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WO2014066726A2 - Composés pour la modulation d'il-17 - Google Patents

Composés pour la modulation d'il-17 Download PDF

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Publication number
WO2014066726A2
WO2014066726A2 PCT/US2013/066749 US2013066749W WO2014066726A2 WO 2014066726 A2 WO2014066726 A2 WO 2014066726A2 US 2013066749 W US2013066749 W US 2013066749W WO 2014066726 A2 WO2014066726 A2 WO 2014066726A2
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WO
WIPO (PCT)
Prior art keywords
compound
alkylene
alkyl
optionally substituted
resin
Prior art date
Application number
PCT/US2013/066749
Other languages
English (en)
Inventor
Sethu L. ALEXANDER
Timothy F. Briggs
Frank G. FAVALORO, Jr.
Stephen P. Hale
Benjamin A. Seigal
Kelley C. SHORTSLEEVES
Cheri SNEDEKER
Michael Taylor
Nicholas K. Terrett
Dingxue Yan
Pawel Wojciech Nowak
Rajiah Aldrin DENNY
Boris Andrew CHRUNYK
Parag Vasant SAHASRABUDHE
Jane Marie WITHKA
Original Assignee
Ensemble Therapeutics Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ensemble Therapeutics Corporation filed Critical Ensemble Therapeutics Corporation
Publication of WO2014066726A2 publication Critical patent/WO2014066726A2/fr

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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
    • C07C239/08—Hydroxylamino compounds or their ethers or esters
    • C07C239/22—Hydroxylamino compounds or their ethers or esters having oxygen atoms of hydroxylamino groups esterified
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    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/13—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
    • C07C309/14—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton
    • C07C309/15—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton the nitrogen atom of at least one of the amino groups being part of any of the groups, X being a hetero atom, Y being any atom
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    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
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    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

  • the invention relates generally to compounds and their therapeutic use. More particularly, the invention relates to compounds that modulate the activity of IL-17 and/or are useful in the treatment of medical conditions, such as inflammatory diseases and other IL-17-associated disorders.
  • Interleukin-17 also known as IL-17A and CTLA-8, is a pro-inflammatory cytokine that stimulates secretion of various other cytokines in a variety of cell types.
  • IL-17 can induce IL-6, IL-8, G-CSF, TNF-a, IL- ⁇ ⁇ , PGE2, and IFN- ⁇ , as well as numerous chemokines and other effectors. See, e.g., Gaffen, SL, Arthritis Research & Therapy 6: 240-247 (2004).
  • IL-17 is expressed by TH17 cells, which are involved in the pathology of
  • IL-17 and Thl7 are linked to pathogenesis of diverse autoimmune and inflammatory diseases, but are essential to host defense against many microbes, particularly extracellular bacteria and fungi.
  • Human IL- 17A is a glycoprotein with a Mr of 17,000 daltons (Spriggs et al, J Clin Immunol, 17: 366-369 (1997)).
  • IL-17 can form homodimers or heterodimers with its family member, IL-17F.
  • IL-17 binds to both IL-17 RA and IL-17 RC to mediate signaling.
  • IL-17 signaling through its receptor, activates the NF-KB transcription factor, as well as various MAPKs. See, e.g., Gaffen, SL, Nature Rev Immunol, 9: 556-567 (2009).
  • IL-17 can act in cooperation with other inflammatory cytokines such as TNF-a, IFN- ⁇ , and IL- ⁇ ⁇ to mediate pro-inflammatory effects. See, e.g., Gaffen, SL, Arthritis
  • IL-17 Increased levels of IL-17 have been implicated in numerous diseases, including rheumatoid arthritis (RA), bone erosion, intraperitoneal abscesses, inflammatory bowel disease, allograft rejection, psoriasis, angiogenesis,
  • IL-17 was found in higher serum concentrations in patients with systemic lupus erythematosus (SLE) and was recently determined to act either alone or in synergy with B-cell activating factor (BAFF) to control B-cell survival, proliferation, and differentiation into immunoglobulin producing cells.
  • SLE systemic lupus erythematosus
  • BAFF B-cell activating factor
  • IL-17 has also been implicated in playing a role in ankylosing spondylitis (H. Appel et al, Arthritis Research and Therapy 201 1, 13R95) and psoriatic arthritis (Mclnnes, I. et al, Arthritis & Rheumatism, 201 1 ; Volume 63, Suppl.10:779.
  • IL-17-expressing TH17 cells were shown to be involved in multiple myeloma, Prabhala et al, Blood, online DOI 10.1182/blood-2009-10-246660, Apr. 15, 2010, and to correlate with poor prognosis in patients with HCC, Zhang et al., J Hepatology 50: 980-89 (2009). Also, IL-17 was found to be expressed by breast-cancer-associated macrophages, Zhu et al, Breast Cancer Research 10:R95 (2008). However, the role of IL-17 in cancer, in many cases, has been unclear. In particular, IL-17 and IL-17-producing TH17 cells have been identified as having both a positive and a negative role in tumor immunity, sometimes in the same type of cancer. For a review, see, Ji and Zhang, Cancer Immunol Immuother 59: 979-987 (2010).
  • the present invention provides compounds, methods of modulating the activity of IL-17, and methods for treating various medical conditions using such compounds.
  • the invention provides a compound represented by Formula I:
  • the invention provides a method of treating a patient suffering from or susceptible to a medical condition that is mediated directly or indirectly by IL-17.
  • a number of medical conditions can be treated.
  • the method comprises administering to the patient a therapeutically effective amount of a composition comprising a compound described herein.
  • the compounds described herein may be used to treat or prevent inflammatory diseases and conditions, proliferative diseases (e.g., cancer), autoimmune diseases and other disease described herein.
  • the invention provides a method of treating a patient suffering from a disease or condition associated with elevated levels of IL-17 comprising the steps of: a) determining whether the patient has an elevated level of IL-17; and b) if the patient does have an elevated level of IL-17, administering to the patient an effective amount of a compound of Formula I for a time sufficient to treat the disease or condition.
  • the invention provides a method of treating a patient suffering from a disease or condition associated with elevated levels of IL-17 comprising the steps of: a) determining whether the patient has an elevated level of one or more IL-17-induced chemokine or effector; and b) if the patient does have an elevated level of the one or more IL-17 chemokine or effector, administering to the patient an effective amount of a compound of Formula I for a time sufficient to treat the disease or condition.
  • the IL-17 chemokine or effector is one or more of IL-6, IL-8, G-CSF, TNF-a, IL- ⁇ ⁇ , PGE2, and IFN- ⁇ .
  • Figure 1 depicts the effect of an orally dosed exemplary compound of the invention on various parameters in a murine delayed hypersensitivity assay, as compared to an IL-17 antibody and a vehicle control.
  • Figure 2 depicts the effect over time of an orally dosed exemplary compound of the invention on paw swelling in a murine collagen-induced arthritis ("CIA") assay, as compared to an IL-17 antibody and a vehicle control.
  • CIA murine collagen-induced arthritis
  • Figure 3 depicts the effect on all paws of an orally dosed exemplary compound of the invention on Clinical Arthritis Score in a murine collagen-induced arthritis ("CIA") assay, as compared to an IL- 17 antibody and a vehicle control.
  • CIA murine collagen-induced arthritis
  • Figure 4 depicts the effect on all joints of an orally dosed exemplary compound of the invention on various pathological parameters in a murine collagen-induced arthritis ("CIA") assay, as compared to an IL-17 antibody and a vehicle control.
  • CIA murine collagen-induced arthritis
  • Figure 5 depicts the sum effect of an orally dosed exemplary compound of the invention on measured pathological parameters in a murine collagen-induced arthritis ("CIA") assay, as compared to an IL-17 antibody and a vehicle control.
  • CIA murine collagen-induced arthritis
  • Figure 6 is a table of exemplary compounds of the invention.
  • the present invention provides compounds, methods of modulating the activity of IL-17, and methods for treating various medical conditions, especially inflammatory conditions and diseases, using such compounds.
  • the practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, and biochemistry. For example, procedures for synthesizing organic compounds are described in the literature, such as "Comprehensive Organic Synthesis” (BM Trost & I Fleming, eds., 1991-1992).
  • BM Trost & I Fleming eds., 1991-1992.
  • aspects of the invention are set forth below in sections; however, aspects of the invention described in one particular section are not to be limited to any particular section. Further, when a variable is not accompanied by a definition, the previous definition of the variable controls.
  • alkyl is art-recognized and refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12 alkyl, C1-C1 0 alkyl, and Ci-Ce alkyl, respectively.
  • exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl,
  • alkenyl and alkynyl are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.
  • cycloalkyl is art-recognized and refers to a monovalent fully saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-10, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as "C4-8 cycloalkyl,” derived from a cycloalkane.
  • exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclopentane, cyclobutane, and cyclopropane.
  • alkylene refers to the diradical of an alkyl group.
  • Co alkylene as used herein means a bond.
  • a moiety defined herein as "-(C0-C6 alkylene)-aryl” includes both -aryl (i.e., Co alkylene-aryl) and -(C1-C6
  • alkylene alkylene-aryl.
  • methylene unit refers to a divalent -CH 2 - group present in an alkyl or alkylene moiety.
  • haloalkyl refers to an alkyl group that is substituted with at least one halogen.
  • halogen for example, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , and the like.
  • carrier means a monocyclic, bicyclic or polycyclic hydrocarbon ring system, wherein each ring is either completely saturated or contains one or more units of unsaturation, but where no ring is aromatic.
  • carbocyclyl refers to a radical of a carbocyclic ring system.
  • carbocyclyl groups include cycloalkyl groups (e.g., cyclopentyl, cyclobutyl, cyclopentyl, cyclohexyl and the like), and cycloalkenyl groups (e.g., cyclopentenyl, cyclohexenyl, cyclopentadienyl, and the like).
  • cycloalkyl groups e.g., cyclopentyl, cyclobutyl, cyclopentyl, cyclohexyl and the like
  • cycloalkenyl groups e.g., cyclopentenyl, cyclohexenyl, cyclopentadienyl, and the like.
  • aromatic ring system refers to a monocyclic, bicyclic or polycyclic hydrocarbon ring system, wherein at least one ring is aromatic.
  • aryl refers to a radical of an aromatic ring system.
  • Representative aryl groups include fully aromatic ring systems, such as phenyl, naphthyl, and anthracenyl, and ring systems where an aromatic carbon ring is fused to one or more non-aromatic carbon rings, such as indanyl, phthalimidyl, naphthimidyl, or tetrahydronaphthyl, and the like.
  • heteromatic ring system refers to monocyclic, bicyclic or polycyclic ring system wherein at least one ring is both aromatic and comprises a heteroatom; and wherein no other rings are heterocyclyl (as defined below).
  • a ring which is aromatic and comprises a heteroatom contains 1, 2, 3, or 4 ring heteroatoms in such ring.
  • heteroaryl refers to a radical of a heteroaromatic ring system.
  • heteroaryl groups include ring systems where (i) each ring comprises a heteroatom and is aromatic, e.g., imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrrolyl, furanyl, thiophenyl pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl; (ii) each ring is aromatic or carbocyclyl, at least one aromatic ring comprises a heteroatom and at least one other ring is a hydrocarbon ring or e.g., indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,
  • benzthiazolyl quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,
  • each ring is aromatic or carbocyclyl, and at least on aromatic ring shares a bridgehead heteroatom with another aromatic ring, e.g., 4H-quinolizinyl.
  • the heteroaryl is a monocyclic or bicyclic ring, wherein each of said rings contain 5 or 6 ring atoms where 1, 2, 3, or 4 of said ring atoms are a heteroatom independently selected from N, O, and S.
  • heterocyclic ring system refers to monocyclic, bicyclic and poly cyclic ring systems where at least one ring is saturated or partially unsaturated (but not aromatic) and comprises a heteroatom.
  • a heterocyclic ring system can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • heterocyclyl refers to a radical of a heterocyclic ring system.
  • heterocyclyls include ring systems in which (i) every ring is non-aromatic and at least one ring comprises a heteroatom, e.g., tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl; (ii) at least one ring is non-aromatic and comprises a heteroatom and at least one other ring is an aromatic carbon ring, e.g., 1,2,3,4-tetrahydroquinolinyl,
  • At least one ring is non-aromatic and comprises a heteroatom and at least one other ring is aromatic and comprises a heteroatom, e.g.,
  • the heterocyclyl is a monocyclic or bicyclic ring, wherein each of said rings contains 3-7 ring atoms where 1, 2, 3, or 4 of said ring atoms are a heteroatom independently selected from N, O, and S.
  • saturated heterocyclyl refers to a radical of heterocyclic ring system wherein every ring is saturated, e.g, tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine and piperazine.
  • arene-diyl refers, respectively to diradicals of an aromatic, heteroaromatic, carbocyclic and heterocyclic ring systems, wherein each radical in the ring system is derived by removal of a hydrogen atom from a different ring atom.
  • benzene- 1,4-diyl refers to a diradical of benzene having the formula: , wherein each represents a connection to the rest of the compound.
  • ohexyl- 1,4-diyl refers to a diradical of cyclohexane having the
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formula:
  • each R independently represent hydrogen or alkyl.
  • alkoxyl or "alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • An “ether” is two hydrocarbons covalently linked by an oxygen.
  • alkenyloxy is art-recognized and refers to an alkenyl group, as defined above, having an oxygen radical attached thereto.
  • substituted means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position.
  • Combinations of substituents envisioned under this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH 2 )o- 4 R°; -(CH 2 )o- 4 OR°; -O-(CH 2 ) 0 - 4 C(O)OR°; -(CH 2 ) 0 - 4 CH(OR°) 2 ; -(CH 2 ) 0 - 4 SR°;
  • each R° may be substituted as defined below and is independently hydrogen, Ci_6 aliphatic, -CH 2 Ph, -O(CH 2 ) 0
  • a suitable monovalent substituent on a substitutable carbon atom of an "optionally substituted" group additionally includes -C(0)-N(R°)-S(0) 2 -R°.
  • Suitable monovalent substituents on R° are independently halogen,
  • each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently selected from Ci_ 4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0 -iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an "optionally substituted” group include: -0(CR 2 ) 2 - 3 0-, wherein each independent occurrence of R is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R * include halogen, -R", -(haloR"), -OH, -OR", -O(haloR'), -CN, -C(0)OH, -C(0)OR e , -NH 2 , -NHR*, -NR' 2 , or -N0 2 , wherein each R' is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently Ci- 4 aliphatic, -CH 2 Ph, -0(CH 2 )o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R ⁇ , -NR ⁇ 2 , -C(0)R ⁇ , -C(0)OR ⁇ , -C(0)C(0)R ⁇ , -C(0)CH 2 C(0)R ⁇ , -S(0) 2 R ⁇ ,
  • each R ⁇ is independently hydrogen, Ci_6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ , taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, -R e , -(haloR*), -OH, -OR", -0(haloR e ), -CN, -C(0)OH, -C(0)OR e , -NH 2 , -NHR", -NR' 2 , or -N0 2 , wherein each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently Ci- 4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0 -iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • moiety refers to a portion of a compound of this invention comprising at least one hydrogen atom and at least one carbon atom.
  • Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • a particular enantiomer of compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl,
  • diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • the term "patient” refers to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans.
  • mammals e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like
  • the term "effective amount” refers to the amount of a compound (e.g. , a compound of the present invention) sufficient to effect beneficial or desired results.
  • An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.
  • the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.
  • composition refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
  • salts of the compounds of the present invention may be derived from inorganic or organic acids and bases.
  • acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic,
  • naphthalene-2-sulfonic naphthalene-2-sulfonic, benzenesulfonic acid, and the like.
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
  • bases include, but are not limited to, alkali metals (e.g., sodium) hydroxides, alkaline earth metals (e.g., magnesium) hydroxides, ammonia, and compounds of formula NW 4 + hydroxide, wherein W is C 1-4 alkyl, and the like.
  • alkali metals e.g., sodium
  • alkaline earth metals e.g., magnesium
  • W is C 1-4 alkyl
  • salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate,
  • salts include anions of the compounds of the present invention compounded with a suitable cation such as Na + , NH 4 + , and NW 4 + (wherein W is a C 1-4 alkyl group), and the like.
  • salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable.
  • non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
  • compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
  • the invention provides a compound represented by Formula I:
  • X is -C(0)-NH- or -NH-C(O)-;
  • R 1 is -OH or -N(R 7c )(R 9 );
  • R 2a is selected from hydrogen, -COOH, -C(0)-NH-Ci-C 4 alkyl, -C(0)0-Ci-C 4 alkyl, and -Ci-C 4 alkylene-OH;
  • R 2b is selected from hydrogen and -Ci-C 4 alkyl
  • R 3 is -[C(R a )(R a )] 2 _ 4 -, wherein:
  • each R a is independently selected from hydrogen and optionally substituted Ci-C 4 alkyl
  • any two R a bound to either the same or different carbon atoms are optionally taken together with any intervening atoms to form aryl, heteroaryl, carbocyclyl or heterocyclyl;
  • R 4 is -[C(R b )(R b )] n -Y-[C(R b )(R b )] m -, wherein:
  • each R b is independently selected from hydrogen and a suitable alkylene substituent
  • Y is selected from arene-diyl, heteroarene-diyl, carbocycle-diyl, heterocycle-diyl and optionally substituted C1-C3 alkylene, wherein the arene-diyl, heteroarene-diyl, carbocycle-diyl, and heterocycle-diyl are optionally substituted with one or more of halo, CF 3 , cyano, -O-C1-C3 alkyl, and C1-C3 alkyl;
  • each of n and m are independently 0, 1, 2 or 3;
  • n + m is 4 or less
  • R 5 is C1-C2 alkylene substituted with one or more -(C 0 -C5 alkylene)-R c , wherein:
  • each R c is independently selected from -CH 3 , -O-C1-C3 alkyl, aryl, heteroaryl, carbocyclyl, and heterocyclyl;
  • R 6 is selected from heteroaryl, -CH 2 -aryl, -C(0)-R 8 , -C(0)-0-R 8 , -C(0)-C(0)-R 8 , -S(0)-R 8 , -S(0) 2 -R 8 , -C(0)-N(R 7d )-R 8 , and -S(0) 2 -N(R 7d )-R 8 ;
  • each of R 7a , R 7b , R 7c , R 7d , R 7e and R 7f is independently selected from hydrogen and d- C 3 alkyl;
  • R 8 is selected from -(C0-C3 alkylene)-aryl, -(C0-C3 alkylene)-heteroaryl, -(C0-C3 alkylene)-carbocyclyl, -(C 0 -C 3 alkylene)-heterocyclyl, and C1-C6 alkyl, wherein:
  • R 8 when R 8 is C1-C6 alkyl, up to two methylene units in the alkyl are optionally and independently replaced with -0-, -N(R 7e ), -S-, -S(O)-, or -S(0) 2 -;
  • R 9 is selected from hydrogen; optionally substituted -C1-C6 alkyl or
  • R 10 is -(C1-C5 alkylene)-R d .
  • R d is independently selected from hydrogen, -OH, -C(0)NH 2 , -O-C1-C3 alkyl, aryl, heteroaryl, carbocyclyl, and heterocyclyl; or
  • R 7c and R 9 are optionally taken together with a nitrogen atom to which they are commonly bound to form an optionally substituted saturated heterocyclyl;
  • any aryl, heteroaryl, carbocyclyl, and heterocyclyl portion of the compound is optionally substituted.
  • X is additionally selected from -NH-C(0)-NH-. In some embodiments of Formula I, X is further additionally selected from -N(CH 3 )-C(0)- and -C(0)-N(CH 3 )-.
  • R 4 is additionally selected from
  • R 7c and R 9 are optionally taken together with a nitrogen atom to which they are commonly bound to form an optionally substituted partially saturated heterocyclyl.
  • R 8 is additionally selected from C2-C6 alkenyl.
  • R 9 is additionally selected from optionally substituted cycloalkyl.
  • R 9 is further additionally selected from optionally substituted heteroaryl and optionally substituted heterocyclyl.
  • the C 0 -C5 alkylene portion of R 5 is further optionally substituted with aryl, which may be optionally substituted.
  • R 7c is selected from hydrogen and -CH 3 ;
  • R 7f is selected from hydrogen and -CH 3 ;
  • R 9 is selected from hydrogen, -C 1 -C 2 alkyl, -C 1 -C 2 alkylene-OH, -C 1 -C 2 alkylene-NH 2 , and -C 1 -C 2 alkylene-0-CH 3 , wherein any alkylene portion of R 9 is optionally substituted with one or two methyl groups; or
  • R 7c and R 9 are taken together with the nitrogen atom to which they are commonly bound to form pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, or morpholinyl, each of which is optionally substituted with -OH, -COOH, methyl, -CH 2 OH, or N(CH 3 ) 2 .
  • R 7c is selected from hydrogen and -CH 3 ;
  • R 7f is selected from hydrogen and -CH 3 ;
  • R 1U is selected from -CH 3 , -CH 2 -cyclohexyl, -CH 2 OH and -(CH 2 ) 2 -C(0)-NH 2 .
  • R 1 is selected from: -OH, -NH-(CH 2 ) 2 -OH, -NH-(CH 2 ) 2 -NH 2 , -NH-C(CH 3 ) 2 -CH 2 OH, -NH-CH 2 -COOH, -NH-C(CH 3 ) 2 -COOH, -N(CH 3 ) 2 -NH(CH 3 ), -NH 2 , -NH-CH 2 -CH(CH 3 ) 2 , -N(CH 3 )-(CH 2 ) 2 -OH, -NH-CH(CH 3 )-COOH, -NH-CH(CH 2 CH 2 C(0)NH 2 )-COOH, N(CH 3 )-CH(CH 3 )-COOH, -NH-CH(CH 2 OH)-COOH,
  • R 1 is additionally selected from:
  • R 1 is further additionally selected from:
  • R 1 is selected from: [0077] In another more specific embodiment of Formula I, R 1 is selected from:
  • R is selected from: -(CH 2 ) 3 -,
  • R is selected from -(CH 2 ) 3 -, -CH2-C(CH 3 )2-CH2-, , , wherein "1" represents a portion of R bound to X.
  • R 3 is selected from -(CH 2 )3-,
  • R 3 is additionally selected from
  • R is selected from
  • R 3 is
  • R 3 is selected from
  • X is *-C(0)-NH-, wherein "*" represents a portion of X bound to R 3 .
  • X is selected from *-NH-C(0)-, *-C(0)-NH- and *-C(0)-N(CH 3 )-. In another more specific embodiment of Formula I, X is *-N(CH 3 )-C(0)-.
  • Y is arene-diyl or carbocycle-diyl; and each of n and m is independently 0 or 1.
  • Y is arene-diyl; and n is 0 or 1 ; and m is 0.
  • R is selected from -(CH 2 )4-,
  • Y is heteroarene-diyl; and each of n and m is independently 0 or 1. In one aspect of these embodiments, Y is heteroarene-diyl; and n is 0 or
  • R 4 is (also referred to as -CH2-(2-methylpyridine-2,5-diyl)- ⁇ ), wherein " ⁇ " represents a portion of R 4 bound to N(R 7a ).
  • R is or
  • R 5 is methylene substituted with one -(C 0 -C3 alkylene)-R c , wherein each R c is independently selected from -CFI 3 , aryl, heteroaryl, and carbocyclyl.
  • R 5 is methylene substituted with one substituent selected from -(CH 2 )o-2-phenyl, wherein the phenyl is optionally substituted with up to 2 substituents independently selected from fluoro, chloro, CN, methyl, methoxy, -OH, CF 3 , phenyl, a branched C2-C4 alkyl, -CH 2 -naphthyl, -CH 2 -pyridyl, -CH 2 -(C3-C6 cycloalkyl), cyclohexyl, and -CH 2 -lH-indolyl.
  • R 5 is methylene substituted with one substituent selected from -(CH 2 )o-2-phenyl, wherein the phenyl is optionally substituted with up to 2 substituents independently selected from fluoro, chloro, CN, methyl, methoxy, -OH, CF 3 , phenyl, a branched C2-C
  • R 5 is meth lene substituted with a substituent
  • R is methylene substituted with a
  • R is methylene substituted with a
  • R 6 is selected from -CH 2 -aryl, -C(0)-R 8 , -C(0)-OR 8 , -C(0)C(0)-R 8 ; and R 8 is selected from -(C 0 -C 3 alkylene)-aryl, -(C 0 -C 3 alkylene)-heteroaryl, -(C 0 -C3 alkylene)-carbocyclyl, and Ci-Ce alkyl.
  • R 6 is additionally selected from heteroaryl. In a more specific aspect of these
  • R 6 is additionally selected from:
  • R 6 is additionally selected from
  • R 6 is selected from [ is selected from
  • R 7a , R 7b , R 7c , R 7d R 7e , and R 7f is independently selected from methyl and hydrogen.
  • the definition of certain variables in Formula I provides that certain groups are optionally substituted.
  • Exemplary substituents on optionally substituted groups are described in, for example, the definitions section above, and as further illustrated by the embodiments and examples herein.
  • the optional substituents are halogen for the optionally substituted C1-C4 alkyl in the definition of variable R a ;
  • the optional substituents on any alkyl, alkenyl or alkylene portion of R 8 are independently selected from halogen, hydroxyl, alkoxy, and C1-C4 alkyl;
  • the optional substituents are independently selected from halogen, hydroxyl, and oxo-substituted partially saturated heterocyclyl for the optionally substituted alkyl in the definition of R 9 ;
  • the optional substituents are independently selected from halogen, hydroxyl, and C1-C4 alkyl for the optionally substituted cycloalkyl in the definition of R 9 ;
  • the optional substituents are independently selected
  • Another aspect of the invention provides a compound represented by Formula la:
  • X is -C(0)-NH- or -NH-C(O)-;
  • R 1 is -OH or -N(R 7c )(R 9 );
  • R 2b is hydrogen or -C1-C4 alkyl
  • R 3 is -[C(R a )(R a )]2-4-, wherein each R a is hydrogen, or any two R a bound to either the same or different carbon atoms are optionally taken together with any intervening atoms to form a carbocyclyl;
  • n and m are independently 0 or 1 ;
  • R 5 is C1-C2 alkylene substituted with -(C 0 -C5 alkylene)-aryl;
  • R 6 is -C(0)-R 8 ;
  • each of R 7a , R 7b , are R 7c are independently hydrogen or C1-C3 alkyl
  • R 8 is -(C 0 -C6 alkylene)-aryl, -(C 0 -C6 alkylene)-heteroaryl, or -(C 0 -C6
  • alkylene -carbocyclyl; wherein any alkylene portion of R 8 is optionally substituted;
  • R 9 is hydrogen or -C1-C6 alkyl
  • R 7c and R 9 are optionally taken together with a nitrogen atom to which they are commonly bound to form an optionally substituted saturated heterocyclyl;
  • Another aspect of the invention provides a compound of Formula lb:
  • Z is CH or ;
  • R is cyclohexyl or 2-chlorobenzyl
  • R is selected from
  • Still another aspect of the invention provides a compound of Formula Ic
  • X' is selected from **-NH-C(0)-, **-C(0)-NH- and **-C(0)-N(CH 3 )-, wherein "**" represents the portion of X' bound to -[CH 2 ]b-;
  • Z is CH or ;
  • R 15 is selected from and
  • R is selected from , and
  • a is 0 or 1 ;
  • b is 0 or 1 ;
  • At least one of a or b is 1
  • R is selected from:
  • X' is further selected from **-N(CH 3 )-C(0)-, wherein " : represents the portion of X' bound to -[CH 2 ]b-.
  • Exemplary compounds of Formula I are set forth in Figure 6. [00110] In one embodiment, the compound of Formula I is selected from any one of the compounds set forth in Figure 6.
  • Any of the compounds of Formula I may also comprise one or more isotopic substitutions.
  • H may be in any isotopic form, including l H, 2 H (D or deuterium),
  • the compounds of this invention may also be represented in multiple tautomeric forms, in such instances, the invention expressly includes all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented (e.g., alkylation of a ring system may result in alkylation at multiple sites, the invention expressly includes all such reaction products). All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.
  • the compounds of the present invention can be prepared using an iterative peptide coupling procedure as illustrated in following synthetic schemes. Exemplary general synthetic protocols are presented in Schemes 1 through 2. The schemes and accompanying description of synthetic procedures are given for the purpose of illustrating the invention, and should not be construed as limiting the scope or spirit of the invention.
  • HATU 0-(7-azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • DIPEA diisopropylethylamine
  • DMF dimethylformamide
  • Fmoc 9-fluorenylmethoxycarbonyl
  • MeOH methanol
  • DCM methylene chloride
  • NMM N-methylmorpholine
  • Scheme 1 depicts a general synthesis method for compounds of Formula I.
  • a 2-chloro-trityl chloride resin 10 is combined with an appropriate protected amine carboxylic acid 11 in DCM and DIEA to form resin 12.
  • Resin 12 is then deprotected with DBU and piperidine and then coupled to a protected R 5 -containing amino acid 13 using HATU and NMM to produce resin 14.
  • Resin 14 is then deprotected with DBU and piperidine and then coupled to R 6 using HATU and NMM to produce resin 15.
  • Resin 15 is treated with TFA in DCM to cleave the compound from the resin to produce a compound of Formula I wherein R 1 is OH.
  • Alternate R 1 moieties may be coupled to the compound by reaction in the presence of treatment with HATU and HOAt in DMF.
  • Scheme 2 depicts another general synthesis method for compounds of Formula I, wherein R 1 is -N(R 7c )-C(R 7f )(R 10 )-COOH.
  • a 2-chloro-trityl chloride resin bound to R 1 ' 20 is deprotected with DBU and piperidine and then coupled with an appropriate protected amine carboxylic acid 11 in the presence of HATU and NMM to provide resin 21.
  • Resin 21 is then deprotected with DBU and piperidine and then coupled to a protected R 5 -containing amino acid 13 using HATU and NMM to produce resin 22.
  • Resin 22 is then deprotected with DBU and piperidine and then coupled to R 6 in the presence of HATU and NMM to provide resin 23.
  • Resin 23 is treated with TFA in DCM to cleave the compound from the resin to produce a compound of Formula I.
  • Scheme 3 depicts another general synthesis method for compounds of Formula I.
  • a 2-chloro-trityl chloride resin 10 is combined with an appropriate protected amine carboxylic acid 70 in DCM and DIEA to form resin 71.
  • Resin 71 is then deprotected with DBU and piperidine and then coupled to a protected R 4 -containing amino acid 72 using HATU and NMM to produce resin 73.
  • Resin 73 is then deprotected with DBU and piperidine and then coupled to a protected R 5 -containing amino acid 74 using HATU and NMM to produce resin 75.
  • Resin 75 is then deprotected with DBU and piperidine and then coupled to R 6 using HATU and NMM to produce resin 76.
  • Resin 76 is treated with TFA in DCM to cleave the compound from the resin to produce compound 77.
  • Compound 77 is combined with HATU, HOAt, DIEA, and R 1 to provide a compound of Formula I.
  • Scheme 4 depicts another general synthesis method for compounds of Formula I.
  • a 2-chloro-trityl chloride resin bound to R 1 20 is combined with R 3 -containing carboxylic acid 70 and DIEA in DCM to provide resin 80.
  • Resin 80 is then deprotected with DBU and piperidine and then coupled to a protected R 4 -containing amino acid 72 using HATU and NMM to produce resin 81.
  • Resin 81 is then deprotected with DBU and piperidine and then coupled to a protected R 5 -containing amino acid 74 using HATU and NMM to produce resin 82.
  • Resin 82 is then deprotected with DBU and piperidine and then coupled to R 6 in the presence of HATU and NMM to provide resin 83.
  • Resin 83 is treated with TFA in DCM to cleave the compound from the resin to produce a compound of Formula I.
  • Combinations of substituents and variables contemplated by the present invention are only those that result in the formation of compounds which possess stability sufficient to allow for their manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into therapeutic products, intermediates for use in production of therapeutic compounds, isolatable or storable intermediate compounds, treating a disease or condition responsive to therapeutic agents).
  • the compounds and pharmaceutical compositions of the present invention are useful in treating or preventing any disease or condition that is mediated directly or indirectly by IL-17.
  • diseases include inflammatory diseases and conditions, proliferative diseases (e.g., cancer), autoimmune diseases and other disease described herein.
  • IL-17 i.e., IL-17A
  • IL-17A IL-17A
  • airway inflammation RA
  • osteoarthritis bone erosion
  • intraperitoneal abscesses and adhesions IBD
  • allograft rejection psoriasis
  • psoriatic arthritis ankylosing spondylitis
  • certain types of cancer angiogenesis, atherosclerosis and MS.
  • Both IL-17 and IL-17R are upregulated in the synovial tissue of RA patients.
  • IL-17 exerts its role in pathogenesis of RA through IL-1- ⁇ and TNF-a dependent and independent pathways.
  • IL-17 stimulates secretion of other cytokines and chemokines, e.g., TNF-a, IL- ⁇ , IL-6, IL-8 and Gro-a.
  • IL-17 directly contributes to disease progression in RA. Injection of IL-17 into the mouse knee promotes joint destruction independently of IL-I ⁇ activity (Ann Rheum Dis 2000, 59:529-32). Anti-IL- ⁇ antibody has no effect on IL-17 induced inflammation and joint damage (J Immunol 2001, 167: 1004-1013).
  • SCW- induced murine arthritis model IL-17 induced inflammatory cell infiltration and proteoglycan depletion in wild-type and IL- ⁇ knockout and TNF-a knockout mice.
  • IL-17 knockout mice are phenotypically normal in the absence of antigenic challenge, but have markedly reduced arthritis following type II collagen immunization (J Immunol 2003,
  • MS Multiple sclerosis
  • CNS central nervous system
  • mRNA-expressing blood MNC are detected during MS clinical exacerbation compared to remission (Multiple Sclerosis, 5: 101-104, 1999). Furthermore, experimental autoimmune encephalomyelitis ("EAE”), a preclinical animal model for MS is significantly suppressed in IL- 17 knockout mice.
  • EAE experimental autoimmune encephalomyelitis
  • the invention provides a method for the treatment or prevention of a condition including, but not limited to, airway inflammation, ankylosing spondylitis, asthma, RA (including juvenile RA), osteoarthritis, bone erosion, intraperitoneal abscesses and adhesions, IBD, Crohn's disease, allograft rejection, psoriasis, psoriatic arthritis, certain types of cancer, angiogenesis, atherosclerosis and MS, as well as other inflammatory disorders, conditions, diseases or states including without limit: erythematosus, response to allergen exposure, Helicobacter pylori associated gastritis, bronchial asthma, allograft rejection (e.g., renal), systemic lupus erythematosus and lupus nephritis.
  • the method comprises the step of administering to a subject in need thereof an amount of a compound or composition of the invention effective to treat the condition.
  • the invention provides a method for the treatment or prevention of a condition including, but not limited to, Behcet's disease, ulcerative colitis, Wegener's granulomatosis, sarcoidosis, systemic sclerosis, insulin-dependent diabetes mellitus, septic shock syndrome, Alzheimer's disease, an inflammatory eye disease, and uveitis.
  • a condition including, but not limited to, Behcet's disease, ulcerative colitis, Wegener's granulomatosis, sarcoidosis, systemic sclerosis, insulin-dependent diabetes mellitus, septic shock syndrome, Alzheimer's disease, an inflammatory eye disease, and uveitis.
  • a compound of the invention or a pharmaceutical composition comprising a compound of the invention may be useful for the treatment or prevention of a condition selected from RA, airway inflammation, MS, psoriasis, psoriatic arthritis, and ankylosing spondylitis.
  • a condition selected from RA, airway inflammation, MS, psoriasis, psoriatic arthritis, and ankylosing spondylitis.
  • the condition is RA.
  • the condition is psoriasis.
  • the invention provides a method of treating a patient suffering from a disease or condition associated with elevated levels of IL-17 comprising the steps of: a) determining whether the patient has an elevated level of IL-17; and b) if the patient does have an elevated level of IL-17, administering to the patient an effective amount of a compound of Formula I for a time sufficient to treat the disease or condition.
  • the invention provides a method of treating a patient suffering from a disease or condition associated with elevated levels of IL-17 comprising the steps of: a) determining whether the patient has an elevated level of one or more IL-17-induced chemokine or effector; and b) if the patient does have an elevated level of the one or more IL-17 chemokine or effector, administering to the patient an effective amount of a compound of Formula I for a time sufficient to treat the disease or condition.
  • the IL-17 chemokine or effector is one or more of IL-6, IL-8, G-CSF, TNF-a, IL- ⁇ ⁇ , PGE2, and IFN- ⁇ .
  • IL-17 or any of its chemokines or effectors in a patient are well-known in the art.
  • a tissue or biological fluid sample is obtained from the patient and is subject to ELISA with commercially available antibodies or kits (e.g., Quantikine IL-17 ELISA; R&D Systems, Abington, UK).
  • Commercially available antibodies and kits are also believed to be available for IL-6, IL-8, G-CSF, TNF-a, IL- ⁇ ⁇ , PGE2, and IFN- ⁇ .
  • the invention also provides for combination therapy of a compound described herein and a second therapeutic agent.
  • “Combination therapy” includes the administration of a compound described herein and at least a second agent as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents.
  • the beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.
  • Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected).
  • Combination therapy is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single dosage form having a fixed ratio of each therapeutic agent or in multiple, single dosage forms for each of the therapeutic agents.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes.
  • a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally.
  • all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection.
  • Combination therapy also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation treatment.)
  • the combination therapy further comprises a non-drug treatment
  • the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.
  • the method further comprises administering a therapeutically effective amount of an anti-inflammatory agent.
  • the anti-inflammatory agent is a salicylate, diclofenac, aceclofenac, acemetacin, alclofenac, bromfenac, etodolac, indometacin, nabumetone, oxametacin, proglumetacin, sulindac, tolmetin, piroxicam, droxicam, lornoxicam, meloxicam, tenoxicam, ibuprofen, alminoprofen, carprofen, dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, ibuproxam, indoprofen, ketorolac, loxoprofen, naproxen, oxaprozin, pirprofen,
  • the method further comprises administering a therapeutically effective amount of an agent for treating multiple sclerosis.
  • the agent for treating multiple sclerosis is interferon beta-2, interferon beta-1, glatiramer, natalizumab, or mitoxantrone.
  • the method further comprises administering infliximab, etanercept, adalimumab, or certolizumab pegol.
  • the method is designed to treat rheumatoid arthritis and further comprises the step of administering to the patient in need thereof a therapeutically effective amount of an agent selected from the group consisting of a salicylate, diclofenac, aceclofenac, acemetacin, alclofenac, bromfenac, etodolac, indometacin, nabumetone, oxametacin, proglumetacin, sulindac, tolmetin, piroxicam, droxicam, lornoxicam, meloxicam, tenoxicam, ibuprofen, alminoprofen, carprofen, dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, ibuproxam, indoprofen, ketorolac, loxoprofen, naproxen
  • an agent selected from the
  • meclofenamic acid meclofenamic acid, tolfenamic acid, phenylbutazone, ampyrone, azapropazone, clofezone, kebuzone, metamizole, mofebutazone, phenazone, sulfinpyrazone, celecoxib, etoricoxib, lumiracoxib, parecoxib, prednisone, methylprednisolone, hydrocortisone, and budesonide.
  • compositions which comprise a therapeutically-effective amount of one or more of the compounds of Formula I, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents, and optionally, one or more additional therapeutic agents described above.
  • compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • phrases "pharmaceutically-acceptable carrier” as used herein means a
  • composition or vehicle such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • a liquid or solid filler diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • manufacturing aid e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid
  • solvent encapsulating material involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier
  • materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention.
  • an aforementioned formulation renders orally bioavailable a compound of the present invention.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a
  • pharmaceutically-acceptable carrier and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • Ophthalmic formulations are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum
  • a liquid suspension of crystalline or amorphous material having poor water solubility The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form.
  • delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • biodegradable polymers such as polylactide-polyglycolide.
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
  • compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient will range from about 0.01 to about 50 mg per kilogram of body weight per day.
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain aspects of the invention, dosing is one administration per day.
  • composition While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).
  • Step 1 Synthesis of 4-(2-aminoethyl)-N- (tert-butoxycarbonyl) phenylamine (2).
  • compound 1 2.5 g, 18.38mmol
  • 10% aqueous AcOH 100 ml
  • B0C2O 4.4 g, 20.2mmol
  • 1,4-dioxane 200 ml
  • Step 2 Synthesis of (l- ⁇ [2-(4-tert-butoxycarbonylaminophenyl)-ethylcarbamoyl] - methyl ⁇ -cyclopentyl)-acetic acid (4).
  • anhydrous THF was added anhydride 3 (4.3g, 25.63mmol) at once at room temperature and resulting mixture was stirred for 2 h at ambient temperature. Progress of the reaction was monitored by TLC. Upon completion of the reaction, THF was removed by distillation under vacuum and crude material was washed well with diethyl ether and then filtered off to give desired title compound 4 in solid form.
  • Step 3 synthesis of (l- ⁇ [2-(4-amino-phenyl)-ethylcarbamoyl] -methylj-cyclopenyl)- acetic acid hydrochloride salt (5).
  • a stirred solution of 4 (7.8g, 19.30 mmol) in 20 ml 1,4- dioxane was added slowly a 4M HC1 in 1,4-dioxane (110ml) at 0°C and after complete addition, reaction mixture was warmed to room temperature and stirred for 30 minutes.
  • Step 4 Synthesis of [ l-( ⁇ 2-[ 4-(9H-fluoren-9-ylmethoxycarbonylamino)-phenylJ- ethylcarbamoyl ⁇ -methyl)-cyclopentyl] -acetic acid (30).
  • 5 6.3g, 18.50mmol
  • 50ml 1,4-dioxane saturated solution of aHC0 3 till pH ⁇ 8 to 9 at 0°C.
  • Reaction mixture was then stirred for 10-15 minutes and Fmoc-Cl (5.25g, 20.35mmol) was added slowly. Reaction was then continued at room temperature for about 3 h and progress was monitored by TLC.
  • 2-Chloro-trityl chloride resin (10; 5.00 g, 6.00 mmol) was swelled in DCM (20 mL) for 10 min and then filtered and washed with DCM (20 mL).
  • Resin 31 (0.075 mmol, 190 mg) was suspended in DMF (2 mL x 5 min) and mixed with a stream of 2 every 30 seconds.
  • the Fmoc group was removed from the resin-supported building block by mixing the resin twice with a solution of 2% DBU, 2% piperidine in DMF (2 mL x 5 min) while agitating with a stream of 2 every 30 seconds.
  • the resin was washed six times with DMF (2 mL x 30 sec).
  • Resin 33 (0.075 mmol, 190 mg) was suspended in DMF (2 mL x 5 min) and mixed with a stream of 2 every 30 seconds.
  • the Fmoc group was removed from the resin-supported building block by mixing the resin twice with a solution of 2% DBU, 2% piperidine in DMF (2 mL x 5 min) while agitating with a stream of 2 every 30 seconds.
  • the resin was washed six times with DMF (2 mL x 30 sec).
  • ⁇ , ⁇ -Difluorophenylacetic acid 34; 0.1 M solution in DMF, 2.5 mL, 3.3 equiv, 0.25 mmol
  • HATU 0.2M solution in DMF, 1.15 mL, 3.1 equiv, 0.23 mmol
  • N-methyl morpholine 1.0 M in DMF, 0.5 mL, 6.7 equiv, 0.5 mmol
  • ⁇ , ⁇ -Difluorophenylacetic acid 0.1 M solution in DMF, 2.5 mL, 3.3 equiv, 0.25 mmol
  • HATU 0.2M solution in DMF, 1.15 mL, 3.1 equiv, 0.23 mmol
  • N-methyl morpholine 1.0 M in DMF, 0.5 mL, 6.7 equiv, 0.5 mmol
  • the reaction mixture was agitated by a stream of nitrogen for 30 min.
  • the reagents were drained from the reaction vessel, and the resin was washed with six times DMF (2 mL x 30 sec), and six times with DCM (2 mL x 30 sec) to produce resin 35.
  • Resin 35 (0.075 mmol, 190 mg) was treated with 5% TFA in CH 2 C1 2 (4 mL x 5 min) then washed with DCM (4 mL). This was repeated two more times. Solvent was removed by evaporation using a Genevac EZ2.2 evaporator. The crude reaction mixture containing compound 36 was carried on to the next reaction.
  • Resin 40 (0.075 mmol, 105 mg) was suspended in DMF (2 mL x 5 min) and mixed with a stream of 2 every 30 seconds. The resin was washed two times with DMF (2 mL x 30 sec). 2- (l-(2-(4-(((9H-Fluoren-9-yl)methoxy)carbonylamino)phenethylamino)-2- oxoethyl)cyclopentyl)acetic acid (30; 0.1 M solution in DMF, 2.5 mL, 3.3 equiv, 0.25 mmol), followed by HATU (0.2M solution in DMF, 1.15 mL, 3.1 equiv, 0.23 mmol) and N-methyl morpholine (1.0 M in DMF, 0.5 mL, 6.7 equiv, 0.5 mmol) were added to the resin. The reaction mixture was agitated by a stream of nitrogen for 2 hours. The reagents were drained from the reaction vessel,
  • Resin 41 (0.075 mmol, 105 mg) was suspended in DMF (2 niL x 5 min) and mixed with a stream of 2 every 30 seconds.
  • the Fmoc group was removed from the resin-supported building block by mixing the resin twice with a solution of 2% DBU, 2% piperidine in DMF (2 mL x 5 min) while agitating with a stream of 2 every 30 seconds.
  • the resin was washed six times with DMF (2 mL x 30 sec).
  • Fmoc-2-chloro-L-phenylalanine 32; 0.1 M solution in DMF, 2.5 mL, 3.3 equiv, 0.25 mmol
  • HATU 0.2M solution in DMF, 1.15 mL, 3.1 equiv, 0.23 mmol
  • N-methyl morpholine 1.0 M in DMF, 0.5 mL, 6.7 equiv, 0.5 mmol
  • Resin 42 (0.075 mmol, 105 mg) was suspended in DMF (2 mL x 5 min) and mixed with a stream of 2 every 30 seconds.
  • the Fmoc group was removed from the resin-supported building block by mixing the resin twice with a solution of 2% DBU, 2% piperidine in DMF (2 mL x 5 min) while agitating with a stream of 2 every 30 seconds.
  • the resin was washed six times with DMF (2 mL x 30 sec).
  • ⁇ , ⁇ -Difluorophenylacetic acid 34; 0.1 M solution in DMF, 2.5 mL, 3.3 equiv, 0.25 mmol
  • HATU 0.2M solution in DMF, 1.15 mL, 3.1 equiv, 0.23 mmol
  • N-methyl morpholine 1.0 M in DMF, 0.5 mL, 6.7 equiv, 0.5 mmol
  • ⁇ , ⁇ -Difluorophenylacetic acid 0.1 M solution in DMF, 2.5 mL, 3.3 equiv, 0.25 mmol
  • HATU 0.2M solution in DMF, 1.15 mL, 3.1 equiv, 0.23 mmol
  • N-methyl morpholine 1.0 M in DMF, 0.5 mL, 6.7 equiv, 0.5 mmol
  • Step 1 To a solution of 2-chloro-5-nitropyridine (44; 20 g, 127 mmol) and potassium carbonate (35 g, 253 mmol) in THF (250 mL) was added tert-butyl 2-cyanoacetate (45; 26.7 g, 190 mmol). The reaction was stirred at 70 °C overnight. Then the mixture solution was concentrated and extracted with EA. The combined organic layers were washed with saturated NaCl, dried over a 2 S0 4 , and filtered. The solvent was removed in vacuum and purified by a silica gel column (eluting with 5 % - 20% EA/PE) to provide 46 (15 g, yield 45.5 %).
  • X H NMR 300 MHz, CDC1 3) ⁇ : 8.7-8.6 (d, 1H), 8.1 (d, 1H), 7.3-7.2 (s, 1H), 1.7-1.5 (s, 9H).
  • Step 2 To a solution of 46 (15 g, 57 mmol) in toluene (200 mL) was added p- toluenesulfonic acid (1.1 g, 5.7 mmol) at room temperature. The reaction was refluxed for 2h. After cooled, saturated aHC0 3 (10 mL) was added. Then the solution was concentrated and extracted with EA. The combined organic layers were washed with saturated NaCl, dried over Na 2 S0 4 , and filtered. The solvent was removed in vacuum and purified by a silica gel column (eluting with 2 % - 10 % EA/PE) to provide 47 (7.1 g, yield 76.3 %).
  • X H NMR 300 MHz, CDC1 3) ⁇ : 9.5-9.4 (s, 1H), 8.6-8.5 (d, 1H), 7.7 (d, 1H), 4.2-4.1 (s, 2H).
  • Step 3 To a solution of 47 (7.1 g, 43.6 mmol) in 40 mL THF was added Pd/C (0.71 g, 10%) at RT. Then the mixture was treated with 1 MPa Hydrogen and stirred at RT for 2 hours. The mixture was filtered and the residue was washed with THF. Then the filtrate was concentrated under vacuum to give 48 (4.8 g, yield 82.8 %).
  • Step 4 To a solution of 48 (4.8 g, 36 mmol) in 30 mL EtOH and 30 mL NH 3 H 2 0 was added Raney-Ni (0.48 g, 10 %) at RT. Then the mixture was treated with 3 MPa Hydrogen and stirred at 60 °C overnight. The mixture was filtered and the residue was washed with EtOH. Then the filtrate was concentrated under vacuum and purified by a silica gel column (eluting with 50 % - 90 % EA/PE- 10 % MeOH) to provide 49 (4.2 g, yield 85.7 %).
  • Step 5 To a solution of 49 (4.2 g, 30.6 mmol) in DCM (50 mL) was added 8- oxaspiro[4.5]decane-7,9-dione (3; 5.1 g, 30.6 mmol) in DCM (10 mL) over 5 minutes under ice bath. Then the mixture was stirred for TLC. The solution was extracted with DCM. The combined organic layers were washed with saturated NaCl, dried over Na 2 S0 4 , and filtered. The filtrate was concentrated to provide 50 (7 g, yield 74.9 %)
  • Step 6 To a solution of 50 (7 g, 22.9 mmol) and DIPEA (7.4 g, 57.4 mmol) in THF (15 mL) and water (5 mL) was added Fmoc-Cl (6.5 g, 25.2 mmol) in THF (10 mL) over 5 minutes under ice bath. The mixture was extracted with EA. The combined organic layers were washed with saturated NaCl, dried over Na 2 S0 4 , and filtered. The filtrate was concentrated and purified by a silica gel column (eluting with 60 % EA/PE, 2 % AcOH) to provide 51 (5.1 g, yield 39.5 %).
  • 2-Chloro-trityl chloride resin (10; 7.41 g, 8.9 mmol) was swelled in DCM (50 mL) for 10 min and then filtered and washed with DCM (50 mL).
  • 2-(l-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)cyclopentyl)acetic acid 52; 3 g, 8.9 mmol
  • N-ethyl-N- isopropylpropan-2-amine (7.8 mL, 44.5 mmol
  • Resin 53 (0.075 mmol, 1 10 mg) was suspended in DMF (2 mL x 5 min) and mixed with a stream of 2 every 30 seconds.
  • the Fmoc group was removed from the resin-supported building block by mixing the resin twice with a solution of 2% DBU, 2% piperidine in DMF (2 mL x 5 min) while agitating with a stream of 2 every 30 seconds.
  • the resin was washed six times with DMF (2 mL x 30 sec).
  • Fmoc-2-(l-aminocyclopentyl)acetic acid 54; 0.1 M solution in DMF, 2.5 mL, 3.3 equiv, 0.25 mmol
  • HATU 0.2M solution in DMF, 1.15 mL, 3.1 equiv, 0.23 mmol
  • N-methyl morpholine 1.0 M in DMF, 0.5 mL, 6.7 equiv, 0.5 mmol
  • Resin 55 (0.075 mmol, 1 10 mg) was suspended in DMF (2 mL x 5 min) and mixed with a stream of 2 every 30 seconds.
  • the Fmoc group was removed from the resin-supported building block by mixing the resin twice with a solution of 2% DBU, 2% piperidine in DMF (2 mL x 5 min) while agitating with a stream of 2 every 30 seconds.
  • the resin was washed six times with DMF (2 mL x 30 sec).
  • Fmoc-3-(4-aminophenyl)propanoic acid (56; 0.1 M solution in DMF, 2.5 mL, 3.3 equiv, 0.25 mmol), followed by HATU (0.2M solution in DMF, 1.15 mL, 3.1 equiv, 0.23 mmol) and N-methyl morpholine (1.0 M in DMF, 0.5 mL, 6.7 equiv, 0.5 mmol) were added to the resin.
  • the reaction mixture was agitated by a stream of nitrogen for 2 hours.
  • the reagents were drained from the reaction vessel, and the resin was washed with six times
  • Resin 57 (0.075 mmol, 1 10 mg) was suspended in DMF (2 mL x 5 min) and mixed with a stream of 2 every 30 seconds.
  • the Fmoc group was removed from the resin-supported building block by mixing the resin twice with a solution of 2% DBU, 2% piperidine in DMF (2 mL x 5 min) while agitating with a stream of 2 every 30 seconds.
  • the resin was washed six times with DMF (2 mL x 30 sec).
  • Resin 59 (0.075 mmol, 1 10 mg) was suspended in DMF (2 niL x 5 min) and mixed with a stream of 2 every 30 seconds.
  • the Fmoc group was removed from the resin-supported building block by mixing the resin twice with a solution of 2% DBU, 2% piperidine in DMF (2 mL x 5 min) while agitating with a stream of 2 every 30 seconds.
  • the resin was washed six times with DMF (2 mL x 30 sec).
  • ⁇ , ⁇ -Difluorophenylacetic acid 34; 0.1 M solution in DMF, 2.5 mL, 3.3 equiv, 0.25 mmol
  • HATU 0.2M solution in DMF, 1.15 mL, 3.1 equiv, 0.23 mmol
  • N-methyl morpholine 1.0 M in DMF, 0.5 mL, 6.7 equiv, 0.5 mmol
  • the reagents were drained from the reaction vessel, and the resin was washed six times with DMF (2 mL x 30 sec) to yield 60.
  • 2-Chloro-trityl chloride resin (10; 0.833 g, 1.00 mmol) was swelled in DCM (10 mL) for 10 min and then filtered and washed with DCM (10 mL).
  • 2-(l-((((9H-Fluoren-9- yl)methoxy)carbonyl)amino)cyclopentyl)acetic acid 54; 0.365 g, 1.00 mmol
  • N-ethyl-N- isopropylpropan-2-amine (0.871 mL, 5.00 mmol) was dissolved in DCM (10 mL). The resulting solution was added to the swelled resin and agitated for 2 hours.
  • Resin 61 (0.150 mmol, 230 mg) was suspended in DMF (4 mL x 5 min) and mixed with a stream of 2 every 30 seconds.
  • the Fmoc group was removed from the resin-supported building block by mixing the resin twice with a solution of 2% DBU, 2% piperidine in DMF (4 mL x 5 min) while agitating with a stream of 2 every 30 seconds.
  • the resin was washed six times with DMF (4 mL x 30 sec).
  • Fmoc-3-(4-aminophenyl)propanoic acid (56; 0.1 M solution in DMF, 3 mL, 2 equiv, 0.3 mmol), followed by HATU (0.2M solution in DMF, 3.15 mL, 2.1 equiv, 0.31 mmol) and N-methyl morpholine (1.0 M in DMF, 1.0 mL, 6.7 equiv, 1.0 mmol) were added to the resin.
  • the reaction mixture was agitated by a stream of nitrogen for 2 hours.
  • the reagents were drained from the reaction vessel, and the resin was washed with six times DMF (4 mL x 30 sec) to yield 62.
  • Resin 62 (0.150 mmol, 230 mg) was suspended in DMF (4 mL x 5 min) and mixed with a stream of 2 every 30 seconds.
  • the Fmoc group was removed from the resin-supported building block by mixing the resin twice with a solution of 2% DBU, 2% piperidine in DMF (4 mL x 5 min) while agitating with a stream of 2 every 30 seconds.
  • the resin was washed six times with DMF (4 mL x 30 sec).
  • Fmoc-2-chloro-L-phenylalanine 32; 0.1 M solution in DMF, 3 mL, 2 equiv, 0.30 mmol
  • HATU 0.2M solution in DMF, 3.15 mL, 2.1 equiv, 0.31 mmol
  • N-methyl morpholine 1.0 M in DMF, 1.0 mL, 6.7 equiv, 1.0 mmol
  • Resin 63 (0.150 mmol, 230 mg) was suspended in DMF (4 mL x 5 min) and mixed with a stream of 2 every 30 seconds.
  • the Fmoc group was removed from the resin-supported building block by mixing the resin twice with a solution of 2% DBU, 2% piperidine in DMF (4 mL x 5 min) while agitating with a stream of 2 every 30 seconds.
  • the resin was washed six times with DMF (4 mL x 30 sec).
  • ⁇ , ⁇ -Difluorophenylacetic acid 34; 0.1 M solution in DMF, 3 mL, 2 equiv, 0.30 mmol
  • HATU 0.2M solution in DMF, 3.15 mL, 2.1 equiv, 0.31 mmol
  • N-methyl morpholine 1.0 M in DMF, 1.0 mL, 6.7 equiv, 1.0 mmol
  • the reaction mixture was agitated by a stream of nitrogen for 30 min.
  • the reagents were drained from the reaction vessel, and the resin was washed six times with DMF (4 mL x 30 sec) and six times with DCM (4 mL x 30 sec) to yield 64.
  • Resin 64 (0.150 mmol, 230 mg) was treated with 5% TFA in CH 2 C1 2 (8 mL x 5 min) then washed with DCM (8 mL). This was repeated two more times. Solvent was removed by evaporation using a Genevac EZ2.2 evaporator. The crude reaction mixture 65 was carried on to the next reaction.
  • Exemplary compounds were tested for the ability to bind to and modulate IL-17 activity in one or more of the below-described assays. Experimental procedures and results are provided below.
  • ELISA I The ability of the compounds of this invention to block binding of IL-17a to its receptor, IL-17R was analyzed in a competition ELISA format. High binding 96-well plates (Costar #9018) were coated with 20 nM of recombinant human IL-17a (R&D Systems #317-ILB) in PBS (0.64 ⁇ g/mL), 100 ⁇ /well, for 30 min at 37°C followed by 5 min at 4°C.
  • ELISA II In this version of a similar ELISA a high binding 96-well plate (Costar #9018) was coated with 20 nM of goat anti-human IgG (KPL 01-10-02) in PBS, 100 ⁇ /well, for 30 min at 37° C followed by 5 min at 4° C. The plate was then washed in PBST
  • b-IL-17 biotinylated human IL-17, R&D Systems #317-ILB; 20 nM
  • Row H received 50 ⁇ ⁇ of PBST and served as the blank row, i.e., no compound and no b-IL-17.
  • the plate was then incubated for 30 min at room temperature on the shaker. [00215] After the wash, 100 ⁇ .
  • Streptavidin-Horseradish Peroxidase (SA-HRP) KPL #14- 30-00
  • NTA Biacore Biosensor chip GE Healthcare BR-1000-3
  • EDTA 0.35 M EDTA
  • the chip was washed with 0.5 mM nickel chloride in NTA buffer (10 mM HEPES buffer, 0.15 M sodium chloride, 10 ⁇ ethylene diamine tetraacetic acid, 0.005% v/v surfactant P20 (GE Healthcare BR- 1000-54)) to form a nickel chelate on the chip.
  • IL-17 protein was immobilized onto a NTA chip through its 6-His tag.
  • IL-17A was typically injected at 0.25 ⁇ for 60-120 seconds, followed by a stabilization step washing with NTA + 0.5% DMSO for 120 seconds or longer.
  • Anti-IL-17 was also injected on the chip to confirm the presence of IL-17;
  • IL-17R was injected onto the chip to confirm that the immobilized IL-17 retained its binding activity for its receptor.
  • Negative controls to access specificity for compound binding were conducted by immobilizing unrelated, but his-tagged, proteins (such as cyclophilin D) and conducting the same analysis as done with IL- 17A.
  • This assay was used to determine the extent of inhibition of IL-17A induced secretion of IL-6 in primary human rheumatoid synovial fibroblast (RASF) cells by the compounds of the invention.
  • IL-17A is known to stimulate IL-6 production in RASF cells.
  • rhIL-17A Prior to addition to cells, rhIL-17A (30ng/ml) in assay medium was incubated with either DMSO alone, compounds, or anti-IL-17 receptor antibody (3 ⁇ g/ml) for 1 hour at 37°C. The final concentration of DMSO in all samples was 0.25%. The final concentration of compounds varied from 0.03 ⁇ to 25 ⁇ .
  • a water-soluble tetrazolium salt (WST1) viability assay was immediately performed on the cells after the conditioned medium was collected using a WST1 reagent purchased from Roche. The concentration of IL-6 obtained from ELISA was normalized by the WST1 data.
  • IL-17 can stimulate epithelial cells and other cells to secrete GROa.
  • IL-17 - induced GROa secretion from the human colorectal adenocarcinoma epithelial cell line HT-29 is tested in this assay.
  • HT-29 cells human colorectal adenocarcinoma epithelial cells, ATCC #HTB-38
  • ATCC #HTB-38 human colorectal adenocarcinoma epithelial cells, ATCC #HTB-38
  • HT-29 cells were grown in tissue culture flasks until they were 50-80% confluent on the day before the assay. The day before the assay, the cells were detached from the culture flasks with trypsin + EDTA. The trypsin was inactivated with complete assay medium.
  • HT-29 cells were then centrifuged at 500Xg for 5 min. at RT.
  • the cell pellet was then re-suspended in Defined Keratinocyte SFM (Invitrogen #10766019) + 10% FCS and 50,000 HT-29 cells (in 100 ⁇ ) were added to each treatment well of the 96-well plates.
  • the 96-well plates were placed in a tissue culture incubator (37°C, 5% CO 2 ) overnight. The next day, the media was removed from the cells and the cells were washed twice with Defined Keratinocyte SFM.
  • the compounds to be tested were serially diluted in Defined Keratinocyte SFM and run in triplicate in 100 ⁇ ⁇ total volume.
  • the plates are centrifuged (500Xg for 5 min. at RT), and the cell culture media is transferred to polypropylene 96-well plates. The supernatant was used neat in the ELISA.
  • GROa levels are measured with a GROa sandwich ELISA (R+D Systems DuoSet #DY275E), as per the manufacturer's instructions.
  • the ELISA plates were previously coated with mAb 275 (R+D Systems) at 4 ⁇ g/ml.
  • GROa is detected using biotinylated goat anti-human GROa (R+D Systems BAF275) at 200 ng/ml using TMB as a substrate.
  • plates are read at 450 nm on a microplate reader and compared to a standard calibration curve.
  • A indicates a K d value of less than 500 nM; "B” a K d value between 500 nM and 1 ⁇ ; “C” a K d value greater than 1 ⁇ and less than or equal to 10 ⁇ ; and “D” a K d value of over 10 ⁇ .
  • a "*" indicates that some binding or activity was observed, but compound concentration was not taken high enough to calculate a value. Blank cells indicate that the compound was not tested in that particular assay. Values displayed as "X/Y" indicate different values obtained in different runs of the same assay.
  • DNFB fluorodinitrobenzene
  • Exemplary compounds of the invention were either suspended at 3 mg/ml in 20% Cremaphor EL (Sigma)/water (20:80) or dissolved at 1 mg/ml or 3 mg/ml in D-a-tocopherol polyethylene glycol 1000 succinate (TPGS; Sigma)/PEG- 400/water (20:60:20). On day 7, test compound was orally administered at either 10 mg/kg or 30 mg/kg to DNFB-treated mice.
  • Commercially available anti-mouse IL- 17A (BioLegend) administered intraperitoneally at 5 mg/kg in PBS was used as a positive control.
  • DNFB olive oil
  • Fig. 1 is a bar graph demonstrating that Compound 286 reduces edema, interleukin-6, and interferon- ⁇ when compared to the TPGS/PEG400/Water vehicle alone and that such reduction was dose-dependent.
  • the results for the positive control IL- 17 antibody are also show for comparison.
  • An exemplary compound of the invention was evaluated in a murine CIA model.
  • DAB-1 mice (10/group) were anaesthetized with Isoflurane, shaved at the base of the tail, and injected intradermally with 150 ⁇ of Freund's Complete Adjuvant (Sigma) containing bovine type II collagen (Elastin Products, Owensville, MO) (2 mg/ml) at the base of the tail on day 0 and again on day 21.
  • onset of arthritis occurred and mice were randomized into treatment groups. Randomization into each group was done after swelling was obviously established in at least one paw (score of 1), and attempts were made to ensure approximately equal mean scores of 0.25 across the groups at the time of enrollment.
  • Fig. 2 shows the time course of the effect of Compound 286 as compared to IL-17 antibody, the 20% Cremophor vehicle control, and mice that were not exposed to Freund's Complete Adjuvant.
  • Compound 286 demonstrated a statistically significant (p ⁇ 0.05) decrease in arthritis score as compared to the vehicle control on days 9-1 1 of administration.
  • Fig. 3 shows that Compound 286 resulted in an average 21% reduction in swelling for all paws over the course of treatment.
  • Anti-IL-17 demonstrated a 25% reduction in swelling for all paws over the same course of treatment.
  • Fig. 4 The effect of compound treatment on inflammation, pannus, cartilage damage, bone resorption and periosteal bone formation is shown in Fig. 4.
  • Compound 286 demonstrated a statistically significant (p ⁇ 0.05) decrease in pannus and bone resorption as compared to vehicle control.
  • Fig. 5 shows the mean summed score for all of the parameters measured in Fig. 4. Similar to the results found for reduction in swelling Compound 286 produced a 21% reduction in overall parameters, while anti-IL-17 demonstrated a 25% reduction.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne en général des composés et leur utilisation thérapeutique. Plus particulièrement, l'invention concerne des composés qui modulent l'activité d'IL-17 et/ou qui sont utiles dans le traitement d'états médicaux, tels que des maladies inflammatoires et d'autres troubles associés à l'IL-17.
PCT/US2013/066749 2012-10-26 2013-10-25 Composés pour la modulation d'il-17 WO2014066726A2 (fr)

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US61/784,133 2013-03-14
US201361856213P 2013-07-19 2013-07-19
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WO2019138017A1 (fr) 2018-01-15 2019-07-18 Ucb Biopharma Sprl Dérivés d'imidazole fusionnés utilisés en tant qu'inhibiteurs d'il-17
WO2020011731A1 (fr) 2018-07-12 2020-01-16 UCB Biopharma SRL Analogues d'indanes spirocycliques utilisés comme modulateurs d'il-17
WO2020120141A1 (fr) 2018-12-11 2020-06-18 UCB Biopharma SRL Dérivés d'amine fonctionnalisés utiles en tant que modulateurs d'il-17
WO2020120140A1 (fr) 2018-12-11 2020-06-18 UCB Biopharma SRL Dérivés de benzimidazolone, et analogues de ceux-ci, en tant que modulateurs d'il-17
WO2020127685A1 (fr) 2018-12-19 2020-06-25 Leo Pharma A/S Anilides d'acides aminés en tant que modulateurs à petites molécules d'il-17
WO2020146194A1 (fr) 2019-01-07 2020-07-16 Eli Lilly And Company Inhibiteurs imidazo [1,2-b]pyridazine il-17 a
WO2020163554A1 (fr) * 2019-02-06 2020-08-13 Dice Alpha, Inc. Modulateurs d'il-17a et leurs utilisations
WO2020182666A1 (fr) 2019-03-08 2020-09-17 Leo Pharma A/S Modulateurs d'il-17 à petites molécules
WO2020261141A1 (fr) 2019-06-26 2020-12-30 UCB Biopharma SRL Dérivés d'imidazopyridine en tant que modulateurs d'il-17
WO2020260426A1 (fr) 2019-06-26 2020-12-30 UCB Biopharma SRL Dérivés d'imidazole fusionnés utilisés en tant que modulateurs d'il-17
WO2020260425A1 (fr) 2019-06-26 2020-12-30 UCB Biopharma SRL Dérivés d'imidazole fusionnés utilisés en tant que modulateurs d'il-17
CN112341440A (zh) * 2019-08-09 2021-02-09 成都先导药物开发股份有限公司 一种免疫调节剂
CN112341439A (zh) * 2019-08-09 2021-02-09 成都先导药物开发股份有限公司 一种免疫调节剂
CN112341441A (zh) * 2019-08-09 2021-02-09 成都先导药物开发股份有限公司 一种免疫调节剂
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WO2021067191A1 (fr) 2019-09-30 2021-04-08 Janssen Biotech, Inc. Compositions et méthodes de dosage d'implication cible d'il-17 avec des modulateurs à petites molécules
WO2021170627A1 (fr) 2020-02-25 2021-09-02 UCB Biopharma SRL Dérivés de difluorocyclohexyle utilisés en tant que modulateurs d'il-17
WO2021170631A1 (fr) 2020-02-25 2021-09-02 UCB Biopharma SRL Dérivés de difluorocyclohexyle utilisés en tant que modulateurs d'il-17
WO2021204800A1 (fr) 2020-04-07 2021-10-14 UCB Biopharma SRL Dérivés de difluorocyclohexyle utilisés en tant que modulateurs d'il-17
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WO2021239743A1 (fr) 2020-05-27 2021-12-02 Sanofi Modulateurs de il-17a
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WO2023209519A1 (fr) 2022-04-25 2023-11-02 Novartis Ag Formes cristallines d'un inhibiteur d'il-17
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