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  • 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
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  • 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
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  • C07D—HETEROCYCLIC COMPOUNDS
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  • 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
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  • 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.

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