WO2010085246A1 - Dérivés de 2,4-diamino-1,3,5-triazine et de 4,6-diamino-pyrimidine et leur emploi en tant qu'inhibiteurs d'aggrécanase - Google Patents

Dérivés de 2,4-diamino-1,3,5-triazine et de 4,6-diamino-pyrimidine et leur emploi en tant qu'inhibiteurs d'aggrécanase Download PDF

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WO2010085246A1
WO2010085246A1 PCT/US2009/031575 US2009031575W WO2010085246A1 WO 2010085246 A1 WO2010085246 A1 WO 2010085246A1 US 2009031575 W US2009031575 W US 2009031575W WO 2010085246 A1 WO2010085246 A1 WO 2010085246A1
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alkyl
hydrogen
cycloalkyl
optionally substituted
heteroaryl
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PCT/US2009/031575
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Yun Ding
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Praecis Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
    • C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/54—Three nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a 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
    • C07D409/02—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
    • 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 invention is directed to compounds that inhibit aggrecanase proteolytic activity which is implicated in joint diseases including osteoarthritis, joint injury, reactive arthritis, acute pyrophosphate arthritis, psoriatic arthritis, rheumatoid arthritis, and other diseases and pathological conditions.
  • the invention is also directed to processes for making the invention compounds, to pharmaceutical compositions, and to methods of treatment osteoarthritis and other joint diseases using the invention compounds.
  • Osteoarthritis is characterized by progressive enzymatic destruction of type II collagen and aggrecan, which are the two major components of cartilage matrix.
  • Type II collagen is essential for cartilage tensile strength and its degradation causes progression of osteoarthritis.
  • Aggrecan is composed of a core protein of approximately 2400 amino acids.
  • the molecule consists of several structural and functional domains (Falnnery et al., Matrix Biology 16, 1998, 507-511). Three domains are defined on the N-terminal side: (1) the Gl, (2) the interglobular, and (3) the G2 domain.
  • the aggrecan C-terminal side comprises two glycosaminoglycan rich domains.
  • the Gl domain is separated from a second globular domain, G2, by about 150 amino acids, known as the interglobular domain. From the G2 domain to the C-terminus there is a long extended region consisting of two glycosaminoglycan-rich domains.
  • the first is rich in keratan sulfate, whereas that which follows is rich in chondroitin sulfate.
  • the Gl domain of aggrecan binds to long hyaluronic acid polymers, thereby forming multi molecular aggregates that effectively immobilize aggrecan within the collagen fibrillar meshwork.
  • the glycosaminoglycan domains provide osmotic pressure, which enables cartilage to resist compression.
  • aggrecan contributes to the progression of osteoarthritis.
  • aggrecan is one of the first cartilage matrix components to undergo measurable loss (Mankin et al., /. Bone Joint Surg. 52A, 424- 434 (1970)).
  • aggrecan degradation is associated with amino acid cleavage within the interglobular domain, at either the Asn 341 -Phe 342 or the GIu 373 - Ala 374 site.
  • NSAIDs have limited symptomatic benefit and have only modest, if any, effects on slowing cartilage destruction in osteoarthritic joints.
  • NSAIDs such as, acetaminophen, act by inhibiting the synthesis of cytokines, such as, prostaglandins that cause pain and swelling. While inhibitors of cartilage degrading enzymes will block cartilage collagen and aggrecan degradation (thereby blocking or slowing the progression of osteoarthritis), NSAIDs do not directly prevent cartilage destruction.
  • Inhibition of aggrecanase should have a more direct and specific effect on cartilage breakdown than cytokine inhibition in the treatment of osteoarthritis, joint injury, reactive arthritis, acute pyrophosphate arthritis, psoriatic arthritis, and rheumatoid arthritis.
  • Y is H, halo, ORi, SRi, (d-C 8 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, aralkyl, (C 3 -
  • Ri is hydrogen, (Ci-C 6 )alkyl, aryl, aralkyl, (C 3 -C 6 )cycloalkyl, (C 3 -
  • R 1 is optionally substituted with 1, 2 or 3 (d-C 6 )alkyl, (Ci-C 6 )alkoxy or (Ci-C 6 )haloalkyl or 1, 2 or 3 groups independently selected from R a ;
  • R 2 is hydrogen, (Ci-C 6 )alkyl, aryl, aralkyl, (C 3 -C 6 )cycloalkyl, (C 3 -
  • R 2 is optionally substituted with 1, 2 or 3 (d-C 6 )alkyl, (Ci-C 6 )alkoxy or (Ci-C 6 )haloalkyl or 1, 2 or 3 groups independently selected from R a ; or Ri and R 2 can be taken together to form a 5-7 membered heterocycle having 1,
  • R 3 is hydrogen or (Ci -C 6 ) alkyl; m is 0, 1, or 2;
  • X is absent, -CONR 4 -, Or -SO 2 -, -SO 2 NR 4 -, or -COO-;
  • R 4 is hydrogen or (Ci-C 6 )alkyl
  • R 5 is hydrogen, (Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which may be optionally substituted with 1, 2, or 3 groups
  • R 12 -N independently selected from R a or 11 in which Rn is hydrogen or (Ci-
  • R 12 is hydrogen, (Ci-C 6 ) alkyl, -CO(d-C 6 )alkyl, -CO(C 1 - C 6 )cycloalkyl, -CO(Ci-C 6 )heterocycloalkyl, -CO(Ci-C 6 ) aryl, -CO(Ci- C 6 )heteroaryl, cycloalkyl, aryl, or heteroaryl, any of which may be optionally substituted with 1, 2, or 3 groups independently selected from Ra; or Rn and Ri 2 can be taken together to form a 5-7 membered heterocycle having 1, 2 or 3 heteroatoms and optionally substituted with R a ;
  • R 6 is hydrogen or (Ci -C 6 ) alkyl;
  • R 7 and Rg are each independently hydrogen, halogen, (Ci-C 6 )alkyl or (Ci-
  • Ce)alkoxy either of which may be optionally substituted on carbon with 1, 2, or
  • Rg is hydrogen, halo or (Ci-C 6 )alkyl
  • R 10 is hydrogen or (Ci-Ce)alkyl
  • Rg and Rio together with the atoms to which they are attached, form a 4-8 membered ring, optionally substituted on carbon with 1, 2, or 3 groups selected from halo,
  • (Ci-C 6 )alkyl, and -O-(d-C 6 )alkyl, -S-(d-C 6 )alkyl, any of which may be optionally substituted on carbon with 1, 2, or 3 halo, or taken together with the attached carbon form C O; is aryl, aryloxy, heteroaryl, cycloalkyl, or heterocycloalkyl; at least two of three of Zi, Z 2 , and Z 3 are N and the other is C-R b , wherein R b is hydrogen, halogen, (Ci-Ce)alkyl, or (Ci-C 6 )alkoxy;
  • R a is halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, (Ci-C 6 )alkyl-NH, ((Ci-C 6 )alkyl) 2 -N, aryl, heteroaryl, (C 3 -C 7 )cycloalkyl, (C 1 - C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (Ci-C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 1 - C 6 )alkynyloxy, (Ci-C 6 )alkylthio, (Ci-C 6 )alkylsulfinyl, (Ci-C 6 )alkylsulfonyl, amino, (Ci-C 6 )alkylamino, di-[(Ci-C 6 )alkyl]
  • R 1 is hydrogen, (Ci-C 6 )alkyl, aryl, aralkyl, (C 3 -C 6 )cycloalkyl, (C 3 -
  • R 1 is optionally substituted with 1, 2 or 3 (C r C 6 )alkyl, (C r C 6 )alkoxy or (C r C 6 )haloalkyl or 1, 2 or 3 groups independently selected from R a ;
  • R 2 is hydrogen, (Ci-C 6 )alkyl, aryl, aralkyl, (C 3 -C 6 )cycloalkyl, (C 3 -
  • R 2 is optionally substituted with 1, 2 or 3 (d-C 6 )alkyl, (Ci-C 6 )alkoxy or (Ci-C 6 )haloalkyl or 1, 2 or 3 groups independently selected from R a ; or Ri and R 2 can be taken together to form a 5-7 membered heterocycle having 1,
  • R 3 is hydrogen or (Ci-C 6 )alkyl; m is 0, 1, or 2;
  • X is absent, -CONR 4 -, Or -SO 2 -, -SO 2 NR 4 -, or -COO-;
  • R 4 is hydrogen or (Ci-C 6 )alkyl
  • R 5 is hydrogen, (Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which may be optionally substituted with 1, 2, or 3 groups
  • R 12 -N independently selected from R a or 11 in which Rn is hydrogen or (Ci-
  • R 12 is hydrogen, (Ci-C 6 ) alkyl, -CO(Ci-C 6 )alkyl, -CO(Ci-
  • R 6 is hydrogen or (Ci -C 6 ) alkyl
  • R 7 and R 8 are each independently hydrogen, halogen, (Ci-C 6 )alkyl or (Ci-
  • R 9 is hydrogen, halo or (Ci -C 6 ) alkyl
  • Rio is hydrogen or (Ci-C 6 )alkyl
  • R 9 and Rio together with the atoms to which they are attached, form a 4-8 membered ring, optionally substituted on carbon with 1, 2, or 3 groups selected from halo,
  • (Ci-C 6 )alkyl, and -O-(Ci-C 6 )alkyl, -S-(Ci-C 6 )alkyl, any of which may be optionally substituted on carbon with 1, 2, or 3 halo, or taken together with the attached carbon form C O; is aryl, aryloxy, heteroaryl, cycloalkyl, or heterocycloalkyl; at least two of three of Zi, Z 2 , and Z 3 are N and the other is C-R b , wherein R b is hydrogen, halogen, (Ci-C 6 )alkyl, or (Ci-C 6 )alkoxy;
  • R a is halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, (Ci-C 6 )alkyl-NH, ((Ci-C 6 )alkyl) 2 -N, aryl, heteroaryl, (C 3 -C 7 )cycloalkyl, (C 1 - C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (Ci-C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (Ci- C 6 )alkynyloxy, (Ci-C 6 )alkylthio, (Ci-C 6 )alkylsulfinyl, (Ci-C 6 )alkylsulfonyl, amino, (Ci-C 6 )alkylamino, di-[(Ci-C 6 )alkyl]a
  • the invention is directed to a compound of formula
  • Y is H, halo, OR 1 , SR 1 , (C r C 8 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, aralkyl, (C 3 - C 6 )heterocycloalkyl, heteroaryl, heteroaralkyl, or NR 1 R 2 ;
  • R 1 is hydrogen, (C 1 -C 6 )alkyl, aryl, aralkyl, (C 3 -C 6 )cycloalkyl, (C 3 - C 6 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 6 )heterocycloalkyl, (C 3 -C 6 )heterocycloalkyl(C 1 - Ce)alkyl, heteroaryl, heteroaralkyl, (C 1 -Ce)carboxyalkyl, ary 1OXy(C 1 -Ce)alkyl, -
  • R 2 is hydrogen, (C 1 -C 6 )alkyl, aryl, aralkyl, (C 3 -C 6 )cycloalkyl, (C 3 - C 6 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 6 )heterocycloalkyl, (C 3 -C 6 )heterocycloalkyl(C 1 - Ce)alkyl, heteroaryl, heteroaralkyl, (C 1 -Ce)carboxyalkyl, ary 1OXy(C 1 -Ce)alkyl, - alkylene-NR'R", wherein R' and R" are each independently hydrogen, (C 1 - Ce)alkyl, or taken together with the nitrogen to which they are attached, form a 3, 4, 5, or 6-membered saturated or partially unsaturated ring optionally containing 0, 1, or 2 additional heteroatoms selected from O, S(O)x, wherein x is 0, 1, or 2,
  • R 3 is hydrogen or (Ci-C 6 )alkyl; m is O, I, or 2;
  • R 4 is hydrogen or (Ci-C 6 )alkyl
  • R 6 is hydrogen or (Ci-C 6 )alkyl
  • R 7 and R 8 are each independently hydrogen, halogen, (Ci-C 6 )alkyl or (Ci-
  • Ce)alkoxy either of which may be optionally substituted on carbon with 1, 2, or
  • R 9 is hydrogen, halo or (Ci-C 6 )alkyl
  • Rio is hydrogen or (Ci-C 6 )alkyl
  • R 9 and Ri 0 together with the atoms to which they are attached, form a 4-8 membered ring, optionally substituted on carbon with 1, 2, or 3 groups selected from halo,
  • (C r C 6 )alkyl, and -O-(C r C 6 )alkyl, -S-(C r C 6 )alkyl, any of which may be optionally substituted on carbon with 1, 2, or 3 halo, or taken together with the attached carbon form C O; is aryl, aryloxy, heteroaryl, cycloalkyl, or heterocycloalkyl;
  • B t is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Rn is hydrogen or (Ci-C 6 ) alkyl
  • R J2 is hydrogen, (Ci-C 6 ) alkyl, -CO(Ci- C 6 )alkyl, -CO(Cj -C 6 )cycloalkyl, -CO(Ci-C 6 )heterocycloalkyl, -CO(Ci-C 6 ) aryl, - CO(Ci-C 6 )heteroaryl, cycloalkyl, aryl, or heteroaryl, any of which may be optionally substituted with 1, 2, or 3 groups independently selected from Ra; or Rn and Ri 2 can be taken together to form a 5-7 membered heterocycle having 1, 2 or 3 heteroatoms and optionally substituted with R a ; at least two of three of Zi, Z 2 , and Z 3 are N and the other is C-R b , wherein R b is hydrogen, halogen, (Ci-C 6 )alkyl, or (Ci-
  • R a is halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, (Ci-C 6 )alkyl-NH, ((Ci-C 6 )alkyl) 2 -N, aryl, heteroaryl, (C 3 -C 7 )cycloalkyl, (C 1 - C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (Ci-C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (Ci- C 6 )alkynyloxy, (Ci-C 6 )alkylthio, (Ci-C 6 )alkylsulfinyl, (Ci-C 6 )alkylsulfonyl, amino, (C r C 6 )alkylamino, di-[(C r C 6 )alkyl]a
  • the invention is directed to a compound of formula
  • Y is H, halo, ORi, SRj, (d-C 8 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, aralkyl, (C 3 - C 6 )heterocycloalkyl, heteroaryl, heteroaralkyl, or NRiR 2 ;
  • Ri is hydrogen, (Ci-C 6 )alkyl, aryl, aralkyl, (C 3 -C 6 )cycloalkyl, (C 3 - C 6 )cycloalkyl(Ci-C 6 )alkyl, (C 3 -C 6 )heterocycloalkyl, (C 3 -C 6 )heterocycloalkyl(Ci- Ce)alkyl, heteroaryl, heteroaralkyl, (Ci-djcarboxyalkyl, aryloxy(Ci-C 6 )alkyl, - alkylene-NR'R", wherein R
  • R 2 is hydrogen, (Ci-C 6 )alkyl, aryl, aralkyl, (C 3 -C 6 )cycloalkyl, (C 3 -
  • R 1 and R 2 can be taken together to form a 5-7 membered heterocycle having 1,
  • R 3 is hydrogen or (C 1 -Ce)alkyl; m is O, I, or 2;
  • X is absent, -CONR 4 -, Or -SO 2 -, -SO 2 NR 4 -, or -COO-;
  • R 4 is hydrogen or (C ⁇ C 6 ) alkyl
  • R 5 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which may be optionally substituted with 1, 2, or 3 groups
  • R 12 -N independently selected from R a or 11 in which R 11 is hydrogen or (C 1 -
  • R 12 is hydrogen, (C 1 -C 6 ) alkyl, -CO(C 1 -C 6 )alkyl, -CO(C 1 - C 6 )cycloalkyl, -COtd-Ce ⁇ eterocycloalkyl, -CO(C 1 -C 6 ) aryl, -CO(C 1 - C 6 )heteroaryl, cycloalkyl, aryl, or heteroaryl, any of which may be optionally substituted with 1, 2, or 3 groups independently selected from Ra; or R 11 and R 12 can be taken together to form a 5-7 membered heterocycle having 1, 2 or 3 heteroatoms and optionally substituted with R a ; R 6 is hydrogen or (Ci-C 6 )alkyl; n is 0, 1, 2 or 3; R 7 and Rg are each independently hydrogen, halogen, (Ci-C 6 )alkyl or (Ci- Ce)alkoxy, either of which may be
  • R a is halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, (Ci-C 6 )alkyl-NH, ((Ci-C 6 )alkyl) 2 -N, aryl, heteroaryl, (C 3 -C 7 )cycloalkyl, (C 1 - C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (Ci-C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 1 - C 6 )alkynyloxy, (Ci-C 6 )alkylthio, (Ci-C 6 )alkylsulfinyl, (Ci-C 6 )alkylsulfonyl, amino, (Ci-C 6 )alkylamino, di-[(Ci-C 6 )alkyl]
  • the invention is directed to a compound of any of formulae I-IV, wherein the compound is selected from:
  • the invention is directed to a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound disclosed herein, e.g., a compound of formulae I- IV, or a pharmaceutically acceptable salt thereof.
  • the invention is directed to a method for treating or preventing an inflammatory disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, e.g., a compound of formulae I-IV, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutically acceptable salt thereof comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, e.g., a compound of formulae I-IV, or a pharmaceutically acceptable salt thereof.
  • the invention is directed to a method of treating a subject suffering from osteoarthritis, joint injury, reactive arthritis, acute pyrophosphate arthritis, psoriatic arthritis, or rheumatoid arthritis, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, e.g., a compound of formulae I-IV, or a pharmaceutically acceptable salt thereof.
  • a compound disclosed herein e.g., a compound of formulae I-IV
  • the invention is directed to a process for making a compound disclosed herein, e.g., a compound of formulae I-IV, comprising the steps outlined in Schemes 1-8 infra.
  • Halogen means fluoro, chloro, iodo, and bromo.
  • Alkyl includes both straight and branched chain alkyl groups.
  • Ce)alkyl means an alkyl group having 6 carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t- pentyl, neo-pentyl, n-hexyl or i-hexyl, t-hexyl.
  • alkylene used alone or as suffix or prefix, refers to divalent straight or branched chain hydrocarbon radicals comprising 1 to about 12 carbon atoms, which serves to links two structures together.
  • Cycloalkyl means a partially or fully saturated ring ring system. "(C 3 -
  • C 7 )cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Heterocycloalkyl means a ring-containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, O and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring(s).
  • Heterocycle may be saturated or partially unsaturated and may contain more than one ring. When a heterocycle contains more than one ring, the rings may be fused or unfused. Fused rings generally refer to at least two rings share two atoms therebetween.
  • (Ci-C 6 )AIkOXy refers to alkyl, alkenyl, and alkynyl groups as defined above that are attached to O. Examples include methoxy, ethoxy, vinyloxy, allyloxy, ethynyloxyy, and 2-propynyloxy.
  • (Ci-C 6 )Alkylthio means an alkyl group attached to S. Examples include methylthio, ethylthio and propylthio.
  • (Ci-C 6 )Alkylsulfinyl means an alkyl group attached to SO. Examples include methylsulphinyl and ethylsulphinyl.
  • (Ci-C 6 )Alkylsulfonyl means an alkyl group attached to SO . Examples include methylsulfonyl and ethylsulfonyl.
  • Amino means NH .
  • (Ci-C 6 )Alkylamino means (C r C 6 )alkyl-NH. Examples include methylamino, ethylamino, propylamino, isopropylamino and butylamino.
  • ((Ci-C 6 )Alkyl) amino means ((Ci-C 6 )alkyl) -N. Examples include dimethylamino, diethylamino, N-ethyl- N-methylamino and diisopropylamino.
  • Carboxy means CO H.
  • (Ci-C 6 )Alkoxycarbonyl means CO (d-C 6 )alkyl. Examples include methoxycarbonyl, ethoxycarbonyl, propoxy- carbonyl and tert-butoxycarbonyl.
  • Examples include N,N- dimethylcarbamoyl, and N,N-diethylcarbamoyl.
  • (Ci-C 6 )alkyl examples include N-methylacetamido and N-methylpropionamido.
  • N-(Ci -C 6 )alkylsulfamoyl means SO 2 -NH(Ci-C 6 )alkyl. Examples include N-methylsulfamoyl and N-ethyl-sulphamoyl.
  • N,N-di-(Ci-C 6 )alkylsulfamoyl means SO 2 -N((Ci-C 6 )alkyl) 2 . Examples include N,N, dimethylsulfamoyl.
  • (Ci-C 6 )alkylsulfonylamino means -NH-SO 2 -(C r C 6 )alkyl.
  • Arylsulfonylamino means -NH-SO 2 -aryl.
  • Aryl means an optionally substituted monocyclic or bicyclic ring system containing at least one aromatic ring. Examples and suitable values of the term
  • aryl are phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indyl and indenyl.
  • Heteroaryl means an optionally substituted monocyclic or bicyclic ring systemcontaining at least one aromatic ring and at least one heteroatom selected independently from N, O or S.
  • heteroaryl include thiophene, thienyl, pyridyl, thiazolyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxadiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolonyl, oxazolonyl, thiazolonyl, tetrazolyl and thiadiazolyl, benzoimidazolyl, benzooxazolyl, tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, benzofuryl, indolyl, isoindolyl, pyridonyl, pyridazinyl,
  • alkyl refers to a substituent that is attached via the alkyl group to an aryl, heteroaryl or cycloalkyl group.
  • a "5- or 6-membered ring” refers to aromatic and heteroaromatic rings, as well as carbocyclic and heterocyclic rings, which may be partially or fully saturated.
  • Such rings include, but are not limited to furyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, imidazolidinyl, imidazolinyl, triazolyl, morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, thiomorpholinyl, phenyl, cyclohexyl, cyclopentyl and cyclohexenyl.
  • the phrase "pharmaceutically acceptable salts” means derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from nontoxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, trifluoroacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, trifluoroacetic, propionic, succ
  • the pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the normal valency of the designated atom is not exceeded, and that the substitution results in a stable compound.
  • any variable such as n, x, R', or R a occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence.
  • that group may optionally be substituted with up to two R 6 groups and R 6 at each occurrence is selected independently from the definition of R 6 .
  • combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • a therapeutically effective amount of a compound of the invention may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. An effective amount is also one in which any toxic or detrimental effects (e.g., side effects) of the compound are outweighed by the therapeutically beneficial effects.
  • a therapeutically effective amount of a compound of the invention may range from about 0.001 to 30 mg/kg body weight, preferably about 0.01 to 25 mg/kg body weight, more preferably about 0. 1 to 30 mg/kg body weight, and even more preferably about 1 to 10 mg/kg, 2 to 9 mg/kg, 3 to 8 mg/kg, 4 to 7 mg/kg, or 5 to 6 mg/kg body weight.
  • an effective dosage may range from about 0.001 to 30 mg/kg body weight, preferably about 0.01 to 25 mg/kg body weight, more preferably about 0. 1 to 30 mg/kg body weight, and even more preferably about 1 to 10 mg/kg, 2 to 9 mg/kg, 3 to 8 mg/kg, 4 to 7 mg/kg, or 5 to 6 mg/kg body weight.
  • the skilled artisan will appreciate that certain factors may influence the dosage required to effectively treat a subject, including, but not limited to, the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present, if any.
  • treatment of a subject with a therapeutically effective amount of a compound of the invention can include a single treatment or, preferably, can include a series of treatments.
  • a subject is treated with a compound of the invention in the range of between about 0.1 and 20 mg/kg body weight, one time per week for between about 1 to 10 weeks, preferably between 2 to 8 weeks, more preferably between about 3 to 7 weeks, and even more preferably for about 4, 5, or 6 weeks.
  • the effective dosage of a compound used for treatment may increase or decrease over the course of a particular treatment.
  • the present invention is directed to compounds of formula I:
  • Y is H, halo, ORi, SRi, (d-C 8 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, aralkyl, (C 3 -
  • Ri is hydrogen, (Ci-C 6 )alkyl, aryl, aralkyl, (C 3 -C 6 )cycloalkyl, (C 3 -
  • R a 0, 1, or 2 additional heteroatoms selected from O, S(O)x, wherein x is 0, 1, or 2, or N-R" ', wherein R" ' is hydrogen or (Ci-C 6 )alkyl; Ri is optionally substituted with 1, 2 or 3 (d-C 6 )alkyl, (Ci-C 6 )alkoxy or (Ci-C 6 )haloalkyl or 1, 2 or 3 groups independently selected from R a ;
  • R 2 is hydrogen, (Ci-C 6 )alkyl, aryl, aralkyl, (C 3 -C 6 )cycloalkyl, (C 3 -
  • R 2 is optionally substituted with 1, 2 or 3 (C r C 6 )alkyl, (C r C 6 )alkoxy or (C r C 6 )haloalkyl or 1, 2 or 3 groups independently selected from R a ; or Ri and R 2 can be taken together to form a 5-7 membered heterocycle with 1, 2 or 3 heteroatoms and optionally substituted with R a ;
  • R 3 is hydrogen or (Ci-C 6 )alkyl; m is O, 1, or 2;
  • X is absent, -CONR 4 - -SO 2 -, -SO 2 NR 4 -, or -COO-;
  • R 4 is hydrogen or (Ci-C 6 )alkyl
  • R 5 is hydrogen, (Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which may be optionally substituted with 1, 2, or 3 groups R 12 -N independently selected from R a or 11 in which R 11 is hydrogen or (C 1 -
  • R 12 is hydrogen, (C 1 -C 6 ) alkyl, -CO(C r C 6 )alkyl, -CO(C 1 -
  • R 11 and R 12 can be taken together to form a 5-7 membered heterocycle having 1, 2, or 3 heteroatoms and optionally substituted with R a ;
  • R 6 is hydrogen or (C 1 -C 6 ) alkyl
  • R 7 and R 8 are each independently hydrogen, halogen, (C 1 -C 6 )alkyl or (C 1 -
  • R 9 is hydrogen, halo or (C 1 -C 6 ) alkyl
  • R 1O is hydrogen or (Q-C ⁇ alkyl
  • R 9 and R 10 together with the atoms to which they are attached, form a 4-8 membered ring, optionally substituted on carbon with 1, 2, or 3 groups selected from halo,
  • (C r C 6 )alkyl, and -O-(C r C 6 )alkyl, -S-(C r C 6 )alkyl, any of which may be optionally substituted on carbon with 1, 2, or 3 halo, or taken together with the attached carbon form C O; is aryl, aryloxy, heteroaryl, cycloalkyl, or heterocycloalkyl; at least two of three of Z 1 , Z 2 , and Z 3 are N and the other is C-R b , wherein R b is hydrogen, halogen, (Q-C ⁇ alkyl, or (Q-C ⁇ alkoxy;
  • Y is selected from the group consisting of H, halo,
  • Y is H. In some embodiments, Y is Cl. In some embodiments, Y is OH. In some embodiments, Y is OMe. In some embodiments, Y is -NRiR 2 , e.g., a compound of formula II.
  • Ri is selected from the group consisting of hydrogen and (Ci-C 6 )alkyl.
  • R 3 is hydrogen. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl.
  • R 4 is hydrogen. In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is propyl. [00064] In some embodiments, R 5 is methyl. In some embodiments, R 5 is ethyl. In
  • R 5 is phenyl. In some embodiments, R 5 is ⁇ wherein
  • R 5 is aryl optionally
  • -X-R 5 is -SO 2 CH 3 . In some embodiments, -X-R 5 is -COOH. In some embodiments, -X-R 5 is
  • Rn is hydrogen. In some embodiments, Rn is methyl. In some embodiments, Ri 2 is hydrogen. In some embodiments, Ri 2 is methyl.
  • Ri 2 is heteroaryl optionally substituted with 1 group selected from R a . In some embodiments, Ri 2 is thiadiazole optionally substituted with 1 group selected from R a . In some embodiments, Ri 2 is-COCH 3 .
  • m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [00067] In some embodiments, R 6 is methyl. In some embodiments, R 6 is fluoro.
  • R 6 is chloro. In some embodiments, R 6 is hydrogen.
  • R 7 is hydrogen. In some embodiments, R 7 is methoxy. In some embodiments, R 7 is methyl. In some embodiments, R 7 is halogen. In some embodiments, R 7 is chloro.
  • Rg is hydrogen. In some embodiments, Rg is methoxy. In some embodiments, R 8 is methyl. In some embodiments, R 8 is halogen. In some embodiments, R 8 is chloro.
  • Rg is hydrogen. In some embodiments, Rg is methyl. In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is methyl.
  • Rg and Rio are taken together to form a 5-6 membered ring.
  • pyridyl In some embodiments, is cyclohexyl.
  • i -s In some embodiments, M ⁇ v, is .
  • Z 1 is N.
  • Z 2 is N.
  • Z 3 is N.
  • each Of Z 1 , Z 2 and Z 3 are independently N.
  • X is -SO 2 -.
  • X is -CONR 4 -
  • X is -COO-. In some embodiments, X is -SO 2 NR 4 - [00074] In some embodiments, R a is fluoro. In some embodiments, R a is chloro.
  • R a is methyl. In some embodiments, R a is ethyl. In some embodiments, R a is trifluoromethyl. In some embodiments, R a is methoxy. In some embodiments, R a is ethoxy. In some embodiments, R a is trifluoromethoxy. In some embodiments, R a is cyano. In some embodiments, R a is nitro. In some embodiments, R a is hydroxyl. In some embodiments, R a is amino. In some embodiments, R a is -NHCH 3 . In some embodiments, R a is -N(CH 3 ) 2 . In some embodiments, R a is phenyl.
  • R a is CON(CH 3 ) 2 . In some embodiments, R a is OC(O)(CH 3 ). In some embodiments, R a is -OC(O)NH 2 . In some embodiments, R a is -OC(O)NH(CH 3 ). [00075] In some embodiments, R c is chloro. In some embodiments, R c is fluoro.
  • R c is methyl. In some embodiments, R c is trifluoromethyl. In some embodiments, R c is trifluoromethoxy. In some embodiments, R c is cyano. In some embodiments, R c is nitro. In some embodiments, R c is hydroxyl. [00076] In one embodiment, the compounds of the invention are compounds of formula IA
  • the compounds of the invention are compounds of formula IA-i
  • the compounds of the invention are compounds of formula IB
  • compounds of the invention are compounds of formula IC
  • compounds of the invention are compounds of formula ID
  • compounds of the invention are compounds of formula IE
  • compounds of the invention are compounds of formula IF
  • compounds of the invention are compounds of formula IG
  • compounds of the invention are compounds of formula IH
  • compounds of the invention are compounds of formula IJ
  • compounds of the invention are compounds of formula IJ-i
  • compounds of the invention are compounds of formula IK
  • compounds of the invention are compounds of formula IK-i
  • compounds of the invention are compounds of formula IK-ii
  • compounds of the invention are compounds of formula IK-iii
  • compounds of the invention are compounds of formula IL
  • compounds of the invention are compounds of formula IL-i
  • compounds of the invention are compounds of formula IM
  • compounds of the invention are compounds of formula IM-i
  • the compounds of the invention are compounds of formula IN
  • the compounds of the invention are compounds of formula IO
  • compounds of the invention are compounds of formula IP
  • the compounds of the invention are compounds of formula IQ
  • R 5 is hydrogen. In some embodiments, R 5 is methyl.
  • the compounds of the invention are compounds of formula IR
  • R 5 is hydrogen. In some embodiments, R 5 is methyl.
  • R 1 is hydrogen, (Ci-C 6 )alkyl, aryl, aralkyl, (C 3 -C 6 )cycloalkyl, (C 3 - C 6 )cycloalkyl(Ci-C 6 )alkyl, (C 3 -C 6 )heterocycloalkyl, (C 3 -C 6 )heterocycloalkyl(Ci- Ce)alkyl, heteroaryl, heteroaralkyl, (Ci-C 6 )carboxyalkyl, aryloxy(Ci-C 6 )alkyl, - alkylene-NR'R", wherein R' and R" are each independently hydrogen, (Ci- Ce)alkyl, or taken together with the nitrogen to which they are attached, form a 3, 4, 5, or 6-membered saturated or partially unsaturated ring optionally containing 0, 1, or 2 additional heteroatoms selected from O, S(O)x, wherein x is 0, 1, or 2, or N-R' "
  • R 2 is hydrogen, (Ci-C 6 )alkyl, aryl, aralkyl, (C 3 -C 6 )cycloalkyl, (C 3 - C 6 )cycloalkyl(Ci-C 6 )alkyl, (C 3 -C 6 )heterocycloalkyl, (C 3 -C 6 )heterocycloalkyl(Ci- Ce)alkyl, heteroaryl, heteroaralkyl, (Ci-C 6 )carboxyalkyl, aryloxy(Ci-C 6 )alkyl, - alkylene-NR'R", wherein R' and R" are each independently hydrogen, (C 1 - C 6 )alkyl, or taken together with the nitrogen to which they are attached, form a 3, 4, 5, or 6-membered saturated or partially unsaturated ring optionally containing 0, 1, or 2 additional heteroatoms selected from O, S(O)x, wherein x is 0, 1, or 2, or N-
  • X is absent, -CONR 4 -, Or -SO 2 -, -SO 2 NR 4 -, or -COO-;
  • R 4 is hydrogen or (Ci-C 6 )alkyl;
  • R 5 is hydrogen, (Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which may be optionally substituted with 1, 2, or 3 groups
  • R 12 -N independently selected from R a or 11 in which R 11 is hydrogen or (C 1 -
  • R 12 is hydrogen, (C 1 -C 6 ) alkyl, -CO(C 1 -C 6 )alkyl, -CO(C 1 - C 6 )cycloalkyl, -COtQ-Cejlieterocycloalkyl, -CO(C 1 -C 6 ) aryl, -CO(C 1 - C 6 )heteroaryl, cycloalkyl, aryl, or heteroaryl, any of which may be optionally substituted with 1, 2, or 3 groups independently selected from Ra; or R 11 and R 12 can be taken together to form a 5-7 membered heterocycle having 1, 2 or 3 heteroatoms and optionally substituted with R a ; R 6 is hydrogen or (C ⁇ C 6 ) alkyl; R 7 and Rg are each independently hydrogen, halogen, (Ci-C 6 )alkyl or (Ci-
  • Ce)alkoxy either of which may be optionally substituted on carbon with 1, 2, or
  • Rg is hydrogen, halo or (Ci-C 6 )alkyl
  • R 10 is hydrogen or (Ci-Ce)alkyl
  • Rg and Rio together with the atoms to which they are attached, form a 4-8 membered ring, optionally substituted on carbon with 1, 2, or 3 groups selected from halo,
  • (Ci-C 6 )alkyl, and -O-(d-C 6 )alkyl, -S-(d-C 6 )alkyl, any of which may be optionally substituted on carbon with 1, 2, or 3 halo, or taken together with the attached carbon form C O; is aryl, aryloxy, heteroaryl, cycloalkyl, or heterocycloalkyl; at least two of three of Zi, Z 2 , and Z 3 are N and the other is C-R b , wherein R b is hydrogen, halogen, (Ci-Ce)alkyl, or (Ci-C 6 )alkoxy;
  • R a is halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, (Ci-C 6 )alkyl-NH, ((Ci-C 6 )alkyl) 2 -N, aryl, heteroaryl, (C 3 -C 7 )cycloalkyl, (C 1 - C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (Ci-C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 1 - C 6 )alkynyloxy, (Ci-C 6 )alkylthio, (Ci-C 6 )alkylsulfinyl, (Ci-C 6 )alkylsulfonyl, amino, (Ci-C 6 )alkylamino, di-[(Ci-C 6 )alkyl]
  • Ri is selected from the group consisting of hydrogen and (Ci-C 6 )alkyl. In some embodiments, Ri is hydrogen. In some embodiments, Ri is methyl. In some embodiments, Ri is ethyl. [000103] In some embodiments, R 2 is methyl. In some embodiments, R 2 is isopropyl. In some embodiments, R 2 is cyclohexyl. In some embodiments, R 2 is benzyl.
  • R 2 is phenyl. In some embodiments, R 2 is wherein "— " indicates the point of attachment. In some embodiments, R 2 is
  • R 2 is , wherein "— " indicates the point of attachment.
  • R 3 is hydrogen. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl.
  • R 4 is hydrogen. In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is propyl. [000106] In some embodiments, R 5 is methyl. In some embodiments, R 5 is ethyl.
  • R 5 is phenyl. In some embodiments, R 5 is wherein "— " indicates the point of attachment. In some embodiments, R 5 is aryl
  • R 12 -N optionally substituted with 1 group selected from R a or 11 .
  • -X-R 5 is -SO 2 CH 3 .
  • -X-R 5 is -COOH.
  • -X-R 5 is -C(CH 3 ) 3 .
  • Rn is hydrogen. In some embodiments, Rn is methyl. In some embodiments, R 12 is hydrogen. In some embodiments, R 12 is methyl. In some embodiments, R 12 is heteroaryl optionally substituted with 1 group selected from R a . In some embodiments, R 12 is thiadiazole optionally substituted with 1 group selected from R a .
  • m is 0. In some embodiments, m is 1. In some embodiments, m is 2.
  • R 6 is methyl. In some embodiments, R 6 is fluoro.
  • R 6 is chloro. In some embodiments, R 6 is hydrogen.
  • R 7 is hydrogen. In some embodiments, R 7 is methoxy. In some embodiments, R 7 is methyl. In some embodiments, R 7 is halogen. In some embodiments, R 7 is chloro.
  • R is hydrogen. In some embodiments, R is
  • R is methyl. In some embodiments, R is halogen. In
  • R is chloro
  • R 9 is hydrogen. In some embodiments, R 9 is methyl. In some embodiments, Rio is hydrogen. In some embodiments, Rio is methyl. In some embodiments, R 9 and Ri 0 are taken together to form a 5-6 membered ring.
  • pyridyl In some embodiments, is cyclohexyl.
  • I iSs N . IInn some embodiments,
  • Z 3 2 is N In some embodiments, Z 3 2 is ⁇ s ⁇ . In some embodiments, Zi is N. In some embodiments, Z 2 is N. In some embodiments, Z 3 is N. In some embodiments, each of Zi, Z 2 and Z 3 are independently N. [000115] In some embodiments, X is -SO 2 -. In some embodiments, X is -CONR 4 - . In some embodiments, X is -COO-. In some embodiments, X is -SO 2 NR 4 -. [000116] In some embodiments, R a is fluoro. In some embodiments, R a is chloro. In some embodiments, R a is methyl. In some embodiments, R a is ethyl.
  • R a is trifluoromethyl. In some embodiments, R a is methoxy. In some embodiments, R a is ethoxy. In some embodiments, R a is trifluoromethoxy. In some embodiments, R a is cyano. In some embodiments, R a is nitro. In some embodiments, R a is hydroxyl. In some embodiments, R a is amino. In some embodiments, R a is -NHCH 3 . In some embodiments, R a is -N(CH 3 ) 2 . In some embodiments, R a is phenyl. In some embodiments, R a is pyridyl.
  • R a is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R a is vinyl, propenyl, or butenyl.
  • R a is acetylenyl, propynyl or butynyl.
  • R a is methylthio.
  • R a is methylsulfinyl.
  • R a is methylsulfonyl.
  • R a is formyl.
  • R a is -OC(O)NH 2 . In some embodiments, R a is -OC(O)NH(CH 3 ).
  • R c is chloro. In some embodiments, R c is fluoro. In some embodiments, R c is methyl. In some embodiments, R c is trifluoromethyl. In some embodiments, R c is trifluoromethoxy. In some embodiments, R c is cyano. In some embodiments, R c is nitro. In some embodiments, R c is hydroxyl. [000118] In one embodiment, compounds of the invention are compounds of formula HA
  • compounds of the invention are compounds of formula HB or pharmaceutically acceptable salts thereof.
  • compounds of the invention are compounds of formula HC
  • compounds of the invention are compounds of formula HD
  • compounds of the invention are compounds of formula HE
  • compounds of the invention are compounds of formula HF
  • compounds of the invention are compounds of formula HG
  • compounds of the invention are compounds of formula IIH
  • compounds of the invention are compounds of formula IU or pharmaceutically acceptable salts thereof.
  • compounds of the invention are compounds of formula HK
  • compounds of the invention are compounds of formula HL
  • compounds of the invention are compounds of formula IIM
  • compounds of the invention are compounds of formula UN
  • the invention is directed to a compound of formula
  • Y is H, halo, ORi, SRi, (d-C 8 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, aralkyl, (C 3 - C 6 )heterocycloalkyl, heteroaryl, heteroaralkyl, or NR 1 R 2 ;
  • Ri is hydrogen, (Ci-C 6 )alkyl, aryl, aralkyl, (C 3 -C 6 )cycloalkyl, (C 3 - C 6 )cycloalkyl(Ci-C 6 )alkyl, (C 3 -C 6 )heterocycloalkyl, (C 3 -C 6 )heterocycloalkyl(Ci- Ce)alkyl, heteroaryl, heteroaralkyl, (Ci-C 6 )carboxyalkyl, aryloxy(Ci-C 6 )alkyl, - alkylene-NR'R", where
  • R 2 is hydrogen, (Ci-C 6 )alkyl, aryl, aralkyl, (C 3 -C 6 )cycloalkyl, (C 3 - C 6 )cycloalkyl(Ci-C 6 )alkyl, (C 3 -C 6 )heterocycloalkyl, (C 3 -C 6 )heterocycloalkyl(Ci- Ce)alkyl, heteroaryl, heteroaralkyl, (Ci-C 6 )carboxyalkyl, aryloxy(Ci-C 6 )alkyl, - alkylene-NR'R", wherein R' and R" are each independently hydrogen, (Ci- Ce)alkyl, or taken together with the nitrogen to which they are attached, form a 3, 4, 5, or 6-membered saturated or partially unsaturated ring optionally containing 0, 1, or 2 additional heteroatoms selected from O, S(O)x, wherein x is 0, 1, or 2, or N-R"
  • R 3 is hydrogen or (Ci-C 6 )alkyl; m is O, I, or 2;
  • R 4 is hydrogen or (Ci -C 6 ) alkyl
  • R 6 is hydrogen or (Ci-C 6 )alkyl
  • R 7 and R 8 are each independently hydrogen, halogen, (Ci-C 6 )alkyl or (Ci-
  • Ce)alkoxy either of which may be optionally substituted on carbon with 1, 2, or
  • R 9 is hydrogen, halo or (Ci -C 6 ) alkyl; Rio is hydrogen or (Ci-C 6 )alkyl; or
  • R 9 and Ri 0 together with the atoms to which they are attached, form a 4-8 membered ring, optionally substituted on carbon with 1, 2, or 3 groups selected from halo,
  • (Ci-C 6 )alkyl, and -O-(d-C 6 )alkyl, -S-(d-C 6 )alkyl, any of which may be optionally substituted on carbon with 1, 2, or 3 halo, or taken together with the attached carbon form C O; is aryl, aryloxy, heteroaryl, cycloalkyl, or heterocycloalkyl;
  • B is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • Rn is hydrogen or (Ci-C 6 ) alkyl
  • R J2 is hydrogen, (Ci-C 6 ) alkyl, -CO(Ci- C 6 )alkyl, -CO(Cj -C 6 )cycloalkyl, -CO(Ci-C 6 )heterocycloalkyl, -CO(Ci-C 6 ) aryl, - CO(Ci-C 6 )heteroaryl, cycloalkyl, aryl, or heteroaryl, any of which may be optionally substituted with 1, 2, or 3 groups independently selected from Ra; or Rn and R 12 can be taken together to form a 5-7 membered heterocycle having 1, 2 or 3 heteroatoms and optionally substituted with R a ; at least two of three of Z 1 , Z 2 , and Z 3 are N and the other is C-R b , wherein R b is hydrogen, halogen, (Ci-C 6 )alkyl, or (C
  • R a is halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, (Ci-C 6 )alkyl-NH, ((Ci-C 6 )alkyl) 2 -N, aryl, heteroaryl, (C 3 -C 7 )cycloalkyl, (C 1 - C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C r C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 1 - C 6 )alkynyloxy, (C r C 6 )alkylthio, (C r C 6 )alkylsulfinyl, (C r C 6 )alkylsulfonyl, amino, (Ci-C 6 )alkylamino, di-[(Ci-C 6 )alkyl]
  • Y is selected from the group consisting of H, halo, OR 1 , (CrC 8 )alkyl, and NR 1 R 2 .
  • Y is H.
  • Y is Cl.
  • Y is OH.
  • Y is OMe.
  • Y is -NRiR 2 .
  • R 1 is selected from the group consisting of hydrogen and (Ci-C 6 )alkyl.
  • Ri is hydrogen.
  • Ri is methyl.
  • Ri is ethyl.
  • R 2 is methyl.
  • R 2 is isopropyl.
  • R 2 is cyclohexyl.
  • R 2 is benzyl.
  • R 2 is phenyl. In some embodiments, R 2 is wherein "— " indicates the point of attachment. In some embodiments, R 2 is
  • R 2 is ' , wherein "— " indicates the point of attachment.
  • R 3 is hydrogen. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl.
  • R 4 is hydrogen. In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is propyl.
  • Rn is hydrogen. In some embodiments, Rn is methyl. In some embodiments, Ri 2 is hydrogen. In some embodiments, Ri 2 is methyl.
  • R 12 is heteroaryl optionally substituted with 1 group selected from R a .
  • Ri 2 is thiadiazole optionally substituted with 1 group selected from R a .
  • R 12 is -COCH 3 .
  • m is 0. In some embodiments, m is 1. In some embodiments, m is 2.
  • R 6 is methyl. In some embodiments, R 6 is fluoro.
  • R 6 is chloro. In some embodiments, R 6 is hydrogen.
  • R 7 is hydrogen. In some embodiments, R 7 is methoxy. In some embodiments, R 7 is methyl. In some embodiments, R 7 is halogen. In some embodiments, R 7 is chloro.
  • R 8 is hydrogen. In some embodiments, R 8 is methoxy. In some embodiments, R 8 is methyl. In some embodiments, R 8 is halogen. In some embodiments, R 8 is chloro. [000143] In some embodiments, Rg is hydrogen. In some embodiments, Rg is methyl. In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is methyl. In some embodiments, R 9 and R 10 are taken together to form a 5-6 membered ring.
  • pyridyl In some embodiments, is cyclohexyl. In some embodiments, is
  • — is pyridyl. In some embodiments, — is cyclohexyl.
  • IInn is IInn : some embodiments,
  • Z 3 2 is N In some embodiments, Z 3 2 is ⁇ s ⁇ . In some embodiments, Zi is N. In some embodiments, Z 2 is N. In some embodiments, Z 3 is N. In some embodiments, each Of Z 1 , Z 2 and Z 3 are independently N. [000146] In some embodiments, X is -SO 2 -. In some embodiments, X is -CONR 4 - . In some embodiments, X is -COO-.
  • R a is fluoro. In some embodiments, R a is chloro. In some embodiments, R a is methyl. In some embodiments, R a is ethyl. In some embodiments, R a is trifluoromethyl. In some embodiments, R a is methoxy. In some embodiments, R a is ethoxy. In some embodiments, R a is trifluoromethoxy. In some embodiments, R a is cyano. In some embodiments, R a is nitro. In some embodiments, R a is hydroxyl. In some embodiments, R a is amino. In some embodiments, R a is -NHCH 3 .
  • R a is -N(CHs) 2 . In some embodiments, R a is phenyl. In some embodiments, R a is pyridyl. In some embodiments, R a is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R a is vinyl, propenyl, or butenyl. In some embodiments, R a is acetylenyl, propynyl or butynyl. In some embodiments, R a is methylthio. In some embodiments, R a is methylsulfinyl. In some embodiments, R a is methylsulfonyl.
  • R a is CON(CH 3 ) 2 . In some embodiments, R a is OC(O)(CH 3 ). In some embodiments, R a is -OC(O)NH 2 . In some embodiments, R a is -OC(O)NH(CH 3 ). [000148] In some embodiments, R c is chloro. In some embodiments, R c is fluoro. In some embodiments, R c is methyl. In some embodiments, R c is trifluoromethyl. In some embodiments, R c is trifluoromethoxy. In some embodiments, R c is cyano. In some embodiments, R c is nitro. In some embodiments, R c is hydroxyl. [000149] In one embodiment, compounds of the invention are compounds of formula IIIA
  • compounds of the invention are compounds of formula IIIB
  • compounds of the invention are compounds of formula IIIC
  • compounds of the invention are compounds of formula HID
  • compounds of the invention are compounds of formula HIE
  • compounds of the invention are compounds of formula IIIF
  • compounds of the invention are compounds of formula IIIG or pharmaceutically acceptable salts thereof.
  • the invention is directed to a compound of formula
  • Y is H, halo, ORi, SRi, (d-C 8 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, aralkyl, (C 3 - C 6 )heterocycloalkyl, heteroaryl, heteroaralkyl, or NR 1 R 2 ;
  • Ri is hydrogen, (Ci-C 6 )alkyl, aryl, aralkyl, (C 3 -C 6 )cycloalkyl, (C 3 - C 6 )cycloalkyl(Ci-C 6 )alkyl, (C 3 -C 6 )heterocycloalkyl, (C 3 -C 6 )heterocycloalkyl(Ci- Ce)alkyl, heteroaryl, heteroaralkyl, (Ci-C 6 )carboxyalkyl, aryloxy(Ci-C 6 )alkyl, - alkylene-NR'R", where
  • R 2 is hydrogen, (Ci-C 6 )alkyl, aryl, aralkyl, (C 3 -C 6 )cycloalkyl, (C 3 - C 6 )cycloalkyl(Ci-C 6 )alkyl, (C 3 -C 6 )heterocycloalkyl, (C 3 -C 6 )heterocycloalkyl(Ci- Ce)alkyl, heteroaryl, heteroaralkyl, (Ci-C 6 )carboxyalkyl, aryloxy(Ci-C 6 )alkyl, - alkylene-NR'R", wherein R' and R" are each independently hydrogen, (Ci- Ce)alkyl, or taken together with the nitrogen to which they are attached, form a 3, 4, 5, or 6-membered saturated or partially unsaturated ring optionally containing 0, 1, or 2 additional heteroatoms selected from O, S(O)x, wherein x is 0, 1, or 2, or N-R"
  • R 3 is hydrogen or (Ci-C 6 )alkyl; m is O, I, or 2;
  • X is absent, -CONR 4 -, Or -SO 2 -, -SO 2 NR 4 -, or -COO-;
  • R 4 is hydrogen or (Ci-C 6 )alkyl
  • R 5 is hydrogen, (Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which may be optionally substituted with 1, 2, or 3 groups
  • R 12 -N independently selected from R a or 11 in which R 11 is hydrogen or (C 1 -
  • R 12 is hydrogen, (C 1 -C 6 ) alkyl, -CO(C 1 -C 6 )alkyl, -CO(C 1 - C 6 )cycloalkyl, -CO(C 1 -C 6 ) aryl, -CO(C 1 - C 6 )heteroaryl, cycloalkyl, aryl, or heteroaryl, any of which may be optionally substituted with 1, 2, or 3 groups independently selected from Ra; or R 11 and R 12 can be taken together to form a 5-7 membered heterocycle having 1, 2 or 3 heteroatoms and optionally substituted with R a ; R 6 is hydrogen or (Ci-C 6 )alkyl; n is 0, 1, 2 or 3;
  • R 7 and Rg are each independently hydrogen, halogen, (C 1 -C 6 )alkyl or (C 1 - C 6 )alkoxy, either of which may be optionally substituted on carbon with 1, 2, or
  • R 3 groups independently selected from R a ; is aryl, aryloxy, heteroaryl, cycloalkyl, or heterocycloalkyl; at least two of three of Z 1 , Z 2 , and Z 3 are N and the other is C-R b , wherein R b is hydrogen, halogen, (CrC ⁇ jalkyl, or (CrC ⁇ jalkoxy;
  • R a is halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, (C 1 -C 6 )alkyl-NH, ((C 1 -C 6 )alkyl) 2 -N, aryl, heteroaryl, (C 3 -C 7 )cycloalkyl, (C 1 - C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 1 - C 6 )alkynyloxy, (Ci-C 6 )alkylthio, (Ci-C 6 )alkylsulfinyl, (Ci-C 6 )alkylsulfonyl, amino, (Ci-C 6 )alkylamino, di-[(Ci-C 6 )al
  • the invention is directed to a compound of any of formulae I-III , wherein the compound is selected from:
  • ADAM TS4 Fluorogenic Assay The biological activity of exemplary compounds disclosed herein was measured using an assay as disclosed in Zhang, Y. et al (2004) Journal of Pharm. And Exp. Therapeutics 309(1): 348-355, the entire contents of which are incorporated herein by reference.
  • the ADAM TS4 (aggrecanase) fluorogenic assay was performed using the WAAG-3R fluorescent substrate (Anaspec, Catalog # 60431-1 Abz-TEGEARGSVI- Dap(Dnp)-KK).
  • the assay buffer contains 5OmM HEPES (pH 7.5) 10OmM NaCl, 5mM CaCl 2 , 0.1% CHAPS, 5% Glycerol.
  • the total reaction volume is 40 ⁇ l.
  • the aggrecanase enzyme full length 68kDa supplied by GSK is used at a final concentration of 48nM.
  • the inhibitor compounds are re-suspended in 100% DMSO and then diluted with Ix assay buffer to a 10x concentration (10% DMSO).
  • the aggrecanase enzyme is incubated with various inhibitor compound concentrations, shaking, for 30 minutes at room temperature.
  • the reaction is initiated by adding the diluted WAAG-3R substrate (final concentration 25 ⁇ M).
  • the fluorescence was monitored at an excitation of 34OnM and an emission of 42OnM.
  • the reaction is run at 37 0 C and readings are taken every 30 seconds for 1 hour.
  • Activity is measured as the % inhibition using the following equation: 100*(l-(slope of enzyme + inhibitor/ slope of enzyme alone). Activities for invention compounds were measured as IC 50 values, which is the concentration of inhibitor that blocks enzyme activity to 50%
  • the compounds of the present invention can be administered orally using any pharmaceutically acceptable dosage form known in the art for such administration.
  • the active ingredient can be supplied in solid dosage forms such as dry powders, granules, tablets or capsules, or in liquid dosage forms, such as syrups or aqueous suspensions.
  • the active ingredient can be administered alone, but is generally administered with a pharmaceutical carrier.
  • a valuable treatise with respect to pharmaceutical dosage forms is Remington's Pharmaceutical Sciences, Mack Publishing.
  • the compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
  • intravenous bolus or infusion
  • intraperitoneal subcutaneous
  • intramuscular form all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.
  • An effective but nontoxic amount of the compound desired can be employed as an anti-inflammatory and anti-arthritic agent.
  • the compounds of this invention can be administered by any means that produces contact of the active agent with the agent's site of action in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • the dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
  • the daily oral dosage of each active ingredient when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day. For a normal male adult human of approximately 70 kg of body weight, this translates into a dosage of 70 to 1400 mg/day.
  • the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
  • the compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches wall known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as carrier materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture.
  • suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide -phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
  • Dosage forms suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit.
  • the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
  • the active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.
  • Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like.
  • Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of e medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. [000175] In general, water, suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
  • citric acid and its salts and sodium EDTA are suitable stabilizing agents.
  • parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
  • Scheme 1 summarizes the preparation of the compounds of the invention.
  • the solution was diluted with dichloromethane (50 ml), which was further washed with saturated sodium bicarbonate (25 ml), water (25 ml), salt (25 ml) and dried over Mg 2 SO 4 .
  • the solvent was removed in vacuo to give tert-butyl A- (ethyl(m-tolyl)carbamoyl)benzylcarbamate.
  • the acylation product was treated with 50% TFA in dichloromethane (25 ml) at room temperature for 20 minutes.
  • the pure product can be obtained through the purification with RP-HPLC (Luna, 5 ⁇ C8(2), 100x21mm, 40-95% CH3C ⁇ /H 2 O, 0.1% TFA, 20 min). MS: calcd for C31H33C1N6O3+H + 573.24, found 573.3.
  • the pure product can be obtained through the purification with RP-HPLC (Luna, 5 ⁇ C8(2), 100x21mm, 40-95% CH 3 C ⁇ /H 2 O, 0.1% TFA, 20 min). MS: calcd for C29H29C1N6O+H + 513.22, found 513.30.
  • reaction solution was neutralized and directly purified with RP- HPLC (Luna, 5 ⁇ C8(2), 100x21mm, 4-40% CH 3 CN/H 2 O, 0.1% TFA, 19 min) to give the desired product as a TFA salt (3.5 mg, 35% yied).
  • reaction solution was acidified and directly purified with RP- ⁇ PLC (Luna, 5 ⁇ C8(2), 100x21mm, 40-95% CH 3 CN/H 2 O, 0.1% TFA, 20 min) to give the desired product as TFA salt (18.9 mg, 57%).

Abstract

La présente invention concerne des composés de formule (I) : qui modulent, par exemple inhibent, l'activité protéolytique de l'aggrécanase, impliquée dans les pathologies articulaires, y compris l'arthrose, les lésions articulaires, l'arthrite réactionnelle, la chondrocalcinose, l'arthrite psoriasique et la polyarthrite rhumatoïde. La présente invention concerne également les procédés de fabrication des composés selon l'invention et les compositions pharmaceutiques contenant lesdits composés. La présente invention concerne en outre des méthodes de traitement des pathologies associées à l'activité de l'aggrécanase, par exemple l'arthrose ou d'autres pathologies articulaires, à l'aide des composés selon l'invention.
PCT/US2009/031575 2009-01-21 2009-01-21 Dérivés de 2,4-diamino-1,3,5-triazine et de 4,6-diamino-pyrimidine et leur emploi en tant qu'inhibiteurs d'aggrécanase WO2010085246A1 (fr)

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WO2012024489A3 (fr) * 2010-08-18 2012-06-07 Emory University Composés et compositions pour ossification et procédés associés à ceux-ci
US11844802B2 (en) 2010-08-18 2023-12-19 Emory University Compounds and compositions for ossification and methods related thereto
US9511071B2 (en) 2010-08-18 2016-12-06 Emory University Compounds and compositions for ossification and methods related thereto
US11471461B2 (en) 2010-08-18 2022-10-18 Emory University Compounds and compositions for ossification and methods related thereto
US9808464B2 (en) 2010-08-18 2017-11-07 Emory University Compounds and compositions for ossification and methods related thereto
US10888565B2 (en) 2010-08-18 2021-01-12 Emory University Compounds and compositions for ossification and methods related thereto
CN104903312A (zh) * 2013-10-07 2015-09-09 卡德门企业有限公司 Rho激酶抑制剂
CN104903312B (zh) * 2013-10-07 2019-01-29 卡德门企业有限公司 Rho激酶抑制剂
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US11254644B2 (en) 2014-08-29 2022-02-22 Tes Pharma S.R.L. Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase
US9708272B2 (en) 2014-08-29 2017-07-18 Tes Pharma S.R.L. Inhibitors of α-amino-β-carboxymuconic acid semialdehyde decarboxylase
CN109438473A (zh) * 2018-12-07 2019-03-08 武汉工程大学 一种氧氟沙星-磺胺醋酰杂合药物及其制备方法和应用
WO2021214637A1 (fr) * 2020-04-20 2021-10-28 St. Jude Children's Research Hospital Compositions et méthodes pour le traitement de maladies respiratoires

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