.19 - 8.31 (m, 2 H), 7.99 (d, J=8.84 Hz, 1 H), 3.89 (d, 1 H), 2.17 - 2.34 (m, 1 H), and 1.16 (dd, 6 H); MS (LCMS-ESI, M+H) 432.10.
Example 171: Preparation of (S)-3-methyl-2-(8-(2-oxo-l,3-oxazinan-3- yl)dibenzo[b,d|furan-3-sulfonamido)butanoic acid
[0356] Following procedures analogous to those described in Example 99 and using chloropropyl chloroformate, (S)-3-methyl-2-(8-(2-oxo-l,3-oxazinan-3- yl)dibenzo[b,d]furan-3-sulfonamido)butanoic acid was obtained as a white solid. HRMS calculated for [C21H22N3O2S + H]+ 447.12205; found (ESI-FTMS, [M+H]l+) 447.12419.
Example 172: Preparation of (S)-3-methyl-2-(7- (benzyl(methyl)amino)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid
Step 1 : Preparation of ("SVtert-butyl 2-(7-(benzylamino)dibenzo[b,d]thiophene-3- sulfonamido)-3-methylbutanoate
[0357] (S)-Tert-butyl 2-(7-aminodibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoate (Example 65, Step 4, 1.1 g, 2.5 mmol) and benzaldehyde (300 mg, 2.75 mmol) were dissolved in dry THF (20 mL), heated at reflux for 4 hours, and cooled. NaBH4 (1 g) and MeOH (2 mL) were added at 00C, and the reaction mixture was stirred 2 hours at room temperature, and partitioned between ethyl acetate (50 mL) and NaHCO3 (30 mL, 5%). The aqueous solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to provide (S)-tert-butyl 2-(7- (benzylamino)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoate (1.1 g). 1H NMR (400 MHz, DMSO-J6) δ ppm 0.82 (d, J=6.9 Hz, 3H), 0.85 (d, J=6.9 Hz, 3H), 1.07 (s, 9H), 1.92 (m, IH), 3.5 (dd, J=9.7 6.0 Hz, IH), 4.39 (d, J=5.8 Hz, 2H), 6.89 (m, 2H), 7.06 (d, J=2.0 Hz, IH), 7.39-7.21 (m, 4H), 7.42 (d, J=7.5 Hz, 2H), 7.72 (dd, J=8.4 1.7 Hz, IH), 8.03 (d, J=9.6 Hz, IH), 8.05 (d, J=8.7 Hz, IH), and 8.16 (d, J=1.5 Hz, IH).
Step 2: Preparation of CS Vtert-butyl 2-C7-
(benzyl(methyl)amino)dibenzo [KdI thiophene-3 -sulfonamido)-3 -methylbutanoate
[0358] (S)-Tert-butyl 2-(7-(benzylamino)dibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoate (525 mg, 1 mmol) from Step 1 was mixed with formaldehyde (40% in water, 150 mg, 2 mmol) and THF (10 mL) and Na(CN)BH3 (1 g) and MeOH (2 mL) were added at O0C. The reaction mixture was stirred at room temperature for 7 days. (S)-Tert-butyl 2-(7-(benzyl(methyl)amino)dibenzo[b,d]thiophene-3- sulfonamido)-3-methylbutanoate was obtained as a white solid following the work- ups analogous to those described in Step 1.
Step 3: Preparation of (S>2-(7-(benzyl(methyl)amino)dibenzo[b,dlthiophene-3- sulfonamido)-3-methylbutanoic acid
[0359] (S)-Tert-butyl 2-(7-(benzyl(methyl)amino)dibenzo [b,d]thiophene-3 - sulfonamido)-3 -methylbutanoate was treated with 30% TFA in DCM at room temperature for 4 hours. (S)-2-(7-(Benzyl(methyl)amino)dibenzo[b,d]thiophene-3- sulfonamido)-3-methylbutanoic acid was obtained as a TFA salt after removal of the solvents and excess TFA. 1H NMR (400 MHz, DMSO-J6) δ ppm 0.81 (d, J=6.9 Hz, 3H), 0.83 (d, J=6.9 Hz, 3H), 1.94 (m, IH), 3.15 (s, 3H), 3.57 (dd, J=9.6 6.1 Hz, IH), 4.74 (s, 2H), 7.02 (dd, J=8.9 2.3 Hz, IH), 7.36-7.20 (m, 6H), 7.74 (dd, J=8.5 1.7 Hz, IH), 7.95 (d, J=9.3 Hz, IH), 8.14 (d, J=8.9 Hz, IH), 8.20 (d, J=8.5 Hz, IH), 8.25 (d, J=I.7 Hz, IH), and 12.43 (br, IH); MS (ES+) 483.1. Example 173: Preparation of N-{[7-(l,l-dioxidoisothiazolidin-2- yl)dibenzo[b,d]thien-3-yl]sulfonyl}-L-valine
[0360] N-{[7-(l,l-Dioxidoisothiazolidin-2-yl)dibenzo[b,d]thien-3-yl]sulfonyl}-L- valine was prepared using (S)-tert-butyl 2-(7-aminodibenzo[b,d]thiophene-3- sulfonamido)-3-methylbutanoate (Example 65, Step 4) and 2-chloroethanesulfonyl chloride following procedures analogous to those described in Example 99. 1H NMR (300 MHz, DMS(W6) δ ppm 0.81 (d, J=6.9 Hz; 3H), 0.84 (d, J=6.9 Hz; 3H), 1.96 (d, J=6.6 Hz; IH), 2.48 (m, 2H), 3.60 (m, IH), 3.60 (t, J= 7.4 Hz, 2H), 3.89 (t, J= 6.3 Hz, 2H), 7.49 (dd, J=8.3, 1.8 Hz, IH), 7.88 (m, 2H), 8.07 (d, J=9.4 Hz; IH), 8.44 (m, 3H), 12.53 (s br, IH); MS (ES+) 482.92.
Example 174: Preparation of N-{[7-(l-oxidoisothiazolidin-2- yl)dibenzo[b,d]thien-3-yl]sulfonyl}-L-valine
[0361] N-{[7-(l -Oxidoisothiazolidin-2-yl)dibenzo [b,d] thien-3 -yl] sulfonyl } -L-valine was prepared following procedures analogous to those described in Example 173 and using 2-chloroethanesulfinic chloride. MS (ES+) 467.18.
Example 175: Preparation of (S)-3-methyI-2-(7-(2-oxooxazolidin-3- yl)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid
[0362] Following procedures analogous to those described in Example 99 and using (S)-tert-butyl 2-(7-aminodibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoate (Example 65, Step 4) and bromoethyl chloroformate, (S)-3-methyl-2-(7-(2- oxooxazolidin-3 -yl)dibenzo [b,d] thiophene-3 -sulfonamido)butanoic acid was prepared as a white powder. MS (ES+) 449.05.
Example 176: Preparation of (S)-2-(7-
(methoxycarbonyl(methyl)amino)dibenzo[b,d]thiophene-3-suIfonamido)-3- methylbutanoic acid
Step 1 : Preparation of (S)-tert-butyl 2-(7-formamidodibenzo[b,d]thiophene-3- sulfonamido)-3-methylbutanoate [0363] To a mixture of acetic formic anhydride (prepared by dropwise addition of 98% formic acid (450 mg, 370 μl, 3.2 mmol) to acetic anhydride (800 mg, 735 μl, 2.6 mmol) at O0C followed by gentle heating at 50°C for 2 h) in THF (10 mL) was added (S)-tert-butyl 2-(7-aminodibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoate (1.3 g, 3 mmol)) dissolved in THF (5 mL). After the reaction was found complete by TLC, it was concentrated to provide 1.38 g of (S)-tert-butyl 2-(7- formamidodibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoate.
Step 2: Preparation of (S Vtert-butyl 3-methyl-2-(7- (methylamino)dibenzo[b1dlthiophene-3-sulfonamido)butanoate
[0364] (S)-Tert-butyl 2-(7-formamidodibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoate (1.38 g, 3 mmol) from Step 1 was dissolved in dry THF (10 mL). The solution was cooled at O0C and borane dimethylsulfide complex (750 μl) was added dropwise. The reaction mixture was stirred at 0°C for 1 h and methanol was added. The resulting mixture was poured in water and extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated to give (S)-tert- butyl 3-methyl-2-(7-(methylamino)dibenzo[b,d]thiophene-3-sulfonamido)butanoate (1-3 g).
Step 3 and 4: Preparation of (SV2-(7-
(methoxycarbonyl(methyl')amino)dibenzo[b,d]thiophene-3-sulfonamido')-3- methylbutanoic acid
[0365] (S)-Tert-butyl 3-methyl-2-(7-(methylamino)dibenzo[b,d]thiophene-3- sulfonamido)butanoate (120 mg, 0.3 mmol) and K2CO3 were suspended in dry THF (3 mL) and methyl chloroformate (0.6 mmol) was added. The reaction mixture was stirred at 65°C for 2 hours , concentrated, and purified by a silica gel column chromatography to provide (S)-tert-butyl 2-(7-
(methoxycarbonyl(methyl)amino)dibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoate, which was treated with LiOH and purified by a preparative HPLC to provide (S)-2-(7-(methoxycarbonyl(methyl)amino)dibenzo[b,d]thiophene-3- sulfonamido)-3 -methylbutanoic acid. 1H NMR (300 MHz, DMSO-t/6) δ ppm 0.80 (d, J=7.0 Hz, 3 H), 0.83 (d, J=7.0 Hz, 3 H), 1.87 - 2.03 (m, 1 H), 3.33 (s, 3 H), 3.55 - 3.64 (m, 1 H), 3.65 (s, 3 H), 7.54 (dd, J=8.7, 1.9 Hz, 1 H), 7.87 (dd, J=8.4, 1.6 Hz, 1 H), 8.08 (d, J=I.8 Hz, 1 H), 8.09 - 8.13 (m, 1 H), 8.44 (d, J=8.8 Hz, 1 H), 8.46 (d, J=I.5 Hz, 1 H), 8.50 (d, J=8.5 Hz, 1 H), and 12.51 (br. s., 1 H); MS (ES+) 451.0.
Example 177: Preparation of (S)-2-(7- (ethoxycarbonyl(methyl)amino)dibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoic acid
[0366] Following procedures analogous to those described in Example 176 and using ethyl chloroformate, (S)-2-(7-
(ethoxycarbonyl(methyl)amino)dibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoic acid was obtained as a white solid. 1H NMR (300 MHz, DMSOd6) δ ppm 0.80 (d, J=6.9 Hz; 3H), 0.83 (d, J=6.9 Hz; 3H), 1.19 (t, J=7.1 Hz; 3H), 1.95 (m, IH), 3.36(s, 3H), 3.59 (m, IH), 4.11 (q, J=7.1 Hz; 2H), 7.54(dd, J= 8.5, 2.1 Hz; IH), 7.87 (dd, J=8.2, 1.7 Hz; IH), 8.07 (d, J=I.9 Hz; IH), 8.10 (s br, IH), 8.43 (d, J=8.7 Hz; IH), 8.46 (d, J=I .4 Hz; IH), and 8.50 (d, J=8.3 Hz; IH); MS (ES+) 465.1.
Example 178: Preparation of (S)-2-(7-
(isopropoxycarbonyl(methyl)amino)dibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoic acid
[0367] Following procedures analogous to those described in Example 176 and using isoproryl chloroformate, (S)-2-(7- (isopropoxycarbonyl(methyl)amino)dibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoic acid was obtained as a white solid. 1H NMR (300 MHz, DMSO-dg + TFA) δ ppm 0.80 (d, J=6.7 Hz, 3 H), 0.83 (d, J=6.7 Hz, 3 H), 1.20 (d, J=6.2 Hz, 6 H), 1.88 - 2.02 (m, 1 H), 3.32 (s, 3 H), 3.61 (dd, J=9.5, 6.0 Hz, 1 H), 4.87 - 4.89 (m, 1 H), 7.53 (dd, J=8.5, 2.1 Hz, 1 H), 8.09 - 8.13 (m, 1 H), 8.44 (d, J=8.8 Hz, 1 H), 8.46 (d, J=I.5 Hz, 1 H), 8.50 (d, J=8.5 Hz, 1 H), and 12.51 (br. s., 1 H); MS (ES+) 479.0.
Example 179: Preparation of (S)-2-(7-(((4- fluorophenoxy)carbonyl)(methyl)amino)dibenzo[b,d]thiophene-3-sulfonamido)- 3-methylbutanoic acid [0368] Following procedures analogous to those described in Example 176 and using 4-fluorophenyl chloroformate, (S)-2-(7-(((4- fluorophenoxy)carbonyl)(methyl)amino)dibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoic acid was obtained as a white solid. 1H NMR (300 MHz, DMSO-ak) δ ppm 0.80 (d, J=7.0 Hz, 3 H), 0.83 (d, J=6.7 Hz, 3 H), 1.87 - 2.01 (m, 1 H), 3.46 (s, 3 H), 3.61 (dd, J=9.4, 5.9 Hz, 1 H), 7.21 - 7.26 (m, 4 H), 7.71 (dd, J=8.5, 2.1 Hz, 1 H), 7.88 (dd, J=8.2, 1.8 Hz, 1 H), 8.11 (d, J=9.4 Hz, 1 H), 8.26 (d, J=2.1 Hz, 1 H), 8.46 - 8.56 (m, 3 H), and 12.52 (br. s., 1 H); MS (ES+) 548.2.
Example 180: Preparation of (S)-3-methyl-2-(7- (methylamino)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid
[0369] (S)-3-Methyl-2-(7-(methylamino)dibenzo[b,d]thiophene-3- sulfonamido)butanoic acid was prepared as a TFA salt by treatment of (S)-tert-butyl 3-methyl-2-(7-(methylamino)dibenzo[b,d]thiophene-3-sulfonamido)butanoate (Example 176, Step 2) with TFA in dichloromethane. MS (ES+) 393.0.
Example 181: Preparation of N-{[7-(l,l-dioxidothiomorpholin-4- y l)dibenzo [b,d] thien-3-yl] sulfonyl}-L-valine
[0370] (S)-Methyl 2-(7-aminodibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoate (392 mg, 1 mmol) and divinyl sulfone (142 mg, 1.2 mmol) in orthophosphoric acid (2.0 mL) was heated at 14O0C for 3 days. After work-up and a preparative HPLC purification, N-{[7-(l,l-dioxidothiomorpholin-4- yl)dibenzo[b,d]thien-3-yl]sulfonyl}-L-valine was obtained as a white solid (298 mg, 60% yield). MS (ES+) 497.14.
Example 182: Preparation of (S)-3-methyl-2-(7-(l,3,3- trimethylureido)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid
[0371] Following procedures analogous to those described in Example 176 and using dimethylcarbamic chloride, (S)-3-methyl-2-(7-(l,3,3- trimethylureido)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid was obtained as a white solid. 1H NMR (300 MHz, OMSO-d6) δ ppm 0.76 (d, J=6.9 Hz; 3H), 0.86 (d, J=6.9 Hz; 3H), 2.3 (m, IH), 2.70 (s, 6H), 3.19 (s, 3H), 3.47 (m, IH), 7.21 (dd, J= 8.9, 2.1 Hz; IH), 7.76 (d, J=2.1 Hz; IH), 7.82 (dd, J=8.5, 1.7 Hz; IH), 8.32 (s br, IH), 8.36 (d, J=8.7 Hz; IH), 8.38 (d, J=7.8 Hz; IH), and 8.39 (d, J=2.1 Hz; IH); MS (ES+) 464.0.
Example 183: Preparation of (S)-2-(7-(3-ethyl-l- methylureido)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid
[0372] Following procedures analogous to those described in Example 176 and using ethylisocyanate, (S)-2-(7-(3-ethyl-l-methylureido)dibenzo[b,d]thiophene-3- sulfonamido)-3-methylbutanoic acid was obtained as a white solid. 1H NMR (300 MHz, DMSO-J6 + TFA) δ ppm 0.80 (d, J=6.9 Hz; 3H), 0.82 (d, J=6.9 Hz; 3H), 1.01 (t, J=7.4 Hz; 3H), 1.95(m, IH), 3.07 (m, 2H), 3.25 (s, 3H), 3.61 (dd, J=9.4, 5.9 Hz; IH), 6.26 (s br, IH), 7.45 (dd, J=8.4, 1.9 Hz; IH), 7.86 (dd, J=8.6, 1.7 Hz; IH), 7.98 (d, J=I.9 Hz; IH), 8.08 (d, J=9.6 Hz; IH), 8.41 (d, J=8.6 Hz; IH), 8.44 (d, J=I.5 Hz; IH), 8.46 (s br, IH), and 8.48 (d, J=8.4 Hz; IH); MS (ES+) 464.1.
Example 184: Preparation of (S)-2-(7-(3-benzyl-l- methylureido)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid
[0373] Following procedures analogous to those described in Example 176 and using benzylisocyanate, (S)-2-(7-(3-benzyl-l-methylureido)dibenzo[b,d]thiophene- 3-sulfonamido)-3-methylbutanoic acid was obtained as a white solid. MS (ES+) 526.09.
Example 185: Preparation of (S)-2-(7-(3-benzyl-l,3- dimethylureido)dibenzo[b,d]thiophene-3-suIfonamido)-3-methylbutanoic acid
[0374] Following procedures analogous to those described in Example 176 and using benzyl(methyl)carbamic chloride, (S)-2-(7-(3-benzyl-l,3- dimethylureido)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid was obtained as a white solid. MS (ES+) 540.10. Example 186: Preparation of (S)-3-methyl-2-(7-(2-oxoimidazolidin-l- yl)dibenzo[b,d]thiophenc-3-sulfonamido)butanoic acid
[0375] Following procedures analogous to those described in Example 99 and using chloropropyl isocyanate, (S)-3-methyl-2-(7-(2-oxoimidazolidin- 1 - yl)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid was prepared. 1H NMR (300 MHz, DMSO-J6 + TFA) δ ppm 0.81 (d, J=6.9 Hz; 3H), 0.84 (d, J=6.9 Hz; 3H), 1.95(m, IH), 3.47(m, 2H), 3.60 (dd, J= 9.5, 5.9 Hz, IH), 3.99 (m, 2H), 7.83 (dd, J=8.5, 1.9 Hz; IH), 7.92 (dd, J=8.8, 1.9 Hz, IH), 8.04 (d, J=9.2 Hz; IH), 8.17 (d, J=I .8 Hz; IH), 8.35 (d, J=9.0 Hz; IH), 8.38 (d, J=I.9 Hz; IH), and 8.39 (d, J=8.2 Hz, IH); MS (ES+) 448.08.
Example 187: Preparation of (S)-3-methyl-2-(7-(2-oxotetrahydropyrimidin- l(2H)-yl)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid
[0376] Following procedures analogous to those described in Example 99 and using chloropropylisocyanate, (S)-3-methyl-2-(7-(2-oxotetrahydropyrimidin-l(2H)- yl)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid was obtained as a white solid. MS (ES+) 462.0.
Example 188: Preparation of (R)-2-(7-
(methoxycarbonyIamino)dibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoic acid
[0377] Following procedures analogous to those described in Example 65 and using D-valine, (R)-2-(7-(methoxycarbonylamino)dibenzo[b,d]thiophene-3-sulfonamido)- 3-methylbutanoic acid was obtained as a white solid. 1H NMR (300 MHz, DMSO- d6) δ ppm 0.80 (d, J=6.7 Hz, 3 H), 0.84 (d, J=6.7 Hz, 3 H), 1.88 - 2.02 (m, 1 H), 3.60 (dd, J=8.9, 6.0 Hz, 1 H), 3.73 (s, 3 H), 7.58 (dd, J=8.7, 1.9 Hz, 1 H), 7.84 (dd, J=8.5, 1.5 Hz, 1 H), 8.05 (d, J=9.4 Hz, 1 H), 8.22 (d, J=I.8 Hz, 1 H), 8.35 (d, J=8.5 Hz, 1 H), 8.38 (d, J=5.6 Hz, 1 H), 8.40 (s, 1 H), 10.04 (s, 1 H), and 12.48 (br. s., 1 H); MS (ES+) 437.0. Example 189: Preparation of (R)-2-(7-
(ethoxycarbonylamino)dibenzo[b,d]thiophene-3-sulfonamido)-3- methylbutanoic acid
[0378] Following procedures analogous to those described in Example 65 and using ethyl chloro formate, (R)-2-(7-(ethoxycarbonylamino)dibenzo[b,d]thiophene-3- sulfonamido)-3-methylbutanoic acid was obtained as a white solid. MS (ES+) 451.01.
Example 190: Preparation of (R)-2-(7-(3- cyclopentylureido)dibenzo[b,d]thiophene-3-sulfonamido)-3-methylbutanoic acid
[0379] Following procedures analogous to those described in Example 65 and using cyclopentyl isocyanate, (R)-2-(7-(3-cyclopentylureido)dibenzo[b,d]thiophene-3- sulfonamido)-3-methylbutanoic acid was obtained as a white solid. MS (ES+) 490.1.
Example 191: Preparation of (R)-3-methyl-2-(7-(3- phenylureido)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid
[0380] Following procedures analogous to those described in Example 65 and using phenylisocyanate, (R)-3-methyl-2-(7-(3-phenylureido)dibenzo[b,d]thiophene-3- sulfonamido)butanoic acid was obtained as a white solid. MS (ES+) 498.1.
Example 192: Pharmacological activity
MMP- 12 FRET Assay
[0381] Compounds according to the present teachings were tested in an MMP- 12 FRET assay as follows. To each well of black polystyrene 96- well plate was added assay buffer (50 niM HEPES (pH 7.4), 100 niM NaCl, 5 mM CaCl2 and 0.005% Brij-35), purified human MMP-12 enzyme, and varied concentrations of test compounds (prepared by serial dilution of a stock solution in 100% DMSO). The plates were incubated at room temperature for 30 minutes. The enzymatic reactions were initiated by addition of a substrate, MCA-Pro-Leu-Gly-Leu-Dpa(DNP)-Ala- Arg, containing a fluorescent group (7-methoxycoumarin, MCA) and a 2,4- dinitrophenyl group (DNP), to a final concentration of 20μιM. The final DMSO concentration in the assay was 10%. The reaction was monitored for 30 minutes at room temperature and the initial rate of the cleavage reaction was determined using a fluorescence plate reader (λex: 325 nm, λem: 395 nm). Plots of the inhibitor concentration vs. the initial cleavage rate were fit to the following equation: y = Vmax*(l-(xn/ (K" + xn))), whereby x = inhibitor concentration, y = initial rate, Vmax = initial rate in the absence of inhibitor, n = slope factor, and K = IC50 for the inhibition curve.
[0382] The results obtained are summarized in Table 2 below. Data presented represent the average value when one or more samples were tested.
TABLE 2
Activity against other MMPs
[0383] Compounds according to the present teachings were tested against various MMPs other than MMP-12, including MMP-I, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP- 13, and MMP- 14. A wide range of activity was observed, for example, when compounds according to the present teachings were tested against MMP-13, IC50 values between 0.3 and > 50000 were measured.
[0384] Variations, modifications, and other implementations of what is described herein will occur to those of ordinary skill in the art without departing from the spirit and the essential characteristics of the present teachings. Accordingly, the scope of the invention is to be defined not by the preceding illustrative description but instead by the following claims, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced herein.

Claims

What is claimed is:
1. A compound of formula I:
I, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein:
R1 is an N-linked, free carboxyl or carboxyl-protected, natural or non-natural amino acid, or an N-linked amino acid derivative; R2 and R3 independently are a) H, b) oxo, c) -OR8, d) -S(O)mR8, e) -S(O)mOR8, f) -S(O)mNR8R9, g) -C(O)R8, h) -C(O)OR8, i) -C(O)NR8R9, j) -C(S)OR8, k) -C(S)R8, 1) -C(S)NR8R9, m) -C(NR8)NR8R9, n) a C1-10 alkyl group, o) a C2-Io alkenyl group, p) a C2-I0 alkynyl group, q) a Ci-I0 haloalkyl group, r) a C3-I0 cycloalkyl group, s) a C6-I4 aryl group, t) a 3-14 membered cycloheteroalkyl group, or u) a 5-13 membered heteroaryl group, wherein each of n) - u) optionally is substituted with 1-4 -Z-R10 groups; or R and R , together with their common nitrogen atom, form a) -N=CR R , b) -N=N-R , c) -N=O, d) a 3-14 membered cycloheteroalkyl group, or e) a 5-13 membered heteroaryl group, wherein each of d) and e) optionally is substituted with 1-4 -Z-R10 groups;
R4 and R5 independently are a) H, b) -CN, c) -NO2, d) halogen, e) -OR8, f) -NR8R9, g) -S(O)mR8, h) -S(O)mOR8, i) -C(O)R8, j) -C(O)OR8, k) -C(O)NR8R9, 1) -C(S)R8, m) -C(S)OR8, n) -C(S)NR8R9, o) a C-10 alkyl group, p) a C2-I0 alkenyl group, q) a C2-10 alkynyl group, r) a C1-10 haloalkyl group, s) a C3-1O cycloalkyl group, t) a C6-I4 aryl group, u) a 3-14 membered cycloheteroalkyl group, or v) a 5-13 membered heteroaryl group, wherein each of o) - v) optionally is substituted with 1-4 -Z-R1 groups; R6 is a) H, b) -S(O)mR8, c) -S(O)mOR8, d) -C(O)R8, e) -C(O)OR8, f) -C(O)NR8R9, g) -C(S)R8, h) -C(S)OR8, i) -C(S)NR8R9J) a CM0 alkyl group, k) a C2-Io alkenyl group, 1) a C2-I0 alkynyl group, or m) a Ci-I0 haloalkyl group, wherein each of j) - m) optionally is substituted with a C6-M aryl group or a 5-13 membered heteroaryl group, wherein each of the C6-H aryl group and the 5-13 membered heteroaryl group optionally is substituted with 1-4 -Z-R10 groups;
R7, at each occurrence, is a) H, b) -CN, c) -NO2, d) halogen, e) oxo, f) -OR8, g) -NR8R9, h) -N(O)R8R9, i) -S(O)111R8, j) -S(O)01O-R8, k) -S(O)mNR8R9, 1) -C(O)R8, m) -C(O)OR8, n) -C(O)NR8R9, o) -C(S)R8, p) -C(S)OR8, q) -C(S)NR8R9, r) -Si(C1-10 alkyl)3, s) a C1-10 alkyl group, t) a C2-10 alkenyl group, u) a C2-I0 alkynyl group, v) a Ci-10 haloalkyl group, w) a C3-10 cycloalkyl group, x) a C6-I4 aryl group, y) a 3-14 membered cycloheteroalkyl group, or z) a 5-13 membered heteroaryl group, wherein each of r) - z) optionally is substituted with 1-4 -Z-R10 groups; R8 and R9, at each occurrence, independently are a) H, b) -OR1 ', c) -SR1 ', d) -S(O)111R", e) -S(O)111-OR11, f) -S(O)111-NR1 1R12, g) -C(O)R1 1, h) -C(O)OR11, i) -C(O)NR11R12J) -C(S)NR1 1R12, k) a C1-10 alkyl group, 1) a C2-I0 alkenyl group, m) a C2-10 alkynyl group, n) a C1-10 alkoxy group,
0) a C1-IO haloalkyl group, p) a C3-I0 cycloalkyl group, q) a C6-14 aryl group, r) a 3-14 membered cycloheteroalkyl group, or s) a 5-13 membered heteroaryl group, wherein each of k) - s) optionally is substituted with 1-4
-Z-R10 groups;
R10, at each occurrence, is a) halogen, b) -CN, c) -NO2, d) oxo, e) -O-Z-R1 ', f) -NR1 '-Z-R12, g) -N(O)R1 '-Z-R12, h) -S(O)111R1 ',
1) -S(O)111O-Z-R1 ', j) -S(O)111NR1 '-Z-R12, k) -C(O)R1 ', 1) -C(O)O-Z-R1 ', m) -C(0)NR"-Z-R12, n) -C(S)NRπ-Z-R12, O) -Si(C1-I0 alkyl)3, p) a CM0 alkyl group, q) a C2-I0 alkenyl group, r) a C2-I0 alkynyl group, s) a Ci-10 haloalkyl group, t) a C3-10 cycloalkyl group, u) a C6-H aryl group, v) a 3-14 membered cycloheteroalkyl group, or w) a 5-13 membered heteroaryl group, wherein each of o) - w) optionally is substituted with 1-4 R13 groups; R1 ' and R12, at each occurrence, independently are a) H, b) -OH, c) -SH, d) -S(O)2OH, e) -C(O)OH, f) -C(O)NH2, g) -C(S)NH2, h) -OC1- 10 alkyl, i) -S(OV-C1-10 alkyl, j) -S(O)m-OC1-10 alkyl, k) -C(O)-C1-10 alkyl, 1) -C(O)-OC1-10 alkyl, m) -C(S)N(C1-10 alkyl)2, n) -C(S)NH-C1-10 alkyl, o) -C(O)NH-C1-10 alkyl, p) -C(O)N(C-10 alkyl)2, q) a C1-10 alkyl group, r) a C2-I0 alkenyl group, s) a C2-I0 alkynyl group, t) a CMO alkoxy group, u) a C1-I0 haloalkyl group, v) a C3-Io cycloalkyl group, w) a C6-14 aryl group, x) a 3-14 membered cycloheteroalkyl group, or y) a 5-13 membered heteroaryl group, wherein each of h) - y) optionally is substituted with 1-4 -R13 groups; R13, at each occurrence, is a) halogen, b) -CN, c) -NO2, d) oxo, e) -OH, f) -NH2, g) -NH(C1-10 alkyl), h) -N(C1-10 alkyl)2, i) -S(O)111H, j) -S(O)111-C1-10 alkyl, k) -S(O)2OH, 1) -S(O)1n-OC10 alkyl, m) -S(O)111NH2, n) -S(O)111NH(C1-1O alkyl), o) -S(O)01N(C1-10 alkyl)2, p) -CHO, q) -C(O)-Ci-10 alkyl, r) -C(O)OH, s) -C(O)-OC1-10 alkyl, t) -C(O)NH2, u) -C(O)NH-C1-10 alkyl, v) -C(O)N(C1-10 alkyl)2, w) -C(S)NH2, x) -C(S)NH-C1-I0 alkyl, y) -C(S)N(C1-10 alkyl)2, z) -Si(C1-10 alkyl)3, aa) a CMO alkyl group, ab) a C2- io alkenyl group, ac) a C2- io alkynyl group, ad) a CMO alkoxy group, ae) a C1-10 haloalkyl group, af) a C3-10 cycloalkyl group, ag) a C6-14 aryl group, ah) a 3-14 membered cycloheteroalkyl group, or ai) a 5-13 membered heteroaryl group; X is O, S, S(O), S(O)2, or NR6; Y is S(O), S(O)2, or C(O); Z, at each occurrence, is a) a divalent Cio alkyl group, b) a divalent C2-1O alkenyl group, c) a divalent C2-10 alkynyl group, d) a divalent C1-10 haloalkyl group, or e) a covalent bond; and m, at each occurrence, is O, 1, or 2.
2. A compound of formula I:
I, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein:
R is an N-linked, free carboxyl or carboxyl-protected, natural or non-natural amino acid, or an N-linked amino acid derivative; R2 and R3 independently are a) H, b) oxo, c) -S(O)01OR8, d) -S(O)111NR8R9, e) -C(O)R8, f) -C(S)OR8, g) -C(S)R8, h) -C(S)NR8R9, i) -C(NR8)NR8R9, j) a Ci-io alkyl group, k) a C2-I0 alkenyl group, 1) a CMO alkynyl group, m) a Ci-io haloalkyl group, n) a C3-I0 cycloalkyl group, o) a C6-I4 aryl group, p) a 3-14 membered cycloheteroalkyl group, or q) a 5-13 membered heteroaryl group, wherein each of j) - q) optionally is substituted with 1-4 -Z-R10 groups; or
R2 and R3, together with their common nitrogen atom, form a) -N=CR7R7, b) -N=N-R8, or C) -N=O; R4 and R5 independently are a) H, b) -CN, c) -NO2, d) halogen, e) -OR8, f) -NR8R9, g) -S(O)mR8, h) -S(O)01OR8, i) -C(O)R8, j) -C(O)OR8, k) -C(O)NR8R9, 1) -C(S)R8, m) -C(S)OR8, n) -C(S)NR8R9, o) a CM0 alkyl group, p) a C2-Io alkenyl group, q) a C2-I0 alkynyl group, r) a CMO haloalkyl group, s) a C3-I0 cycloalkyl group, t) a C6-H aryl group, u) a 3-14 membered cycloheteroalkyl group, or v) a 5-13 membered heteroaryl group, wherein each of o) - v) optionally is substituted with 1-4 -Z-R10 groups; R6 is a) H, b) -S(O)mR8, c) -S(O)01OR8, d) -C(O)R8, e) -C(O)OR8, f) -C(O)NR8R9, g) -C(S)R8, h) -C(S)OR8, i) -C(S)NR8R9J) a C1-10 alkyl group, k) a C2-10 alkenyl group, 1) a C2-10 alkynyl group, or m) a Ci-I0 haloalkyl group, wherein each of j) - m) optionally is substituted with a C6-I4 aryl group or a 5-13 membered heteroaryl group, wherein each of the C6-J4 aryl group and the 5-13 membered heteroaryl group optionally is substituted with 1-4 -Z-R10 groups; R7, at each occurrence, is a) H, b) -CN, c) -NO2, d) halogen, e) oxo, f) -OR8, g) -NR8R9, h) -N(O)R8R9, i) -S(O)mR8, j) -S(O)111O-R8, k) -S(O)01NR8R9, 1) -C(O)R8, m) -C(O)OR8, n) -C(O)NR8R9, o) -C(S)R8, p) -C(S)OR8, q) -C(S)NR8R9, r) -Si(C-10 alkyl)3, s) a Ci-I0 alkyl group, t) a C2-I0 alkenyl group, u) a C2- io alkynyl group, v) a C MO haloalkyl group, w) a C3-Io cycloalkyl group, x) a C6-H aryl group, y) a 3-14 membered cycloheteroalkyl group, or z) a 5-13 membered heteroaryl group, wherein each of r) - z) optionally is substituted with 1-4 -Z-R10 groups; R8 and R9, at each occurrence, independently are a) H, b) -OR1 ', c) -SR1 ', d) -S(O)111R1 ', e) -S(O)111-OR1 \ f) -S(O)111-NR1 1R12, g) -C(O)R1 ', h) -C(O)OR11, i) -C(O)NR1 1R12J) -C(S)NR1 1R12, k) a CM0 alkyl group, 1) a C2-10 alkenyl group, m) a C2-I0 alkynyl group, n) a C MO alkoxy group, o) a CMO haloalkyl group, p) a C3-I0 cycloalkyl group, q) a C6-I4 aryl group, r) a 3-
14 membered cycloheteroalkyl group, or s) a 5-13 membered heteroaryl group, wherein each of k) - s) optionally is substituted with 1-4 -Z-R1 groups; R10, at each occurrence, is a) halogen, b) -CN, c) -NO2, d) oxo, e) -O-Z-R1 1, f) -NRπ-Z-R12, g) -N(O)R1 '-Z-R12, h) -S(O)111R11, i) -S(O)111O-Z-R1 1J) -S(O)111NR1 '-Z-R12, k) -C(O)R11, 1) -C(O)O-Z-R1 1, m) -C(O)NR1 '-Z-R12, n) -C(S)NR1 '-Z-R12, o) -Si(C1-10 alkyl)3, p) a C1-10 alkyl group, q) a C2-I0 alkenyl group, r) a C2-I0 alkynyl group, s) a CM0 haloalkyl group, t) a C3-10 cycloalkyl group, u) a C6- π aryl group, v) a 3-14 membered cycloheteroalkyl group, or w) a 5-13 membered heteroaryl group, wherein each of o) - w) optionally is substituted with 1-4 R13 groups; R11 and R12, at each occurrence, independently are a) H, b) -OH, c) -SH, d) -S(O)2OH, e) -C(O)OH, f) -C(O)NH2, g) -C(S)NH2, h) -S(O)111-CM O alkyl, i) -S(O)111-OCMO alkyl J) -OCI- 10 alkyl, k) -C(O)-C1-10 alkyl, 1) -C(O)-OCL 10 alkyl, m) -C(S)N(C1-10 alkyl)2, n) -C(S)NH-C1-IO alkyl, o) -C(0)NH-CMO alkyl, p) -C(O)N(CM0 alkyl)2, q) a CLIO alkyl group, r) a C2-I0 alkenyl group, s) a C2-I0 alkynyl group, t) a CMO alkoxy group, u) a CM0 haloalkyl group, v) a C3-1O cycloalkyl group, w) a C6-I4 aryl group, x) a 3-14 membered cycloheteroalkyl group, or y) a 5- 13 membered heteroaryl group, wherein each of h) - y) optionally is substituted with 1-4 -R13 groups;
R13, at each occurrence, is a) halogen, b) -CN, c) -NO2, d) oxo, e) -OH, f) -NH2, g) -NH(C10 alkyl), h) -N(C1-10 alkyl)2, i) -S(O)01H, j) -S(O)01-C1-Io alkyl, k) -S(O)2OH, 1) -S(O)111-OC1-1O alkyl, m) -S(O)01NH2, n) -S(O)111NH(C1-1O alkyl), o) -S(O)111N(C1-10 alkyl)2, p) -CHO, q) -C(O)-C1-10alkyl, r) -C(O)OH, s) -C(O)-OC1-10alkyl, t) -C(O)NH2, u)-C(O)NH-C1-IO alkyl, v) -C(O)N(C1-10 alkyl)2, w)-C(S)NH2, x) -C(S)NH-C1-10 alkyl, y) -C(S)N(CM0 alkyl)2, z) -Si(C1-10 alkyl)3, aa) a Ci-io alkyl group, ab) a C2-I0 alkenyl group, ac) a C2-10 alkynyl group, ad) a Ci-io alkoxy group, ae) a Ci-I0 haloalkyl group, af) a C3-I0 cycloalkyl group, ag) a C6-I4 aryl group, ah) a 3-14 membered cycloheteroalkyl group, or ai) a 5-13 membered heteroaryl group;
X is O, S, S(O), S(O)2, or NR6; Y is S(O), S(O)2, or C(O);
Z, at each occurrence, is a) a divalent Ci-io alkyl group, b) a divalent C2-I0 alkenyl group, c) a divalent C2-I0 alkynyl group, d) a divalent C1-Io haloalkyl group, or e) a covalent bond; and m, at each occurrence, is 0, 1, or 2.
3. The compound of claim 2, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R2 and R3 independently are selected from H, oxo, -C(O)R , a Ci-io alkyl group, a C2-I0 alkenyl group, a C2-I0 alkynyl group, and a C3-I0 cycloalkyl group, wherein each of the Ci-I0 alkyl groups, the C2-I0 alkenyl group, the C2-io alkynyl group, and the C3-io cycloalkyl group optionally is substituted with 1-4 -Z-R10 groups.
4. The compound of claim 2, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R2 and R independently are selected from H, oxo, -C(O)CH3, -C(O)CH2CH3, -C(O)CH(CH3)2, a methyl group, and an ethyl group.
5. The compound of claim 2, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R and R , together with their common nitrogen atom, form -N=CR7R7, wherein R7, at each occurrence, is H, halogen, -OR8, -NR R , a do alkyl group, a C2-io alkenyl group, a C2-io alkynyl group, a
Ci-IO haloalkyl group, a C3-I0 cycloalkyl group, a C6-I4 aryl group, a 3-14 membered cycloheteroalkyl group, or a 5-13 membered heteroaryl group, and each of the do alkyl group, the C2-io alkenyl group, the C2-io alkynyl group, the Ci-I0 haloalkyl group, the C3-I0 cycloalkyl group, the C6-I4 aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-13 membered heteroaryl group optionally is substituted with 1-4 -Z-R10 groups.
6. The compound of claim 2, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R2 and R3, together with their common nitrogen atom, form -N=CHR7, wherein R7 is -NH2, -NH(Ci-I0 alkyl), or -N(C1-10 alkyl)2.
7. The compound of claim 2, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein -NR2R3 is -NH2, -NO2, -NHC(O)CH3,
-N(CH2CH2OH)C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)2, -NHCH2CH2OH, -NHCH2CH2Cl, or -N=CHN(CH3)2.
8. A compound or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein the compound is
(R)-2-(7-aminodibenzo[b,d]furan-2-sulfonamido)-3-methyl-butanoic acid, (S)-2-(7-aminodibenzo[b,d]furan-2-sulfonamido)-3-methyl-butanoic acid, (S)-2-(8-aminodibenzo[b,d]furan-3-sulfonamido)-3-methyl-butanoic acid, (S)-2-(8-(diethylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methyl- butanoic acid,
(S)-2-(8-(ethylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methyl- butanoic acid,
(S,E)-2-(8-((dimethylamino)methyleneamino)dibenzo[b,d]furan-3- sulfonamido)-3-methyl-butanoic acid, (R)-3-methyl-2-(7-(4-(trifluoromethyl)thiazol-2- ylamino)dibenzo[b,d]furan-2-sulfonamido)butanoic acid, (S)-2-(7-aminodibenzo[b,d]furan-3-sulfonamido)-3-methyl-butanoic acid, (S)-2-(7-(2-chloroethylamino)dibenzo[b,d]furan-3-sulfonamido)-3- methyl-butanoic acid,
(S)-2-(7-(N-(2-hydroxyethyl)acetamido)dibenzo[b,d]furan-3- sulfonamido)-3-methyl-butanoic acid,
(S)-2-(8-bromo-7-nitrodibenzo[b,d]furan-3-sulfonamido)-3-methyl- butanoic acid,
(S)-3-methyl-2-(7-nitrodibenzo[b,d]furan-3-sulfonamido)butanoic acid, (S)-2-(7-amino-8-bromodibenzo[b,d]furan-3-sulfonamido)-3-methyl- butanoic acid,
(R)-3-methyl-2-(7-nitrodibenzo[b,d]furan-3-sulfonamido)butanoic acid, (S)-2-(7-(ethylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methyl- butanoic acid,
(S)-2-(7-(ethyl(methyl)amino)dibenzo [b,d] furan-3 -sulfonamido)-3 - methyl-butanoic acid,
(S)-3-methyl-2-(7-(benzyl(methyl)amino)dibenzo[b,d]thiophene-3- sulfonamido)butanoic acid, or
(S)-3-methyl-2-(7-(methylamino)dibenzo[b,d]thiophene-3- sulfonamido)butanoic acid. A compound of formula I:
I, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein:
R1 is an N-linked, free carboxyl or carboxyl-protected, natural or non-natural amino acid, or an N-linked amino acid derivative; R2 is a) -C(O)OR8 or b) -C(O)NR8R9;
R3 is a) H, b) -S(O)mR8, c) -S(O)mOR8, d) -S(O)01NR8R9, e) -C(O)R8, f) -C(S)OR8, g) -C(S)R8, h) -C(S)NR8R9, i) -C(NR8)NR8R9, j) a C1-10 alkyl group, k) a d-io alkenyl group, 1) a C2- io alkynyl group, m) a C1-I0 haloalkyl group, n) a C3-I0 cycloalkyl group, o) a C6-I4 aryl group, p) a 3-14 membered cycloheteroalkyl group, or q) a 5-13 membered heteroaryl group, wherein each of j) - q) optionally is substituted with 1-4 -Z-R10 groups; or
O O R3 and the R8 portion of R2, taken together with N X ° or N X N'R9 to which they are attached, form a 3-14 membered cyclic urea group or a 3-14 membered cyclic carbamate group, each of which optionally is substituted with 1-4 -Z-R10 groups; R4 and R5 independently are a) H, b) -CN, c) -NO2, d) halogen, e) -OR8, f) -NR8R9, g) -S(O)01R8, h) -S(O)01OR8, i) -C(O)R8, j) -C(O)OR8, k) -C(O)NR8R9, 1) -C(S)R8, m) -C(S)OR8, n) -C(S)NR8R9, o) a C1-10 alkyl group, p) a C2-10 alkenyl group, q) a C2-10 alkynyl group, r) a C1-10 haloalkyl group, s) a C3-14 cycloalkyl group, t) a C6-14 aryl group, u) a 3-14 membered cycloheteroalkyl group, or v) a 5-13 membered heteroaryl group, wherein each of o) - v) optionally is substituted with 1-4 -Z-R10 groups;
R6 is a) H, b) -S(O)mR8, c) -S(O)111OR8, d) -C(O)R8, e) -C(O)OR8, f) -C(O)NR8R9, g) -C(S)R8, h) -C(S)OR8, i) -C(S)NR8R9J) a C1-10 alkyl group, k) a C2-Io alkenyl group, 1) a C2-10 alkynyl group, or m) a Ci-I0 haloalkyl group, wherein each of j) - m) optionally is substituted with a C6-I4 aryl group or a 5-13 membered heteroaryl group, wherein each of the C6-I4 aryl group and the 5-13 membered heteroaryl group optionally is substituted with 1-4 -Z-R10 groups;
R8 and R9, at each occurrence, independently are a) H, b) -OR11, c) -SR1 1, d) -S(O)1nR11, e) -S(O)n-OR", f) -S(O)111-NR1 1R12, g) -C(O)R1 1, h) -C(O)OR", i) -C(O)NR11R12J) -C(S)NR1 1R12, k) a CMo alkyl group, 1) a C2-I0 alkenyl group, m) a C2-I0 alkynyl group, n) a CM0 alkoxy group, o) a Ci-IO haloalkyl group, p) a C3-I0 cycloalkyl group, q) a C6-I4 aryl group, r) a 3- 14 membered cycloheteroalkyl group, or s) a 5-13 membered heteroaryl group, wherein each of k) - s) optionally is substituted with 1-4 -Z-R10 groups;
R10, at each occurrence, is a) halogen, b) -CN, c) -NO2, d) oxo, e) -O-Z-R", f) -NR1 '-Z-R12, g) -N(O)R1 '-Z-R12, h) -S(O)1nR1 ', i) -S(O)01O-Z-R1 ', j) -S(O)111NR1 '-Z-R12, k) -C(O)R1 ', 1) -C(O)O-Z-R1 1, m) -C(O)NR1 '-Z-R12, n) -C(S)NR1 '-Z-R12, o) -Si(Ci0 alkyl)3, p) a C1-I0 alkyl group, q) a C2-I0 alkenyl group, r) a C2-I0 alkynyl group, s) a Ci-I0 haloalkyl group, t) a C3-I0 cycloalkyl group, u) a C6-H aryl group, v) a 3-14 membered cycloheteroalkyl group, or w) a 5-13 membered heteroaryl group, wherein each of o) - w) optionally is substituted with 1-4 R13 groups; R1 ' and R12, at each occurrence, independently are a) H, b) -OH, c) -SH, d) -S(O)2OH, e) -C(O)OH, f) -C(O)NH2, g) -C(S)NH2, h) -S(0)m-C,,,o alkyl, i) -S(O)111-OC1-10 alkyl, j) -OC1-10 alkyl, k) -C(O)-C1-10 alkyl, 1) -C(O)-OC1-10 alkyl, m) -C(S)N(C1-10 alkyl)2, n) -C(S)NH-C1-10 alkyl, o) -C(O)NH-Ci-I0 alkyl, p) -C(O)N(C- 10 alkyl)2, q) a Ci-I0 alkyl group, r) a C2-I0 alkenyl group, s) a C2-I0 alkynyl group, t) a
Ci-io alkoxy group, u) a Ci-I0 haloalkyl group, v) a C3-I0 cycloalkyl group, w) a C6-I4 aryl group, x) a 3-14 membered cycloheteroalkyl group, or y) a 5- 13 membered heteroaryl group, wherein each of h) - y) optionally is substituted with 1-4 -R13 groups; R13, at each occurrence, is a) halogen, b) -CN, c) -NO2, d) oxo, e) -OH, f) -NH2, g) -NH(C1-10 alkyl), h) -N(C1-10 alkyl)2, i) -S(O)mH, j) -S(O)01-C1-10 alkyl, k) -S(O)2OH, 1) -S(O)01-OC1-10 alkyl, m) -S(O)01NH2, n) -S(O)mNH(CM0 alkyl), o) -S(O)111N(C1-10 alkyl)2, p) -CHO, q) -C(O)-Ci-10 alkyl, r) -C(O)OH, s) -C(O)-OC M0 alkyl, t) -C(O)NH2, u) -C(O)NH-C1-I0 alkyl, v) -C(O)N(Ci-10 alkyl)2, w) -C(S)NH2, x) -C(S)NH-C1-10 alkyl, y) -C(S)N(C1-10 alkyl)2, z) -Si(C1-I0 alkyl)3, aa) a C1-10 alkyl group, ab) a C2-10 alkenyl group, ac) a C2-10 alkynyl group, ad) a
C1-I0 alkoxy group, ae) a C1-10 haloalkyl group, af) a C3-I0 cycloalkyl group, ag) a C6-I4 aryl group, ah) a 3-14 membered cycloheteroalkyl group, or ai) a 5-13 membered heteroaryl group; X is O, S, S(O), S(O)2, or NR6; Y is S(O), S(O)2, or C(O);
Z, at each occurrence, is a) a divalent C1-1O alkyl group, b) a divalent C2-10 alkenyl group, c) a divalent C2-10 alkynyl group, d) a divalent Ci-I0 haloalkyl group, or e) a covalent bond; and m, at each occurrence, is O, 1, or 2. 10. The compound of claim 9, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R3 is H or a Ci-I0 alkyl group.
11. The compound of claim 9, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R is selected from H, a methyl group, and an ethyl group. 12. The compound of any of claims 9- 11 , or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R2 is -C(O)OR8.
13. The compound of claim 12, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R8 is selected from H, -C(O)R1 ', -C(O)OR1 ', -C(O)NR1 1R12, a Ci-I0 alkyl group, a C2-I0 alkenyl group, a C2-I0 alkynyl group, a Ci-10 haloalkyl group, a C3-I0 cycloalkyl group, a C6-H aryl group, a
3-14 membered cycloheteroalkyl group, and a 5-13 membered heteroaryl group, wherein each of the Ci-10 alkyl group, the C2- io alkenyl group, the C2-io alkynyl group, the Ci-I0 haloalkyl group, the C3-I0 cycloalkyl group, the C6-I4 aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-13 membered heteroaryl group optionally is substituted with 1-4 -Z-R10 groups.
14. The compound of claim 12, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R8 is selected from H, a C1-Io alkyl group, a C2-I0 alkenyl group, a C2- io alkynyl group, and a C6-I4 aryl group, wherein each of the Ci-io alkyl group, the C2-I0 alkenyl group, the C2- io alkynyl group, and the C6-I4 aryl group optionally is substituted with 1-4 -Z-R10 groups.
15. The compound of claim 12, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R8 is selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a butyl group, a hexyl group, and a butynyl group, each of which optionally is substituted with 1-4 groups independently selected from a halogen, -S(O)1nR1 ' , -S(O)01O-Z-R1 ' ,
-S(O)01NR1 '-Z-R12, -C(O)R", -C(O)O-Z-R1 1, -C(O)NR1 '-Z-R12, a C6-14 aryl group, and a 5-13 membered heteroaryl group.
16. The compound of claim 12, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R8 is selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a butyl group, a hexyl group, a 3-butynyl group, a 4-butynyl group, a 2-fluoroethyl group, a 2- chloroethyl group, a 2-bromoethyl group, a 2-methanesulfonylethyl group, a 3-chloropropyl group, and a benzyl group.
17. The compound of claim 12, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R is a phenyl group optionally substituted with 1-4 groups independently selected from a halogen and a Ci. io alkyl group.
18. The compound of claim 12, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R is selected from a phenyl group, a tolyl group, a fluorophenyl group, and a chlorophenyl group. 19. The compound of any of claims 9-11, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R2 is -C(O)NR8R9.
20. The compound of claim 19, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R and R independently are selected from H, a CM0 alkyl group, a C2-I0 alkenyl group, a C2-I0 alkynyl group, a C3.10 cycloalkyl group, a C6-I4 aryl group, a 3-14 membered cycloheteroalkyl group, and a 5- 13 membered heteroaryl group, and each of the Ci-I0 alkyl group, the C2-I0 alkenyl group, the C2-I0 alkynyl group, the C3- 10 cycloalkyl group, the C6-^ aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-13 membered heteroaryl group optionally is substituted with 1-4 -Z-R10 groups.
21. The compound of claim 19 or 20, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R9 is H or a methyl group.
22. The compound of any of claims 19-21, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R8 is selected from H, a CMO alkyl group, a C3-Io cycloalkyl group, a C6-I4 aryl group, and a 5-13 membered heteroaryl group, and each of the Ci.io alkyl group, the C3-I0 cycloalkyl group, the C6-I4 aryl group, and the 5-13 membered heteroaryl group optionally is substituted with 1-4 -Z-R10 groups.
23. The compound of claim 22, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R is selected from H, a methyl group, an ethyl group, an isopropyl group, a cyclopentyl group, a benzyl group, a fluorobenzyl group, a phenethyl group, a thienylmethyl group, and a thienylethyl group.
24. The compound of claim 22, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R8 is a phenyl group or a 5-13 heteroaryl group, each of which optionally is substituted with 1-4 -Z-R10 groups.
25. The compound of claim 22, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R is selected from a phenyl group, a 2,3- dihydrobenzo[b][l,4]dioxinyl group, a thienyl group, a pyridyl group, and an isoxazolyl group, and each of the phenyl group, the thienyl group, the pyridyl group, and the isoxazolyl group optionally is substituted with 1-3 groups independently selected from halogen, -0-Z-R" , -NR1 '-Z-R12, a CMO alkyl group, and a Ci-I0 haloalkyl group.
26. The compound of any of claims 9, 12, and 19, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R3 and the R8 portion of R2,
O O taken together with N υ or N N to which they are attached, form a 5-12 membered cyclic urea group or a 5-12 membered cyclic carbamate group, each of which optionally is substituted with 1-4 -Z-R10 groups.
27. The compound of claim 26, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R9 is H or a methyl group.
28. The compound of claim 26 or 27, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein the 5-12 membered cyclic urea group or the 5-12 membered cyclic carbamate group is 5-membered cyclic urea group, a 6-membered cyclic urea group, a 5-membered cyclic carbamate group, or a 6-membered cyclic carbamate group.
29. A compound or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein the compound is
(R)-2-(7-methoxycarbonylamino-dibenzofuran-2-sulfonylamino)-3-methyl- butyric acid,
(R)-3 -methyl-2-(7-(propoxycarbonylamino)dibenzo [b,d] furan-2- sulfonamido)butanoic acid,
(R)-2-(7-(isopropoxycarbonylamino)dibenzo[b,d]furan-2-sulfonamido)-3- methyl-butanoic acid,
(R)-3-methyl-2-(7-(phenoxycarbonylamino)dibenzo[b,d]furan-2- sulfonamido)butanoic acid,
(R)-2-(7-(3-ethylureido)dibenzo[b,d]furan-2-sulfonamido)-3- methylbutanoic acid,
(R)-2-(7-(3-(4-fluoro-benzyl)-ureido)-dibenzofuran-2-sulfonylamino)-3- methyl-butyric acid,
(R)-2-(7-(3-cyclopentylmethylureido)-dibenzofuran-2-sulfonylamino)-3- methyl-butyric acid,
(R)-2-(7-(3-isopropylureido)-dibenzofuran-2-sulfonylamino)-3-methyl- butyric acid,
(R)-3-methyl-2-(7-(3-(3,4,5-trimethoxy-phenyl)-ureido)-dibenzofuran-2- sulfonylamino)-butyric acid,
(R)-2-(7-(3-(3,4-difluorophenyl)ureido)dibenzo[b,d]furan-2-sulfonamido)-
3-methyl-butanoic acid,
(R)-2-(7-(3 -(4-(dimethylamino)phenyl)ureido)dibenzo [b,d] furan-2- sulfonamido)-3-methyl-butanoic acid,
(R)-3-methyl-2-(7-(3-(3-phenoxyphenyl)ureido)dibenzo[b,d]furan-2- sulfonamido)-butanoic acid, (R)-3-methyl-2-(7-ureidodibenzo[b,d]furan-2-sulfonamido)butanoic acid,
(R)-3-methyl-2-(7-(3-(4-
(trifluoromethoxy)phenyl)ureido)dibenzo[b,d]furan-2-sulfonamido)butanoic acid,
(R)-2-(7-(3 -(2 ,6-dichloropyridin-4-yl)ureido)dibenzo [b,d] furan-2- sulfonamido)-3-methyl-butanoic acid,
(R)-3 -methyl-2-(7-(3 -(2-(thiophen-2-yl)ethyl)ureido)dibenzo [b,d] furan-2- sulfonamido)butanoic acid,
(S)-2-(7-(3-ethylureido)dibenzo[b,d]furan-2-sulfonamido)-3-methyl- butanoic acid,
(S)-2-(7-methoxycarbonylamino-dibenzo[b,d]thiophene-2-sulfonamido)-3- methyl-butanoic acid,
(R)-2-(7-(methoxycarbonylamino)dibenzo[b,d]thiophene-2-sulfonamido)-3- methyl-butanoic acid,
(S)-2-(8-(isobutoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3- methyl-butanoic acid,
(S)-2-(8-((2-chloroethoxy)carbonylamino)dibenzo[b,d]furan-3- sulfonamido)-3-methyl-butanoic acid,
(S)-2-(8-((2-bromoethoxy)carbonylamino)dibenzo[b,d]furan-3- sulfonamido)-3-methyl-butanoic acid,
(S)-2-(8-(isopropoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3- methyl-butanoic acid,
(S)-2-(8-((4-fluorophenoxy)carbonylamino)dibenzo [b,d] furan-3 - sulfonamido)-3-methyl-butanoic acid,
(S)-2-(8-((2-chlorophenoxy)carbonylamino)dibenzo[b,d]furan-3- sulfonamido)-3-methyl-butanoic acid,
(S)-2-(8-(but-2-ynyloxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-
3-methyl-butanoic acid,
(S)-3-methyl-2-(8-(p-tolyloxycarbonylamino)dibenzo[b,d]furan-3- sulfonamido)butanoic acid,
(S)-3-methyl-2-(8-(phenoxycarbonylamino)dibenzo[b,d]furan-3- sulfonamido)butanoic acid,
(S)-2-(8-(benzyloxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3- methyl-butanoic acid,
(S)-2-(8-(hexyloxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3- methyl-butanoic acid,
(S)-2-(8-((2-fluoroethoxy)carbonylamino)dibenzo [b,d] furan-3 - sulfonamido)-3-methyl-butanoic acid,
(S)-2-(8-(methoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3- methyl-butanoic acid,
(S)-2-(8-(ethoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3- methyl-butanoic acid,
(S)-3 -methyl-2-(8-propoxycarbonylamino)dibenzo [b,d] furan-3 - sulfonamidobutanoic acid,
(S)-2-(8-(butoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3- methyl-butanoic acid,
(S)-2-(8-((but-3-ynyloxy)carbonylamino)dibenzo[b,d]furan-3- sulfonamido)-3-methyl-butanoic acid, (S)-2-(8-(3-(3,5-dimethylisoxazol-4-yl)ureido)dibenzo[b,d]furan-3- sulfonamido)-3-methyl-butanoic acid,
(S)-3 -methyl-2-(8-(3 -thiophen-3 -ylureido)dibenzo [b,d] furan-3 - sulfonamido)butanoic acid,
(S)-3-methyl-2-(8-(3-(3,4,5-trimethoxyphenyl)ureido)dibenzo[b,d]furan-3- sulfonamido)butanoic acid,
(S)-2-(8-(3-(3,4-difluorophenyl)ureido)dibenzo[b,d]furan-3-sulfonamido)-
3-methyl-butanoic acid, /
(S)-3-methyl-2-(8-(3-(3-phenoxyphenyl)ureido)dibenzo[b,d]furan-3- sulfonamido)butanoic acid,
(S)-3-methyl-2-(8-ureidodibenzo[b,d]furan-3-sulfonamido)butanoic acid,
(S)-2-(8-(3-(2,6-dichloropyridin-4-yl)ureido)dibenzo[b,d]furan-3- sulfonamido)-3-methyl-butanoic acid,
(S)-2-(8-(3 -(4-(dimethylamino)phenyl)ureido)dibenzo [b,d] furan-3 - sulfonamido)-3 -methyl -butanoic acid,
(S)-3-methyl-2-(8-(3-(2-(thiophen-2-yl)ethyl)ureido)dibenzo[b,d]furan-3- sulfonamido)butanoic acid,
(S)-3-methyl-2-(8-(3-(4-
(trifluoromethoxy)phenyl)ureido)dibenzo[b,d]furan-3-sulfonamido)butanoic acid,
(S)-2-(8-(3-cyclopentylureido)dibenzo[b,d]furan-3-sulfonamido)-3-methyl- butanoic acid,
(S)-2-(8-(3-(4-fluorobenzyl)ureido)dibenzo[b,d]furan-3-sulfonamido)-3- methyl-butanoic acid,
(S)-2-(8-(methoxycarbonylamino)dibenzo[b,d]thiophene-3-sulfonamido)-3- methyl-butanoic acid,
(R)-2-(8-(methoxycarbonylamino)dibenzo[b,d]thiophene-3-sulfonamido)-3- methyl-butanoic acid,
(S)-2-(7-(3-cyclopentylureido)dibenzo[b,d]thiophene-3-sulfonamido)-3- methyl-butanoic acid,
(S)-3-methyl-2-(7-(3-(2-(thiophen-2-yl)ethyl)ureido)dibenzo[b,d]thiophene-
3-sulfonamido)butanoic acid,
(S)-2-(7-(3-(4-fluorophenyl)ureido)dibenzo[b,d]thiophene-3-sulfonamido)-
3-methyl-butanoic acid,
(S)-3-methyl-2-(7-(3-phenethylureido)dibenzo[b,d]thiophene-3- sulfonamido)butanoic acid,
(S)-2-(7-(3-benzylureido)dibenzo[b,d]thiophene-3-sulfonamido)-3-methyl- butanoic acid,
(S)-2-(7-(3-(4-fluorobenzyl)ureido)dibenzo[b,d]thiophene-3-sulfonamido)-
3-methyl-butanoic acid,
(S)-3-methyl-2-(7-(3-p-tolylureido)dibenzo[b,d]thiophene-3- sulfonamido)butanoic acid,
(S)-3-methyl-2-(7-(3-(3,4,5- trimethoxyphenyl)ureido)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid,
(S)-2-(7-(3-ethylureido)dibenzo[b,d]thiophene-3-sulfonamido)-3-methyl- butanoic acid,
(S)-2-(7-(3-(3,4-difluorophenyl)ureido)dibenzo[b,d]thiophene-3- sulfonamido)-3 -methyl-butanoic acid,
(S)-3-methyl-2-(7-(3-(4-
(trifluoromethyl)phenyl)ureido)dibenzo[b,d]thiophene-3- sulfonamido)butanoic acid,
(S)-2-(7-(3-(2,3-dihydrobenzo[b][l,4]dioxin-6- yl)ureido)dibenzo[b,d]thiophene-3-sulfonamido)-3-methyl-butanoic acid,
(S)-3-methyl-2-(7-(3-phenylureido)dibenzo[b,d]thiophene-3- sulfonamido)butanoic acid,
(S)-2-(7-(3-(4-(dimethylamino)phenyl)ureido)dibenzo[b,d]thiophene-3- sulfonamido)-3 -methyl-butanoic acid,
(S)-3-methyl-2-(7-(3 -pyridin-4-ylureido)dibenzo [b,d] thiophene-3 - sulfonamido)butanoic acid,
(S)-2-(7-(3-(3,5-dimethylisoxazol-4-yl)ureido)dibenzo[b,d]thiophene-3- sulfonamido)-3 -methyl-butanoic acid,
(S)-2-(7-(methoxycarbonylamino)dibenzo[b,d]thiophene-3-sulfonamido)-3- methyl-butanoic acid,
(S)-2-(7-(ethoxycarbonylamino)dibenzo[b,d]thiophene-3-sulfonamido)-3- methyl-butanoic acid,
(S)-2-(7-(isobutoxycarbonylamino)dibenzo[b,d]thiophene-3-sulfonamido)-
3 -methyl-butanoic acid,
(S)-2-(6-chloro-7-(methoxycarbonylamino)dibenzo[b,d]thiophene-3- sulfonamido)-3 -methyl-butanoic acid,
(S)-2-(7-(isopropoxycarbonylamino)dibenzo[b,d]thiophene-3-sulfonamido)-
3 -methyl-butanoic acid,
(S)-3-methyl-2-(7-(p-tolyloxycarbonylamino)dibenzo[b,d]thiophene-3- sulfonamido)butanoic acid,
(S)-2-(7-((4-fluorophenoxy)carbonylamino)dibenzo[b,d]thiophene-3- sulfonamido)-3 -methyl-butanoic acid,
(S)-3-methyl-2-(7-(phenoxycarbonylamino)dibenzo[b,d]thiophene-3- sulfonamido)butanoic acid,
(S)-2-(7-((but-3-ynyloxy)carbonylamino)dibenzo[b,d]thiophene-3- sulfonamido)-3 -methyl-butanoic acid,
(S)-3-methyl-2-(7-((2-
(methylsulfonyl)ethoxy)carbonylamino)dibenzo [b,d] thiophene-3 - sulfonamido)butanoic acid,
(S)-2-(7-(benzyloxycarbonylamino)dibenzo[b,d]thiophene-3-sulfonamido)-
3-methyl-butanoic acid,
(S)-3-methyl-2-(8-(2-oxooxazolidin-3-yl)dibenzofuran-3- sulfonamido)butanoic acid,
(S)-2-(8-(ethyl(methoxycarbonyl)amino)dibenzo[b,d]furan-3-sulfonamido)-
3 -methyl-butanoic acid,
(R)-3-methyl-2-(7-(2-oxooxazolidin-3-yl)dibenzo[b,d]furan-2- sulfonamido)butanoic acid,
(S)-2-(8-((3-chloropropoxy)carbonylamino)dibenzo[b,d]furan-3- sulfonamido)-3-methyl-butanoic acid,
(R)-2-(8 -bromo-7-(methoxycarbonylamino)dibenzo [b,d] furan-2- sulfonamido)-3-methyl-butanoic acid,
(S)-2-(8-bromo-7-(methoxycarbonylamino)dibenzo[b,d]furan-2- sulfonamido)-3-methyl-butanoic acid,
(S)-3 -methyl-2-(7-(2-oxooxazolidin-3 -yl)dibenzo [b,d] furan-3 - sulfonamido)butanoic acid,
(R)-2-(7-(methoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3- methyl-butanoic acid,
(R)-2-(7-(3-(3,4-difluorophenyl)ureido)dibenzo[b,d]furan-3-sulfonamido)-
3-methyl-butanoic acid,
(S)-2-(7-(methoxycarbonylamino)dibenzo[b,d] furan-3 -sulfonamido)-3- methyl-butanoic acid,
(S)-2-(7-((2-fluoroethoxy)carbonylamino)dibenzo[b,d]furan-3- sulfonamido)-3 -methyl -butanoic acid,
(S)-2-(7-((but-2-ynyloxy)carbonylamino)dibenzo[b,d]furan-3- sulfonamido)-3 -methyl-butanoic acid,
(S)-2-(7-((4-fluorophenoxy)carbonylamino)dibenzo[b,d]furan-3- sulfonamido)-3 -methyl-butanoic acid,
(S)-3-methyl-2-(7-(3-thiophen-3-ylureido)dibenzo[b,d]furan-3- sulfonamido)butanoic acid,
(S)-3 -methyl-2-(7-(3 -(2-(thiophen-2-yl)ethyl)ureido)dibenzo [b,d] furan-3 - sulfonamido)butanoic acid,
(S)-3-methyl-2-(7-ureidodibenzo[b,d] furan-3 -sulfonamido)butanoic acid,
(S)-2-(7-(3-(3,4-difluorophenyl)ureido)dibenzo[b,d]furan-3-sulfonamido)-
3-methyl-butanoic acid,
(S)-2-(7-(ethyl(methoxycarbonyl)amino)dibenzo[b,d]furan-3-sulfonamido)-
3-methyl-butanoic acid,
(S)-3-methyl-2-(8-(2-oxo-l,3-oxazinan-3-yl)dibenzo[b,d]furan-3- sulfonamido)butanoic acid,
(S)-3-methyl-2-(7-(2-oxooxazolidin-3-yl)dibenzo[b,d]thiophene-3- sulfonamido)butanoic acid,
(S)-2-(7-(methoxycarbonyl(methyl)amino)dibenzo[b,d]thiophene-3- sulfonamido)-3-methyl-butanoic acid,
(S)-2-(7-(ethoxycarbonyl(methyl)amino)dibenzo[b,d]thiophene-3- sulfonamido)-3-methyl-butanoic acid,
(S)-2-(7-(isopropoxycarbonyl(methyl)amino)dibenzo[b,d]thiophene-3- sulfonamido)-3 -methyl-butanoic acid,
(S)-2-(7-(((4- fluorophenoxy)carbonyl)(methyl)amino)dibenzo[b,d]thiophene-3- sulfonamido)-3 -methyl-butanoic acid,
(S)-3-methyl-2-(7-(l,3,3-trimethylureido)dibenzo[b,d]thiophene-3- sulfonamido)butanoic acid,
(S)-2-(7-(3 -ethyl- 1 -methylureido)dibenzo [b,d] thiophene-3 -sulfonamido)-3 - methyl-butanoic acid,
(S)-2-(7-(3-benzyl-l-methylureido)dibenzo[b,d]thiophene-3-sulfonamido)-
3 -methyl-butanoic acid,
(S)-2-(7-(3-benzyl-l,3-dimethylureido)dibenzo[b,d]thiophene-3- sulfonamido)-3 -methyl-butanoic acid,
(S)-3-methyl-2-(7-(2-oxoimidazolidin-l-yl)dibenzo[b,d]thiophene-3- sulfonamido)butanoic acid,
(S)-3-methyl-2-(7-(2-oxotetrahydropyrimidin-l(2H)- yl)dibenzo[b,d]thiophene-3-sulfonamido)butanoic acid,
(R)-2-(7-(methoxycarbonylamino)dibenzo[b,d]thiophene-3-sulfonamido)-3- methyl-butanoic acid,
(R)-2-(7-(ethoxycarbonylamino)dibenzo[b,d]thiophene-3-sulfonamido)-3- methyl-butanoic acid,
(R)-2-(7-(3-cyclopentylureido)dibenzo[b,d]thiophene-3-sulfonamido)-3- methyl-butanoic acid, or
(R)-3 -methyl-2-(7-(3 -phenylureido)dibenzo [b,d] thiophene-3 - sulfonamido)butanoic acid.
3.0. A compound of formula I:
I, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein:
R1 is an N-linked, free carboxyl or carboxyl-protected, natural or non-natural amino acid, or an N-linked amino acid derivative; R2 is -S(O)R8 or -SO2R8; R3 is a) H, b) -S(O)mR8, c) -S(O)mOR8, d) -S(O)111NR8R9, e) -C(O)R8, f) -C(S)OR8, g) -C(S)R8, h) -C(S)NR8R9, i) -C(NR8)NR8R9, j) a C-I0 alkyl group, k) a C2-I0 alkenyl group, 1) a C2-Io alkynyl group, m) a Ci-1O haloalkyl group, n) a C3-Io cycloalkyl group, o) a C6-I4 aryl group, p) a 3-14 membered cycloheteroalkyl group, or q) a 5-13 membered heteroaryl group, wherein each of j) - q) optionally is substituted with 1-4 -Z-R10 groups; or
R and the R portion of R , taken together with N and S, to which they are respectively attached, form a 3-14 membered cyclic sulfinamide group or a 3-14 membered cyclic sulfonamide group, each of which optionally is substituted with 1-4 -Z-R10 groups; R4 and R5 independently are a) H, b) -CN, c) -NO2, d) halogen, e) -OR8, f) -NR8R9, g) -S(O)mR8, h) -S(O)01OR8, i) -C(O)R8, j) -C(O)OR8, k) -C(O)NR8R9, 1) -C(S)R8, m) -C(S)OR8, n) -C(S)NR8R9, o) a C1-10 alkyl group, p) a C2-IO alkenyl group, q) a C2- 10 alkynyl group, r) a C MO haloalkyl group, s) a C3-14 cycloalkyl group, t) a C6-I4 aryl group, u) a 3-14 membered cycloheteroalkyl group, or v) a 5-13 membered heteroaryl group, wherein each of o) - v) optionally is substituted with 1-4 -Z-R10 groups; R6 is a) H, b) -S(O)01R8, c) -S(O)111OR8, d) -C(O)R8, e) -C(O)OR8, f) -C(O)NR8R9, g) -C(S)R8, h) -C(S)OR8, i) -C(S)NR8R9, j) a Ci0 alkyl group, k) a C2-)O alkenyl group, 1) a C2-I0 alkynyl group, or m) a C MO haloalkyl group, wherein each of j) - m) optionally is substituted with a C6-14 aryl group or a 5-13 membered heteroaryl group, wherein each of the C6-I4 aryl group and the 5-13 membered heteroaryl group optionally is substituted with 1-4 -Z-R10 groups; R8 and R9, at each occurrence, independently are a) H, b) -OR1 ' , c) -SR1 ' , d) -S(O)111R1 ', e) -S(O)111-OR1 ', f) -S(O)111-NR11R12, g) -C(O)R1 ', h) -C(O)OR1 1, i) -C(O)NR11R12J) -C(S)NR1 1R12, k) a CM0 alkyl group, 1) a C2-Io alkenyl group, m) a C2-I0 alkynyl group, n) a CM0 alkoxy group, o) a CMO haloalkyl group, p) a C3-Io cycloalkyl group, q) a C6-I4 aryl group, r) a 3- 14 membered cycloheteroalkyl group, or s) a 5-13 membered heteroaryl group, wherein each of k) - s) optionally is substituted with 1-4 -Z-R10 groups; R10, at each occurrence, is a) halogen, b) -CN, c) -NO2, d) oxo, e) -0-Z-R1 ', f) -NR1 '-Z-R12, g) -N(O)R1 '-Z-R12, h) -S(O)1nR1 ', i) -S(O)111O-Z-R1 ', j) -S(O)111NR1 '-Z-R12, k) -C(O)R1 ', 1) -C(O)O-Z-R1 ', m) -C(0)NR"-Z-R12, n) -C(S)NR1 '-Z-R12, o) -Si(Ci0 alkyl)3, p) a C1-10 alkyl group, q) a C2-I0 alkenyl group, r) a C2-10 alkynyl group, s) a CM0 haloalkyl group, t) a C3-I0 cycloalkyl group, u) a C6-14 aryl group, v) a 3-14 membered cycloheteroalkyl group, or w) a 5-13 membered heteroaryl group, wherein each of o) - w) optionally is substituted with 1-4 R13 groups;
R11 and R12, at each occurrence, independently are a) H, b) -OH, c) -SH, d) -S(O)2OH, e) -C(O)OH, f) -C(O)NH2, g) -C(S)NH2, h) -S(O)111-C1-1Oalkyl, i) -S(O)111-OC1-10alkyl,j) -OC1-10alkyl, k) -C(O)-CM0alkyl, 1)-C(O)-OC1-10alkyl, m) -C(S)N(Ci-10 alkyl)2, n) -C(S)NH-C1-10 alkyl, o) -C(O)NH-CM0 alkyl, p) -C(O)N(C1-10 alkyl)2, q) a C1-10 alkyl group, r) a C2-1O alkenyl group, s) a C2-I0 alkynyl group, t) a Ci-10 alkoxy group, u) a CM0 haloalkyl group, v) a C3-I0 cycloalkyl group, w) a C6-I4 aryl group, x) a 3-14 membered cycloheteroalkyl group, or y) a 5-13 membered heteroaryl group, wherein each of h) - y) optionally is substituted with 1-4 -R13 groups;
R13, at each occurrence, is a) halogen, b) -CN, c) -NO2, d) oxo, e) -OH, f) -NH2, g) -NH(C1-10 alkyl), h) -N(C1-10 alkyl)2, i) -S(O)1nH, j) -S(0)m-C.-io alkyl, k) -S(O)2OH, 1) -S(O)01-OC1-10 alkyl, m) -S(O)1nNH2, n) -S(0)mNH(C,.,o alkyl), o) -S(O)mN(C,.,0 alkyl)2, p) -CHO, q) -C(O)-C1-10 alkyl, r) -C(O)OH, s) -C(O)-OC1-10 alkyl, t) -C(O)NH2, u) -C(O)NH-C1-10 alkyl, v) -C(O)N(C1-10 alkyl)2, w) -C(S)NH2, x) -C(S)NH-C1-10 alkyl, y) -C(S)N(C1-10 alkyl)2, z) -Si(C1-10 alkyl)3, aa) a
C1-10 alkyl group, ab) a C2-I0 alkenyl group, ac) a C2-I0 alkynyl group, ad) a C1-10 alkoxy group, ae) a C1-10 haloalkyl group, af) a C3-10 cycloalkyl group, ag) a C6-I4 aryl group, ah) a 3-14 membered cycloheteroalkyl group, or ai) a 5-13 membered heteroaryl group; X is O, S, S(O), S(O)2, or NR6;
Y is S(O), S(O)2, or C(O);
Z, at each occurrence, is a) a divalent C1-10 alkyl group, b) a divalent C2-I0 alkenyl group, c) a divalent C2-I0 alkynyl group, d) a divalent Ci-I0 haloalkyl group, or e) a covalent bond; and m, at each occurrence, is O, 1 , or 2.
31. The compound of claim 30, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R is H or -S(O)mR .
32. The compound of claim 30, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R3 is H or a fluorophenylsulfonyl group. 33. The compound of any of claims 30-32, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R2 is -SO2R8.
34. The compound of claim 33, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R8 is selected from H, a CMO alkyl group, a C2-I0 alkenyl group, a C2-10 alkynyl group, a Ci-I0 haloalkyl group, a C3-10 cycloalkyl group, a C6-14 aryl group, a 3-14 membered cycloheteroalkyl group, and a 5-13 membered heteroaryl group, wherein each of the C1-10 alkyl group, the C2-I0 alkenyl group, the C2-I0 alkynyl group, the Ci-I0 haloalkyl group, the C3. i0 cycloalkyl group, the C6-H aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-13 membered heteroaryl group optionally is substituted with 1-4 -Z-R10 groups.
35. The compound of claim 33, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R8 is selected from H, a Ci- I0 alkyl group, a C6-I4 aryl group, and a 5-13 heteroaryl group, wherein each of the Ci-I0 alkyl group, the C6-I4 aryl group and the 5-13 heteroaryl group optionally is substituted with 1-4 -Z-R10 groups.
36. The compound of claim 33, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R8 is selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a butyl group, and a hexyl group, each of which optionally is substituted with 1-4 groups independently selected from a halogen and a Ci.jo haloalkyl group.
37. The compound of claim 33, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R is selected from a methyl group, an ethyl group, an isopropyl group, a 2-chloromethyl group, and a 2-trifluoromethyl group.
38. The compound of claim 33, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R is selected from a phenyl group, a thienyl group, and an isoxazolyl group, each of which optionally is substituted with 1 -3 groups independently selected from a halogen and a C MO alkyl group.
39. The compound of claim 33, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R is selected from a phenyl group, a fluorophenyl group, a dimethylisoxazolyl group, and a dichlorothienyl group.
40. The compound of claim 30, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R3 and the R8 portion of R2, taken together with N and
S, to which they are respectively attached, form a 5-12 membered cyclic sulfinamide group or a 5-12 membered cyclic sulfonamide group, each of which optionally is substituted with 1-4 -Z-R10 groups.
41. The compound of claim 40, wherein the 5-12 membered cyclic sulfinamide group or a 5-12 membered cyclic sulfonamide group is a S- oxoisothiazolidin-2-yl group, a S-oxothiazinan-2-yl group, a S, S- dioxoisothiazolidin-2-yl group, or a S,S-dioxothiazinan-2-yl group.
42. A compound or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein the compound is
(R)-3-methyl-2-(7-(methylsulfonamido)dibenzo[b,d]furan-2- sulfonamido)butanoic acid,
(S)-3 -methyl-2-(7-(methylsulfonamido)dibenzo [b,d] furan-2- sulfonamido)butanoic acid,
(R)-2-(7-(chloromethylsulfonamido)dibenzo[b,d]furan-2-sulfonamido)-3- methyl-butanoic acid,
(R)-3-methyl-2-(7-(l-methylethylsulfonamido)dibenzo[b,d]furan-2- sulfonamido)butanoic acid,
(R)-2-(7-(3,5-dimethylisoxazol-4-yl-sulfonamido)dibenzo[b,d]furan-2- sulfonamido)-3-methyl-butanoic acid,
(R)-3 -methyl-2-(7-(phenylsulfonamido)dibenzo [b,d] furan-2- sulfonamido)butanoic acid,
(S)-3-methyl-2-(7-(methylsulfonamido)dibenzo[b,d]thiophene-2- sulfonamido)butanoic acid,
(R)-3-methyl-2-(7-(methylsulfonamido)dibenzo[b,d]thiophene-2- sulfonamido)butanoic acid,
(S)-3 -methyl-2-(8-(methylsulfonamido)-dibenzo [b,d] furan-3 - sulfonamido)butanoic acid,
(S)-3-methyl-2-(8-(methylsulfonamido)dibenzo[b,d]thiophene-3- sulfonamido)butanoic acid,
(R)-3 -methyl-2-(8-(methylsulfonamido)dibenzo [b,d] thiophene-3 - sulfonamido)butanoic acid,
(S)-3-methyl-2-(8-(2,2,2-trifluoroethylsulfonamido)dibenzo[b,d]furan-3- sulfonamido)butanoic acid,
(S)-2-(8-(4-fluoro-N-(4- fluorophenylsulfonyl)phenylsulfonamido)dibenzo[b,d]furan-3- sulfonamido)-3-methyl-butanoic acid,
(S)-2-(8-(4,5-dichlorothiophene-2-sulfonamido)dibenzo[b,d]furan-3- sulfonamido)-3-methyl-butanoic acid,
N-{[7-(l,l-dioxidoisothiazolidin-2-yl)dibenzo[b,d]thien-3-yl]sulfonyl}-L- valine, or
N-{[7-(l-oxidoisothiazolidin-2-yl)dibenzo[b,d]thien-3-yl]sulfonyl}-L- valine.
43. A compound of formula I:
I, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein: R1 is an N-linked, free carboxyl or carboxyl-protected, natural or non-natural amino acid, or an N-linked amino acid derivative; R and R , together with their common nitrogen atom, form a) a 3-14 membered cycloheteroalkyl group or b) a 5-13 membered heteroaryl group, wherein each of a) and b) optionally is substituted with 1-4 -Z-R10 groups; provided that the 3-14 membered cycloheteroalkyl group is not a 3-14 membered cyclic urea group, a 3-14 membered cyclic carbamate group, a 3- 14 membered cyclic sulfinamide group, or a 3-14 membered cyclic sulfonamide group; R4 and R5 independently are a) H, b) -CN, c) -NO2, d) halogen, e) -OR8, f) -NR8R9, g) -S(O)mR8, h) -S(O)mOR8, i) -C(O)R8, j) -C(O)OR8, k) -C(O)NR8R9, 1) -C(S)R8, m) -C(S)OR8, n) -C(S)NR8R9, o) a Ci-10 alkyl group, p) a C2-I0 alkenyl group, q) a C2-I0 alkynyl group, r) a Ci-I0 haloalkyl group, s) a C3-I4 cycloalkyl group, t) a C6-H aryl group, u) a 3-14 membered cycloheteroalkyl group, or v) a 5-13 membered heteroaryl group, wherein each of o) - v) optionally is substituted with 1-4 -Z-R10 groups; R6 is a) H, b) -S(O)mR8, c) -S(O)mOR8, d) -C(O)R8, e) -C(O)OR8, f) -C(O)NR8R9, g) -C(S)R8, h) -C(S)OR8, i) -C(S)NR8R9, j) a CM0 alkyl group, k) a C2-Io alkenyl group, 1) a C2-I0 alkynyl group, or m) a C MO haloalkyl group, wherein each of j) - m) optionally is substituted with a C6-M aryl group or a 5-13 membered heteroaryl group, wherein each of the C6-H aryl group and the 5-13 membered heteroaryl group optionally is substituted with 1-4 -Z-R10 groups; R8 and R9, at each occurrence, independently are a) H, b) -OR1 1, c) -SR11, d) -S(O)111R1 ', e) -S(O)m-ORu, f) -S(O)111-NR11R12, g) -C(O)R1 1, h) -C(O)OR", 0 -C(O)NR11R12J) -C(S)NR1 1R12, k) a Ci0 alkyl group, 1) a C2-I0 alkenyl group, m) a C2. io alkynyl group, n) a CM0 alkoxy group, o) a CMO haloalkyl group, p) a C3-I0 cycloalkyl group, q) a aryl group, r) a 3- 14 membered cycloheteroalkyl group, or s) a 5-13 membered heteroaryl group, wherein each of k) - s) optionally is substituted with 1-4 -Z-R10 groups; R10, at each occurrence, is a) halogen, b) -CN, c) -NO2, d) oxo, e) -O-Z-R1 1, f) -NR"-Z-R12, g) -N(O)R1 '-Z-R12, h) -S(O)mRπ, i) -S(O)01O-Z-R", j) -S(O)01NR1 '-Z-R12, k) -C(O)R1 1, 1) -C(O)O-Z-R1 ', m) -C(O)NR1 '-Z-R12, n) -C(S)NR1 '-Z-R12, o) -Si(Ci0 alkyl)3, p) a C1-10 alkyl group, q) a C2-I0 alkenyl group, r) a C2-I0 alkynyl group, s) a C1.1o haloalkyl group, t) a C3-J0 cycloalkyl group, u) a C6-I4 aryl group, v) a 3-14 membered cycloheteroalkyl group, or w) a 5-13 membered heteroaryl group, wherein each of o) - w) optionally is substituted with 1-4 R13 groups; R1 ' and R12, at each occurrence, independently are a) H, b) -OH, c) -SH, d) -S(O)2OH, e) -C(O)OH, f) -C(O)NH2, g) -C(S)NH2, h) -S(O)m-C1-10 alkyl, i) -S(O)01-OC1-10 alkyl, j) -OC1-10 alkyl, k) -C(O)-Ci-10 alkyl, 1) -C(O)-OC1-10 alkyl, m) -C(S)N(C1-10 alkyl)2, n) -C(S)NH-C1-10 alkyl, o) -C(O)NH-Ci-I0 alkyl, p) -C(O)N(Ci-I0 alkyl)2, q) a Ci-10 alkyl group, r) a C2-I0 alkenyl group, s) a C2-I0 alkynyl group, t) a Ci-I0 alkoxy group, u) a Ci-I0 haloalkyl group, v) a C3.10 cycloalkyl group, w) a C6-14 aryl group, x) a 3-14 membered cycloheteroalkyl group, or y) a 5- 13 membered heteroaryl group, wherein each of h) - y) optionally is substituted with 1-4 -R13 groups; R13, at each occurrence, is a) halogen, b) -CN, c) -NO2, d) oxo, e) -OH, f) -NH2, g) -NH(C1-10 alkyl), h) -N(C1-10 alkyl)2, i) -S(O)01H, j) -S(O)01-C1-10 alkyl, k) -S(O)2OH, 1) -S(O)01-OC1-10 alkyl, m) -S(O)01NH2, n) -S(O)01NH(C1-10 alkyl), o) -S(O)01N(C1-10 alkyl)2, p) -CHO, q) -C(O)-Ci-I0 alkyl, r) -C(O)OH, s) -C(O)-OC1-10 alkyl, t) -C(O)NH2, u) -C(O)NH-Ci-I0 alkyl, v) -C(O)N(C1-10 alkyl)2, w) -C(S)NH2, x) -C(S)NH-C1-10 alkyl, y) -C(S)N(C10 alkyl)2, z) -Si(C1-10 alkyl)3, aa) a
Ci-I0 alkyl group, ab) a C2-I0 alkenyl group, ac) a C2-10 alkynyl group, ad) a CJ - 1O alkoxy group, ae) a Cio haloalkyl group, af) a C3-I0 cycloalkyl group, ag) a C6-I4 aryl group, ah) a 3-14 membered cycloheteroalkyl group, or ai) a 5-13 membered heteroaryl group; X is O, S, S(O), S(O)2, or NR6;
Y is S(O), S(O)2, or C(O); Z, at each occurrence, is a) a divalent C MO alkyl group, b) a divalent C2-I0 alkenyl group, c) a divalent C2-I0 alkynyl group, d) a divalent Ci-I0 haloalkyl group, or e) a covalent bond; and m, at each occurrence, is 0, 1, or 2. 44. The compound of claim 43, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R2 and R3, together with their common nitrogen atom, form a 5 or 6 membered cycloheteroalkyl group optionally substituted with 1-4 -Z-R10 groups. 45. The compound of claim 44, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein the 5 or 6 membered cycloheteroalkyl group is selected from a pyrrolidinyl group, an oxazolinyl group, an thiazolinyl group, an isothiazolinyl group, an imidazolinyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, a thiomorpholinyl group, and a 1,3- oxazinanyl group. 46. The compound of claim 44, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein -Z-R10 is selected from halogen, oxo and a Ci-6 alkyl group.
47. The compound of claim 43, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R2 and R , together with their common nitrogen atom, form a 5 or 6 membered heteroaryl group optionally substituted with 1-4
-Z-R10 groups.
48. The compound of claim 47, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein the 5 or 6 membered heteroaryl group is selected from a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, and a tetrazolyl group.
49. The compound of claim 47, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein Z is selected from a divalent Ci-4 alkyl group and a covalent bond.
50. The compound of claim 47, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R10 is selected from -CN, -O-Z-R1 ', -NR1 '-Z-R12,
-C(O)O-Z-R1 1, -C(O)NR"-Z-R12, -Si(C1-10 alkyl)3, a C1-I0 alkyl group, a C1-I0 haloalkyl group, a C3-I0 cycloalkyl group, a C6-14 aryl group, and a 5-13 membered heteroaryl group, wherein each of the CMO alkyl group, the C3-I0 cycloalkyl group, the C6-I4 aryl group, and the 5-13 membered heteroaryl group optionally is substituted with 1-4 R13 groups.
51. A compound or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein the compound is
(R)-2-(7-(4-(2-hydroxy-ethyl)-(l,2,3)triazol-l-yl)dibenzofuran-2- sulfonylamino)-3 -methyl-butyric acid,
(R)-2-(7-(4-isobutyl-(l,2,3)triazol-l-yl)-dibenzofuran-2-sulfonylamino)-
3 -methyl-butyric acid,
(R)-2-(7-(4-hydroxymethyl-(l,2,3)triazol-l-yl)-dibenzofuran-2- sulfonylamino)-3-methyl-butyric acid,
(R)-2-(7-(4-cyclohexyl-(l ,2,3)triazol-l -yl)-dibenzofuran-2- sulfonylamino)-3-methyl-butyric acid,
(R)- 1 -(8-( 1 -carboxy-2-methyl-propylsulfamoyl)-dibenzofuran-3 -yl)- 1 H-
( 1 ,2,3)-triazol-4-carboxylic acid,
(R)-3-methyl-2-(7-(4-phenyl-(l,2,3)triazol-l-yl)-dibenzofuran-2- sulfonylamino)-butyric acid,
(R)-2-(7-(4-dimethylaminomethyl-(l,2,3)triazol-l-yl)-dibenzofuran-2- sulfonylamino)-3 -methyl-butyric acid,
(S)-3-methyl-2-(8-moφholinodibenzo[b,d]furan-3-sulfonamido)butanoic acid,
(S)-3-methyl-2-(8-(3-(trifluoromethyl)-lH-pyrazol-l-yl)dibenzofuran-3- sulfonamido)butanoic acid,
(S)-2-(8-(lH-pyrazol-l-yl)dibenzo[b,d]furan-3-sulfonamido)-3-methyl- butanoic acid,
(S)-3-methyl-2-(8-(piperazin-l-yl)dibenzo[b,d]furan-3- sulfonamido)butanoic acid,
(S)-2-(8-(lH-imidazol-l-yl)dibenzo[b,d]furan-3-sulfonamido)-3-methyl- butanoic acid,
(S)-2-(8-(4,5-dimethyl-lH-imidazol-l-yl)dibenzo[b,d]furan-3- sulfonamido)-3-methyl-butanoic acid,
(R)-3-methyl-2-(7-(4-((trimethylsilyl)methyl)- 1 H- 1 ,2,3-triazol- 1 - yl)dibenzo[b,d]furan-2-sulfonamido)butanoic acid,
(S)-2-(8-(4-cyclohexyl-lH-l,2,3-triazol-l-yl)dibenzo[b,d]furan-3- sulfonamido)-3 -methyl-butanoic acid,
(S)-2-(8-(4-(2-hydroxyethyl)-lH-l,2,3-triazol-l-yl)dibenzo[b,d]furan-3- sulfonamido)-3 -methyl-butanoic acid,
(S)-2-(8-(4-((dimethylamino)methyl)- 1 H- 1 ,2,3-triazol- 1 - yl)dibenzo[b,d]furan-3-sulfonamido)-3-methyl-butanoic acid,
(S)-3-methyl-2-(8-(4-phenyl-lH-l,2,3-triazol-l-yl)dibenzo[b,d]furan-3- sulfonamido)butanoic acid,
(S)-2-(8-(4-isobutyl-lH-l,2,3-triazol-l-yl)dibenzo[b,d]furan-3- sulfonamido)-3 -methyl-butanoic acid,
(S)-3-methyl-2-(7-(4-( 1 -methyl- 1 H-pyrrol-2-yl)- 1 H- 1 ,2,3-triazol- 1 - yl)dibenzo [b,d] thiophene-3 -sulfonamido)butanoic acid, (S)-3-methyl-2-(7-(4-phenyl-lH-l,2,3-triazol-l-yl)dibenzo[b,d]thiophene-
3-sulfonamido)butanoic acid,
(S)-2-(7-(4-cyclohexyl- 1 H- 1 ,2,3-triazol- 1 -yl)dibenzo[b,d]thiophene-3- sulfonamido)-3-methyl-butanoic acid,
(S)-2-(7-(4-(methoxymethyl)- 1 H- 1 ,2,3-triazol- 1 - yl)dibenzo[b,d]thiophene-3-sulfonamido)-3-methyl-butanoic acid,
(S)-2-(7-(4-tert-butyl-lH-l,2,3-triazol-l-yl)dibenzo[b,d]thioρhene-3- sulfonamido)-3-methyl-butanoic acid,
(S)-2-(7-(4-((dimethylamino)methyl)- 1 H- 1 ,2,3-triazol- 1 - yl)dibenzo[b,d]thiophene-3-sulfonamido)-3-methyl-butanoic acid,
(S)-2-(7-(4-(hydroxymethyl)- 1 H- 1 ,2,3-triazol- 1 - yl)dibenzo[b,d]thiophene-3-sulfonamido)-3-methyl-butanoic acid,
(S)-2-(7-(4-(methoxycarbonyl)- 1 H- 1 ,2,3-triazol- 1 - yl)dibenzo[b,d]thiophene-3-sulfonamido)-3-methyl-butanoic acid,
(S)-l-(7-(N-(l-carboxy-2-methylpropyl)sulfamoyl)dibenzo[b,d]thiophen-
3-yl)- 1 H- 1 ,2,3-triazole-4-carboxylic acid,
(S)-2-(7-(4-cyano- 1 H- 1 ,2,3-triazol- 1 -yl)dibenzo[b,d]thiophene-3- sulfonamido)-3-methyl-butanoic acid,
(S)-2-(7-(4-isopropyl-lH-l,2,3-triazol-l-yl)dibenzo[b,d]thiophene-3- sulfonamido)-3-methyl-butanoic acid,
(S)-2-(7-(4-carbamoyl-lH-l,2,3-triazol-l-yl)dibenzo[b,d]thiophene-3- sulfonamido)-3-methyl-butanoic acid,
(S)-2-(7-(4-(furan-2-yl)-lH-l,2,3-triazol-l-yl)dibenzo[b,d]thiophene-3- sulfonamido)-3-methyl-butanoic acid,
(R)-2-(7-(4H-l,2,4-triazol-4-yl)dibenzo[b,d]furan-2-sulfonamido)-3- methyl-butanoic acid,
(R)-2-(7-(2,5-dimethyl-lH-pyrrol-l-yl)dibenzo[b,d]furan-2-sulfonamido)-
3-methyl-butanoic acid,
(S)-3 -methyl-2-(8-(3 -(4-nitrophenyl)- 1 H-pyrazol- 1 -yl)dibenzo [b,d] furan-
3-sulfonamido)butanoic acid,
(R)-2-(7-( 1 H-pyrrol- 1 -yl)dibenzo [b,d] furan-2-sulfonamido)-3 -methyl- butanoic acid,
(S)-2-(7-(lH-pyrrol-l-yl)dibenzo[b,d]furan-3-sulfonamido)-3-methyl- butanoic acid,
(S)-2-(7-(2,5-dimethyl-lH-ρyrrol-l-yl)dibenzo[b,d]furan-3-sulfonamido)-
3-methyl-butanoic acid,
(S)-3-methyl-2-(7-(3-(trifluoromethyl)-lH-pyrazol-l- yl)dibenzo[b,d]furan-3-sulfonamido)butanoic acid,
(S)-3-methyl-2-(8-(4-methylpiperazin-l-yl)dibenzo[b,d]furan-3- sulfonamido)butanoic acid,
(S)-2-(8-(lH-l,2,4-triazol-l-yl)dibenzo[b,d]furan-3-sulfonamido)-3- methyl-butanoic acid,
(S)-2-(8-(4,4-difluoropiperidin-l-yl)dibenzo[b,d]furan-3-sulfonamido)-3- methyl-butanoic acid,
(S)-3-methyl-2-(8-(4-methyl-lH-imidazol-l-yl)dibenzo[b,d]furan-3- sulfonamido)butanoic acid,
(R)-2-(7-(5-methoxy-2H-tetrazol-2-yl)dibenzo[b,d]furan-2-sulfonamido)-
3-methyl-butanoic acid, (R)-2-(7-(5-hydroxy-2H-tetrazol-2-yl)dibenzo[b,d]furan-2-sulfonamido)-
3-methyl-butanoic acid, or
N- { [7-( 1 , 1 -dioxidothiomorpholin-4-yl)dibenzo [b,d] thien-3 -yl] sulfonyl } -
L-valine.
52. The compound of any of claims 1-7, 9-28, 30-41, and 43-50, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein the compound of formula I is selected from
53. The compound of claim 52, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R4 and R5 independently are selected from H and a halogen. 54. The compound of claim 52, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R4 is H and R5 is selected from H, Cl, and Br.
55. The compound of any of claims 52-54, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein X is O.
56. The compound of any of claims 52-54, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein X is S.
57. The compound of any of claims 52-56, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein Y is S(O)2.
58. The compound of any of claims 52-57, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R1 is W-V-NH-, wherein:
W is a) -C(O)R14, b) -S(O)mR14, c) -S(O)01OR14, d) -S(O)111NR14R15, e) -C(O)OR14, f) -C(O)NR14R15, g) -C(S)R14, h) -C(S)OR14, i) -NR14R15, j) -C(NR14)NR14R15, k) -P(O)(OR14)2, or 1) -B(OR14)2;
V is a) -CR14R16- b) -CH2CR14R16-, C) -(CH=CR14R16)-, or d) -BHR16-; R14 and R15, at each occurrence, independently are a) H, b) -OH, c) -SH, d) -S(O)2OH, e) -C(O)OH, f) -C(O)NH2, g) -C(S)NH2, h) -S(O)01-C1-10 alkyl, i) -S(OV-OC1-10 alkyl, j) -C(O)-C1-10 alkyl, k) -C(O)-OC1-10 alkyl, 1) -C(O)NH-Ci-10 alkyl, m) -C(O)N(C1-10 alkyl)2, n) -C(S)NH-C1-10 alkyl, o) -C(S)N(C1-10 alkyl)2, p) a C1-10 alkyl group, q) a C2-I0 alkenyl group, r) a
C2-10 alkynyl group, s) a C1-10 alkoxy group, t) a C MO haloalkyl group, u) a C3-10 cycloalkyl group, v) a C6-14 aryl group, w) a 3-14 membered cycloheteroalkyl group, or x) a 5-13 membered heteroaryl group, wherein each of the Ci-I0 alkyl groups, the C2-I0 alkenyl group, the C2-10 alkynyl group, the Ci-IO alkoxy group, the C M0 haloalkyl group, the C3-I0 cycloalkyl group, the C6-I4 aryl group, the 3-14 membered cycloheteroalkyl group, and the a 5-13 membered heteroaryl group optionally is substituted with 1-4 R17 groups; R16 independently is H or a side chain of a natural or non-natural amino acid; and
R17, at each occurrence, independently is a) halogen, b) -CN, c) -NO2, d) oxo, e) -OH, f) -NH2, g) -NH(C1-10 alkyl), h) -N(C1-10 alkyl)2, i) -S(O)mH, j) -S(O)111-C1-10 alkyl, k) -S(O)2OH, 1) -S(O)m-OC,-10 alkyl, m) -S(0)mNH2, n) -S(O)111NH(C1-10 alkyl), o) -S(O)mN(C1-10 alkyl)2, p) -CHO, q) -C(O)-C1-10 alkyl, r) -C(O)OH, s) -C(O)-OC1-10 alkyl, t) -C(O)NH2, u) -C(O)NH-C1-10 alkyl, v) -C(O)N(C1-10 alkyl)2, w) -C(S)NH2, x) -C(S)NH-C1-10 alkyl, y) -C(S)N(C1-10 alkyl)2, z) -Si(Ci-10 alkyl)3, aa) a C1-10 alkyl group, ab) a C2-10 alkenyl group, ac) a C2-10 alkynyl group, ad) a C1-10 alkoxy group, ae) a C1-10 haloalkyl group, af) a C3-1O cycloalkyl group, ag) a C6-14 aryl group, ah) a 3-14 membered cycloheteroalkyl group, or ai) a 5-13 membered heteroaryl group.
59. The compound of claim 58, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein W is -C(O)OR14 and V is -CR14R16-.
60. The compound of any of claims 52-59, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R1 is an N-linked, free carboxyl or carboxyl-protected, natural or non-natural D-alpha-amino acid.
61. The compound of any of claims 52-59, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R1 is an N-linked, free carboxyl or carboxyl-protected, natural or non-natural L-alpha-amino acid.
62. The compound of any of claims 52-61 , or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein the N-linked amino acid derivative is derived from a natural amino acid.
63. The compound of claim 58 or 59, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R1 is an isopropyl group.
64. The compound of any of claims 52-63, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R1 is an N-linked valine.
65. The compound of any of claims 52-60 and 62-64, or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R1 is an N-linked D-valine.
66. A pharmaceutical composition comprising the compound of any of claims 1- 65 or a pharmaceutically acceptable salt, hydrate, or ester thereof and a pharmaceutically acceptable carrier or excipient.
67. A method of treating or inhibiting a pathologic condition or disorder mediated wholly or in part by a matrix metalloproteinase in a mammal, the method comprising administering to the mammal an effective amount of one or more compounds of any of claims 1-65 or a pharmaceutically acceptable salt, hydrate, or ester thereof.
68. The method of claim 67, wherein the matrix metalloproteinase is MMP- 12.
69. The method of claim 67 or 68, wherein the pathologic condition or disorder is selected from osteoarthritis, rheumatoid arthritis, atherosclerosis, heart failure, fibrosis, pulmonary emphysema, tumor growth, asthma, and chronic obstructive pulmonary disorder.
70. The method of claim 69, wherein the mammal is a human.
EP07839790A 2006-10-27 2007-10-26 Tricyclic compounds as matrix metalloproteinase inhibitors Withdrawn EP2074107A2 (en)

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