WO2006019768A1 - Hydantoin derivatives for the treatment of inflammatory disorders - Google Patents

Hydantoin derivatives for the treatment of inflammatory disorders Download PDF

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Publication number
WO2006019768A1
WO2006019768A1 PCT/US2005/024771 US2005024771W WO2006019768A1 WO 2006019768 A1 WO2006019768 A1 WO 2006019768A1 US 2005024771 W US2005024771 W US 2005024771W WO 2006019768 A1 WO2006019768 A1 WO 2006019768A1
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compound
group
alkyl
aryl
mmol
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PCT/US2005/024771
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French (fr)
Inventor
Wensheng Yu
Ling Tong
Lei Chen
Joseph A. Kozlowski
Brian J. Lavey
Neng-Yang Shih
Vincent S. Madison
Gouwei Zhou
Peter Orth
Zhuyan Guo
Michael K. C. Wong
De-Yi Yang
Seong Heon Kim
Bandarpalle Shankar
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Schering Corporation
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Priority to JP2007521589A priority Critical patent/JP4943327B2/en
Priority to MX2007000668A priority patent/MX2007000668A/en
Priority to EP05771446A priority patent/EP1778676B1/en
Priority to CA002573764A priority patent/CA2573764A1/en
Priority to AT05771446T priority patent/ATE478864T1/en
Application filed by Schering Corporation filed Critical Schering Corporation
Priority to DE602005023172T priority patent/DE602005023172D1/en
Priority to KR1020077001084A priority patent/KR20070032787A/en
Priority to BRPI0513433-1A priority patent/BRPI0513433A/en
Priority to AU2005275213A priority patent/AU2005275213A1/en
Publication of WO2006019768A1 publication Critical patent/WO2006019768A1/en
Priority to IL180736A priority patent/IL180736A0/en
Priority to NO20070893A priority patent/NO20070893L/en

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Definitions

  • This invention relates generally to novel hydantoin derivatives that can inhibit matrix metalloproteinases (MMPs), a disintegrin and metalloproteases (ADAMs) and/or tumor necrosis factor alpha - converting enzyme (TACE) and in so doing prevent the release of tumor necrosis factor alpha (TNF- ⁇ ), pharmaceutical compositions comprising such compounds, and methods of treatment using such compounds.
  • MMPs matrix metalloproteinases
  • ADAMs disintegrin and metalloproteases
  • TACE tumor necrosis factor alpha - converting enzyme
  • Osteo- and rheumatoid arthritis are destructive diseases of articular cartilage characterized by localized erosion of the cartilage surface. Findings have shown that articular cartilage from the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabeled sulfate over controls, suggesting that there must be an enhanced rate of cartilage degradation in OA (Mankin et al. J. Bone Joint Surg. 52A (1970) 424-434).
  • MMPs Metalloproteases
  • these catabolic enzymes are tightly regulated at the level of their synthesis as well as at their level of extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIiVlPs (tissue inhibitor of MPs), which form inactive complexes with the MMP 1 S.
  • specific inhibitors such as alpha-2-macroglobulins and TIiVlPs (tissue inhibitor of MPs), which form inactive complexes with the MMP 1 S.
  • Tumor necrosis factor alpha is a cell-associated cytokine that is processed from a 26 kDa precursor form to a 17 kd active form. See Black R.A. "Tumor necrosis factor-alpha converting enzyme” lnt J Biochem Cell Biol. 2002 Jan; 34(1): 1-5 and Moss ML, White JM, Lambert MH, Andrews RC.'TACE and other ADAM proteases as targets for drug discovery" Drug Discov Today. 2001 Apr 1 ;6(8):417-426, each of which is incorporated by reference herein.
  • TNF- ⁇ has been shown to play a pivotal role in immune and inflammatory responses. Inappropriate or over-expression of TNF- ⁇ is a hallmark of a number of diseases, including RA, Crohn's disease, multiple sclerosis, psoriasis and sepsis. Inhibition of TNF- ⁇ production has been shown to be beneficial in many preclinical models of inflammatory disease, making inhibition of TNF- ⁇ production or signaling an appealing target for the development of novel anti-inflammatory drugs.
  • TNF- ⁇ is a primary mediator in humans and animals of inflammation, fever and acute phase responses, similar to those observed during acute infection and shock. Excess TNF- ⁇ has been shown to be lethal. Blocking the effects of TNF- ⁇ with specific antibodies can be beneficial in a variety of conditions, including autoimmune diseases such as RA (Feldman et al, Lancet, (1994) 344, 1105), non-insulin dependent diabetes mellitus (Lohmander L. S. et al., Arthritis Rheum. 36 (1993) 1214-22) and Crohn's disease (Macdonald T. et al., Clin. Exp. Immunol. 81 (1990) 301).
  • RA Paindman et al, Lancet, (1994) 344, 1105
  • non-insulin dependent diabetes mellitus Lihmander L. S. et al., Arthritis Rheum. 36 (1993) 1214-22
  • Crohn's disease Macdonald T. e
  • TNF- ⁇ Compounds that inhibit the production of TNF- ⁇ are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently it has been shown that metalloproteases, such as TACE, are capable of converting TNF- ⁇ from its inactive to active form (Gearing et al Nature, 1994, 370, 555). Since excessive TNF- ⁇ production has been noted in several disease conditions also characterized by MMP-mediated tissue degradation, compounds which inhibit both MiViPs and TNF- ⁇ production may also have a particular advantage in diseases where both mechanisms are involved.
  • TACE is a member of the ADAM family of type I membrane proteins and mediates the ectodomain shedding of various membrane-anchored signaling and adhesion proteins. TACE has become increasingly important in the study of several diseases, including inflammatory disease, because of its role in cleaving TNF- ⁇ from its "stalk" sequence and thus releasing the soluble form of the TNF- ⁇ protein (Black R.A. lnt J Biochem Cell Biol. 2002 34,1-5).
  • the present invention provides a novel class of compounds as inhibitors of TACE, the production of TNF- ⁇ , MiVlPs, ADAMs or any combination thereof, methods of preparing such compounds, pharmaceutical compositions comprising one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition or amelioration of one or more diseases associated with TACE, TNF- ⁇ , MMPs, ADAMs or any combination thereof using such compounds or pharmaceutical compositions.
  • the present application discloses a compound, or pharmaceutically acceptable salts or solvates of said compound, said compound having the general structure shown in formula (I):
  • X is selected from the group consisting of -S-, -C(R ) 2 - or -N(R )- ;
  • T is selected from the group consisting of H (with U and V being absent), alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, and arylalkyl, said aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl being optionally fused with one or more moieties selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl, wherein each of any of the aforementioned alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl groups of T is unsubstituted or optionally independently substituted with one to four R 10 moieties which can be the same or different, each R 10 moiety being independently selected from the group of R 10 moieties below;
  • U is absent or present, and if present U is selected from the group consisting of a covalent bond, -N(R 4 )-, -N(R 4 )C(R 4 ) 2 -, -N(R 4 )C(O)-, -O-,
  • V is absent or present, and if present V is selected from the group consisting of alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl, said aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl being optionally fused with one or more moieties selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl, wherein each of any of the aforementioned alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl is unsubstituted or optionally independently substituted with one to four R 10 moieties which can be the same or different, each R 10 moiety being independently selected from the group of R 10 moieties below;
  • Y is absent or present, and if present Y is selected from the group consisting of a covalent bond, -(C(R 4 ) 2 ) n -, -N(R 4 )-, -C(O)N(R 4 )-, -N(R 4 )C(O)-, -N(R 4 )C(O)N(R 4 )-, -S(O) 2 N(R 4 )-, -N(R 4 )-S(O) 2 , -O- -S-, -C(O)-, -S(O)-, and -S(O) 2 -;
  • Z is absent or present, and if present Z is selected from the group consisting of a covalent bond, -(C(R 4 ) 2 ) n -, -N(R 4 )-, -C(O)N(R 4 )-, -N(R 4 )C(O)-, -N(R 4 )C(O)N(R 4 )-, -S(O) 2 N(R 4 )-, -N(R 4 )-S(O) 2 -, -O- -S-, -C(O)-, -S(O)-, and -S(O) 2 -; n is 1 to 3;
  • R is selected from the group consisting of H, -OR 4 , halogen, alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl, wherein each of the alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl groups of R is unsubstituted or optionally independently substituted with one to four R 20 moieties which can be the same or different, each R 20 moiety being independently selected from the group of R 20 moieties below, with the proviso that when Y is present and Y is N, S or O, then R 1 is not halogen; R is selected from the group consisting of H, -OR 4 , halogen, alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroary
  • R alkylaryl, alkylheteroaryl and arylalkyl groups of R is unsubstituted or optionally independently substituted with one to four R 20 moieties which can be the same or different, each R 20 moiety being independently selected from the group of R 20 moieties below, with the proviso that when Z is present and Z is N, S or O, then R 2 is not halogen;
  • each R is the same or different and is independently selected from the group consisting of H and alkyl
  • R is selected from the group consisting of -OR 4 , -N(R ) 2, -S(O)-,
  • R is selected from the group consisting of halogen, alkyl, fluoroalkyl
  • R is selected from the group consisting of halogen, alkyl, and fluoroalkyl.
  • the compounds of Formula I can be useful as inhibitors of TACE and may be useful in the treatment and prevention of diseases associated with TACE, TNF- ⁇ , MMPs, ADAMs or any combination thereof.
  • the present invention provides a novel class of inhibitors of TACE, the production of TNF- ⁇ , MMPs, ADAMs or any combination thereof, pharmaceutical compositions containing one or more of the compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention or amelioration of one or more of the symptoms of inflammation.
  • the present invention provides compounds which are represented by structural Formula (I) above or a pharmaceutically acceptable salt, solvate or isomer thereof, wherein the various moieties are as described above.
  • the isomer referred to the in the preceding paragraph is a stereoisomer.
  • T is alkyl or aryl; X is -C(R ) 2 -; Y is absent; Z is
  • R is selected from the group consisting of H, halogen and alkyl; and if Z is present Z is -O-.
  • T is alkyl or aryl; X is -C(R ) 2 -; Y is absent; Z
  • R is selected from the group consisting of alkylaryl and alkylheteroaryl.
  • T is alkyl or aryl; X is -N(R )- ; Y is absent; Z is
  • R is selected from the group consisting of H, halogen and alkyl; and if Z is present Z is -O-.
  • X is -CH 2 - or -N(R )- . In yet another embodiment, X is -CH 2 -.
  • X is -N(R )-.
  • R is H
  • T is alkyl
  • T is -CH 3 .
  • T is aryl and said aryl is unsubstituted or optionally independently substituted with one to five R 10 moieties which can be the same or different, each R 10 moiety being independently selected from the group of R 10 moieties.
  • R 10 is halogen
  • R 10 is heteroaryl
  • R 10 is aryl
  • U selected from the group consisting of a covalent bond, -N(R 4 )-, -N(R 4 )C(C>)-, and -N(R 4 )S(O) 2 -.
  • LJ is a covalent bond.
  • U is -N(R )-.
  • U is -N(R )C(O)-.
  • V is selected from the group consisting of aryl, heteroaryl, heterocyclyl and cycloalkyl, said aryl, heteroaryl, heterocyclyl, and cycloalkyl being optionally fused with one or more moieties selected from the group consisting of aryl, heteroaryl, heterocyclyl, or cycloalkyl, wherein each of any of said aryl, heteroaryl, heterocyclyl and cycloalkyl is unsubstituted or optionally independently substituted with one to four R 10 moieties which can be the same or different, each R 10 moiety being independently selected from the group of R 10 moieties.
  • Y is selected from the group consisting of a covalent bond, -(G(R 4 ) 2 ) n -, -C(O)- and -O-.
  • Y is -O-.
  • Y is -(G(R 4 ) 2 ) n -.
  • Y is -C(O)-.
  • Y is a covalent bond.
  • R 1 is selected from the group consisting of -OR 4 , H, alkyl, fluoroalkyl, alkylaryl, halogen, and heteroaryl.
  • R 1 is H.
  • R 1 is alkylaryl
  • R 1 is alkyl
  • R 1 is fluoroalkyl
  • R 1 is halogen
  • R 1 is -OR 4 .
  • R 4 is -CH 2 C ⁇ CCH 3 .
  • R 4 is ⁇ CH 2 ⁇ J_
  • the alkyl is -CH 3 .
  • the alkyl is -CH 2 CH 3 .
  • T, U, and V are taken together to
  • R 1 is selected from the group consisting of F, Cl, OH,
  • R 1 is selected from the group consisting of F, Cl, OH,
  • R is selected from the group consisting of F, Cl, OH,
  • R 1 is selected from the group consisting of F, Cl, OH,
  • R 2 is selected from the group consisting of F, Cl,
  • R 2 is selected from the group consisting of F, Cl, OH,
  • R 2 is selected from the group consisting of F, Cl, OH, -OCH 2 C ⁇ CCH 3, -OCH 2 C ⁇ CCH 2 OH, -OCH 3 , and -QGH 2 O-
  • R 2 is selected from the group consisting of F, Cl, OH,
  • the fluoroalkyl is -CH 2 CF 3 .
  • halogen is selected from the group consisting of -Br, -Cl and -F.
  • R 4 is -CH 3 .
  • alkyl of R 1 is substituted with one to four R 20 moieties which can be the same or different, each R 20 moiety being independently selected from the group of R 20 moieties.
  • R 20 is aryl
  • Z is selected from the group consisting of a covalent bond, -N(R 4 )-, -(C(R 4 ) 2 ) n -, -C(O)- and -O-. In yet another embodiment, Z is -O-.
  • Z is a covalent bond
  • Z is -N(R )-.
  • Z is -C(O)-.
  • R is alkyl
  • R 2 is selected from the group consisting of -OR 4 , H, alkyl, fluoroalkyl, alkylaryl, halogen, and heteroaryl.
  • R 4 is -CH 2 C ⁇ CCH 3 . In another embodiment wherein R 2 is -OR 4 , R 4 is -CH 2 C ⁇ CCH 2 OH.
  • R 4 is ⁇ CH 2 ⁇ .
  • R 2 is hydrogen.
  • R 2 is alkyl.
  • R 2 is alkylaryl.
  • R 2 is fluoroalkyl.
  • R 2 is -CH 2 CF 3 .
  • R 2 is halogen.
  • R 2 is heteroaryl.
  • R 4 is -CH 3 .
  • Another embodiment of the invention discloses the following compounds shown in T ⁇ ifole h below.
  • Another embodiment of the invention discloses the more preferred compounds shown in Table C below.
  • Patient includes both human and animals.
  • “Mammal” means humans and other mammalian animals.
  • Alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched.
  • the alkyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), -N(alkyl) 2 , carboxy and -C(O)O-alkyl.
  • substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), -N(alkyl) 2 , carboxy and -C(O)O-alkyl.
  • suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl
  • Alkenyl means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
  • Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain.
  • “Lower alkenyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
  • suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2- enyl, n-pentenyl, octenyl and decenyl.
  • Alkynyl means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
  • Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain.
  • “Lower alkynyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
  • Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3- methylbutynyl.
  • substituted alkynyl means that the alkynyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.
  • Aryl means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
  • the aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • suitable aryl groups include phenyl and naphthyl.
  • Heteroaryl means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms.
  • the "heteroaryl” can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
  • a nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide.
  • suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, fhiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1 ,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazoly
  • Aralkyl or “arylalkyl” means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2- phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
  • Alkylaryl means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non- limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.
  • Cycloalkyl means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms.
  • the cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
  • suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • Non-limiting examples of suitable rnulticyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like, as well as partially saturated species such as, for example, indanyl, tetrahydronaphthyl and the like.
  • Halogen means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.
  • Ring system substituent means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system.
  • Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio
  • Ring system substituent may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system.
  • Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CH 3 ) 2 - and the like which form moieties such as, for example:
  • Heterocyclyl means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclyls contain about 5 to about 6 ring atoms.
  • the prefix a ⁇ a, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention.
  • the heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyi, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like.
  • Alkynylalkyl means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.
  • Heteroaralkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.
  • Hydroxyalkyl means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
  • acyl means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described.
  • the bond to the parent moiety is through the carbonyl.
  • Preferred acyls contain a lower alkyl.
  • suitable acyl groups include formyl, acetyl and propanoyl.
  • Aroyl means an aryl-C(O)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl.
  • suitable groups include benzoyl and 1- naphthoyl.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
  • suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Aryloxy means an aryl-O- group in which the aryl group is as previously described.
  • suitable aryloxy groups include phenoxy and naphthoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Alkyloxy means an aralkyl-O- group in which the aralkyl group is as previously described.
  • suitable aralkyloxy groups include benzyloxy and 1 - or 2-naphthalenemethoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Alkylthio means an alkyl-S- group in which the alkyl group is as previously described.
  • suitable alkylthio groups include methylthio and ethylthio.
  • the bond to the parent moiety is through the sulfur.
  • Arylthio means an aryl-S- group in which the aryl group is as previously described.
  • suitable arylthio groups include phenylthio and naphthylthio.
  • the bond to the parent moiety is through the sulfur.
  • Alkylthio means an aralkyl-S- group in which the aralkyl group is as previously described.
  • Non-limiting example of a suitable aralkylthio group is benzylthio.
  • the bond to the parent moiety is through the sulfur.
  • Alkoxycarbonyl means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.
  • Aryloxycarbonyl means an aryl-Q-G(O)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.
  • Alkoxycarbonyl means an aralkyl-O-C(O)- group.
  • a suitable aralkoxycarbonyl group is benzyloxycarbonyl.
  • the bond to the parent moiety is through the carbonyl.
  • Alkylsulfonyl means an alkyl-S(O 2 )- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is
  • Arylsulfonyl means an aryl-S(O 2 )- group. The bond to the parent moiety is through the sulfonyl.
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • isolated or “in isolated form” for a compound refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof.
  • purified or “in purified form” for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
  • protecting groups When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene ⁇ t al, Protective Groups in organic Synthesis (1991), Wiley, New York.
  • variable e.g., aryl, heterocycle, R 2 , etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Prodrugs and solvates of the compounds of the invention are also contemplated herein.
  • the term "prodrug”, as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of Formula I or a salt and/or solvate thereof.
  • a discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversihle Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto.
  • Solvate means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • Solvate encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
  • Effective amount or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in inhibiting TACE, the production of TiMF- ⁇ , iVJMPs, ADAMS or any combination thereof and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
  • the compounds of Formula I can form salts which are also within the scope of this invention.
  • Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • zwitterions inner salts may be formed and are included within the term "salt(s)" as used herein.
  • Salts of the compounds of the Formula I may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
  • dimethyl, diethyl, and dibutyl sulfates dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides
  • aralkyl halides e.g. benzyl and phenethyl bromides
  • All stereoisomers for example, geometric isomers, optical isomers and the like
  • of the present compounds including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs
  • those which may exist due to asymmetric carbons on various substituents including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl).
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • the use of the terms "salt”, “solvate” "prodrug” and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
  • the compounds according to the invention have pharmacological properties; in particular, the compounds of Formula I can be inhibitors of TACE, TNF- ⁇ and/or MMP activity.
  • the invention provides a pharmaceutical composition comprising as an active ingredient at least one compound of formula 1.
  • the invention provides a pharmaceutical composition of formula 1 additionally comprising at least one pharmaceutically acceptable carrier.
  • the invention provides a method of treating disorders associated with TACE, TNF- ⁇ , MMPs, ADAMs or any combination thereof, said method comprising administering to a patient in need of such treatment a pharmaceutical composition which comprises therapeutically effective amounts of at least one compound of formula 1.
  • the invention provides a use of a compound of formula 1 for the manufacture of a medicament to treat disorders associated with TACE, TNF- ⁇ , MMPs, ADAMs or any combination thereof.
  • the compounds of Formula I can have anti-inflammatory activity and/or immunomodulatory activity and can be useful in the treatment of diseases including but not limited to septic shock, haemodynamic shock, sepsis syndrome, post ischaemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancers such as cutaneous T-cell lymphoma, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, inflammatory bowel diseases such as Crohn's disease and colitis, OA and RA, ankylosing spondylitis, psoriatic arthritis, adult Still's disease, ureitis, Wegener's granulomatosis, Behcehe disease, Sjogren's syndrome, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, complex regional pain syndrome, radiation damage, hyperoxic alveolar injury, periodontal
  • the invention provides a method of preparing a pharmaceutical composition for treating the disorders associated with TACE, TNF- ⁇ , MMPs, ADAMs or any combination thereof, said method comprising bringing into intimate contact at least one compound of formula 1 and at least one pharmaceutically acceptable carrier.
  • the invention provides a compound of formula (I) exhibiting TACE, TNF- ⁇ , MMPs, ADAMs or any combination thereof inhibitory activity, including enantiomers, stereoisomers and tautomers of said compound, and pharmaceutically acceptable salts or solvates of said compound, said compound being selected from the compounds of structures listed in Table A set forth above.
  • the invention provides a pharmaceutical composition for treating disorders associated with TACE, TNF- ⁇ , MMP, ADAM or any combination thereof in a subject comprising, administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
  • the invention provides a compound of formula 1 in purified form.
  • the invention provides a method of treating a condition or disease mediated by TACE, MMPs, TNF- ⁇ , aggrecanase, or any combination thereof in a subject comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
  • the invention provides a method of treating a condition or disease selected from the group consisting of rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumor growth and tumor invasion by secondary metastases, neovascular glaucoma, inflammatory bowel disease, multiple sclerosis and psoriasis in a subject, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
  • the invention provides a method of treating a condition or disease selected from the group consisting of fever, cardiovascular conditions, hemorrhage, coagulation, cachexia, anorexia, alcoholism, acute phase response, acute infection, shock, graft versus host reaction, autoimmune disease and HIV infection in a subject comprising administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
  • the invention provides a method of treating a condition or disease selected from the group consisting of septic shock, haemodynamic shock, sepsis syndrome, post ischaemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancers such as cutaneous T-cell lymphoma, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, inflammatory bowel diseases such as Crohn's disease and colitis, osteo and rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, adult Still's disease, ureitis, Wegener's granulomatosis, Behcehe disease, Sjogren's syndrome, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, complex regional pain syndrome, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV
  • the invention provides a method of treating a condition or disease associated with COPD, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
  • the invention provides a method of treating a condition or disease associated with rheumatoid arthritis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
  • the invention provides a method of treating a condition or disease associated with Crohn's disease, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
  • the invention provides a method of treating a condition or disease associated with psoriasis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
  • the invention provides a method of treating a condition or disease associated with ankylosing spondylitis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
  • the invention provides a method of treating a condition or disease associated with sciatica, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
  • the invention provides a method of treating a condition or disease associated with complex regional pain syndrome, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
  • the invention provides a method of treating a condition or disease associated with psoriatic arthritis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
  • the invention provides a method of treating a condition or disease associated with multiple sclerosis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof, in combination with a compound selected from the group consisting of Avonex®, Betaseron, Copaxone or other compounds indicated for the treatment of multiple sclerosis.
  • a compound of the present invention may be co ⁇ administered or used in combination with disease-modifying antirheumatic drugs (DMARDS) such as methotrexate, azathioprine, leflunomide, pencillinamine, gold salts, mycophenolate mofetil, cyclophosphamide and other similar drugs.
  • DARDS disease-modifying antirheumatic drugs
  • NSAIDs non-steroidal anti-inflammatory drugs
  • COX-2 selective (COX-2) inhibitors such as Vioxx® and Celebrex®
  • immunosuppressives such as steroids, cyclosporin, Tacrolimus, rapamycin and the like
  • biological response modifiers BRMs
  • other anti-inflammatory agents such as p38 kinase inhibitors, PDE4 inhibitors, other chemically different TACE inhibitors, chemokine receptor antagonists, Thalidomide and other small molecule inhibitors of pro-inflammatory cytokine production.
  • a compound of the present invention may be co-administered or used in combination with an H1 antagonist for the treatment of seasonal allergic rhinitis and/or asthma.
  • H1 antagonists may be, for example, Claritin®, Clarinex®, Allegra®, or Zyrtec®.
  • the invention provides a method of treating a condition or disease mediated by TACE, fvlMPs, TNF- ⁇ , aggrecanase, or any combination thereof in a subject comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof in combination with a therapeutically effective amount of at least one medicament selected from the group consisting of disease modifying anti-rheumatic drugs (DMARDS), NSAIDs, COX-2 inhibitors, COX-1 inhibitors, immunosuppressives, biological response modifiers (BRMs), anti ⁇ inflammatory agents and H1 antagonists.
  • DARDS disease modifying anti-rheumatic drugs
  • NSAIDs NSAIDs
  • COX-2 inhibitors COX-1 inhibitors
  • immunosuppressives biological response modifiers
  • H1 antagonists anti ⁇ inflammatory agents and H1 antagonists.
  • the invention provides a method of treating a condition or disease selected from the group consisting of rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumor growth and tumor invasion by secondary metastases, neovascular glaucoma, inflammatory bowel disease, multiple sclerosis and psoriasis in a subject, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or isomer thereof in combination with a therapeutically effective amount of at least one medicament selected from the group consisting of DMARDS, NSAIDs, COX-2 inhibitors, COX-1 inhibitors, immunosuppressives, BRMs, anti-inflammatory agents and H1 antagonists.
  • a condition or disease selected from the group consisting of rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumor growth and tumor invasion by secondary met
  • the invention provides a method of treating a condition or disease selected from the group consisting of septic shock, haemodynamic shock, sepsis syndrome, post ischaernic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancers such as cutaneous T-cell lymphoma, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, inflammatory bowel diseases such as Crohn's disease and colitis, osteo and rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, adult Still's disease, ureitis, Wegener's granulomatosis, Behcehe disease, Sjogren's syndrome, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, complex regional pain syndrome, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV
  • the invention provides a method for treating RA comprising administering a compound of the formula I in combination with compound selected from the class consisting of a COX-2 inhibitor e.g. Celebrex® or Vioxx®; a COX- 1 inhibitor e.g. Feldene®; an immunosuppressive e.g. methotrexate or cyclosporin; a steroid e.g. ⁇ - methasone; and anti-TiMF- ⁇ compound, e.g. Enbrel® or Remicade®; a PDE IV inhibitor, or other classes of compounds indicated for the treatment of RA.
  • a COX-2 inhibitor e.g. Celebrex® or Vioxx®
  • a COX- 1 inhibitor e.g. Feldene®
  • an immunosuppressive e.g. methotrexate or cyclosporin
  • a steroid e.g. ⁇ - methasone
  • anti-TiMF- ⁇ compound e.g. Enbrel® or Rem
  • the invention provides a method for treating multiple sclerosis comprising administering a compound of the formula I in combination with a compound selected from the group consisting of Avonex®, Betaseron, Copaxone or other compounds indicated for the treatment of multiple sclerosis.
  • TACE activity is determined by a kinetic assay measuring the rate of increase in fluorescent intensity generated by TACE catalyzed cleavage of an internally quenched peptide substrate (SPDL-3).
  • SPDL-3 internally quenched peptide substrate
  • the purified catalytic domain of recombinant human TACE (rhTACEc, Residue 215 to 477 with two mutation (S266A and N452Q) and a 6xHis tail) is used in the assay. It is purified from the baculovirus/Hi5 cells expression system using affinity chromatography.
  • the substrate SPDL-3 is an internally quenched peptide (MCA-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Ser-Dpa-Arg-NH2), with its sequence derived from the pro-TNF ⁇ cleavage site.
  • MCA is (7- Methoxycoumarin-4-yl)acetyl.
  • Dpa is N-3-(2,4-Dinitrophenyl)-L-2,3- diaminopropionyl.
  • a 50 ⁇ l assay mixture contains 20 mM HEPES, pH 7.3, 5 mM CaCI 2 , 100 ⁇ M ZnCI 2 , 2 % DMSO, 0.04% Methylcellulose, 30 ⁇ M SPDL-3, 70 pM rhTACEc and a test compound.
  • RhTACEc is pre-incubated with the testing compound for 90 min. at 25 0 C. Reaction is started by addition of the substrate. The fluorescent intensity (excitation at 320 nm, emission at 405 nm) was measured every 45 seconds for 30 min. using a fluorospectrometer (GEMINI XS, Molecular Devices). Rate of enzymatic reaction is shown as Units per second. Effect of a test compound is shown as % of TACE activity in the absence of the compound.
  • Useful compounds for TACE inhibitory activity can exhibit Ki values of less than about 1000 nm, preferably about 0.01 nm to about 1000 nm, more preferably about 0.1 nm to about 100 nm, and most preferably less than about 15 nm.
  • Ki values The TACE inhibitory activity (Ki values) of some representative compounds of the present invention are listed in the "EXAMPLES" section hereinbelow.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlled release.
  • composition is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients.
  • the bulk composition and each individual dosage unit can contain fixed amounts of the afore-said "more than one pharmaceutically active agents".
  • the bulk composition is material that has not yet been formed into individual dosage units.
  • An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like.
  • the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredients is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or a soft gelatin capsules where in the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorb
  • the aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl, p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example, ethyl or n-propyl, p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., sodium EDTA
  • suspending agent e.g., sodium EDTA
  • preservatives e.g., sodium EDTA, sodium sulfate, sodium bicarbonate
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the oily phase may be a vegetable oil, e.g., olive oil or arachis oil, or a mineral oil, e.g., liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, e.g., soy beans, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, e.g., polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • sweetening agents for example, glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, e.g., as a solution in 1 ,3-butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the invention are employed.
  • topical application shall include mouthwashes and gargles.
  • the compounds for the present invention can be administered in the intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • Compounds of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed.
  • a physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, arrest or reverse the progress of the condition.
  • Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
  • doses of the compound of Formula I useful in the method of the present invention range from 0.01 to 1000 rng per day. More preferably, dosages range from 0.1 to 1000 mg/day. Most preferably, dosages range from 0.1 to 500 mg/day.
  • the compositions are preferably provided in the form of tablets containing 0.01 to 1000 milligrams of the active ingredient, particularly 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg/kg to about 50 mg/kg of body weight per day. The range is more particularly from about 0.001 mg/kg to 1 mg/kg of body weight per day.
  • the active agent of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in dividend doses of two, three or four time daily.
  • the amount of active ingredient that may be combined with the carrier materials to produce single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the compounds of the invention may be produced by processes known to those skilled in the art and as shown in the following reaction schemes and in the preparations and examples described below.
  • NMR spectra were acquired on the following instruments: 400 MHZ NMR (Bruker), 500 MHZ NMR (Bruker), 400 MHz NMR (Varian), 300 MHZ NMR (Varian) using CD 3 OD, CDCI 3 or DMSO-d 6 as solvents.
  • LC-MS data were obtained using a PESciex API 150EX quadropole mass spectrometer using electroscopy ionization.
  • Normal phase silica gel chromatography was either accomplished on a Biotage instrument using a 60 A 12/iVJ, 25/M, or 40/iVl flash cartridges, or on a Jones Flash Master Personal instrument using lsolute flash SI 5g, 1Og, 2Og, 5Og, or 70 g cartridges.
  • the compounds of formula (I) may be produced by processes known to those skilled in the art and as shown in the following reaction schemes and in the preparations and examples described below. These preparations and examples should not be construed to limit the scope of the disclosure. Alternate mechanistic pathways and analogous structures may be apparent to those skilled in the art. Some of the compounds made by these processes are listed in the tables below. All kinds of isomeric forms of the compounds are considered to be within the scope of this invention.
  • step 1 Compound 1A (either commercially available, or prepared by a procedure similar to that described by Abdalla, G. M. and Sowell, J. W. Journal of Heterocyclic Chemistry, 1987, 24(2), 297-301) was treated with one equivalent of Di-tert-butyl dicarbonate in polar solvent, such as DMF, for 30 minutes to 12 hours. The solvent was removed and compound 1B could be used without further purification or purified by silica gel chromatography.
  • polar solvent such as DMF
  • step 2 compound 1B was reacted with potassium cyanide and ammonium carbonate in appropriated alcohol and water solution, at 50 0 C to 90 0 C, for 5 hours to 48 hours. After cooling down, water was added and compound 1C could be collected by filtration.
  • step 3 compound 1C was stirred with 2 to 20 equivalents of hydrogen chloride in methanol for 5 to 48 hours. After ethyl ether was added, compound 1 D could be collected by filtration.
  • step 1 5-Hydroxy-2-nitro-benzoic acid (compound 3A) was dissolved in a suitable solvent, such as DMF, and reacted with an alkyl chloride or alkyl bromide in the presence of cesium carbonate at room temperature for 2 to16 hours. Water and EtOAc were added. The organic phase was washed by water 1 to 5 times to remove DMF. The organic phase was washed with brine, dried, concentrated to give the crude product (compound 3B) which was used without further purification.
  • a suitable solvent such as DMF
  • step 2 compound 3B was dissolved in dioxane/water (3:1) and treated with lithium hydroxide at room temperature for 3 to 6 hours.
  • the solution was made acidic by addition of 1 N HCI solution and extracted with EtOAc.
  • the products (compound 3C) were either used without further purification or purified by chromatography depending on the boiling point of the alcohol side products.
  • step 3 compound 3C was dissolved in a suitable solvent, such as DMF, and coupled with compound 3D using EDCI and HOBT at room temperature overnight. After an aqueous/EtOAc work up, the product (compound 3E) was isolated by chromatography.
  • a suitable solvent such as DMF
  • those compounds having a Ki value of less than 10 nM are designated with letter "A"; those with a Ki value of from 10 to less than 100 nM (10 - ⁇ 100 nM) are designated with letter "B”; those with a Ki value of from 100 to 1000 nM are designated with letter "C”; and those with a Ki value of more than 1000 nM (>1000 nM) are designated with letter "D”.
  • step 1 4-Bromo-2-nitro-ben ⁇ oic acid (compound Bh) was dissolved in a suitable solvent, such as DiViF, and reacted with methyl iodide in the presence of cesium carbonate at room temperature for 2-16 hours. Water and EtOAc were added and the organic phase was washed by water 1 -5 times to remove DMF. The organic phase was washed with brine, dried, concentrated, and dried to give the crude product (compound @B>) which used without further
  • step 2 the methyl ester (compound 6B) was mixed with Pd(OAc) 2 , Cs 2 CO 3 , and an appropriate ligand, such as racemic-2-(Di-if-butylphosphino)-1 ,1'- binaphthyl.
  • Pd(OAc) 2 Cs 2 CO 3
  • an appropriate ligand such as racemic-2-(Di-if-butylphosphino)-1 ,1'- binaphthyl.
  • An alcohol and toluene were added and the solution was stirred at 50 0 C to reflux temperature for 12 to 72 hours. After cooling to room temperature, the solid was removed by filtration and the solvent was removed.
  • the product could be purified by chromatography. During this reaction, the methyl ester may be partially converted to the ester of the alcohol used. This side product was also collected and hydrolyzed in the next step.
  • step 3 compound 6C was dissolved in Dioxane/water (3:1) and treated with lithium hydroxide at room temperature for 3-6 hours.
  • the solution was made acidic by addition of 1 N HCI solution and subjected to aqueous/EtOAc work up.
  • the products (compound 6D) were either used without further purification or purified by chromatography depending on the boiling point of the alcohol side products.
  • step 4 compound 6D was dissolved in a suitable solvent, such as DMF, and coupled with compound 6E under EDCI and HOBT conditions at room temperature overnight. After an aqueous/EtOAc work up, the product (compound 6F) could be isolated by chromatography.
  • step 1 Compound SA was dissolved in a suitable solvent, such as DiViF, and reacted with methyl iodide in the presence of cesium carbonate at room temperature for 2-16 hours. Water and EtOAc were added and the organic phase was washed by water 1-5 times to remove DMF. The organic phase was washed with brine, dried, concentrated, and dried to give the crude product (compound 8B) which was used without further purification.
  • a suitable solvent such as DiViF
  • step 2 when alcohol was used, the reaction was operated in a similar manner as step 2 in es ⁇ ample 6.
  • the reaction was operated in the following manner.
  • the aromatic or heterocyclic stannane was added into a dry flask, followed by addition of the 4-Bromo-2-methyl-benzoic acid methyl ester (compound 8B), a base, such as Cs 2 COa, K3PO4, and a palladium catalyst, such as Pd(PPh 3 ) 2 CI 2 .
  • the flask was placed under vacuum for 1 to 10 minutes to remove oxygen and was refilled with N 2 .
  • An appropriate solvent, such as dry CH 3 CN, was added and the solution was stirred at 60 0 C to reflux temperature overnight to 3 days. The solid was removed by filtration and the solvent was removed.
  • Compound 8C was isolated by chromatography.
  • step 3 compound 8C was dissolved in a suitable inert solvent, such as benzene, CCI 4 or ⁇ , ⁇ , ⁇ -Trifluorotoluene. NBS and benzoyl peroxide were added and the solution was stirred at 50 0 C to 90 0 C for 1 to 24 hours. The solid was filtered and the solvent was removed. The residue was dissolved in ether and washed by water. The ether was removed to afford the compound 8D which was used without further purification.
  • a suitable inert solvent such as benzene, CCI 4 or ⁇ , ⁇ , ⁇ -Trifluorotoluene.
  • step 4 the benzyl bromide (compound 8D) was mixed with hydantoin methyl amine 8E, K 2 CO 3 , and DMF. The solution was stirred at room temperature for 12 to 24 hours. Then the solid was removed by filtration. The product could be purified by reverse phase HPLC. Compounds 8F and 8G could be obtained in a variable ratio.
  • Step 5 is used when the compound SF was isolated in step 4. Compound SF was dissolved in an appropriate solvent, such as MeOH, and stirred at 50 0 C to reflux temperature for 1 to 12 hours. The product could be obtained by removing the solvent by rotary evaporator or purifying via reverse phase chromatography.
  • step 1 racemic compound 12A was treated with one equivalent of di-tert- butyl dicarbonate and 4-N,N-dimethylaminopyridine in polar solvent, such as DMF, for 30 minutes to 12 hours. The solvent was removed and the product (compound 12B) was isolated by silica gel (pretreated with 1% triethylamine in Hexane) chromatography.
  • polar solvent such as DMF
  • step 2 compound 12B was dissolved in proper solvents allowed by HPLC column, and resolved by HPLC using a preparative Chiralpak AD or Chiralcel OD column to give compound 12C and 12D.
  • step 3 compound 12C and 12D were treated with excess HCI in methanol at 25 0 C to 60 0 C for one hour to 12 hours. The solvent was concentrated to give compound 12E and 12F.
  • step 1 compound 14A (prepared as described in Example 1) was treated with a benzyl bromide (Compound 14B) and DIPEA base in DfVlF at 25 0 C to 60 0 C for 12 to 24 hours.
  • the reaction solution was purified via C18 reverse phase chromatography to give compound 14C.
  • step 2 compound 14C was treated with one equivalent di-tert-butyl dicarbonate in polar solvent, such as DMF, for 30 minutes to 12 hours. The solvent was removed and the product (compound 14D) was isolated by silica gel (pretreated with 1% triethylamine in Hexane) chromatography.
  • polar solvent such as DMF
  • step 3 compound 14D was subjected to either a Pd catalyzed reaction with a heterocyclic boronic acid or a heterocyclic stannane, or a copper catalyzed reaction with a heterocyclic amine.
  • the reaction were heated in appropriate solvents, such as DMF and acetonitrile, at 60 0 C to 150 0 C, for 5 minutes to 12 hours. In some cases, a microwave reactor was used.
  • the product was purified by silica gel chromatography to give compound 14E or compound 14F.
  • step 4 compound 14E was dissolved in methanol and was stirred with HCI for 1 hour to 12 hours at 25 0 C to 60 0 C. The solvent was removed to give compound 14F.
  • Step 1
  • stepi compound 19A was treated with two equivalent of Boc 2 O in a suitable solvent, such as dichloromethane, for 30 min. to 12 h. The solvent was removed and the compound 19B could be used without further purification or purified by silica gel chromatography.
  • a suitable solvent such as dichloromethane
  • step 2 compound 19B was treated with PCC and celite in a suitable solvent such as dichloromethane, for 2 hr to 12 hr.
  • Compound 19C was purified by silica gel chromatography.
  • step 3 compound 19C was reacted with potassium cyanide and ammonium carbonate in appropriated alcohol and water solution, at 50 0 C to 90 0 C, for 5 hours to 48 hours. After cooling down, water was added and compound 1SD could be collected by filtration.
  • step 4 compound 19D was stirred with 2 to 20 equivalents of hydrogen chloride in methanol for 5 to 48 hours. The solvent was removed and the compound 1SE could be used without further purification.
  • step 5 the benzyl bromide (compound 1SG) was mixed with hydantoin methyl amine 1SE, DIPEA, and DMF. The solution was stirred at room temperature for 12 to 24 hours. The product (1SF) was either removed by filtration or purified by silica gel chromatography.
  • stepi OH step 2 OH step 3 O step 4 HN --f
  • step 1 Compound 2OA was treated with BOC-ON in a suitable solvent such as dichloromethane, for 2 hr to 12 hr.
  • Compound 2OB was purified by silica gel chromatography.
  • step 2 Compound 2QB was treated with CbzCI and a base such as DIPEA, in a suitable solvent, such as dichloromethane, for 2 hr to 12 hr.
  • Compound 2OC was purified by silica gel chromatography.
  • step 3 compound 2 ⁇ C was treated with PCC and celite in a suitable solvent such as dichloromethane, for 2 hr to 12 hr.
  • Compound 2OD was purified by silica gel chromatography.
  • step 4 compound 200 was reacted with potassium cyanide and ammonium carbonate in appropriated alcohol and water solution, at 50 0 C to 90 0 C, for 1 hour to 48 hours. After cooling down, water was added and compound 2OE could be collected by filtration.
  • step 5 Compound 2OE was treated with Pd/C in a suitable solvent such as methanol, in a par shaker under H 2 atmosphere. After filtering off the catalyst and concentration of solvent, the product was used without further purification.
  • a suitable solvent such as methanol
  • step 6 the benzyl bromide (compound 20R ⁇ ) was mixed with hydantoin methyl amine 2OF, DIPEA, and DMF. The solution was stirred at at room temperature to 80 ° C for 12 to 24 hours. The product was either removed by filtration or purified by silica gel chromatography.
  • step 7 compound 2OG was stirred with 2 to 20 equivalents of hydrogen chloride in dioxane for 1 to 12 hours. The solvent was removed and the compound 2OH was used without further purification.
  • step 8 Compound 2OH was coupling with carboxylic acid to give compound 2OJ which was purified by silica gel chromatography.
  • step 9 Compound 2OH was coupling with sulphonyl chloride compound to give compound 2OL which was purified by silica gel chromatography.
  • step 10 Compound 2OH was reacted with carbonyl compound under reductive amination condition to give compound 201.
  • compound 2OH was treated with a suitable electrophile and a base to give the product 201, which was purified by silica gel chromatography.
  • step 11 compound 201 was reacted with carbonyl compound under reductive amination condition to give product 2OtC.
  • compound 201 was treated with a suitable electrophile and a base to give the product 20E €, which was purified by silica gel chromatography.
  • Compound 21 B Compound 21 A (7 g, 77.7 mmol), and di-tert-butyl dicarbonate (35.6 g, 163 mmol) were stirred in methylene chloride (100 ml_) at 25 0 C for 2 hr. Saturated aqueous NaCI (150 mL) was added. The aqueous layer was extracted with CH2CI2 (100 mL) twice. The organic phase was washed with brine (100 mL), dried over Na 2 SO 4 . The solvent was removed by rotary evaporator to give compound 21 B (17g, 76%) which was used without further purification.
  • Compound 210 Compound 21 C (3.62, 12.6 mmol), KCN (1.23g, 18.9 mrnol), and (NH 4 ⁇ CO 3 (3.62 g, 37.7 mmol) were suspended in a mixture of ElOH (30 rnl_) and water (30 ml). The solution was stirred at 80 0 C overnight. After cooling down, water (35 ml) was added. The solid was filtered and washed with water three times. The solid was dried under vacuum to give compound 210 (3 g, 67%).
  • Compound 21 E Compound 21 D (3.0 g) was suspended in methanol (50 ml) and HCI (4iVi in dioxane, 20 ml) was added. The solution was stirred at 25 0 C for 3 hours. Ethyl ether (50 ml) was added. The solid was filtered, washed by ethyl ether twice, and dried under vacuum compound 21 E (1.34 g, 70%).
  • Compound 21 F Compound 21 E (130 mg, 0.82 mmol), compound 21 H (0.27 g, 1 mmol) and DIPEA (0.55 mL, 2 mmol) were mixed in DMF (5 mL). The solution was stirred at room temperature overnight. Solvent was removed and the crude material was and purified via sgc (5% NH 3 ⁇ MeOHZCH 2 GI 2 ) to give 129 mg (35%) of compound 21 E.
  • Compound 22B Compound 22 ⁇ (7.3 g, 81 mmol) was treated with BOC-ON (21.9 g, 89 rnmol) in dichloromethane for 3 hr. Solvent was removed and the crude material was purified via sgc (10% NH 3 O JVJeOHZCH 2 CI 2 ) to give 6.5 (42%) of compound 22S.
  • Compound 22E Compound 22D (1.86, 5.8 mmol), KCN (0.56 g, 8.65 mmol), and (NH-O 2 CO 3 (1.66 g, 17.3 mmol) were suspended in a mixture of EtOH (20 mL) and water (20 mL). The solution was stirred at 80 0 C overnight. After cooling down, EtOH was removed. The solid was filtered and washed with water three times. The solid was dried under vacuum to give compound 22E (1.45 g, 64%).
  • Compound 22F Compound 22E (1.45 g, 3.68 mmol) was treated with Pd/C in methanol in a par shaker under H 2 atmosphere of 50 psi for 60 hr. After filtering off the catalyst and concentration of solvent, Compound 22E (0.95 g, 99%) was used without further purification.
  • Compound 22G5 Compound 22F (150 mg, 0.58 mmol), compound 22M (170 mg, 0.64 mmol) and DIPEA (0.22 rnL, 1.28 mmol) were mixed in DMF (5 m!_). The solution was stirred at 70 0 C overnight. Solvent was removed and the crude material was and purified via sgc (5% NH 3 0 JVIeOHZCH 2 CI 2 ) to give 166 mg (71%) of compound 22CS.
  • Compound 221 Compound 22H (42 mg, 0.12 mmol) and compound 22J (26 mg, 0.16 mmol) were dissolved in DiVlF (20 ml). EDCI (30 mg, 0.16 mmol), HOBT (21 mg, 0.16 mmol) and DIPEA (0.05 ml, 0.28 mmol) were added and the reaction mixture was stirred at room temperature for 2 hr. Solvent was removed and the crude material was and purified via sgc (10% NH 3 *>MeOH/GH 2 Cl 2 ) to give 7 mg (13%) of compound 221.
  • Compound 22L Compound 22H (25 mg, 0.073 mmol) and cyclopentanone (7.5 mg, 0.088 mmol) were stirred in methylene chloride (5 mL). Titanium tetraisopropoxide (0.043 mL, 0.15 mmol) was added followed by addition of DIPEA (0.015 mL, 0.088 mmol). The reaction mixture was stirred at room temperature for 2h. Then, Na(OAc) 3 BH (31 mg, 0.15 mmol) was added and the mixture was stirred at rt overnight. Saturated K 2 CO 3 aq. (20 mL) was added, and the mixture was stirred at rt briefly. The solid was filtered off through a celite pad.
  • Compound 22K Compound 22H (20 mg, 0.06 mmol) and isopropyl sulphonyl (27 mg, 0.18 mmol) were dissolved in methylene chloride (10 mL). DIPEA (0.04 mL, 0.26 mmol) were added and the reaction mixture was stirred at room temperature for 48 hr. Solvent was removed and the crude material was and purified via sgc (10% NH 3 oMeOH/CH 2 CI 2 ) to give 2 mg (8%) of compound 22K.
  • Compound 1001 B was resolved by Chiralcel OD column (Mobile phase: Hexane/2-propanol 3:1). The first peak was collected and concentrated to give compound 1001 C.
  • Compound 1001 C was prepared as described in Example 1001.
  • Compound 1005A was treated with one equivalent of hexamethylene tetraamine in chloroform or other suitable solvent for about 5 hours. The product was collected by filtration and then treated with HCI in ethanol for one day to three days. The solid was then collected by filtration to give compound
  • step 1 Compound 1012A was treated with nitromethane and KO f Bu in a mixture of THF and f-BuOH for 2 to 12 h.
  • compound 1012A was treated with nitromethane and TBAF in a suitable solvent such as THF for 2 to 12 h.
  • Compound 1012B was purified by silica gel chromatography.
  • step 2 Compound 1012B was treated with Pd/C in a suitable solvent such as methanol, in a Parr shaker under H 2 atmosphere. After filtering off the catalyst and concentration of solvent, the product was used without further purification.
  • a suitable solvent such as methanol
  • step 3 the benzyl bromide (compound 1012D) was mixed with compound 1012C, DIPEA, and DMF. The solution was stirred at 0 ° C to room temperature for 12 to 24 hours. The product was either removed by filtration or purified by silica gel chromatography.
  • step 4 compound 1 ⁇ 12E was treated with PCC and Celite in a suitable solvent such as dichlorornethane for 2 to 12 h.
  • Compound 1012F was purified by silica gel chromatography.
  • step 5 compound 1012F was reacted with potassium cyanide and ammonium carbonate in an appropriate alcohol and water solution, at 50 0 C to 90 0 C, for 5 to 48 hours. After cooling, water was added and compound 1012Gi was collected by filtration.
  • Compound 1013C Compound 1013B (1.24 g, 4.5 mmol) was treated with Pd/C in methanol in a Parr shaker under H 2 atmosphere (50 psi) overnight. After filtering off the catalyst and concentration of solvent, compound 1013C (1.1 g, 99%) was used without further purification.
  • Compound 1013E Compound 1013C (1.02 g, 4.2 mmol) was dissolved in dichloromethane (30 mL) at 0 0 C.
  • Compound 101SD (1.13 g, 4.2 mmol) and DIPEA (0.73 mL, 4.2 mmol) were added and the reaction was stirred at 0 0 C and slowly warmed up to rt overnight.
  • Compound 1013G Compound 1013F (1.01 g, 2.6 mmol), KCN (0.25 g, 3.9 mmol), and (NhU) 2 GO 3 (0.75 g, 7.8 mmol) were suspended in a mixture of NH 3 in Methanol (7 N, 10 mL) and water (10 mL). The solution was stirred at 90 0 C overnight. After cooling, water (20 mL) was added. The solid was filtered and washed with water three times. The solid was dried under vacuum to give compound 1013G (0.86 g, 72%).
  • Compound 1 ⁇ MB was reacted with carbonyl compound under reductive amination conditions to give compound 1014 E.
  • compound 1014 B was treated with a suitable electrophile and a base to give compound 1014 E, which was purified by silica gel chromatography.
  • Compound 1015B Compound 1015A(0.86 g) was suspended in methanol (10 mL) and HCI (4M in dioxane, 10 mL) was added. The solution was stirred at 25 0 C for 3 hours. Solvent was removed and the material was dried under vacuum to give compound 1015B (0.74 g, 99%).
  • Compound 1015C Compound 1015B (40 mg, 0.11 mmol) and benzoic acid anhydride (25 mg, 0.11 mmol) were dissolved in DMF (1 mL). DIPEA (0.06 mL, 0.33 mmol) was added and the reaction mixture was stirred at room temperature overnight. Solvent was removed and the crude material was purified via sgc (5% NH 3 -MeOHZCH 2 CI 2 ) to give 3.7 mg (7%) of compound 1015C.
  • Compound 1015D Compound 1015B (40 mg, 0.11 mmol) and compound 1015H (30 mg, 0.11 mmol) were dissolved in DMF (1 mL). DIPEA (0.25 mL, 1.4 mmol) was added and the reaction mixture was stirred at room temperature overnight. Solvent was removed and the crude material was purified via sgc (5% NH 3 O iVIeOHZCH 2 CI 2 ) to give 2.2 mg (3%) of compound 1015D.
  • Compound 101 SF Compound 101 SB (46 mg, 0.13 mmol) and cyclobutanone (0.2 ml) were stirred in methylene chloride (1 ml). Titanium tetraisopropoxide (0.045 ml, 0.15 mmol) was added followed by addition of DIPEA (0.027 ml, 0.16 mmol). The reaction mixture was stirred at room temperature for 2 h. Then, NaCNBH 3 (41 mg, 0.65 mmol) was added and the mixture was stirred at rt overnight. The solvent was removed. The crude material was purified via PTLC (10% NH 3 6 MeOHZCH 2 CI 2 ) to give 3.1 mg (6%) of compound 1015F.
  • Compound 1015G Compound 1015B (80 mg, 0.24 mmol) and ethyl isocyanate (0.018 mL, 0.24 mmol) were dissolved in DMF (1 mL). DIPEA (0.17 mL, 0.97 mmol) was added and the reaction mixture was stirred at room temperature overnight. Solvent was removed and the crude material was purified via sgc (9% NH 3 -MeOHZCH 2 CI 2 ) to give 11 mg (11%) of compound 1015G.
  • Compound 101613 Compound 101 SA (500 mg, 1.77 mmol) was suspended in CH 3 CN (5 mL) followed by addition of NaN(CHO) 2 (202 mg, 2.12 mmol). The reaction mixture was stirred at rt for 30 min before warmed up to 70 0 C and stirred for 2 h. Solid was collected by suction filtration and washed with acetonitrile to give 1016B (380 mg, 78%) as brown solid.
  • Compound 1016C Compound 1016B (380 mg, 1.38 mmol) was stirred with HCI (36% aq., 1 mL) and EtOH (10 mL) at rt for 2 days. It was then heated to 60 0 C for 2 hr. Solvent was removed and it was dried under vacuum to give 1016C (345 mg, 98%). The material was used without further purification.
  • Compound 1017C Compound 1017A (1.5 g, 8.26 mmol) was dissolved in dichloromethane (20 ml_) and methanol (10 ml_) at 0 0 C.
  • Compound 1017B (2.64 g, 10 mmol) and DIPEA (2.9 mL, 16.5 mmol) were added and the reaction was stirred at 0 0 C and slowly warmed up to rt overnight. The reaction mixture was then heated to 50 0 C and stirred for 2 h. The reaction mixture was washed with brine (50 mL). The organic layer was dried and concentrated to dryness. The crude material was purified via PTLC (50% EtOAc/hexanes) to give 0.7g (29%) of compound 1017C.
  • Compound 1017D Compound 1017C (200 mg, 0.68 mmol) was stirred in CH 2 Cl 2 (15 mL) at O 0 C followed by addition of compound 10171 (0.5 mL, 2.04 mmol) and TMS-OTf (13 ⁇ L, 0.07 mmol). The reaction mixture was stirred at 0 0 C to 5 0 C for 6 hr before warmed up to rt and stirred overnight. The solvent was removed and the crude material was purified via PTLC (EtOAc) to give 0.21 g (91%) of compound 1017D.
  • Compound 1017G Compound 1017F (60 mg, 0.15 mmol) was heated in a sealed tube with HCI (3 ml, 4N in dioxane) at 65 0 C for 48 hr. Solvent was removed and the crude material was purified via sgc (5% NH 3 e MeOH/GH 2 GI 2 ) to give 35 mg (66%) of compound 1017G.
  • Compound 1017H Compound 1017G (34 mg, 0.1 mmol), KCN (10 mg, 0.15 mmol), and (NH 4 ) 2 CO 3 (30 mg, 0.3 mmol) were suspended in a mixture of NH 3 » H 2 O (1 mL) and ethanol (1 mL). The solution was stirred at 90 0 C overnight. Solvent was removed and the crude material was purified via sgc (10% NH 3 -MeOH/CH 2 CI 2 ) to give 6 mg (15%) of compound 1017H.
  • Compound 1018A Compound 1018A was synthesized following procedures in Example 1012.
  • Compound 1020A Compound 1020A was synthesized following the procedures described in Example 22.
  • Compound 1020B Compound 1020A (855 mg, 1.86 mmol) was stirred in MeOH (10 ml_) and HCI (10 ml_, 4N in dioxane) at rt for 2 hr. Solvent was removed and the material was dried to give 1020B (735 mg, 99%).
  • a flask containing AICI 3 (2.55 g, 19.1 mmol), and LiCI (0.41 g, 9.6 mmol) was placed in a -30 0 C cold bath.
  • a solution of 1021 B (1.0 g, 6.38 mmol) and acetyl chloride (0.75 g, 9.5 mmol) in 20 ml of CH 2 CIa was added dropwise.
  • the reaction mixture was stirred for 1 h at -30 0 C, then allowed to warm to rt and stirred overnight at rt.
  • the reaction mixture was poured into a mixture of ice and EtOAc.
  • the organic layer was washed with water, saturated aq NaHCO 3 , and water, then dried with Na 2 SO 4 , and concentrated to dryness to give 1.18 g of Compound 1021 C.

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Abstract

This invention relates to compounds of Formula (1) or a pharmaceutically acceptable salt, solvate or isomer thereof, which can be useful for the treatment of diseases or conditions mediated by MMPs, ADAMs, TACE, TNF- or combinations thereof.

Description

HYDANTOIN DERIVATIVES FOR THE TREATMENT OF INFLAMMATORY DISORDERS
BACKGROUND OF THE INVENTION
Field of the Invention
This invention relates generally to novel hydantoin derivatives that can inhibit matrix metalloproteinases (MMPs), a disintegrin and metalloproteases (ADAMs) and/or tumor necrosis factor alpha - converting enzyme (TACE) and in so doing prevent the release of tumor necrosis factor alpha (TNF-α), pharmaceutical compositions comprising such compounds, and methods of treatment using such compounds.
Figure imgf000002_0001
Osteo- and rheumatoid arthritis (OA and RA, respectively) are destructive diseases of articular cartilage characterized by localized erosion of the cartilage surface. Findings have shown that articular cartilage from the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabeled sulfate over controls, suggesting that there must be an enhanced rate of cartilage degradation in OA (Mankin et al. J. Bone Joint Surg. 52A (1970) 424-434). There are four classes of protein degradative enzymes in mammalian cells: serine, cysteine, aspartic and metalloproteases. The available evidence supports the belief that it is the metalloproteases that are responsible for the degradation of the extracellular matrix of articullar cartilage in OA and RA. Increased activities of collagenases and stromelysin have been found in OA cartilage and the activity correlates with severity of the lesion (Mankin et al. Arthritis Rheum. 21 , 1978, 761 -766, Woessner et al. Arthritis Rheum. 26, 1983, 63-68 and Ibid. 27, 1984, 305-312). In addition, aggrecanase (a newly identified metalloprotease) has been identified that provides the specific cleavage product of proteoglycan, found in RA and OA patients (Lohmander L S. et al. Arthritis Rheum. 36, 1993, 1214-22).
Metalloproteases (MPs) have been implicated as the key enzymes in the destruction of mammalian cartilage and bone. It can be expected that the pathogenesis of such diseases can be modified in a beneficial manner by the administration of MP inhibitors (see Wahl et al. Ann. Rep. Med. Chem. 25, 175-184, AP, San Diego, 1990). MMPs are a family of over 20 different enzymes that are involved in a variety of biological processes important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. This is a feature of many pathological conditions, such as RA and OA, corneal, epidermal or gastric ulceration; tumor metastasis or invasion; periodontal disease and bone disease. Normally these catabolic enzymes are tightly regulated at the level of their synthesis as well as at their level of extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIiVlPs (tissue inhibitor of MPs), which form inactive complexes with the MMP1S.
Tumor necrosis factor alpha (TNF-α) is a cell-associated cytokine that is processed from a 26 kDa precursor form to a 17 kd active form. See Black R.A. "Tumor necrosis factor-alpha converting enzyme" lnt J Biochem Cell Biol. 2002 Jan; 34(1): 1-5 and Moss ML, White JM, Lambert MH, Andrews RC.'TACE and other ADAM proteases as targets for drug discovery" Drug Discov Today. 2001 Apr 1 ;6(8):417-426, each of which is incorporated by reference herein.
TNF-α has been shown to play a pivotal role in immune and inflammatory responses. Inappropriate or over-expression of TNF-α is a hallmark of a number of diseases, including RA, Crohn's disease, multiple sclerosis, psoriasis and sepsis. Inhibition of TNF-α production has been shown to be beneficial in many preclinical models of inflammatory disease, making inhibition of TNF-α production or signaling an appealing target for the development of novel anti-inflammatory drugs.
TNF-α is a primary mediator in humans and animals of inflammation, fever and acute phase responses, similar to those observed during acute infection and shock. Excess TNF-α has been shown to be lethal. Blocking the effects of TNF-α with specific antibodies can be beneficial in a variety of conditions, including autoimmune diseases such as RA (Feldman et al, Lancet, (1994) 344, 1105), non-insulin dependent diabetes mellitus (Lohmander L. S. et al., Arthritis Rheum. 36 (1993) 1214-22) and Crohn's disease (Macdonald T. et al., Clin. Exp. Immunol. 81 (1990) 301). Compounds that inhibit the production of TNF-α are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently it has been shown that metalloproteases, such as TACE, are capable of converting TNF-α from its inactive to active form (Gearing et al Nature, 1994, 370, 555). Since excessive TNF-α production has been noted in several disease conditions also characterized by MMP-mediated tissue degradation, compounds which inhibit both MiViPs and TNF-α production may also have a particular advantage in diseases where both mechanisms are involved.
One approach to inhibiting the harmful effects of TNF-α is to inhibit the enzyme, TACE before it can process TNF-α to its soluble form. TACE is a member of the ADAM family of type I membrane proteins and mediates the ectodomain shedding of various membrane-anchored signaling and adhesion proteins. TACE has become increasingly important in the study of several diseases, including inflammatory disease, because of its role in cleaving TNF- α from its "stalk" sequence and thus releasing the soluble form of the TNF-α protein (Black R.A. lnt J Biochem Cell Biol. 2002 34,1-5).
There are numerous patents and publications which disclose hydroxamate, sulphonamide, hydantoin, carboxylate and/or lactam based MMP inhibitors.
US 6,677,355 and US 6,534,491 (B2), describe compounds that are hydroxamic acid derivatives and MMP inhibitors.
US 6,495,565 discloses lactam derivatives that are potential inhibitors of MMPs and/or TNF-α.
PCT Publications WO2002/074750, WO2002/096426, WO20040067996, WO2004012663, WO200274750 and WO2004024721 disclose hydantoin derivatives that are potential inhibitors of MMPs.
PCT Publications WO2004024698 and WO2004024715 disclose sulphonamide derivatives that are potential inhibitors of MMPs.
PCT Publications WO2004056766, WO2003053940 and WO2003053941 also describe potential inhibitors of TACE and MMPs.
There is a need in the art for inhibitors of MMPs, ADAMs, TACE, and TNF-α, which can be useful as anti-inflammatory compounds and cartilage protecting therapeutics. The inhibition of TNF-α, TACE and or other MMPs can prevent the degradation of cartilage by these enzymes, thereby alleviating the pathological conditions of OA and RA as well as many other auto-immune
SUMMARY OF THE IWVEOTIOW
In its many embodiments, the present invention provides a novel class of compounds as inhibitors of TACE, the production of TNF-α, MiVlPs, ADAMs or any combination thereof, methods of preparing such compounds, pharmaceutical compositions comprising one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition or amelioration of one or more diseases associated with TACE, TNF-α, MMPs, ADAMs or any combination thereof using such compounds or pharmaceutical compositions.
In one embodiment, the present application discloses a compound, or pharmaceutically acceptable salts or solvates of said compound, said compound having the general structure shown in formula (I):
Figure imgf000005_0001
or a pharmaceutically acceptable salt, solvate or isomer thereof, wherein:
4 4
X is selected from the group consisting of -S-, -C(R )2- or -N(R )-;
T is selected from the group consisting of H (with U and V being absent), alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, and arylalkyl, said aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl being optionally fused with one or more moieties selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl, wherein each of any of the aforementioned alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl groups of T is unsubstituted or optionally independently substituted with one to four R10 moieties which can be the same or different, each R10 moiety being independently selected from the group of R10 moieties below;
U is absent or present, and if present U is selected from the group consisting of a covalent bond, -N(R4)-, -N(R4)C(R4)2-, -N(R4)C(O)-, -O-,
-N(R4)S(O)2-, -N(R4)C(O)N(R4)-, and -N(R4)C(S)N(R4)-;
V is absent or present, and if present V is selected from the group consisting of alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl, said aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl being optionally fused with one or more moieties selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl, wherein each of any of the aforementioned alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl is unsubstituted or optionally independently substituted with one to four R10 moieties which can be the same or different, each R10 moiety being independently selected from the group of R10 moieties below;
Y is absent or present, and if present Y is selected from the group consisting of a covalent bond, -(C(R4)2)n-, -N(R4)-, -C(O)N(R4)-, -N(R4)C(O)-, -N(R4)C(O)N(R4)-, -S(O)2N(R4)-, -N(R4)-S(O)2, -O- -S-, -C(O)-, -S(O)-, and -S(O)2-;
Z is absent or present, and if present Z is selected from the group consisting of a covalent bond, -(C(R4)2)n-, -N(R4)-, -C(O)N(R4)-, -N(R4)C(O)-, -N(R4)C(O)N(R4)-, -S(O)2N(R4)-, -N(R4)-S(O)2-, -O- -S-, -C(O)-, -S(O)-, and -S(O)2-; n is 1 to 3;
R is selected from the group consisting of H, -OR4, halogen, alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl, wherein each of the alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl groups of R is unsubstituted or optionally independently substituted with one to four R20 moieties which can be the same or different, each R20 moiety being independently selected from the group of R20 moieties below, with the proviso that when Y is present and Y is N, S or O, then R1 is not halogen; R is selected from the group consisting of H, -OR4, halogen, alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl, wherein each of the alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl,
2 alkylaryl, alkylheteroaryl and arylalkyl groups of R is unsubstituted or optionally independently substituted with one to four R20 moieties which can be the same or different, each R20 moiety being independently selected from the group of R20 moieties below, with the proviso that when Z is present and Z is N, S or O, then R2 is not halogen;
4 each R is the same or different and is independently selected from the group consisting of H and alkyl;
R is selected from the group consisting of -OR4, -N(R )2, -S(O)-,
-S(O)2-, -N(R4)S(O)2-, -S(O)2N(R4)-, -O(fluoroalkyl), halogen, alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl, wherein each of the alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl groups of R is unsubstituted or optionally independently substituted with one to four R30 moieties which can be the same or different, each R30 moiety being independently selected from the group of R30 moieties below;
20
R is selected from the group consisting of halogen, alkyl, fluoroalkyl; and
30
R is selected from the group consisting of halogen, alkyl, and fluoroalkyl.
The compounds of Formula I can be useful as inhibitors of TACE and may be useful in the treatment and prevention of diseases associated with TACE, TNF-α, MMPs, ADAMs or any combination thereof.
DETAILED DESCRIPTION OF THE INVENTION
In its several embodiments, the present invention provides a novel class of inhibitors of TACE, the production of TNF-α, MMPs, ADAMs or any combination thereof, pharmaceutical compositions containing one or more of the compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention or amelioration of one or more of the symptoms of inflammation.
In one embodiment, the present invention provides compounds which are represented by structural Formula (I) above or a pharmaceutically acceptable salt, solvate or isomer thereof, wherein the various moieties are as described above.
In another embodiment, the isomer referred to the in the preceding paragraph is a stereoisomer.
In one embodiment, T is alkyl or aryl; X is -C(R )2-; Y is absent; Z is
2 absent or present; R is selected from the group consisting of H, halogen and alkyl; and if Z is present Z is -O-.
4
In another embodiment, T is alkyl or aryl; X is -C(R )2-; Y is absent; Z
2 is absent or present, and if present Z is -O-; and R is selected from the group consisting of alkylaryl and alkylheteroaryl.
4
In another embodiment, T is alkyl or aryl; X is -N(R )-; Y is absent; Z is
2 absent or present; R is selected from the group consisting of H, halogen and alkyl; and if Z is present Z is -O-.
In another embodiment, X is -CH2- or -N(R )-. In yet another embodiment, X is -CH2-.
4
In still another embodiment, X is -N(R )-.
4
In another embodiment, R is H.
In another embodiment, T is alkyl.
In yet another embodiment, T is -CH3.
In still another embodiment, T is aryl and said aryl is unsubstituted or optionally independently substituted with one to five R10 moieties which can be the same or different, each R10 moiety being independently selected from the group of R10 moieties.
In another embodiment, R10 is halogen.
In yet another embodiment, R10 is heteroaryl.
In still another embodiment, R10 is aryl.
In an embodiment U selected from the group consisting of a covalent bond, -N(R4)-, -N(R4)C(C>)-, and -N(R4)S(O)2-. In yet another embodiment LJ is a covalent bond.
4
In still another embodiment U is -N(R )-.
In yet still another embodiment, U is -N(R )C(O)-.
In another embodiment, V is selected from the group consisting of aryl, heteroaryl, heterocyclyl and cycloalkyl, said aryl, heteroaryl, heterocyclyl, and cycloalkyl being optionally fused with one or more moieties selected from the group consisting of aryl, heteroaryl, heterocyclyl, or cycloalkyl, wherein each of any of said aryl, heteroaryl, heterocyclyl and cycloalkyl is unsubstituted or optionally independently substituted with one to four R10 moieties which can be the same or different, each R10 moiety being independently selected from the group of R10 moieties.
In another embodiment, Y is selected from the group consisting of a covalent bond, -(G(R4)2)n-, -C(O)- and -O-.
In yet another embodiment, Y is -O-.
In still another embodiment, Y is -(G(R4)2)n-.
In yet still another embodiment, Y is -C(O)-.
In another embodiment, Y is a covalent bond.
In an embodiment, R1 is selected from the group consisting of -OR4, H, alkyl, fluoroalkyl, alkylaryl, halogen, and heteroaryl.
In another embodiment, R1 is H.
In yet another embodiment, R1 is alkylaryl.
In still another embodiment, R1 is alkyl.
In yet still another embodiment, R1 is fluoroalkyl.
In a further embodiment, R1 is halogen.
In another embodiment, R1 is -OR4.
In another embodiment, where R1 is -OR4, R4 is -CH2C≡CCH3.
In another embodiment, where R1 is -OR4, R4 is -CH2C=CCH2OH.
In another embodiment, where R1 is -OR4, R4 is ~CH2 <J_
In another embodiment, the alkyl is -CH3.
In still another embodiment, the alkyl is -CH2CH3. In another embodiment, in formula (I), T, U, and V are taken together to
form V=/ \-J and R1 is selected from the group consisting of F, Cl, OH, -QGH2G=GGH31 -OGH2C=GGH2OH, -OCH3, and ~0CH2-<]p
In another embodiment, in formula (I), T, U, and V are taken together to
form
Figure imgf000010_0001
and R1 is selected from the group consisting of F, Cl, OH,
-OCH2GSCCH31 -OGH2GSCCH2OH, -OCH3, and ~0CH2^.
In another embodiment, in formula (I), T, U, and V are taken together to
form
Figure imgf000010_0002
and R1 is selected from the group consisting of F, Cl, OH,
-OCH2C=CCH3, -OCH2C=CCH2OH, -OCH3, and -0CH2<|
In another embodiment, in formula (I), T, U, and V are taken together to
form
Figure imgf000010_0003
H and R is selected from the group consisting of F, Cl, OH,
-OCH2C=CCH31 -OCH2CSCCH2OH, -OCH3, and -0CH2<]
In another embodiment, in formula (I), T, U, and V are taken together to
Figure imgf000010_0004
and R1 is selected from the group consisting of F, Cl, OH,
-OCH2C=CCH3, -OCH2C=CCH2OH, -OCH3, and -OCH2<j
In another embodiment, in formula (I), T, U, and V are taken together to
form \=/ \_-? and R2 is selected from the group consisting of F, Cl,
OH, -OCH2C≡CCH3,-OCH2C≡CCH2OH, -OCH3, and -0CH2<]
In another embodiment, in formula (I), T, U, and V are taken together to
form
Figure imgf000010_0005
and R2 is selected from the group consisting of F, Cl, OH,
-OCH2C≡CCH3, -OCH2C≡CCH2OH, -OCH3, and ~0CH2<]
In another embodiment, in formula (I), T, U, and V are taken together to
form
Figure imgf000010_0006
and R2 is selected from the group consisting of F, Cl, OH, -OCH2C≡CCH3,-OCH2C≡CCH2OH, -OCH3, and -QGH2O-
In another embodiment, in formula (I), T, U, and V are taken together to
form
Figure imgf000011_0001
is selected from the group consisting of F, Cl, OH,
-OGH2G≡GCH3, -OCH2G≡GGH2OH, -OGH3, and ~OCH2-<3.
In another embodiment, in formula (I), T, U, and V are taken together to
form \L_-7 and R2 is selected from the group consisting of F, Cl, OH,
-OCH2G≡CCH3,-OGH2C≡CCH2OH, -OCH3, and ~0CH2-<.
In another embodiment, the fluoroalkyl is -CH2CF3.
In an embodiment, halogen is selected from the group consisting of -Br, -Cl and -F.
In another embodiment, R4 is -CH3.
In yet another embodiment, alkyl of R1 is substituted with one to four R20 moieties which can be the same or different, each R20 moiety being independently selected from the group of R20 moieties.
In another embodiment, R20 is aryl.
In another embodiment, Z is selected from the group consisting of a covalent bond, -N(R4)-, -(C(R4)2)n-, -C(O)- and -O-. In yet another embodiment, Z is -O-.
In still another embodiment, Z is a covalent bond.
4 In yet still another embodiment, Z is -N(R )-.
In a further embodiment, Z is -C(O)-.
4 In another embodiment, R is alkyl.
In another embodiment, R2 is selected from the group consisting of -OR4, H, alkyl, fluoroalkyl, alkylaryl, halogen, and heteroaryl.
In another embodiment wherein R2 is -OR4, R4 is -CH2C≡CCH3. In another embodiment wherein R2 is -OR4, R4 is -CH2C≡CCH2OH.
In another embodiment wherein R2 is -OR4, R4 is ~CH2 ^. In yet another embodiment, R2 is hydrogen. In still another embodiment, R2 is alkyl. In yet still another embodiment, R2 is alkylaryl. In yet further embodiment, R2 is fluoroalkyl. In another embodiment, R2 is -CH2CF3. In yet another embodiment, R2 is halogen. In another embodiment, R2 is heteroaryl. In another embodiment, R4 is -CH3.
Another embodiment of the invention discloses the following compounds shown in Tεifole h below.
Table A
Structures
Figure imgf000012_0001
Figure imgf000012_0002
Figure imgf000012_0003
Figure imgf000012_0004
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000024_0002
Figure imgf000024_0003
Figure imgf000024_0004
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000031_0002
Figure imgf000031_0003
Figure imgf000031_0004
Figure imgf000031_0005
Figure imgf000031_0006
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Another embodiment of the invention discloses the preferred compounds shown in Table B below:
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
40
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Another embodiment of the invention discloses the more preferred compounds shown in Table C below.
Figure imgf000053_0001
Figure imgf000054_0001
As used above, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
"Patient" includes both human and animals.
"Mammal" means humans and other mammalian animals.
"Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. The alkyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), -N(alkyl)2, carboxy and -C(O)O-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.
"Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. "Lower alkenyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2- enyl, n-pentenyl, octenyl and decenyl.
"Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3- methylbutynyl. The term "substituted alkynyl" means that the alkynyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.
"Aryl" means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.
"Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non- limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, fhiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1 ,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1 ,2,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
"Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2- phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
"Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non- limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.
"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable rnulticyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like, as well as partially saturated species such as, for example, indanyl, tetrahydronaphthyl and the like.
"Halogen" means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.
"Ring system substituent" means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, -C(=N-CN)-NH2, -C(=NH)-NH2, - C(=NH)-NH(alkyl), G1G2N-, GiG2N-alkyl-, G1G2NC(O)-, G1G2NSO2- and - SO2NG1G2, wherein G1 and G2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring system substituent" may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CH3)2- and the like which form moieties such as, for example:
Figure imgf000058_0001
"Heterocyclyl" means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix a∑a, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention. The heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyi, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like.
It should be noted that tautomeric forms such as, for example, the moieties:
Figure imgf000059_0001
are considered equivalent in certain embodiments of this invention.
"Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.
"Heteroaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.
"Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
"Acyl" means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non- limiting examples of suitable acyl groups include formyl, acetyl and propanoyl.
"Aroyl" means an aryl-C(O)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1- naphthoyl.
"Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen.
"Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.
"Aralkyloxy" means an aralkyl-O- group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1 - or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen.
"Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through the sulfur.
"Arylthio" means an aryl-S- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur.
"Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur.
"Alkoxycarbonyl" means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl. "Aryloxycarbonyl" means an aryl-Q-G(O)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.
"Aralkoxycarbonyl" means an aralkyl-O-C(O)- group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.
"Alkylsulfonyl" means an alkyl-S(O2)- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is
"Arylsulfonyl" means an aryl-S(O2)- group. The bond to the parent moiety is through the sulfonyl.
The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.
The term "isolated" or "in isolated form" for a compound refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof. The term "purified" or "in purified form" for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.
When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene θt al, Protective Groups in organic Synthesis (1991), Wiley, New York.
When any variable (e.g., aryl, heterocycle, R2, etc.) occurs more than one time in any constituent or in Formula I, its definition on each occurrence is independent of its definition at every other occurrence.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term "prodrug", as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of Formula I or a salt and/or solvate thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversihle Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto.
"Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H2O.
"Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention effective in inhibiting TACE, the production of TiMF-α, iVJMPs, ADAMS or any combination thereof and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
The compounds of Formula I can form salts which are also within the scope of this invention. Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the Formula I may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl etal, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge etal, Journal of Pharmaceutical Sciences (1977) 86(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistiγ (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D. C. on their website). These disclosures are incorporated herein by reference thereto.
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Compounds of Formula I, and salts, solvates and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate" "prodrug" and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
Polymorphic forms of the compounds of Formula I, and of the salts, solvates and prodrugs of the compounds of Formula I, are intended to be included in the present invention.
The compounds according to the invention have pharmacological properties; in particular, the compounds of Formula I can be inhibitors of TACE, TNF-α and/or MMP activity.
In one aspect, the invention provides a pharmaceutical composition comprising as an active ingredient at least one compound of formula 1.
In another aspect, the invention provides a pharmaceutical composition of formula 1 additionally comprising at least one pharmaceutically acceptable carrier.
In another aspect, the invention provides a method of treating disorders associated with TACE, TNF-α, MMPs, ADAMs or any combination thereof, said method comprising administering to a patient in need of such treatment a pharmaceutical composition which comprises therapeutically effective amounts of at least one compound of formula 1.
In another aspect, the invention provides a use of a compound of formula 1 for the manufacture of a medicament to treat disorders associated with TACE, TNF-α, MMPs, ADAMs or any combination thereof.
The compounds of Formula I can have anti-inflammatory activity and/or immunomodulatory activity and can be useful in the treatment of diseases including but not limited to septic shock, haemodynamic shock, sepsis syndrome, post ischaemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancers such as cutaneous T-cell lymphoma, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, inflammatory bowel diseases such as Crohn's disease and colitis, OA and RA, ankylosing spondylitis, psoriatic arthritis, adult Still's disease, ureitis, Wegener's granulomatosis, Behcehe disease, Sjogren's syndrome, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, complex regional pain syndrome, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV, non-insulin dependent diabetes mellitus, systemic lupus erythematosus, glaucoma, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinal disease, scleroderma, osteoporosis, renal ischemia, myocardial infarction, cerebral stroke, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing aveolitis, psoriasis, transplant rejection, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, reversible airway obstruction, adult respiratory distress syndrome, asthma, chronic obstructive pulmonary disease (COPD) and/or bronchitis. It is contemplated that a compound of this invention may be useful in treating one or more of the diseases listed.
In another aspect, the invention provides a method of preparing a pharmaceutical composition for treating the disorders associated with TACE, TNF-α, MMPs, ADAMs or any combination thereof, said method comprising bringing into intimate contact at least one compound of formula 1 and at least one pharmaceutically acceptable carrier.
In another aspect, the invention provides a compound of formula (I) exhibiting TACE, TNF-α, MMPs, ADAMs or any combination thereof inhibitory activity, including enantiomers, stereoisomers and tautomers of said compound, and pharmaceutically acceptable salts or solvates of said compound, said compound being selected from the compounds of structures listed in Table A set forth above.
In another aspect, the invention provides a pharmaceutical composition for treating disorders associated with TACE, TNF-α, MMP, ADAM or any combination thereof in a subject comprising, administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
In another aspect, the invention provides a compound of formula 1 in purified form. In another aspect, the invention provides a method of treating a condition or disease mediated by TACE, MMPs, TNF-α, aggrecanase, or any combination thereof in a subject comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
In another aspect, the invention provides a method of treating a condition or disease selected from the group consisting of rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumor growth and tumor invasion by secondary metastases, neovascular glaucoma, inflammatory bowel disease, multiple sclerosis and psoriasis in a subject, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
In another aspect, the invention provides a method of treating a condition or disease selected from the group consisting of fever, cardiovascular conditions, hemorrhage, coagulation, cachexia, anorexia, alcoholism, acute phase response, acute infection, shock, graft versus host reaction, autoimmune disease and HIV infection in a subject comprising administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
In another aspect, the invention provides a method of treating a condition or disease selected from the group consisting of septic shock, haemodynamic shock, sepsis syndrome, post ischaemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancers such as cutaneous T-cell lymphoma, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, inflammatory bowel diseases such as Crohn's disease and colitis, osteo and rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, adult Still's disease, ureitis, Wegener's granulomatosis, Behcehe disease, Sjogren's syndrome, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, complex regional pain syndrome, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV, non- insulin dependent diabetes mellitus, systemic lupus erythematosus, glaucoma, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinal disease, scleroderma, osteoporosis, renal ischemia, myocardial infarction, cerebral stroke, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing aveolitis, psoriasis, transplant rejection, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, reversible airway obstruction, adult respiratory distress syndrome, asthma, chronic obstructive pulmonary disease (COPD) and bronchitis in a subject comprising administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
In another aspect, the invention provides a method of treating a condition or disease associated with COPD, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
In another aspect, the invention provides a method of treating a condition or disease associated with rheumatoid arthritis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
In another aspect, the invention provides a method of treating a condition or disease associated with Crohn's disease, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
In another aspect, the invention provides a method of treating a condition or disease associated with psoriasis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof. In another aspect, the invention provides a method of treating a condition or disease associated with ankylosing spondylitis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
In another aspect, the invention provides a method of treating a condition or disease associated with sciatica, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
In another aspect, the invention provides a method of treating a condition or disease associated with complex regional pain syndrome, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
In another aspect, the invention provides a method of treating a condition or disease associated with psoriatic arthritis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
In another aspect, the invention provides a method of treating a condition or disease associated with multiple sclerosis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof, in combination with a compound selected from the group consisting of Avonex®, Betaseron, Copaxone or other compounds indicated for the treatment of multiple sclerosis.
Additionally, a compound of the present invention may be co¬ administered or used in combination with disease-modifying antirheumatic drugs (DMARDS) such as methotrexate, azathioprine, leflunomide, pencillinamine, gold salts, mycophenolate mofetil, cyclophosphamide and other similar drugs. They may also be co-administered with or used in combination with non-steroidal anti-inflammatory drugs (NSAIDs) such as piroxicam, naproxen, indomethacin, ibuprofen and the like; cycloxygenase-2 selective (COX-2) inhibitors such as Vioxx® and Celebrex®; immunosuppressives such as steroids, cyclosporin, Tacrolimus, rapamycin and the like; biological response modifiers (BRMs) such as Enbrel®, Rernicade®, 11-1 antagonists, anti-CD40, anti-CD28, 11-10, anti-adhesion molecules and the like; and other anti-inflammatory agents such as p38 kinase inhibitors, PDE4 inhibitors, other chemically different TACE inhibitors, chemokine receptor antagonists, Thalidomide and other small molecule inhibitors of pro-inflammatory cytokine production.
Also, a compound of the present invention may be co-administered or used in combination with an H1 antagonist for the treatment of seasonal allergic rhinitis and/or asthma. Suitable H1 antagonists may be, for example, Claritin®, Clarinex®, Allegra®, or Zyrtec®.
In another aspect, the invention provides a method of treating a condition or disease mediated by TACE, fvlMPs, TNF-α, aggrecanase, or any combination thereof in a subject comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof in combination with a therapeutically effective amount of at least one medicament selected from the group consisting of disease modifying anti-rheumatic drugs (DMARDS), NSAIDs, COX-2 inhibitors, COX-1 inhibitors, immunosuppressives, biological response modifiers (BRMs), anti¬ inflammatory agents and H1 antagonists.
In another aspect, the invention provides a method of treating a condition or disease selected from the group consisting of rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumor growth and tumor invasion by secondary metastases, neovascular glaucoma, inflammatory bowel disease, multiple sclerosis and psoriasis in a subject, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or isomer thereof in combination with a therapeutically effective amount of at least one medicament selected from the group consisting of DMARDS, NSAIDs, COX-2 inhibitors, COX-1 inhibitors, immunosuppressives, BRMs, anti-inflammatory agents and H1 antagonists.
In another aspect, the invention provides a method of treating a condition or disease selected from the group consisting of septic shock, haemodynamic shock, sepsis syndrome, post ischaernic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancers such as cutaneous T-cell lymphoma, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, inflammatory bowel diseases such as Crohn's disease and colitis, osteo and rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, adult Still's disease, ureitis, Wegener's granulomatosis, Behcehe disease, Sjogren's syndrome, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, complex regional pain syndrome, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV, non- insulin dependent diabetes mellilus, systemic lupus erythematosus, glaucoma, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinal disease, scleroderma, osteoporosis, renal ischemia, myocardial infarction, cerebral stroke, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing aveolitis, psoriasis, transplant rejection, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, reversible airway obstruction, adult respiratory distress syndrome, asthma, chronic obstructive pulmonary disease (COPD) and bronchitis in a subject comprising administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or isomer thereof in combination with a therapeutically effective amount of at least one medicament selected from the group consisting of DMARDS, NSAIDs, COX-2 inhibitors, COX-1 inhibitors, immunosuppressives, BRMs, anti-inflammatory agents and H1 antagonists.
In another aspect, the invention provides a method for treating RA comprising administering a compound of the formula I in combination with compound selected from the class consisting of a COX-2 inhibitor e.g. Celebrex® or Vioxx®; a COX- 1 inhibitor e.g. Feldene®; an immunosuppressive e.g. methotrexate or cyclosporin; a steroid e.g. β- methasone; and anti-TiMF-α compound, e.g. Enbrel® or Remicade®; a PDE IV inhibitor, or other classes of compounds indicated for the treatment of RA.
In another aspect, the invention provides a method for treating multiple sclerosis comprising administering a compound of the formula I in combination with a compound selected from the group consisting of Avonex®, Betaseron, Copaxone or other compounds indicated for the treatment of multiple sclerosis.
TACE activity is determined by a kinetic assay measuring the rate of increase in fluorescent intensity generated by TACE catalyzed cleavage of an internally quenched peptide substrate (SPDL-3). The purified catalytic domain of recombinant human TACE (rhTACEc, Residue 215 to 477 with two mutation (S266A and N452Q) and a 6xHis tail) is used in the assay. It is purified from the baculovirus/Hi5 cells expression system using affinity chromatography. The substrate SPDL-3 is an internally quenched peptide (MCA-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Ser-Dpa-Arg-NH2), with its sequence derived from the pro-TNFα cleavage site. MCA is (7- Methoxycoumarin-4-yl)acetyl. Dpa is N-3-(2,4-Dinitrophenyl)-L-2,3- diaminopropionyl.
A 50 μl assay mixture contains 20 mM HEPES, pH 7.3, 5 mM CaCI2, 100 μM ZnCI2, 2 % DMSO, 0.04% Methylcellulose, 30 μM SPDL-3, 70 pM rhTACEc and a test compound. RhTACEc is pre-incubated with the testing compound for 90 min. at 25 0C. Reaction is started by addition of the substrate. The fluorescent intensity (excitation at 320 nm, emission at 405 nm) was measured every 45 seconds for 30 min. using a fluorospectrometer (GEMINI XS, Molecular Devices). Rate of enzymatic reaction is shown as Units per second. Effect of a test compound is shown as % of TACE activity in the absence of the compound.
Useful compounds for TACE inhibitory activity can exhibit Ki values of less than about 1000 nm, preferably about 0.01 nm to about 1000 nm, more preferably about 0.1 nm to about 100 nm, and most preferably less than about 15 nm. The TACE inhibitory activity (Ki values) of some representative compounds of the present invention are listed in the "EXAMPLES" section hereinbelow.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlled release.
The term pharmaceutical composition is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients. The bulk composition and each individual dosage unit can contain fixed amounts of the afore-said "more than one pharmaceutically active agents". The bulk composition is material that has not yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like. Similarly, the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredients is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or a soft gelatin capsules where in the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl, p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, e.g., sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, e.g., olive oil or arachis oil, or a mineral oil, e.g., liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, e.g., soy beans, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, e.g., polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, e.g., as a solution in 1 ,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Compounds of the invention may also be administered in the form of suppositories for rectal administration of the drug. The compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the invention are employed. (For purposes of this application, topical application shall include mouthwashes and gargles.)
The compounds for the present invention can be administered in the intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. Compounds of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, arrest or reverse the progress of the condition. Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug. Preferably, doses of the compound of Formula I useful in the method of the present invention range from 0.01 to 1000 rng per day. More preferably, dosages range from 0.1 to 1000 mg/day. Most preferably, dosages range from 0.1 to 500 mg/day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01 to 1000 milligrams of the active ingredient, particularly 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg/kg to about 50 mg/kg of body weight per day. The range is more particularly from about 0.001 mg/kg to 1 mg/kg of body weight per day.
Advantageously, the active agent of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in dividend doses of two, three or four time daily.
The amount of active ingredient that may be combined with the carrier materials to produce single dosage form will vary depending upon the host treated and the particular mode of administration.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route or administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
The compounds of the invention may be produced by processes known to those skilled in the art and as shown in the following reaction schemes and in the preparations and examples described below.
EXAMPLES
The following abbreviations are used in the procedures and schemes:
ACN Acetonitrile
AcOH Acetic acid
Aq Aqueous
BOC tert-Butoxycarbonyl
BOC-ON [2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitril]
BOC2O BOC Anhydride C degrees Celsius
CBZCI Benzyl chloroformate
DBU 1 ,8-Diazabicyclo[5.4.0]undec-7-ene
DCiVi Dichlorornethane
DEAD Diethyl azodicarboxylate (DHQ)2PHAL Hydroquinine 1 ,4-phthalazinediyl diether
Figure imgf000078_0001
DIPEA Diisopropylethylamine
DiVlA N,N-DimβthylaGetamide
DMAP 4-Dimethylaminopyridine
DME Dimethoxyethane
DMF Dimethylformamide
DMFDMA N.N-Dimethylformamide dimethylacetal
DMPU 1 ,3-Dimethyl-3,4,5J6-tetrahydro-2(1 h)-pyrimidinone
DMSO Dimethyl sulfoxide
EDCI 1 -(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
El Electron ionization
Eq Equivalents
EtOAc Ethyl acetate
EtOH Ethanol g grams h. hours
1H proton
HATU N,N,N',N'-Tetramethyl-O-(7-Azabenzotriazol-1-yl)Uronium hexafluorophosphate
Hex hexanes
HOBT 1 -Hydroxybenzotriazole
HPLC High pressure liquid chromatography
LAH Lithium aluminum hydride
LDA Lithium diisopropylamide
M Molar mmol milimolar mCPBA mefa-Chloroperoxybenzoic acid Me Methyl
MeCN Acefonitrile
MeOH Methanol min Minutes mg Milligrams
MHZ Megahertz rnL Milliliter
MPLC Medium Pressure Liquid Chromatography
NMR Nuclear Magnetic Resonance
MS Mass Spectroscopy
NBS N-Bromosuccinimide
NMM N-Methylmorpholine
NMP 1-methyl-2-pyrrolidone
ON Overnight
PCC Pyridinium Chlorochromate
PTLC Preparative thin layer chromatography
PyBrOP Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate
Pyr Pyridine
RT Room temperature sgc Silica gel 60 chromatography tBOC tert-Butoxycarbonyl
TACE TNF-alpha converting enzyme
TEA Triethylamine
TFA Trifluoroacetic acid
THF Tetrahydrofuran
TLC Thin layer chromatography
NMR spectra were acquired on the following instruments: 400 MHZ NMR (Bruker), 500 MHZ NMR (Bruker), 400 MHz NMR (Varian), 300 MHZ NMR (Varian) using CD3OD, CDCI3 or DMSO-d6 as solvents. LC-MS data were obtained using a PESciex API 150EX quadropole mass spectrometer using electroscopy ionization.
Purification via reverse phase chromatography (Gilson) was accomplished using a C18 reverse phase column with a gradient of (0.1 % formic acid) 5:95 to 90:10 acetonitrile:water, at a flow rate of 14 ml/min. Samples were collected using UV detection. Alternatively an ISCO Companion with (0.1% formic acid) 5:95 to 95:5 acetonitrile:water, at a flow rate = 10 - 55 rnl/min.
Normal phase silica gel chromatography was either accomplished on a Biotage instrument using a 60 A 12/iVJ, 25/M, or 40/iVl flash cartridges, or on a Jones Flash Master Personal instrument using lsolute flash SI 5g, 1Og, 2Og, 5Og, or 70 g cartridges.
The compounds of formula (I) may be produced by processes known to those skilled in the art and as shown in the following reaction schemes and in the preparations and examples described below. These preparations and examples should not be construed to limit the scope of the disclosure. Alternate mechanistic pathways and analogous structures may be apparent to those skilled in the art. Some of the compounds made by these processes are listed in the tables below. All kinds of isomeric forms of the compounds are considered to be within the scope of this invention.
SYNTHETIC ROUTES AMO EXAMPLES
Example 1
Figure imgf000081_0001
General procedures for Example 1:
In step 1 , Compound 1A (either commercially available, or prepared by a procedure similar to that described by Abdalla, G. M. and Sowell, J. W. Journal of Heterocyclic Chemistry, 1987, 24(2), 297-301) was treated with one equivalent of Di-tert-butyl dicarbonate in polar solvent, such as DMF, for 30 minutes to 12 hours. The solvent was removed and compound 1B could be used without further purification or purified by silica gel chromatography.
In step 2, compound 1B was reacted with potassium cyanide and ammonium carbonate in appropriated alcohol and water solution, at 50 0C to 90 0C, for 5 hours to 48 hours. After cooling down, water was added and compound 1C could be collected by filtration.
In step 3, compound 1C was stirred with 2 to 20 equivalents of hydrogen chloride in methanol for 5 to 48 hours. After ethyl ether was added, compound 1 D could be collected by filtration.
Example 2
Figure imgf000081_0002
Step 1
Compound 2A (Abdalla, G. M. and Sowell, J. W. Journal of Heterocyclic Chemistry, 1987, 24(2), 297-301) (Hydrochloride salt, 8.6Og, 45.4 mmol), triethyl amine (19.0 ml_, 136 mmol), and di-tert-butyl dicarbonate (11.9g, 54.4 mmol) were stirred in methylene chloride (100 ml_) at 25 0C for 16 hours. Saturated aqueous NaHCOs (150 ml_) was added. The aqueous layer was extracted with CHaCI2 (100 rnL) twice. The organic phase was washed with brine (100 rnL) and dried over Na2SO4. The solvent was removed by rotary evaporator to give compound 2B which was used without further purification.
Compound 2B (9.06g, 35.8 mmol), KCN (3.49g, 53.7 mmol), and (NH4)2CO3 (12.0 g, 125.2 mmol) were suspended in a mixture of EtOH (35 ml) and water (35 ml). The solution was stirred at 70 0C for three days. After cooling down, water (35 ml) was added. The solid was filtered and washed with water three times. The solid was dried under vacuum at 40 0C for 16 hours to give compound 20 (7.9 g, 68%).
Step S
Compound 2C (4.0 g) was suspended in methanol (50 ml) and HCI (4M in dioxane, 20 ml) was added. The solution was stirred at 25 0C for 3 hours.
Ethyl ether (50 ml) was added. The solid was filtered, washed with ethyl ether twice, and dried under vacuum for 12 hours to give compound 2D (2.7 g,
84%).
The following intermediates were prepared as described in Examples 1 and 2.
Figure imgf000082_0001
xample 3
Figure imgf000083_0001
3F
General praeedyres for Example 3
In step 1 , 5-Hydroxy-2-nitro-benzoic acid (compound 3A) was dissolved in a suitable solvent, such as DMF, and reacted with an alkyl chloride or alkyl bromide in the presence of cesium carbonate at room temperature for 2 to16 hours. Water and EtOAc were added. The organic phase was washed by water 1 to 5 times to remove DMF. The organic phase was washed with brine, dried, concentrated to give the crude product (compound 3B) which was used without further purification.
In step 2, compound 3B was dissolved in dioxane/water (3:1) and treated with lithium hydroxide at room temperature for 3 to 6 hours. The solution was made acidic by addition of 1 N HCI solution and extracted with EtOAc. The products (compound 3C) were either used without further purification or purified by chromatography depending on the boiling point of the alcohol side products.
In step 3, compound 3C was dissolved in a suitable solvent, such as DMF, and coupled with compound 3D using EDCI and HOBT at room temperature overnight. After an aqueous/EtOAc work up, the product (compound 3E) was isolated by chromatography.
In step 4, compound 3E was suspended in MeOH/water (1 :1) under N2 atmosphere. NaOH and Zinc powder were added and the reaction mixture was stirred at 70 0C to SO 0C for 8 to 24 hours. After cooling to room temperature, the solution was adjusted to pH=6~7 with 1 N HCI solution. The product (compound 3F) was extracted with EtOAc and purified by reverse phase HPLC.
Example 4
Figure imgf000084_0001
Step S
A 25 ml flask was charged with compound 40 (331 mg, 1.68 mmol), compound 40 (Stratford, E. S. and Curley, R. W. Jr, J. Med. Chem. 1983, 26, 1463-1469) (200 mg, 1.4 mmol), EDCI (403 mg, 2.1 mmol), HOBT (227 mg, 1.68 mmol), NMM (0.46 ml_, 4.2 mmol), and DMF (7 ml_). The solution was stirred at room temperature overnight. Saturated aqueous NaHCO3 (30 ml_) and EtOAc (50 ml_) were added. The organic phase was separated and washed with water (20 ml_) and brine (20 mL), then dried over Na2SO4. The solvent was evaporated and the crude product was isolated by silica gel chromatography (CH2CI2/MeOH/NH4OH 20:1 :0.1 to 10:1 :0.1) to give compound 4E (201 mg, 45%).
Step 4
To a 10 mL flask was added compound 4E (50 mg, 0.155 mmol), NaOH (25 mg, 0.62 mmol), Zinc powder (62 mg, 0.47 mmol), MeOH (0.5 mL), and water (0.5 mL). The solution was stirred at 75 0C for 16 hours. After cooling to room temperature, solid was removed by filtration. The filtrate was adjusted to pH=5 by adding 2N HCI. The aqueous phase was extracted by EtOAc (10 mL). The organic solution was dried over Na2SO4 and concentrated. The product was isolated by silica gel chromatography (CH2CI2/MeOH/NH4OH, 40:1 :0.1 to 20:1 :0.1 to 10:1 :0.1) to give compound 4F 6.5 mg (14%). Example 5
Figure imgf000085_0001
5A 5B SC
1
Compound 5A (1.33 g, 7.26 mmol), benzyl bromide (2.73 g, 16.0 mmol), and Cs2CO3 (7.1 g, 22.0 mmol) were mixed in DiVlF (30 ml) and stirred at room temperature overnight. Saturated aqueous NaHCO3 (100 ml) was added and the aqueous phase was extracted with EtOAc (100 ml) twice. The combined organic phases were washed with brine (50 ml), dried over Na2SO4, filtered, and concentrated by rotary evaporator. The product was isolated by silica gel chromatography (Hexane/EtOAc: 10:1 to 5:1) to give compound 5B (2.25 g, 89%).
Step 2
Compound 5B (2.25 g, 6.44 mmol) was dissolved in dioxane/water (3:1 , 35 mL) and LiOH (810 mg, 19.3 mmol) was added. The solution was stirred at room temperature for 3 hours. Water (30 mL) was added followed by addition of 2N HCI (30 mL). The aqueous phase was extracted with EtOAc (50 mL) three times. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated by rotary evaporator. The crude product was purified by silica gel chromatography (CH2CI2/MeOH/HCO2H: 40:1 :0.1 to 20:1 :0.1) to give compound 5C (1.6 g, 91 %).
The following compounds were prepared as described in Examples 3-5.
In each of the tables below, those compounds having a Ki value of less than 10 nM (<10 nM) are designated with letter "A"; those with a Ki value of from 10 to less than 100 nM (10 - <100 nM) are designated with letter "B"; those with a Ki value of from 100 to 1000 nM are designated with letter "C"; and those with a Ki value of more than 1000 nM (>1000 nM) are designated with letter "D".
Figure imgf000086_0001
Figure imgf000086_0002
General procedures for Example 6
In step 1 , 4-Bromo-2-nitro-ben∑oic acid (compound Bh) was dissolved in a suitable solvent, such as DiViF, and reacted with methyl iodide in the presence of cesium carbonate at room temperature for 2-16 hours. Water and EtOAc were added and the organic phase was washed by water 1 -5 times to remove DMF. The organic phase was washed with brine, dried, concentrated, and dried to give the crude product (compound @B>) which used without further
Figure imgf000087_0001
In step 2, the methyl ester (compound 6B) was mixed with Pd(OAc)2, Cs2CO3, and an appropriate ligand, such as racemic-2-(Di-if-butylphosphino)-1 ,1'- binaphthyl. The mixture was placed under vacuum for 1 to 10 minutes to remove oxygen, and refilled with N2. An alcohol and toluene were added and the solution was stirred at 50 0C to reflux temperature for 12 to 72 hours. After cooling to room temperature, the solid was removed by filtration and the solvent was removed. The product could be purified by chromatography. During this reaction, the methyl ester may be partially converted to the ester of the alcohol used. This side product was also collected and hydrolyzed in the next step.
In step 3, compound 6C was dissolved in Dioxane/water (3:1) and treated with lithium hydroxide at room temperature for 3-6 hours. The solution was made acidic by addition of 1 N HCI solution and subjected to aqueous/EtOAc work up. The products (compound 6D) were either used without further purification or purified by chromatography depending on the boiling point of the alcohol side products.
In step 4, compound 6D was dissolved in a suitable solvent, such as DMF, and coupled with compound 6E under EDCI and HOBT conditions at room temperature overnight. After an aqueous/EtOAc work up, the product (compound 6F) could be isolated by chromatography. In step 5, compound @F was suspended in MeOH/water (1 :1) under N2 atmosphere. NaOH and ∑inc powder were added and the reaction mixture was stirred at 70 0C to 80 0C for 8 to 24 hours. After cooling to room temperature, the solution was adjusted to pH=6~7 with 1 N HCI solution. Compound SG was extracted with EtOAc and isolated by reverse phase HPLC.
Figure imgf000088_0001
7A 7B 7C 7D
Step l
Compound 7 A (10.0 g, 40.7 mmol) was dissolved in DMF (100 ml_). Cs2CO3 (27.Og, 81.3 mmol) and methyl iodide (7.60 ml, 122.0 mmol) were added. The solution was stirred at room temperature overnight. EtOAc (250 ml) and water (100 mL) were added. The organic phase was separated and washed with water (100 mL) three times and brine (50 mL), then dried over Na2SO4, filtered, and concentrated using a rotary evaporator. The product was dried under vacuum to give compound 7B (10.3 g, 97%).
Step 2
Pd(OAc) 2 (43 mg, 0.19 mmol), racemic-2-(di-f-butylphosphino)-1 ,1'-binaphthyl (92 mg, 0.23 mmol), and Cs2CO3 (1.88 g, 5.76 mmol) were placed in a 50 mL flask. The flask was placed under vacuum for 2 minutes and refilled with N2. Compound 7B (1.00 g, 3.84 mmol) and MeOH (0.311 mL, 7.69 mmol) were dissolved in toluene (10 mL). The resulting solution was added to the above flask by pipette. The reaction mixture was stirred at 70 0C oil bath for 48 hours. After cooling to room temperature, the solid was filtered and the solvent was removed using a rotary evaporator. The product was isolated by silica gel chromatography (Hexane/EtOAc 20:1 to 10:1) to give compound 7C (380 mg, 47%). Compound 70 (380 mg, 1.80 mrnol) was dissolved in dioxane/water (3:1 , 8 ml) and LiOH (378 mg, 9.0 mrnol) was added. The solution was stirred at room temperature for 3 hours. Water (5 ml) was added followed by addition of 2N HCI to adjust the pH = 2-4. The aqueous phase was extracted with EtOAc (10 ml) three times. The organic phase was washed with brine, dried over Na2Sθ4, filtered, and concentrated. The crude product was dried under vacuum to give compound 70 which was used without further purification.
The following compounds were prepared as described in Examples 6-7
Taføl© 2
Figure imgf000089_0003
Example 8
Figure imgf000089_0001
8A 8B 8C 8D
Figure imgf000089_0002
e
8G 8F Genernl proeedlyre for Example 8
In step 1 , Compound SA was dissolved in a suitable solvent, such as DiViF, and reacted with methyl iodide in the presence of cesium carbonate at room temperature for 2-16 hours. Water and EtOAc were added and the organic phase was washed by water 1-5 times to remove DMF. The organic phase was washed with brine, dried, concentrated, and dried to give the crude product (compound 8B) which was used without further purification.
In step 2, when alcohol was used, the reaction was operated in a similar manner as step 2 in es∑ample 6. When an aromatic or heterocyclic stannane was used, the reaction was operated in the following manner. The aromatic or heterocyclic stannane was added into a dry flask, followed by addition of the 4-Bromo-2-methyl-benzoic acid methyl ester (compound 8B), a base, such as Cs2COa, K3PO4, and a palladium catalyst, such as Pd(PPh3)2CI2. The flask was placed under vacuum for 1 to 10 minutes to remove oxygen and was refilled with N2. An appropriate solvent, such as dry CH3CN, was added and the solution was stirred at 60 0C to reflux temperature overnight to 3 days. The solid was removed by filtration and the solvent was removed. Compound 8C was isolated by chromatography.
In step 3, compound 8C was dissolved in a suitable inert solvent, such as benzene, CCI4 or α,α,α-Trifluorotoluene. NBS and benzoyl peroxide were added and the solution was stirred at 50 0C to 90 0C for 1 to 24 hours. The solid was filtered and the solvent was removed. The residue was dissolved in ether and washed by water. The ether was removed to afford the compound 8D which was used without further purification.
In step 4, the benzyl bromide (compound 8D) was mixed with hydantoin methyl amine 8E, K2CO3, and DMF. The solution was stirred at room temperature for 12 to 24 hours. Then the solid was removed by filtration. The product could be purified by reverse phase HPLC. Compounds 8F and 8G could be obtained in a variable ratio. Step 5 is used when the compound SF was isolated in step 4. Compound SF was dissolved in an appropriate solvent, such as MeOH, and stirred at 50 0C to reflux temperature for 1 to 12 hours. The product could be obtained by removing the solvent by rotary evaporator or purifying via reverse phase chromatography.
Example S
Figure imgf000091_0001
9E
Step S
Compound SC (prepared according to the procedure described by Wyrick, S. D. et al. Journal of Medicinal Chemistry, 1987, 30{10), 1798-806) (3.33 g, 18.5 mmol) was dissolved in dry benzene (40 ml_). NBS (3.45 g, 19.4 mmol) and benzoyl peroxide (134 mg, 0.55 mmol) were added. The solution was stirred in a 75 0C oil bath for about 2 hours. After cooling down, the solid was filtered and washed with Et2O (150 ml_). The organic solution was then washed with water (50 ml_) twice, dried over Na2SO4 or MgSO4, filtered, and concentrated by rotary evaporator. The crude product was dried under vacuum to give compound 9D which was used without further purification. 1H-NMR appeared to indicate that approximately 75% of this material was compound 9D.
Step 4
Compound 9D (4.62 mmol), Compound 9E (824 mg, 4.62 mmol), and K2CO3 (1.28 g, 9.24 mmol) were mixed in DMF (30 mL). The solution was stirred at room temperature for 20 hours. DMF (15 mL) was added and the solid was filtered and washed with DMF. All the DMF solution was combined and concentrated to 25 mL. The resulting solution was applied to reverse phase MPLC (CH3CN/water, 5% to 90%, containing 0.1%HCO2H) to give compound 9F (198 mg, 15%). Example 10
Figure imgf000092_0001
Step 4
Compound 1OO (prepared in example 9) (902 mg, 2.07 mmol, factor = 0.75), Compound 10E (prepared as described in Example 1 , 500 mg, 2.07 mmol), and K2CO3 (629 mg, 4.56 mmol) were mixed in DMF (15 ml). The solution was stirred at room temperature for 20 hours. DMF (15 ml) was added and the solid was filtered and washed with DMF. All the DMF solution was combined and concentrated to 20 ml. It was applied to reverse phase MPLC (CH3CN/water: 5% to 90%, containing 0.1% HCO2H) to give compound 1OF.
Step 5
Compound 1OF (prepared in step 4) was dissolved in MeOH (5 mL), stirred at 65 0C for 5 hours, then concentrated to dryness. The compound was suspended in water and dried with lyophilizer to give compound 1OG (68.3 mg, 9.4%).
Example 11
Figure imgf000092_0002
Step 2
Compound 11 B (500 mg, 2.18 mmol), 2-tributylstannylthiazole (0.97 mL, 2.84 mmol), Pd(PPh3)2CI2, and dry CH3CN were stirred under nitrogen at reflux temperature overnight. After cooling to room temperature, the solid was filtered. The product was isolated by silica gel chromatography (Hexane/EtOAc: 20:1 to 10:1 to 5:1) to give compound 11C (480 mg, 94%). The following compounds were prepared as described in Examples 8-11.
Figure imgf000093_0001
Figure imgf000094_0001
The following additional compounds were prepared as described in Example 8 to 11.
Table 4
Figure imgf000094_0002
E∑sεimpl© 12
Figure imgf000095_0001
12E 12F
General procedures for Example 12:
In step 1 , racemic compound 12A was treated with one equivalent of di-tert- butyl dicarbonate and 4-N,N-dimethylaminopyridine in polar solvent, such as DMF, for 30 minutes to 12 hours. The solvent was removed and the product (compound 12B) was isolated by silica gel (pretreated with 1% triethylamine in Hexane) chromatography.
In step 2, compound 12B was dissolved in proper solvents allowed by HPLC column, and resolved by HPLC using a preparative Chiralpak AD or Chiralcel OD column to give compound 12C and 12D.
In step 3, compound 12C and 12D were treated with excess HCI in methanol at 25 0C to 60 0C for one hour to 12 hours. The solvent was concentrated to give compound 12E and 12F.
Example 13
Figure imgf000096_0001
13A 13B 13C | Step 3 | 13D
Figure imgf000096_0002
13E 13F
1
Compound 13A (810 mg, 2.07 mmol), di-tert-butyl dicarbonate (429 mg, 1.97 mmol), and 4-dimethylaminopyridine (20 mg) were dissolved in a mixture of DiViF (10 ml) and THF (20 ml_). The solution was stirred at 25 0C overnight. Solvents were removed by rotary evaporator. The product was isolated by C18 chromatography (CH3CN/water: 5% to 90%) to give product 13B (650 mg, 70%).
Step 2
Compound 13B (600 mg) was dissolved in a mixture of iso-propanol (6 ml_) and CHCI3 (4 ml_). 2.5 ml_ was separated via HPLC with preparative chiralcel OD column (Mobile phase: iso-propanol/Hexane: 1 :4). Fractions for each peak were collected and concentrated by rotary evaporator to give compound 13C (First peak, 197 mg) and compound 13D (second peak, 178 mg).
Step 3
Compound 13C (197 mg) was dissolved in methanol (3 ml_). HCI (4M in
Dioxane, 0.5 ml_) was added. The solution was stirred in a 60 0C oil bath for three hours. Methanol was removed by rotary evaporator to give compound
13E.
Compound 13F was prepared in the same way as compound 13D (178 mg).
The following compounds were prepared as described in Examples 12-13 Table 5
Figure imgf000097_0001
Proton NMR Spectral Data for Selected Compounds in Table 5.
Compound 25. 1H NMR (500 Hz, DMSO-d6) 64.06 (d, J = 14Hz, 1H), 4.20 (d, J = 14 Hz, 1H), 4.32 (d, J = 18 Hz, 1H), 4.38 (d, J = 18 Hz, 1H), 7.19-7.39 (m, 2H), 7.55-7.80 (m, 5H), 8.93 (s, 1H), 10.96 (s, 1H). xample 14
Figure imgf000098_0001
General procedure for E2∑ample 14
In step 1 , compound 14A (prepared as described in Example 1) was treated with a benzyl bromide (Compound 14B) and DIPEA base in DfVlF at 25 0C to 60 0C for 12 to 24 hours. The reaction solution was purified via C18 reverse phase chromatography to give compound 14C.
In step 2, compound 14C was treated with one equivalent di-tert-butyl dicarbonate in polar solvent, such as DMF, for 30 minutes to 12 hours. The solvent was removed and the product (compound 14D) was isolated by silica gel (pretreated with 1% triethylamine in Hexane) chromatography.
In step 3, compound 14D was subjected to either a Pd catalyzed reaction with a heterocyclic boronic acid or a heterocyclic stannane, or a copper catalyzed reaction with a heterocyclic amine. The reaction were heated in appropriate solvents, such as DMF and acetonitrile, at 60 0C to 150 0C, for 5 minutes to 12 hours. In some cases, a microwave reactor was used. The product was purified by silica gel chromatography to give compound 14E or compound 14F.
In step 4, compound 14E was dissolved in methanol and was stirred with HCI for 1 hour to 12 hours at 25 0C to 60 0C. The solvent was removed to give compound 14F.
The following compounds were prepared as described in step 1 of Example 14 above.
Figure imgf000099_0001
E-sampile 15
Figure imgf000100_0001
Step 1
Compound 15A (prepared as described in Essampl© 1, 1.0 g, 3.12 mmol), Compound 15B (prepared in Eisampl© S, 1.06 g, 3.12 mmol, factor = 0.76), and DIPEA base (1.14 mL, 6.55 mmol) were mixed in DMF (22 ml). The solution was stirred at 55 0C for 20 hours. The reaction solution was purified via C18 reverse phase MPLG (13Og column, CH3CN/water/0.1% HCO2H, 5% to 90%, two separations) to give compound 15C (900 mg, 67%).
Step 2
Compound 15C (2.7 g, 6.28 mmol) was suspended in a mixture of DMF (20 mL) and THF (40 mL). Di-tert-butyl dicarbonate (1.51 g, 6.91 mmol) and 4- dimethyaminopyridine (38 mg, 0.31 mmol) were added. The solution was stirred at 25 0C for 16 hours. The solvents were removed by rotary evaporator. The residue was subjected to silica gel chromatography (Hexane/EtOAc: 2:1 to 1 :1) to give compound 15D (2.36 g, 71%).
Step 3
Compound 15D (100 mg, 0.19 mmol), 3,4,5-trifluorophenyl boronic acid (40 mg, 0.23 mmol), 1 ,1'-bis(triphenylphosphino)ferrocene palladium (II) chloride (15 mg, 0.02 mmol), potassium carbonate (1 M in water, 1 mL) and acetonitrile ( 1 mL) were added to a microwave reactor tube. The tube was sealed and reacted in the microwave reactor at 150 0C for 10 minutes. After cooling down, the aqueous layer was removed and the organic layer was concentrated. The crude product was purified by silica gel chromatography
(CH2CI2ZMeOHZNH3: 40:1 :0.1) to give compound 15E.
Step 4
Compound 15E obtained from step 3 was suspended in MeOH. HCI (2M in ethyl ether, 0.5 ml) was added. The reaction mixture was stirred at 50 0C for five hours. The solvent was removed. The product was purified via C18 reverse phase chromatography (CH3CNZwaterZ0.1% HCO2H, 5% to 90%) to give compound 15F (8 mg, 8.8% from compound 15D).
Example 16
Figure imgf000101_0001
Step s
Compound 16D (50 mg, 0.094 mmol, prepared in example 13), 2- tributylstannylthiazole (53 mg, 0.14 mmol), dichlorobis(triphenylphosphine) palladium (II) (7 mg, 0.01 mmol), and acetonitrile (1 ml_) were added to a microwave reactor tube. The tube was sealed and reacted in a microwave reactor at 150 0C for 10 minutes. The solvent was evaporated and the product was purified by silica gel chromatography (CH2CI2ZMeOHZNH3: 40:1 :0.1 to 20:1 :0.1) to give compound 16F (15 mg, 37%).
Example 17
Figure imgf000101_0002
Step 3
Compound 17D (100 mg, 0.19 mmol, prepared in example 13), pyrazole (15.4 mg, 0.23 mmol), cesium carbonate (124 mg, 0.38 mmol), copper iodide (7.2 mg, 0.038 mmol), 1 ,10-phenanthroline (14 mg, 0.076 mmol), and N1N- dimethylacetamide (0.5 ml_) were added to a dry reaction tube and filled with nitrogen. The reaction tube was sealed and heated in a 120 0C oil bath for two days. After cooling down, the reaction solution was purified by C18 chromatography (CH3CN/water/0.1% HCO2H, 5% to 90%) to give compound
17F (5 mg, 6.4%).
The following compounds were prepared as described in Examples 14-17 Table 7.
Figure imgf000102_0001
Ez ;ampl© 1 ©
Figure imgf000103_0001
Step 1 :
Compound 18A (1.0 g, 6.4 mmol) and compound 18B (1.324 g, 7.68 mmol) were dissolved in toluene (4 ml) and stirred at 80 0C for 24 hours. After cooling to room temperature, the solvent was removed by rotary evaporator. Half of the crude product was dissolved in THF/1 N HCI (1 :1 , 14 ml) and stirred at room temperature for 2 hours. EtOAc (15 ml) and water (5 ml) were added. The organic phase was separated and the aqueous phase was extracted with EtOAc (15 ml) twice. The combined organic phase was dried over Na2SO4 and concentrated by rotary evaporator to give compound 18G which was used without further purification.
Step 2
Compound 18C (prepared in step 1) was dissolved in DMF (15 mL) and was cooled to O 0C in an ice-water bath. Compound 18D (571 mg, 3.2 mmol) was added in one portion. The solution was allowed to warm up to room temperature over 2 hours, and stirred at room temperature for 3 days. A 2N HCI solution (20 mL) was added and the aqueous phase was extracted with EtOAc (50 mL) three times. The organic phases were combined, dried over Na2SO4, and concentrated to dryness. The product was isolated by reverse phase LC (CH3CN/water/0.1% HCO2H: 5% to 90%) to give compound 18E (65 mg, 7.4% from step 1) and Compound 18F (16 mg, 1.8% from step 1).
The following compounds were prepared as described in Example 18 Table S
Figure imgf000104_0002
Eimmple 19
Figure imgf000104_0001
General procedures for Example 19:
In stepi , compound 19A was treated with two equivalent of Boc2O in a suitable solvent, such as dichloromethane, for 30 min. to 12 h. The solvent was removed and the compound 19B could be used without further purification or purified by silica gel chromatography.
In step 2, compound 19B was treated with PCC and celite in a suitable solvent such as dichloromethane, for 2 hr to 12 hr. Compound 19C was purified by silica gel chromatography.
In step 3, compound 19C was reacted with potassium cyanide and ammonium carbonate in appropriated alcohol and water solution, at 50 0C to 90 0C, for 5 hours to 48 hours. After cooling down, water was added and compound 1SD could be collected by filtration.
In step 4, compound 19D was stirred with 2 to 20 equivalents of hydrogen chloride in methanol for 5 to 48 hours. The solvent was removed and the compound 1SE could be used without further purification.
In step 5, the benzyl bromide (compound 1SG) was mixed with hydantoin methyl amine 1SE, DIPEA, and DMF. The solution was stirred at room temperature for 12 to 24 hours. The product (1SF) was either removed by filtration or purified by silica gel chromatography.
Example 20.
stepi OH step 2 OH step 3 O step 4 HN --f
NH2 NH2 BocHN NH2 BocHN NHCbz BocHN Λ NHCbz BocHN NHCb∑ 2OA 2OB 2OC 2OD 2OE
Figure imgf000105_0001
2OL
General procedures for Example 20:
In step 1 , Compound 2OA was treated with BOC-ON in a suitable solvent such as dichloromethane, for 2 hr to 12 hr. Compound 2OB was purified by silica gel chromatography. In step 2, Compound 2QB was treated with CbzCI and a base such as DIPEA, in a suitable solvent, such as dichloromethane, for 2 hr to 12 hr. Compound 2OC was purified by silica gel chromatography.
In step 3, compound 2ΘC was treated with PCC and celite in a suitable solvent such as dichloromethane, for 2 hr to 12 hr. Compound 2OD was purified by silica gel chromatography.
In step 4, compound 200 was reacted with potassium cyanide and ammonium carbonate in appropriated alcohol and water solution, at 500C to 90 0C, for 1 hour to 48 hours. After cooling down, water was added and compound 2OE could be collected by filtration.
In step 5, Compound 2OE was treated with Pd/C in a suitable solvent such as methanol, in a par shaker under H2 atmosphere. After filtering off the catalyst and concentration of solvent, the product was used without further purification.
In step 6, the benzyl bromide (compound 20RΛ) was mixed with hydantoin methyl amine 2OF, DIPEA, and DMF. The solution was stirred at at room temperature to 80 °C for 12 to 24 hours. The product was either removed by filtration or purified by silica gel chromatography.
In step 7, compound 2OG was stirred with 2 to 20 equivalents of hydrogen chloride in dioxane for 1 to 12 hours. The solvent was removed and the compound 2OH was used without further purification.
In step 8, Compound 2OH was coupling with carboxylic acid to give compound 2OJ which was purified by silica gel chromatography.
In step 9, Compound 2OH was coupling with sulphonyl chloride compound to give compound 2OL which was purified by silica gel chromatography.
In step 10, Compound 2OH was reacted with carbonyl compound under reductive amination condition to give compound 201. Alternatively, compound 2OH was treated with a suitable electrophile and a base to give the product 201, which was purified by silica gel chromatography.
In step 11 , compound 201 was reacted with carbonyl compound under reductive amination condition to give product 2OtC. Alternatively, compound 201 was treated with a suitable electrophile and a base to give the product 20E€, which was purified by silica gel chromatography.
Example 21 :
Figure imgf000107_0001
Compound 21 B: Compound 21 A (7 g, 77.7 mmol), and di-tert-butyl dicarbonate (35.6 g, 163 mmol) were stirred in methylene chloride (100 ml_) at 25 0C for 2 hr. Saturated aqueous NaCI (150 mL) was added. The aqueous layer was extracted with CH2CI2 (100 mL) twice. The organic phase was washed with brine (100 mL), dried over Na2SO4. The solvent was removed by rotary evaporator to give compound 21 B (17g, 76%) which was used without further purification.
Compound 21 C: compound 21 B (17 g, 58.6 mmol) was dissolved in methylene chloride (100 mL). PCC (25.2 g, 117 mmol) and celite (15 g) were added and the reaction mixture was stirred at 25 0C overnight. The solid was filtered off and the resulting solution was concentrated and purified via sgc (40% EtOAc/Hexanes) to give 3.62 g (22%) of compound 21 C. Compound 210: Compound 21 C (3.62, 12.6 mmol), KCN (1.23g, 18.9 mrnol), and (NH4^CO3 (3.62 g, 37.7 mmol) were suspended in a mixture of ElOH (30 rnl_) and water (30 ml). The solution was stirred at 80 0C overnight. After cooling down, water (35 ml) was added. The solid was filtered and washed with water three times. The solid was dried under vacuum to give compound 210 (3 g, 67%).
Compound 21 E: Compound 21 D (3.0 g) was suspended in methanol (50 ml) and HCI (4iVi in dioxane, 20 ml) was added. The solution was stirred at 25 0C for 3 hours. Ethyl ether (50 ml) was added. The solid was filtered, washed by ethyl ether twice, and dried under vacuum compound 21 E (1.34 g, 70%).
Compound 21 F: Compound 21 E (130 mg, 0.82 mmol), compound 21 H (0.27 g, 1 mmol) and DIPEA (0.55 mL, 2 mmol) were mixed in DMF (5 mL). The solution was stirred at room temperature overnight. Solvent was removed and the crude material was and purified via sgc (5% NH3^MeOHZCH2GI2) to give 129 mg (35%) of compound 21 E.
Example 22:
Figure imgf000108_0001
Compound 22B: Compound 22Λ (7.3 g, 81 mmol) was treated with BOC-ON (21.9 g, 89 rnmol) in dichloromethane for 3 hr. Solvent was removed and the crude material was purified via sgc (10% NH3 OJVJeOHZCH2CI2) to give 6.5 (42%) of compound 22S.
Compound 22C: Compound 22B (1.5g, 7.9 mmol) was dissolved in dichloromethane (50 ml) at 0 0C. CbzCI (1.24 ml, 8.7 mmol) and DIPEA (1.52 ml, 8.7 mmol) were added and the reaction was stirred at O 0C for 30 min. The reaction mixture was washed by HCI (1 N, 50 ml) and brine (50 mL). The organic layer was dried and concentrated to give crude compound 22C (2.6 g, 99%) which was used without further purification.
Compound 22D: Compound 22C (2.78g, 8.57 mmol) was dissolved in methylene chloride (100 mL). PCC (4.62 g, 21.4 mmol) and celite (4.6 g) were added and the reaction mixture was stirred at 25 0C overnight. Another 0.5 eq. of PCC (923 mg, 4.3 mmol) was added and it was stirred for 3 hr at room temperature. The solid was filtered off and the resulting solution was concentrated and purified via sgc (50% EtOAc/Hexanes) to give 1.86 g (73%) of compound 22D.
Compound 22E: Compound 22D (1.86, 5.8 mmol), KCN (0.56 g, 8.65 mmol), and (NH-O2CO3 (1.66 g, 17.3 mmol) were suspended in a mixture of EtOH (20 mL) and water (20 mL). The solution was stirred at 80 0C overnight. After cooling down, EtOH was removed. The solid was filtered and washed with water three times. The solid was dried under vacuum to give compound 22E (1.45 g, 64%).
Compound 22F: Compound 22E (1.45 g, 3.68 mmol) was treated with Pd/C in methanol in a par shaker under H2 atmosphere of 50 psi for 60 hr. After filtering off the catalyst and concentration of solvent, Compound 22E (0.95 g, 99%) was used without further purification. Compound 22G5: Compound 22F (150 mg, 0.58 mmol), compound 22M (170 mg, 0.64 mmol) and DIPEA (0.22 rnL, 1.28 mmol) were mixed in DMF (5 m!_). The solution was stirred at 70 0C overnight. Solvent was removed and the crude material was and purified via sgc (5% NH3 0JVIeOHZCH2CI2) to give 166 mg (71%) of compound 22CS.
Compound 22H: Compound 22Ca (166 mg) was suspended in methanol (10 rnl) and HCI (4M in dioxane, 4 ml) was added. The solution was stirred at 25 0C for 2 hours. Ethyl ether (50 ml) was added. Solvent was removed and give compound 22H (0.14 g, 99%).
Compound 221: Compound 22H (42 mg, 0.12 mmol) and compound 22J (26 mg, 0.16 mmol) were dissolved in DiVlF (20 ml). EDCI (30 mg, 0.16 mmol), HOBT (21 mg, 0.16 mmol) and DIPEA (0.05 ml, 0.28 mmol) were added and the reaction mixture was stirred at room temperature for 2 hr. Solvent was removed and the crude material was and purified via sgc (10% NH3*>MeOH/GH2Cl2) to give 7 mg (13%) of compound 221.
Compound 22L: Compound 22H (25 mg, 0.073 mmol) and cyclopentanone (7.5 mg, 0.088 mmol) were stirred in methylene chloride (5 mL). Titanium tetraisopropoxide (0.043 mL, 0.15 mmol) was added followed by addition of DIPEA (0.015 mL, 0.088 mmol). The reaction mixture was stirred at room temperature for 2h. Then, Na(OAc)3BH (31 mg, 0.15 mmol) was added and the mixture was stirred at rt overnight. Saturated K2CO3 aq. (20 mL) was added, and the mixture was stirred at rt briefly. The solid was filtered off through a celite pad. The filtrate was diluted with methylene chloride (30 mL), and it was extracted with brine. The organic layer was dried and concentrated to dryness. The crude material was purified via PTLC (10% NH3-MeOH/CH2CI2) to give 7 mg (26%) of compound 22L.
Compound 22K: Compound 22H (20 mg, 0.06 mmol) and isopropyl sulphonyl (27 mg, 0.18 mmol) were dissolved in methylene chloride (10 mL). DIPEA (0.04 mL, 0.26 mmol) were added and the reaction mixture was stirred at room temperature for 48 hr. Solvent was removed and the crude material was and purified via sgc (10% NH3oMeOH/CH2CI2) to give 2 mg (8%) of compound 22K.
The following compounds were prepared as described in Examples
19-22.
Table 9
Figure imgf000111_0001
Figure imgf000112_0002
Example 1001:
1001E IOOID Step 1
To a solution of compound 1001 A (1.65 g, 3.95 mmol) in anhydrous DiViF (35 ml) was added 2-(trimethylsilyl)ethoxymethyl chloride (SEMCI, 0.93 ml, 4.73 mmol) and DIPEA (0.9 ml, 5.14 mmol). The solution was stirred at 25 0C for overnight. DiViF was removed under vacuum. The product 1001 IB was purified by SGC (Hexane/EtOAc, 2:1. yield: 1.6 g, 74%).
Step 2
Compound 1001 B was resolved by Chiralcel OD column (Mobile phase: Hexane/2-propanol 3:1). The first peak was collected and concentrated to give compound 1001 C.
Step S
To a dry flask was added compound 1001 C (1.5 g, 2.73 mmol) and 4-pyridyl boronic acid (670 mg, 5.50 mmol). The flask was vacuumed and refilled with nitrogen three times. Pd(dppf)CI2 (220 mg, 0.30 mmol) was added and followed by addition of CH3CN (20 mL) and aq. K2CO3 (1 M, 15 mL). The solution was stirred at 80 0C (oil bath) for 16 hours. After cooling down, CH3CN (100 mL) was added and the solid was removed by filtration. The aqueous layer was separated and extracted with EtOAc (20 mL) once. The organic solution was combined and concentrated. The product was purified by SGC (CH2CI2/MeOH/NH4OH: 20:1 :0.1) to give compound 1001 D.
Step 4
Compound 1001 D was dissolved in a mixture of methanol and HCI (4M in dioxane) (2:1 , 30 mL) and was stirred overnight in a sealed pressure flask at 90 0C (oil bath). After the solution was cooled, the solution was transferred into a 250 mL round bottom flask. It was concentrated and dried under vacuum. The crude mixture was dissolved in methanol (50 mL) and Et3N (0.5 mL) was added and stirred overnight at 25 0C. The solvent was then removed and the product was purified by C18 reverse phase chromatography (CH3CN/water 5% to 90%, with addition of 0.1% HCO2H) to give compound 1001 E (815g, 71% from compound 1001C). Example 1002
Figure imgf000114_0001
1003A 1003B
To a flamed dried flask was added compound 1Θ03A (100 mg, 0.182 mmol), [1 ,4-bis(diphenylphosphino)butane] palladium(ll) dichloride [Pd(dppb)CI2, 12 mg, 0.02 mmol], and copper (II) oxide (15 mg, 0.18 mmol). The flask was vacuumed and refilled with nitrogen. 2-Tri-n-butylstannylpyridine (0.076 ml, 0.237 mmol) and DiWlF (1 ml) were added. The solution was stirred at 100 0C oil bath for 5 hours. After cooling, the DMF was removed by rotary evaporator. The product was purified by SGC (Hexane/EtOAc 2:1) to give 1003B (84 mg, 84%).
Example 1003
Figure imgf000114_0002
1003A 1003B
To a dry pressure tube was added compound 1003A (50 mg, 0.091 mmol), bis(dibenzylideneacetone) palladium [Pd(dba)2, 1.6 mg, 0.0018 mmol], 9,9- dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos, 3.0 mg, 0.0055 mmol), and Cs2CO3 (60 mg, 0.182 mmol). The pressure tube was vacuumed and refilled with nitrogen. Pyrrolidinone (14 mg, 0.16 mmol) and dioxane(0.5 mL) were added. The tube was sealed and stirred overnight at 100 0C (oil bath). After cooling, dioxane (2 mL) was added and the solid was removed by filtration. The solution was concentrated and purified by SGC (CH2CI2/Me0H: 40:1) to give compound 1003B (27 rng).
Example 1004:
Figure imgf000115_0001
IOOIC 1004A 1004B 1004C
Step i
Compound 1001 C was prepared as described in Example 1001.
A mixture of compound 1001 C (0.3 g, 0.55 mmol), bis(pinacolato)diboron (1004A; 170 mg, 0.65 mmol), potassium acetate (170 mg, 1.70 mmol), and [PdCI2(dppf)]CH2CI2 (50 mg, 0.05 mmol) in 1 ,4-dioxane (10 ml_) was vacuumed and refilled with argon three times. The reaction mixture was stirred at 100 0C (oil bath) for 1.5 hours. After cooling down, the mixture was diluted in EtOAc (50 ml_) and filtered through a Celite pad. The filtrate was concentrated in vacuo and the residual material was purified by silica gel column chromatography (2% MeOH in CH2CI2) to afford compound 1004B (300 mg, 91% yield).
Step 2
A solution of compound 1004B (60 mg, 0.10 mmol), 3-bromoimidazo[1 ,2- ajpyridine (30 mg, 0.15 mmol), and [PdCI2(dppf)]CH2CI2 (8.2 mg, 0.01 mmol) in CH3CN (3 ml_) was treated with potassium carbonate (0.6 mL, 0.6 mmol, 1 M in H2O). The mixture was vacuumed and refilled with argon three times. The reaction mixture was stirred at 900C (oil bath) for 17 hours. After cooling, the mixture was diluted in EtOAc (20 mL) and filtered through a Celite pad. The filtrate was concentrated in vacuo and the residual material was purified by preparative TLC (10% MeOH in CH2CI2) to afford compound 1004C (42 mg, 71 % yield).
The following compounds were prepared as described in Examples 1001, 1002. 1003, or 1004.
Table 1000
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Proton NMR Spectral Data for Selected Compounds in Table 1000.
Compound 111. 1H-NMR (500 MHz, DMSO-Cl6) δ 9.0 (s, 1 H), 8.7 9(d, J = 6.0 Hz, 2H), 7.92 (d, J = 8.7 Hz, 2H), 7.79 (d, J = 8.7 Hz, 2H), 7.76 (d, J = 6.0 Hz, 2H), 7.65 (m, 1 H), 7.48 (m, 2H), 4.40 (d, J = 17.3 H, 1 H), 4.31 (d, J = 17.3 Hz, 1 H), 4.27 (d, J = 14.2 Hz, 1 H), 4.14 (d, J = 14.2 Hz, 1 H).
Compound 120. 1H-NMR (500 MHz, DMSO-d6) δ 8.99 (s, 1 H), 8.03 (d, J = 8.8 Hz, 2H), 7.96 (d, J = 3.3 Hz, 1 H), 7.84 (d, J = 3.3 Hz, 1 H), 7.77 (d, J = 8.8 Hz, 2H), 7.65 (s, 1 H), 7.47 (m, 2H), 4.38 (d, J = 17.6 Hz, 1 H), 4.28 (d, J = 17.6 Hz, 1 H), 4.27 (d, J = 14.3 Hz, 1 H), 4.13 (d, J = 14.3 Hz, 1 H).
Compound 123. 1H-NMR (500 MHz, DMSO-d6) δ 8.99 (s, 1 H), 7.84 (s, 1 H), 7.74 (d, J = 8.4 Hz, 2H), 7.66 (dd, J = 8.5, 4.6 Hz, 1 H), 7.54 (d, J = 8.4 Hz, 2H), 7.49 ( m, 2H), 8.65 (s, 1 H), 4.40 (d, J = 17.5 Hz, 1 H), 4.31 (d, J = 17.5 Hz, 1 H), 4.29 (d, J = 14.2 Hz, 1 H), 4.10 9d, J = 14.2 Hz5 1 H).
Compound 139. 1H NMR (500 MHz, CD3OD) 53.17-3.21 (m, 4H), 3.83- 3.88 (m, 4H), 4.14-4.52 (m, 4H)1 7.01 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8 Hz,
1 H), 7.46-7.48 (m, 3H), 7.75 (s, 1 H).
Compound 143. 1H NMR (400 MHz, CDCI3) 54.21-4.50 (m, 4H), 7.498 (d, J = 0.8 Hz, 1 H), 7.52 (d, J = 0.4 Hz, 1 H), 7.73-7.76 (m, 3H), 7.76-7.87 (m, 4H), 8.60 (d, J = 6 Hz, 2H).
Compound 155. 1H NMR (500 MHz, CD3OD) 58.84 (dd, J = 1.89, 4.1 Hz, 1 H); 8.43 (dd, J = 1.58, 8.2 Hz, 1 H); 7.99 {dd, J = 1.58, 8.2 Hz; 1 H); 7.85 (m, 3H); 7.8 (dd, J = 1.26 Hz, 6.94 Hz, 1 H); 7.75 (m, 3H), 7.70 (dd, J = 7.25 Hz, 0.95 Hz, 1 H); 7.59 (dd, J = 4.73 Hz, 7.57 Hz, 1 H); 7.58 (dd, J = 4.4Hz, 8.2Hz, 1 H); 7.51 (dd, J = 2.5 Hz, 7.8 Hz, 1 H); 7.40 (m, 1 H); 4.54 (d, J=17.0 Hz, 1 H); 4.48 (d, J = 17.0 Hz, 1H); 4.48 (d, J = 14.5 Hz, 1 H); 4.32 (1 H, d, J = 14.5 Hz, 1 H).
Example 1005:
R
Y^ Br ^. R Y^ NH2-HCI
O O
1005A 1005B
General procedure for example 1005
Compound 1005A was treated with one equivalent of hexamethylene tetraamine in chloroform or other suitable solvent for about 5 hours. The product was collected by filtration and then treated with HCI in ethanol for one day to three days. The solid was then collected by filtration to give compound
1005B. Example 1006
Figure imgf000124_0001
1006A
1-Benzofuran-2-yl-2-bromo-ethanone (100SA, 3.Og, 12.55 mmol), hexamethylene tetraamine (1.94 g, 13.80 mmol), and NaI (350 mg) were stirred in CHCI3 (40 mL) for five hours. The solid was collected by filtration and dried under vacuum. The solid was then suspended in ethanol (30 mL) and HCI (cone, 36% in water, 10 mL) was added. The solution was stirred at 25 0C for 4 d. The solid was collected by filtration and washed by ethanol, dried under vacuum to give compound 1006B (3.05 g, contained NH4CI).
Example 1007
Figure imgf000124_0002
1007A 1007B 1007C
Step i
To a flame dried flask was added 2-bromo-1 H-benzimidazole (1007A, 2.94 g, 14.92 mmol), anhydrous THF (75 mL), and NaH (95%, 490 mg, 19.4 mmol). The solution was stirred at 25 0C for 45 minutes; SEMCI (3.17 mL, 17.9 mmol) was added. The solution was stirred at 25 0C for 2.5 hours. Water (50 mL) and EtOAc (100 mL) were added. The aqueous layer was separated and extracted with EtOAc (100 mL) once. The organic layers were combined and concentrated under vacuum. The product was purified by SGC (Hexane/EtOAc: 3:1) to give compound 1007B (3.6 g, 74%). To a flame dried flask was added compound 1007Es (1.42/ g, 4.35 mmol) and anhydrous ethyl ether/THF (2:1 , 15 rnL). The solution was cooled to -780C. n-Butyllithium (1.6 M, 0.46 mL, 0.73 mmol) was added and stirred at -78 0C for 30 minutes. In another flamed dried pear shaped flask was added i\!-(tert- butoxycarbonyl)glycine-N'-methoxy-N'-methylamide (949 mg, 4.35 mmol) and anhydrous THF (2 mL). lsopropyl magnesium chloride (2 SVl, 2.5 mL, 5.0 mmol) was added at 0 0C. The solution was stirred at 0 0C for 5 minutes and was added into the compound 1003C solution via cannula at -78 0C. The solution was then gradually warmed up to -20 0C and stirred between -20 0C and 10 0C for 4 hours. Saturated NH4CI solution was added and the aqueous solution was extracted with EtOAc (50 mL) three times. The organic phases were combined and concentrated. The product was purified by SGC (Hexane/EtOAc: 3:1) to give compound 1007C (1.0 g, 57%).
The following compounds were prepared as described in Example 1, 1005. 1006, and/or 1007.
Table 1001
Figure imgf000125_0001
Figure imgf000126_0001
Proton MiVIR Spectral Data for Selected Compounds in Table 1003.
Compound 181. 1 H-NMR (500 MHz, DMSO-Cl6) δ 11.3 (s, 1 H), 9.34 (s, 1 H), 8.18 (Cl, J = 8.5 Hz, 1 H), 8.12 (d, J = 7.6 Hz, 1 H), 7.67 (m, 1 H), 7.61 (m, 1 H), 7.50 (m, 3H), 4.65 (d, J = 14.3 Hz, 1 H), 4.44 (d, J = 17.3 Hz, 1 H), 4.38 (d, J = 17.3 Hz, 1 H), 4.34 (d, J = 14.3 Hz, 1 H).
Example 1008
Figure imgf000126_0002
1008A 1008B 1008C
Compound 1008A (2Og, 81.61 mmol), 1008B (13.36 mL, 97.93 mmol), Pd(dppf)CI2 (1.0g, 1.36 mmol), dioxane (350 mL), water (50 mL), and Cs2CO3 (22.5g, 163 rnmol) were stirred at 110 °C (oil bath) under nitrogen for 16 hours. After cooling, the solid was removed by filtration. The solution was concentrated and purified by SGC (Hexane/EtOAc, 10:1) to give 1Θ08C (12.1g, 80%).
The following compounds were prepared as described in Examples 14 and
Table 1002
Figure imgf000127_0001
Example 1000
Figure imgf000128_0001
Figure imgf000128_0003
Figure imgf000128_0002
1009E 1009D
Stepl
Compound 1009A (1.18g, 3.36mmol) and pyridine hydrochloride (2.33g, 20.17 mmol) were added into a 20 m!_ microwave reactor tube and reacted at 200 0C for 1 hour. After cooling down, the solid was dissolved in DMF and purified by C18 chromatography (CH3CN/water 5% to 90%, with 0.1% HCO2H) to give compound 1009B (0.87 g, 77%).
Step 2
Compound 1009B (0.75 g, 2.22 mmol) was dissolved in DMF (12 ml_). SEMCI (0.48 mL, 2.44 mmol) and DIPEA (0.775 ml_, 4.44 mmol) were added and the solution was stirred at 25 0C for 4 hours. DMF was removed under vacuum and the product was purified by SGC (Hexane/EtOAc: 3:1 to 1 :1) to give compound 1009C (0.81 g, 78%).
Step 3
Compound 1009C was resolved on Chiralcel OD column by using Hexane and 2-propanol as mobile phase. The first peak was collected and concentrated to give compound 1009D. Step 4
Compound 1QQ90 (IQOrng, 0.214 mmol), 1 -bromo-2-butyne (34 mg, 0.257 mmol), and Cs2CO3 (140 rng, 0.428 rnmol) were stirred in DMF (2 ml) at O 0C for 2 hours, then at 25 0C for overnight. Water (5 ml) was added and the aqueous solution was extracted with EtOAc (10 ml) three times. The organic phases were combined and concentrated. The product was purified by SGC (Hexane/EtOAc: 3:1) to give compound 1Θ0SE (81 mg).
Example 1010
Figure imgf000129_0001
IOIOA IOIOB
Figure imgf000129_0002
101OD
Step 1
Compound 101OA (1.03g, 1.88 mmol), (BOC)2O (493 mg, 2.26 mmol), and Cs2CO3 (741 mg, 2.26 mmol) were stirred overnight in CHCI3 (20 mL). Water was added. The aqueous layer was extracted with EtOAc (3x50 mL). The combined organic layers were concentrated and purified by SGC (Hexane/EtOAc 5% to 90%) to give compound 1010B (1.01 g, 83%).
Step 2
To a dry flask was added compound 1010B (500 mg, 0.77 mmol) and 4- pyridyl boronic acid (190 mg, 1.55 mmol). The flask was vacuumed and refilled with nitrogen three times. Pd(dppf)Cl2 (28 rng, 0.04 minol) was added and followed by addition of CH3CN (5 rnl) and K2CO3 (1 M, 4 rnl). The solution was stirred at 80 0C (oil bath) for 16 hours. After cooling down, CH3CN (100 ml) was added and the solid was removed by filtration. The aqueous layer was separated and extracted once with EtOAc (20 ml). The organic solution was combined and concentrated. The product was purified by SGC (CH2Cl2/MeOH/NH4OH: 20:1 :0.1) to give compound 1010C.
Step s
Compound 1010C obtained in step 2 was dissolved in MeOH (10 ml) and HCI (4M in dioxane, 3 ml) was added and stirred overnight at 25 0C. MeOH was then removed and the product was dried under vacuum to give compound 1010D (315 mg, 75% from compound 10100).
The following compounds were prepared as described in Examples 14 and 1009 or 1010.
Table 1003
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Proton NMR Spectral Data for Selected Compounds in Table 1003.
Compound 198. 1H-NMR (400 MHz, DMSO-Cl6) δ 9.22 (s, 1 H), 7.64 (m,2H). 7.43 (m, 4H), 7.22 (t, J = 2.2 Hz, 1 H), 7.16 (dd, J = 9.6, 1.2 Hz, 1 H). 4.82 (d, J = 2.0 Hz, 2H), 4.16 (m, 4H), 3.33 (s, 3H). Compound 203. 1H-NMR (400 MHz, DMSO-Cl6) δ 7.63 (dd, J = 8.8, 5.6 Hz1 2H), 7.43 (d, J = 8.4 Hz, 1H)57.13 (m, 4H), 4.80 (d, J = 0.8 H∑s 1H), 4,39 (d, J = 17.6 Hz, 1H), 4.17 (d, J = 17.6 Hz, 1H), 4.13 (d, J = 13.6 Hz, 1H), 3.71 (d, J = 13.6 Hz, 1H) 3.34 (s, 3H).
Compound 213. 1H NiViR (500 Hz, CD3OD) δ 4.11 (d, J = 15Hz, 1H), 4.27 (d, J = 15Hz,1H), 4.29 (d, J = 17Hz, 1H), 4.38 (d, J = 17Hz, 1H), 6.84-6.89
(m,2H), 7.16-7.21 (m,2H), 7.56-7.60 (m, 1H), 7.71-7.76 (m,2H)
Compound 219. 1H NMR (500 Hz, CD3OD) δ 0.36-0.40 (m,2H), 0.61-0.68 (m, 2H), 1.25-1.35 (m,1H), 3.91 (d, J = 7Hz, 2H), 4.14 (d, J = 15Hz,1H), 4.30 (d, J = 15Hz,1H), 4.34 (d, J = 17Hz,1H), 4.43 (d, J = 17Hz,1H), 7.01-7.05 (m,2H), 7.17-7.23 (m,2H), 7.65-7.69 (m,1H), 7.72-7.77 (m,2H)
Compound 232. 1H NMR (500 Hz, CD3OD) δ 1.13 (I1 J = 8Hz, 3H), 2.21- 2.27 (m, 2H), 4.15 (d, J = 14Hz1IH)14.31 (d, J = 14Hz, 1H), 4.36 (d, J = 17Hz, 1H), 4.45 (d, J = 17Hz,1H), 4.79 (t, J =2Hz, 2H), 7.04-7.14 (m, 2H), 7.16-7.25 (m,2H), 7.64-7.79 (m, 3H).
Compound 233. 1H NMR (500 Hz, CD3OD) δ 7.678 (d, J = 8.5Hz, 1H); 7.455 (d, J = 4.1Hz, 1H), 7.817 (d, J = 4.1Hz, 1H); 7.099 (s, 1H); 7.052 (dd, J = 2.207, 6.305Hz, 1H); 4.515 (d, J = 17.3 Hz, 1H), 4.450 (d, J = 17.3 Hz, 1H); 4.065 (d, J = 14.5 Hz, 1H); 3.89 (s, 3H); 3.87(d, J = 14.5 Hz, 1H); 3.85 (m, 1H); 2.46 (m.2H); 2.09 (m, 1H)1.89 (m, 1H); 1.76 (m, 1H); 1.67(m, 1H); 1.54 (m,1H); 1.32 (m, 1H).
Compound 239. 1H NMR (500 Hz, DMSO-d6) 64.11 (d, J = 15 Hz, 1H), 4.27 (d, J = 15 Hz1IH), 4.29 (d, J = 17 Hz, 1H), 4.38 (d, J = 17 Hz, 1H), 6.84- 6.89 (m,2H), 7.16-7.21 (m,2H), 7.56-7.60 (m, 1H), 7.71-7.76 (m,2H)
Compound 243. 1H-NMR (500 MHz, CD3OD) δ 8.53 (s, 1H), 7.67 (dd, J = 8.5, 5 Hz, 2H), 7.46 (d, J = 8 Hz, 1H), 7.27 (t, J = 8.5 Hz, 2H), 7.15 (m, 2H), 4.319d, J = 17.0 Hz, 1H), 4.22 (d, J = 17 Hz, 1H), 4.13 (d, J = 14.2 Hz, 1H), 4.06 (d, J = 14.2 Hz1 1 H), 3.88 9d, J = 6.5 Hz, 2H), 3.35 9m, 2H), 1.22 (m, 1 H), 0.57 (d, J = 8 Hz, 1 H), 0.33 (d, J = 5 Hz, 1 H).
Example 1011
Figure imgf000139_0001
1011A 1011B
To a solution of compound 1011 A (100mg) in DMF (5 ml) was added m- chlorobenzoyl peroxide (MCPBA, 100mg). The solution was stirred overnight at 25 0C. The product was purified by C18 reverse phase chromatography (CHsCN/water 5% to 90%, with 0.1 % HCO2H) to give compound 1011 B (73 mg).
The following compounds were prepared as described in Examples 1010 and 1011.
Table 1004
Compound £■
Stryetyr© Rtøss Mass ©foswS KI (sift A)
247
.12 433.1 A
Example 1012.
Figure imgf000140_0001
In step 1 , Compound 1012A was treated with nitromethane and KOfBu in a mixture of THF and f-BuOH for 2 to 12 h. Alternatively, compound 1012A was treated with nitromethane and TBAF in a suitable solvent such as THF for 2 to 12 h. Compound 1012B was purified by silica gel chromatography.
In step 2, Compound 1012B was treated with Pd/C in a suitable solvent such as methanol, in a Parr shaker under H2 atmosphere. After filtering off the catalyst and concentration of solvent, the product was used without further purification.
In step 3, the benzyl bromide (compound 1012D) was mixed with compound 1012C, DIPEA, and DMF. The solution was stirred at 0 °C to room temperature for 12 to 24 hours. The product was either removed by filtration or purified by silica gel chromatography. In step 4, compound 1Θ12E was treated with PCC and Celite in a suitable solvent such as dichlorornethane for 2 to 12 h. Compound 1012F was purified by silica gel chromatography.
In step 5, compound 1012F was reacted with potassium cyanide and ammonium carbonate in an appropriate alcohol and water solution, at 50 0C to 90 0C, for 5 to 48 hours. After cooling, water was added and compound 1012Gi was collected by filtration.
Example 1013.
Figure imgf000141_0001
Compound 1013B: To a solution of THF (15 ml_) and t-BuOH (15 ml_) was added compound 1013A (1.2 g, 5.6 mmol) and nitromethane (0.61 ml_, 11.2 mmol) followed by addition of KOfBu (0.63 g, 5.6 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was adjusted to pH 6 using HOAc. The reaction mixture was diluted with EtOAc (30 ml_), and was extracted with brine. The aqueous layer was extracted with EtOAc (30 ml_ x 2) The combined organic layers were washed with brine, dried, and concentrated to dryness. The crude material was purified via PTLC (25% EtOAc/Hexanes) to give 1.24 g (81%) of compound 1013B.
Compound 1013C: Compound 1013B (1.24 g, 4.5 mmol) was treated with Pd/C in methanol in a Parr shaker under H2 atmosphere (50 psi) overnight. After filtering off the catalyst and concentration of solvent, compound 1013C (1.1 g, 99%) was used without further purification. Compound 1013E: Compound 1013C (1.02 g, 4.2 mmol) was dissolved in dichloromethane (30 mL) at 0 0C. Compound 101SD (1.13 g, 4.2 mmol) and DIPEA (0.73 mL, 4.2 mmol) were added and the reaction was stirred at 0 0C and slowly warmed up to rt overnight. The reaction mixture was washed with HCI (1 N, 50 mL) and brine (50 mL). The organic layer was dried and concentrated to dryness. The crude material was purified via PTLC (50% EtOAc/Hexanes) to give 0.88 g (54%) of compound 1013E.
Compound 1013F: Compound 1013E (0.88 g, 2.25 mmol) was dissolved in methylene chloride (30 mL). PCC (1.22 g, 5.63 mmol) and Celite (1.22 g) were added and the reaction mixture was stirred at 25 0C overnight. The solid was filtered off and the resulting solution was concentrated and purified via sgc (90% EtOAc/Hexanes) to give 0.62 g (71%) of compound 1013F.
Compound 1013G: Compound 1013F (1.01 g, 2.6 mmol), KCN (0.25 g, 3.9 mmol), and (NhU)2GO3 (0.75 g, 7.8 mmol) were suspended in a mixture of NH3 in Methanol (7 N, 10 mL) and water (10 mL). The solution was stirred at 90 0C overnight. After cooling, water (20 mL) was added. The solid was filtered and washed with water three times. The solid was dried under vacuum to give compound 1013G (0.86 g, 72%).
Example 1014.
Figure imgf000143_0001
Step 1.
Compound 1014A was stirred with 2 to 20 equivalents of hydrogen chloride in methanol for 5 to 48 hours. The solvent was removed and the compound 1014B could be used without further purification.
Step 2.
Compound 1014B was treated with carboxylic anhydride and DIPEA to give compound 1014C which was purified by silica gel chromatography.
Step 3.
Compound 1014B was coupled with sulphonyl chloride compound to give compound 1014D, which was purified by silica gel chromatography. Step 4.
Compound 1ΘMB was reacted with carbonyl compound under reductive amination conditions to give compound 1014 E. Alternatively, compound 1014 B was treated with a suitable electrophile and a base to give compound 1014 E, which was purified by silica gel chromatography.
Step 5.
Compound 1014B was reacted with isocyanate compound and DIPEA to give compound 1014F, which was purified by silica gel chromatography.
Example 1015.
Figure imgf000145_0001
1015F
Compound 1015B: Compound 1015A(0.86 g) was suspended in methanol (10 mL) and HCI (4M in dioxane, 10 mL) was added. The solution was stirred at 25 0C for 3 hours. Solvent was removed and the material was dried under vacuum to give compound 1015B (0.74 g, 99%).
Compound 1015C: Compound 1015B (40 mg, 0.11 mmol) and benzoic acid anhydride (25 mg, 0.11 mmol) were dissolved in DMF (1 mL). DIPEA (0.06 mL, 0.33 mmol) was added and the reaction mixture was stirred at room temperature overnight. Solvent was removed and the crude material was purified via sgc (5% NH3-MeOHZCH2CI2) to give 3.7 mg (7%) of compound 1015C.
Compound 1015D: Compound 1015B (40 mg, 0.11 mmol) and compound 1015H (30 mg, 0.11 mmol) were dissolved in DMF (1 mL). DIPEA (0.25 mL, 1.4 mmol) was added and the reaction mixture was stirred at room temperature overnight. Solvent was removed and the crude material was purified via sgc (5% NH3 OiVIeOHZCH2CI2) to give 2.2 mg (3%) of compound 1015D.
Compound 1015E: Compound 1015B (40 mg, 0.11 mmol) and compound 10151 (0.024 ml, 0.22 mmol) were dissolved in DMF (1 ml). K2CO3 (46 mg, 0.33 mmol) was added and the reaction mixture was stirred at 90 0C overnight. Solvent was removed and the crude material was purified via sgc (5% NH3 OiVJeOHZCH2CI2) to give 2.6 mg (5%) of compound 1015E.
Compound 101 SF: Compound 101 SB (46 mg, 0.13 mmol) and cyclobutanone (0.2 ml) were stirred in methylene chloride (1 ml). Titanium tetraisopropoxide (0.045 ml, 0.15 mmol) was added followed by addition of DIPEA (0.027 ml, 0.16 mmol). The reaction mixture was stirred at room temperature for 2 h. Then, NaCNBH3 (41 mg, 0.65 mmol) was added and the mixture was stirred at rt overnight. The solvent was removed. The crude material was purified via PTLC (10% NH3 6MeOHZCH2CI2) to give 3.1 mg (6%) of compound 1015F.
Compound 1015G: Compound 1015B (80 mg, 0.24 mmol) and ethyl isocyanate (0.018 mL, 0.24 mmol) were dissolved in DMF (1 mL). DIPEA (0.17 mL, 0.97 mmol) was added and the reaction mixture was stirred at room temperature overnight. Solvent was removed and the crude material was purified via sgc (9% NH3-MeOHZCH2CI2) to give 11 mg (11%) of compound 1015G.
The following compounds were prepared as described in Examples 1012 to 1015.
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Proton MMR Spectral Bats for Selected Compounds in t able 1005.
Compound 262. 1H NMR (500 Hz, CD3OD) δ 8.921 (m, 1 H); 8.433 (d, J = 8.6 Hz, 1 H); 8.357 (s, 1 H); 8.072 (m, 4H); 7.622 (m, 1 H); 7.545 (m, 1 H); 7.476 (in, 1 H); 7.369 (rn, 1 H); 4.522 (d, J = 17 Hz, 1 H); 4.510 (d, J = 14.5 Hz, 1 H); 4.425 (d, J = 17 Hz, 1 H), 4.350 (d, J = 14.5 Hz, 1 H).
Eissmpl© 1016.
Figure imgf000150_0001
Compound 101613: Compound 101 SA (500 mg, 1.77 mmol) was suspended in CH3CN (5 mL) followed by addition of NaN(CHO)2 (202 mg, 2.12 mmol). The reaction mixture was stirred at rt for 30 min before warmed up to 70 0C and stirred for 2 h. Solid was collected by suction filtration and washed with acetonitrile to give 1016B (380 mg, 78%) as brown solid.
Compound 1016C: Compound 1016B (380 mg, 1.38 mmol) was stirred with HCI (36% aq., 1 mL) and EtOH (10 mL) at rt for 2 days. It was then heated to 60 0C for 2 hr. Solvent was removed and it was dried under vacuum to give 1016C (345 mg, 98%). The material was used without further purification.
The following compounds were prepared as described in Example 1016, Example 2 and Example 8. Table 1006
Figure imgf000151_0001
spectral Data for Selected Compounds in Table 1006. Compound 278. 1H NMR (500 Hz, CD3OD) δ 8.503 (d, J = 4.73 Hz, 1 H); 7.84 (m, 2H); 7.67 (d, J = 3.8 Hz, 1 H); 7.56 (dd, J = 4.4 Hz, 8.5 Hz, 1 H); 7.50 (dd, J = 2.5 Hz,7.8 Hz, 1 H); 7.38 (m, 1 H); 7.33 (d, J = 4.1 Hz, 2H); 7.3 (m, 1 H); 4.52 (d, J = 17 Hz, 1 H); 4.45 (d, J = 17 Hz, 1 H); 4.43 (d, J = 14.2 Hz, 1 H); 4.28 (d, J = 14.2 Hz, 1 H).
E-xampl© 1017.
Figure imgf000152_0001
Compound 1017C: Compound 1017A (1.5 g, 8.26 mmol) was dissolved in dichloromethane (20 ml_) and methanol (10 ml_) at 0 0C. Compound 1017B (2.64 g, 10 mmol) and DIPEA (2.9 mL, 16.5 mmol) were added and the reaction was stirred at 0 0C and slowly warmed up to rt overnight. The reaction mixture was then heated to 50 0C and stirred for 2 h. The reaction mixture was washed with brine (50 mL). The organic layer was dried and concentrated to dryness. The crude material was purified via PTLC (50% EtOAc/hexanes) to give 0.7g (29%) of compound 1017C.
Compound 1017D: Compound 1017C (200 mg, 0.68 mmol) was stirred in CH2Cl2 (15 mL) at O 0C followed by addition of compound 10171 (0.5 mL, 2.04 mmol) and TMS-OTf (13 μL, 0.07 mmol). The reaction mixture was stirred at 0 0C to 5 0C for 6 hr before warmed up to rt and stirred overnight. The solvent was removed and the crude material was purified via PTLC (EtOAc) to give 0.21 g (91%) of compound 1017D. Compound 1017E: Compound 101TO (210 mg, 0.62 mmol) was heated in a sealed tube with NH2NH2 (0.2 ml, 6.2 mmol) and EtOH (2 ml) at 60 0C overnight. Solvent was removed and gave crude material 1017E (210 mg, 99%) which was used without further purification.
Compound 1017F: Compound 1017E (210 mg, 0.62 mmol) and ethyl isocyanate (59 μl, 0.74 mmol) were dissolved in CH2CI2 (10 ml). The reaction mixture was stirred at room temperature overnight. To this mixture was added Et3N (0.43 ml, 3.1 mmol), DMAP (15 mg, cat.) and p-TsCI (141 mg, 0.74 mmol). The reaction was stirred at rt overnight. Solvent was removed and the crude material was purified via sgc (10% NH3 0MeOHZCH2CI2) to give 60 mg (25%) of compound 1017F.
Compound 1017G: Compound 1017F (60 mg, 0.15 mmol) was heated in a sealed tube with HCI (3 ml, 4N in dioxane) at 65 0C for 48 hr. Solvent was removed and the crude material was purified via sgc (5% NH3 eMeOH/GH2GI2) to give 35 mg (66%) of compound 1017G.
Compound 1017H: Compound 1017G (34 mg, 0.1 mmol), KCN (10 mg, 0.15 mmol), and (NH4)2CO3 (30 mg, 0.3 mmol) were suspended in a mixture of NH3 »H2O (1 mL) and ethanol (1 mL). The solution was stirred at 90 0C overnight. Solvent was removed and the crude material was purified via sgc (10% NH3-MeOH/CH2CI2) to give 6 mg (15%) of compound 1017H.
The following compounds were prepared as described in Example 1017
Table 1007
Figure imgf000154_0003
■ Example 1018.
Figure imgf000154_0001
1018A 1018B
Compound 1018A: Compound 1018A was synthesized following procedures in Example 1012.
Compound 1018B: Compound 1018A (180 mg, 047 mmol) was stirred in MeOH (1 ml_) at rt. HCI (3 m!_, 4N in dioxane) was added and the reaction mixture was heated to 70 0C overnight. Solvent was evaporated. The crude material was taken up in water and the solid was collected by suction filtration to give 1018B (115 mg, 71%).
Example 1019.
Figure imgf000154_0002
1019A 1019B 1019C Compound 1019A: Compound 1019A was synthesized following procedures described in Example 1012.
Compound 1019B: Compound 101SA (/4 mg, 0.18 mmol) was dissolved in EtOH (2 ml) and HCI (0.4 ml, aq. 36%) was added and the reaction mixture was heated to 70 °C overnight. Solvent was removed and gave 1019B as a light yellow solid (74 mg, 99%).
Compound 1019C: Compound 1019B (20 mg, 0.05 mmol) was stirred in DMF (1 ml) and HCI (cat., 4 N in dioxane) at 120 °C overnight. Solvent was removed and the crude material was purified via PTlC (9% NH3oMeOH/CH2CI2) to give 8 mg (37%) of Compound 1019C
The following compounds were prepared as described in Example 1012,
Table 1008
Figure imgf000155_0001
Figure imgf000156_0002
Example 1020.
B
Figure imgf000156_0001
Compound 1020A: Compound 1020A was synthesized following the procedures described in Example 22.
Compound 1020B: Compound 1020A (855 mg, 1.86 mmol) was stirred in MeOH (10 ml_) and HCI (10 ml_, 4N in dioxane) at rt for 2 hr. Solvent was removed and the material was dried to give 1020B (735 mg, 99%).
The following compounds were prepared as described in Example 22 and Example 1020.
Table 1009
Figure imgf000156_0003
Figure imgf000157_0002
Example 1021
Figure imgf000157_0001
1021E 1021D 1
DMF ( 100 m!_), cesium carbonate (41.13 g, 126 rnrnol), and 2-chloro-5- methylphenol (1021 A) (15.0 g, 105 mmol) were added to a flask. Methyl iodide (17.92 g, 126 mmol) was added dropwise via addition funnel. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc, washed with water and brine, and dried with Na2SO^ The resulting material was filtered, and concentrated to dryness. The crude product was purified via flash sgc using 1 :4 EtOAc:hexanes as the mobile phase to give 15.93 g of 1021 E.
Step 2
A flask containing AICI3 (2.55 g, 19.1 mmol), and LiCI (0.41 g, 9.6 mmol) was placed in a -30 0C cold bath. A solution of 1021 B (1.0 g, 6.38 mmol) and acetyl chloride (0.75 g, 9.5 mmol) in 20 ml of CH2CIa was added dropwise. The reaction mixture was stirred for 1 h at -30 0C, then allowed to warm to rt and stirred overnight at rt. The reaction mixture was poured into a mixture of ice and EtOAc. The organic layer was washed with water, saturated aq NaHCO3, and water, then dried with Na2SO4, and concentrated to dryness to give 1.18 g of Compound 1021 C.
Step S
Sodium hydroxide (58 g, 1.45 mol) was dissolved in water (260 mL) and the flask was cooled in an ice-water bath. Bromine (19 mL) was added dropwise to the flask with stirring. The reaction mixture was stirred for 0.5 h after the addition was complete. The resulting solution was added dropwise to an ice- water cooled flask containing Compound 1021C (18.5 g, 93.1 mmol). After the addition was complete, the reaction mixture was allowed to warm to rt and left stirring overnight. The reaction mixture was heated at 40 °C for 2 h. NaHSO3 (55 g) was added. The reaction mixture was stirred for 1 h. The resulting material was diluted with 10% aq NaOH and extracted with EtOAc to remove starting material. The aqueous layer was adjusted to pH 1 and extracted with additional EtOAc. The organic layer was dried with Na2SO4, filtered, and concentrated to dryness to give 12.31 g of 1021 D. Step 4
DiVlF (10 ITiL), Compound 10210 (0.50 g, 2.49 mmol), and K2CO3 (0.41 g, 2.96 mmol) were added Io a flask. Methyl iodide (0.42 g, 2.96 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated to dryness to give 0.52 g of 1021 E.
The following compounds were prepared as described in step 1 in Example
14 and Example 1021.
Table 1010
Figure imgf000159_0001
Proton NMR Spectral Data for Selected Compounds in Table 1010.
Compound 296. 1H NMR (500 Hz, DMSO-d6) δ 3.93 (s, 3H), 4.00 (d, J = 14 Hz, 1 H), 4.19 (d, J = 14 Hz, 1 H), 4.23 (d, J = 18 HzJ H), 4.34 (d, J = 18 Hz, 1 H), 7.24-7.34 (m, 2H), 7.42 (s, 1 H), 7.62-7.73 (m, 3H), 8.92 (s, 1 H), 10.95 (s, 1 H).
Specific TACE inhibitory activity (Ki values) of some representative compounds of the present invention are set forth below.
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications that are within the spirit and scope of the invention, as defined by the appended claims.

Claims

THEREFORE, WE CLAIM:
1. A compound represented by Formula (I):
Figure imgf000163_0001
or a pharmaceutically acceptable salt, solvate or isomer thereof, wherein:
4 4
X is selected from the group consisting of -S-, -C(R )2- or -N(R )-;
T is selected from the group consisting of H (with U and V being absent), alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, and arylalkyl, said aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl being optionally fused with one or more moieties selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl, wherein each of any of the aforementioned alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl groups of T is unsubstituted or optionally independently substituted with one to four R10 moieties which can be the same or different, each R10 moiety being independently selected from the group of R10 moieties below;
U is absent or present, and if present U is selected from the group consisting of a covalent bond, -N(R4)-, -N(R4)C(R4)2-> -N(R4)C(O)-, -O-, -N(R4)S(O)2-, -N(R4)C(O)N(R4)-, and -N(R4)C(S)N(R4)-;
V is absent or present, and if present V is selected from the group consisting of alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl, said aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl being optionally fused with one or more moieties selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl, wherein each of any of the aforementioned alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl is unsubstituted or optionally independently substituted with one to four R10 moieties which can be the same or different, each R10 moiety being independently selected from the group of R10 moieties below; Y is absent or present, and if present Y is selected from the group consisting of a covalent bond, -(C(R4)2)n-, -N(R4)-. -C(O)N(R4)-, -N(R4)C(O)-, -N(R4)G(Q)N(R4)-, -S(O)2N(R4)-, -N(R4)-S(O)2, -O- -S-, -C(O)-, -S(O)-, and -S(O)2-;
Z is absent or present, and if present Z is selected from the group consisting of a covalent bond, -(C(R4)2)n-, -N(R4)-, -C(O)N(R4)-, -N(R4)C(0)-, -N(R4)C(O)N(R4)-, -S(O)2N(R4)-, -N(R4)-S(O)2-, -O- -S-, -C(O)-, -S(O)-, and -S(O)2-; n is 1 to 3;
R is selected from the group consisting of H, -OR4, halogen, alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl, wherein each of the alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl groups of R is unsubstituted or optionally independently substituted with one to four R20 moieties which can be the same or different, each R20 moiety being independently selected from the group of R20 moieties below, with the proviso that when Y is present and Y is N, S or O, then R1 is not halogen;
R is selected from the group consisting of H, -OR4, halogen, alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl, wherein each of the alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl,
2 alkylaryl, alkylheteroaryl and arylalkyl groups of R is unsubstituted or optionally independently substituted with one to four R20 moieties which can be the same or different, each R20 moiety being independently selected from the group of R20 moieties below, with the proviso that when Z is present and Z is N, S or O, then R2 is not halogen;
4 each R is the same or different and is independently selected from the group consisting of H and alkyl;
R is selected from the group consisting of -OR4, -N(R )2, -S(O)-,
-S(O)2-, -N(R4)S(O)2-, -S(O)2N(R4)-, -O(fluoroalkyl), halogen, alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl, wherein each of the alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and
10 arylalkyl groups of R is unsubstituted or optionally independently substituted with one to four R30 moieties which can be the same or different, each R30 moiety being independently selected from the group of R30 moieties below;
20
R is selected from the group consisting of halogen, alkyl, fluoroalkyl; and
30
R is selected from the group consisting of halogen, alkyl, and fluoroalkyl.
2. The compound of claim 1 , wherein said isomer is a stereoisomer.
3. The compound of claim 1 wherein T is alkyl or aryl; X is -C(R )2-;
2
Y is absent; Z is absent or present; R is selected from the group consisting of H, halogen and alkyl; and if Z is present Z is -O-.
4. The compound of claim 1 wherein T is alkyl or aryl; X is
4 2
-C(R )2-; Y is absent; Z is absent or present, and if present Z is -O-; and R is selected from the group consisting of alkylaryl and alkylheteroaryl.
5. The compound of claim 1 wherein T is alkyl or aryl; X is -N(R )-; Y
2 is absent; Z is absent or present; R is selected from the group consisting of H, halogen and alkyl; and if Z is present Z is -O-.
6. The compound of claim 1 wherein X is -CH2- or -N(R )-.
7. The compound of claim 6 wherein X is -CH2-.
4
8. The compound of claim 6 wherein X is -N(R )-.
4
9. The compound of claim 8 wherein R is H.
10. The compound of claim 1 wherein T is alkyl.
11. The compound of claim 10 wherein T is -CH3.
12. The compound of claim 1 wherein T is aryl and said aryl is unsubstituted or optionally independently substituted with one to five R10 moieties which can be the same or different, each R10 moiety being independently selected from the group of R10 moieties.
13. The compound of claim 12 wherein R10 is halogen.
14. The compound of claim 12 wherein R10 is heteroaryl.
15. The compound of claim 12 wherein R10 is aryl.
16. The compound of claim 1 wherein U selected from the group consisting of a covalent bond, -N(R4)-, -N(R4)C(O)-, and -N(R4)S(O)2-.
17. The compound of claim 16 wherein U is a covalent bond.
18. The compound of claim 16 wherein U is -N(R )-.
A
19. The compound of claim 16 wherein U is -N(R )C(O)-.
20. The compound of claim 1 wherein V is selected from the group consisting of aryl, heteroaryl, heterocyclyl and cycloalkyl, said aryl, heferoaryl, heterocyclyl, and cycloalkyl being optionally fused with one or more moieties selected from the group consisting of aryl, heteroaryl, heterocyclyl, or cycloalkyl, wherein each of any of said aryl, heteroaryl, heterocyclyl and cycloalkyl is unsubstituted or optionally independently substituted with one to four R10 moieties which can be the same or different, each R10 moiety being independently selected from the group of R10 moieties.
21. The compound of claim 1 wherein Y is selected from the group consisting of a covalent bond, -(G(R4)2)n-, -C(O)- and -O-.
22. The compound of claim 21 wherein Y is -O-.
23. The compound of claim 21 wherein Y is -(G(R4)2)n-.
24. The compound of claim 21 wherein Y is -C(O)-.
25. The compound of claim 21 wherein Y is a covalent bond.
26. The compound of claim 1 wherein R1 is selected from the group consisting of -OR4, H, alky!, fluoroalkyl, alkylaryl, halogen, and heteroaryl.
27. The compound of claim 26 wherein R1 is H.
28. The compound of claim 26 wherein R1 is alkylaryl.
29. The compound of claim 26 wherein R1 is alkyl.
30. The compound of claim 26 wherein R1 is fluoroalkyl.
31. The compound of claim 26 wherein R1 is halogen.
32. The compound of claim 26 wherein R1 is -OR4.
33. The compound of claim 32 wherein R4 is -CH2C≡CCH3.
34. The compound of claim 32 wherein R4 is -CH2C=CCH2OH.
35. The compound of claim 32 wherein R4 is ""CH2 <J_
36. The compound of claim 29 wherein said alkyl is -CH3.
37. The compound of claim 29 wherein said alkyl is -CH2CH3.
38. The compound of claim 1 wherein T, U, and V when taken
together form
Figure imgf000167_0001
and R1 is selected from the group consisting
Figure imgf000167_0008
39. The compound of claim 1 wherein T, U, and V when taken
together form
Figure imgf000167_0002
and R1 is selected from the group consisting of F,
Cl1 OH1-OCH2OCCH31 -OCH2OCCH2OH, -OCH3, and ~OCH2<]
40. The compound of claim 1 wherein T, U, and V when taken
Figure imgf000167_0003
and R1 is selected from the group consisting of F,
Figure imgf000167_0013
41. The compound of claim 1 wherein T, U, and V when taken together
form
Figure imgf000167_0004
and R1 is selected from the group consisting of F, Cl, OH,
Figure imgf000167_0009
42. The compound of claim 1 wherein T, U, and V when taken
together form
Figure imgf000167_0005
and R1 is selected from the group consisting of F,
Figure imgf000167_0010
43. The compound of claim 1 wherein T, U, and V when taken
together form
Figure imgf000167_0006
and R2 is selected from the group consisting
Figure imgf000167_0011
44. The compound of claim 1 wherein T, U, and V when taken
together for ^^^ ^^ and R2 is selected from the group consisting of F,
Figure imgf000167_0007
Figure imgf000167_0012
45. The compound of claim 1 wherein T, U, and V when taken
together form S""^^ and R2 is selected from the group consisting of F,
Cl1 OH, -OCH2C^CCH3. -OCH2CsCCH2OH, -OCH3, and -OCH2<3.
46. The compound of claim 1 wherein T, U, and V when taken together
Figure imgf000168_0001
and R is selected from the group consisting of F, Cl, OH,
Figure imgf000168_0002
47. The compound of claim 1 wherein T, U, and V when taken
together form
Figure imgf000168_0003
and R2 is selected from the group consisting of F1
Cl, OH1 -OCH2C≡CCH3, -OCH2CsCCH2OH, -OCH3, and "OCH2O
48. The compound of claim 30 wherein said fluoroalkyl is -CH2CF3.
49. The compound of claim 31 wherein said halogen is selected from the group consisting of -Br, -Cl and -F.
50. The compound of claim 32 wherein R4 is -CH3.
51. The compound of claim 29 wherein said alkyl is substituted with one to four R20 moieties which can be the same or different, each R20 moiety being independently selected from the group of R20 moieties.
52. The compound of claim 51 wherein R20 is aryl.
53. The compound of claim 1 wherein Z is selected from the group consisting of a covalent bond, -N(R )-, -(C(R4)2)n-, -C(O)- and -0-.
54. The compound of claim 53 wherein Z is -O-.
55. The compound of claim 53 wherein Z is a covalent bond.
4
56. The compound of claim 53 wherein Z is -N(R )-.
57. The compound of claim 53 wherein Z is -C(O)-.
58. The compound of claim 53 wherein R is alkyl.
59. The compound of claim 58 wherein said alkyl is -CH3.
60. The compound of claim 53 wherein R2 is selected from the group consisting of -OR4, hydrogen, alkyl, fluoroalkyl, alkylaryl, halogen, and heteroaryl.
61. The compound of claim 60 wherein R2 is hydrogen.
62. The compound of claim 60 wherein R2 is alkyl.
63. The compound of claim 60 wherein R2 is alkylaryl.
64. The compound of claim 60 wherein R2 is fluoroalkyl.
65. The compound of claim 64 wherein said fluoroalkyl is - CH2CF3.
66. i he compound of claim 60 wherein R is halogen.
67. The compound of claim 66 wherein said halogen is selected from the group consisting of -Br, -Cl and -F.
68. The compound of claim 60 wherein R2 is heteroaryl.
69. The compound of claim 60 wherein R4 is -CH3.
70. The compound of claim 60 wherein R4 is -CH2CsCCH3.
71. The compound of claim 60 wherein R4 is -CH2CsCCH2OH.
72. The compound of claim 60 wherein R4 is ~CH2 <J.
73. The compound of claim 60 wherein said alkyl is -CH3.
74. A compound exhibiting inhibitory activity of a tumor necrosis factor-alpha-converting enzyme (TACE), tumor necrosis factor-alpha (TNF-α), matrix metalloproteinases (MMPs), a disintegrin and metalloproteases (ADAMs) or any combination thereof, including enantiomers, stereoisomers and tautomers of said compound, and pharmaceutically acceptable salts or solvates of said compound, said compound being selected from the compounds of structures listed below:
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
75. The compound of claim 74, wherein said compound is selected from the compounds of structures listed below:
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
76. The compound of claim 75, wherein said compound is selected from the compounds of structures listed below:
Figure imgf000209_0002
Figure imgf000210_0001
Figure imgf000211_0001
77. The pharmaceutical composition of claim 1 additionally comprising at least one pharmaceutically acceptable carrier.
78. A method of treating disorders associated with TACE, TNF-α, MMPs, ADAMs or any combination thereof, said method comprising administering to a patient in need of such treatment a pharmaceutical composition which comprises therapeutically effective amounts of at least one compound of claim 1.
79. The use of a compound of claim 1 for the manufacture of a medicament to treat disorders associated with TACE, TNF-α, MMPs, ADAMs, or any combination thereof.
80. A method of preparing a pharmaceutical composition for treating the disorders associated with TACE, TNF-α, WiMPs, ADAMs or any combination thereof, said method comprising bringing into intimate contact at least one compound of claim 1 and at least one pharmaceutically acceptable carrier.
81. A pharmaceutical composition for treating disorders associated with TACE, TNF-α, MMF, ADAM or any combination thereof in a subject comprising, administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
82. A compound of claim 1 in purified form.
83. A method of treating a condition or disease mediated by TACE, MMPs, TNF-α, aggrecanase, or any combination thereof in a subject comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
84. A method of treating a condition or disease selected from the group consisting of rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumor growth and tumor invasion by secondary metastases, neovascular glaucoma, inflammatory bowel disease, multiple sclerosis and psoriasis in a subject, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
85. A method of treating a condition or disease selected from the group consisting of fever, cardiovascular conditions, hemorrhage, coagulation, cachexia, anorexia, alcoholism, acute phase response, acute infection, shock, graft versus host reaction, autoimmune disease and HIV infection in a subject comprising administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
86. A method of treating a condition or disease selected from the group consisting of septic shock, haemodynamic shock, sepsis syndrome, post ischaemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancers such as cutaneous T-cell lymphoma, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, inflammatory bowel diseases such as Crohn's disease and colitis, osteo and rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, aduit Siiii's disease, ureitis, Wegener's granulomatosis, Behcehe disease, Sjogren's syndrome, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, complex regional pain syndrome, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV, non-insulin dependent diabetes mellitus, systemic lupus erythematosus, glaucoma, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinal disease, scleroderma, osteoporosis, renal ischemia, myocardial infarction, cerebral stroke, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing aveolitis, psoriasis, transplant rejection, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, reversible airway obstruction, adult respiratory distress syndrome, asthma, chronic obstructive pulmonary disease (COPD) and bronchitis in a subject comprising administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
87. A method of treating a condition or disease associated with COPD, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
88. A method of treating a condition or disease associated with rheumatoid arthritis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
89. A method of treating a condition or disease associated with Crohn's disease, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
90. A method of treating a condition or disease associated with psoriasis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
91. A method of treating a condition or disease associated with ankylosing spondyiiiis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
92. A method of treating a condition or disease associated with sciatica, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
93. A method of treating a condition or disease associated with complex regional pain syndrome, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
94. A method of treating a condition or disease associated with psoriatic arthritis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.
95. A method of treating a condition or disease associated with multiple sclerosis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or isomer thereof, in combination with a compound selected from the group consisting of Avonex®, Betaseron, Copaxone or other compounds indicated for the treatment of multiple sclerosis.
96. The method or claim 83 further comprising administering to said subject a therapeutically effective amount of at least one medicament selected from the group consisting of disease modifying anti-rheumatic drugs (DMARDS), non-steroidal anti-inflammatory drugs (NSAIDs), cycloxygenase-2 selective (COX-2) inhibitors, COX- 1 inhibitors, immunosuppressives, biological response modifiers (BRMs)1 anti-inflammatory agents and H1 antagonists.
97. A method of claim 84, further comprising administering to said subject a therapeutically effective amount of at least one medicament selected from the group consisting of DMARDS. NSAIDs. COX-2 inhibitors. COX-1 inhibitors, immunosuppressives, BRMs, anti-inflammatory agents and H1 antagonists.
98. A method of claim 85, further comprising administering to said subject a therapeutically effective amount of at least one medicament selected from the group consisting of DMARDS, NSAIDs, COX-2 inhibitors, COX-1 inhibitors, immunosuppressives, BRMs, anti-inflammatory agents and H1 antagonists.
PCT/US2005/024771 2004-07-16 2005-07-13 Hydantoin derivatives for the treatment of inflammatory disorders WO2006019768A1 (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
AU2005275213A AU2005275213A1 (en) 2004-07-16 2005-07-13 Hydantoin derivatives for the treatment of inflammatory disorders
MX2007000668A MX2007000668A (en) 2004-07-16 2005-07-13 Hydantoin derivatives for the treatment of inflammatory disorders.
EP05771446A EP1778676B1 (en) 2004-07-16 2005-07-13 Hydantoin derivatives for the treatment of inflammatory disorders
CA002573764A CA2573764A1 (en) 2004-07-16 2005-07-13 Hydantoin derivatives for the treatment of inflammatory disorders
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