CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to United States Provisional Application serial number 61/719,273, filed October 26, 2012; United States Provisional Application serial number 61/784, 133, filed March 14, 2013; and United States Provisional Application serial number 61/856,213, filed July 19, 2013; the contents of each of which are hereby incorporated by reference.

FIELD OF THE INVENTION

[0002] 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.

BACKGROUND OF THE INVENTION

[0003] Interleukin-17 ("IL-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. For example, IL-17 can induce IL-6, IL-8, G-CSF, TNF-a, IL-Ι β, PGE2, and IFN-γ, as well as numerous chemokines and other effectors. See, e.g., Gaffen, SL, Arthritis Research & Therapy 6: 240-247 (2004).

[0004] IL-17 is expressed by TH17 cells, which are involved in the pathology of

inflammation and autoimmunity. It is also expressed by CD8+ T cells, γδ cells, NK cells, NKT cells, macrophages and dendritic cells. 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).

[0005] IL-17 can act in cooperation with other inflammatory cytokines such as TNF-a, IFN-γ, and IL-Ι β to mediate pro-inflammatory effects. See, e.g., Gaffen, SL, Arthritis

Research & Therapy 6: 240-247 (2004). 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,

atherosclerosis, asthma, and multiple sclerosis. See, e.g., Gaffen, SL, Arthritis Research & Therapy 6: 240-247 (2004); US Publ No 20080269467 Al, published Oct. 30, 2008. 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. Doreau et al, Nature Immunology 7:778-785 (2009). IL-17 has also been associated with ocular surface disorders, such as dry eye (PCT publication WO2010062858 and

WO2011 163452). 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.

[0006] IL-17 and IL-17-producing TH17 cells have recently been implicated in certain cancers, Ji and Zhang, Cancer Immunol Immunother 59: 979-987 (2010). For example,

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).

[0007] It can be seen from above that modulation of IL-17 has important therapeutic implications. Although various antibodies to IL-17 have been described in the prior art, very few small molecule-type, specific modulators of IL- 17 with oral bioavailability are known. Accordingly, there is a need for the development of small molecule-like modulators of IL-17.

SUMMARY

[0008] The present invention provides compounds, methods of modulating the activity of IL-17, and methods for treating various medical conditions using such compounds. In one aspect, the invention provides a compound represented by Formula I:

, including pharmaceutically acceptable salts thereof, wherein the variables are as defined in the detailed description.

[0009] In another aspect, 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. For example, 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.

[0010] In another aspect, 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.

[0011] In still another aspect, 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. In certain aspects the IL-17 chemokine or effector is one or more of IL-6, IL-8, G-CSF, TNF-a, IL-Ι β, PGE2, and IFN-γ.

[0012] The foregoing and other aspects and embodiments of the invention may be more fully understood by reference to the following detailed description and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013] 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.

[0014] 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.

[0015] 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.

[0016] 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.

[0017] 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.

[0018] Figure 6 is a table of exemplary compounds of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0019] 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). Various 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.

I. Definitions

[0020] To facilitate an understanding of the present invention, a number of terms and phrases are defined below.

[0021] The term "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,

2-methyl-2-propyl, 2-methyl-l -butyl, 3 -methyl- 1 -butyl, 2-methyl-3-butyl,

2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3 -methyl- 1-pentyl, 4-methyl-l-pentyl,

2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl,

3,3-dimethyl-l-butyl, 2-ethyl- 1 -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.

[0022] The terms "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. Exemplary alkenyl groups include, but are not limited to, -CH=CH ₂ and -CH ₂ CH=CH ₂ .

[0023] The term "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.

[0024] The term "alkylene" refers to the diradical of an alkyl group.

[0025] The term "Co alkylene" as used herein means a bond. Thus, a moiety defined herein as "-(C0-C6 alkylene)-aryl" includes both -aryl (i.e., Co alkylene-aryl) and -(C1-C6

alkylene)-aryl. [0026] The terms "alkenylene" and "alkynylene" refer to the diradicals of an alkenyl and an alkynyl group, respectively.

[0027] The term "methylene unit" refers to a divalent -CH ₂ - group present in an alkyl or alkylene moiety.

[0028] The term "haloalkyl" refers to an alkyl group that is substituted with at least one halogen. For example, -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CF ₃ , -CF ₂ CF ₃ , and the like.

[0029] The term "carbocyclic ring system", as used herein, 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.

[0030] The term "carbocyclyl" refers to a radical of a carbocyclic ring system.

Representative 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).

[0031] The term "aromatic ring system" is art-recognized and refers to a monocyclic, bicyclic or polycyclic hydrocarbon ring system, wherein at least one ring is aromatic.

[0032] The term "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.

[0033] The term "heteroaromatic ring system" is art-recognized and 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). In certain instances, a ring which is aromatic and comprises a heteroatom contains 1, 2, 3, or 4 ring heteroatoms in such ring.

[0034] The term "heteroaryl" refers to a radical of a heteroaromatic ring system.

Representative 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,

pyrido[2,3-b]-l,4-oxazin-3(4H)-one, 5,6,7,8-tetrahydroquinolinyl and

5,6,7,8-tetrahydroisoquinolinyl; and (iii) each ring is aromatic or carbocyclyl, and at least on aromatic ring shares a bridgehead heteroatom with another aromatic ring, e.g., 4H-quinolizinyl. In certain embodiments, 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.

[0035] The term "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.

[0036] The term "heterocyclyl" refers to a radical of a heterocyclic ring system.

Representative 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,

1,2,3,4-tetrahydroisoquinolinyl; and (iii) 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.,

3,4-dihydro-lH-pyrano[4,3-c]pyridine, and l,2,3,4-tetrahydro-2,6-naphthyridine. In certain embodiments, 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.

[0037] The term "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. [0038] The terms "arene-diyl," "heteroarene-diyl," "carbocycle-diyl," and "heterocycle-diyl" refer, 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.

term "benzene- 1,4-diyl" refers to a diradical of benzene having the formula: , wherein each represents a connection to the rest of the compound.

[0040] ohexyl- 1,4-diyl" refers to a diradical of cyclohexane having the

formula: , wherein each represents a connection to the rest of the compound.

[0041] The terms "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:

R ,60 wherein each R independently represent hydrogen or alkyl.

[0042] The terms "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. Term "alkenyloxy" is art-recognized and refers to an alkenyl group, as defined above, having an oxygen radical attached thereto.

[0043] In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, 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. The term "stable", as used herein, 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.

[0044] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group (such as an alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene or the carbon atom of a carbocyclyl, aryl, heterocyclyl or heteroaryl) 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°;

-(CH ₂ )o- ₄ Ph, which may be substituted with R°; -(CH ₂ ) ₀ - ₄ O(CH ₂ ) ₀ -iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -N0 ₂ ; -CN; -N ₃ ; -(CH ₂ ) ₀ - ₄ N(R°) ₂ ; -(CH ₂ )o- ₄ N(R°)C(0)R°; -N(R°)C(S)R°; -(CH ₂ ) ₀ - ₄ N(R°)C(O)NR° ₂ ; -N(R°)C(S)NR° ₂ ;

-(CH ₂ )o- ₄ N(R°)C(0)OR°; -N(R°)N(R°)C(0)R°; -N(R°)N(R°)C(0)NR° ₂ ;

-N(R°)N(R°)C(0)OR°; -(CH ₂ ) ₀ - ₄ C(O)R°; -C(S)R°; -(CH ₂ ) ₀ - ₄ C(O)OR°; -(CH ₂ ) ₀ - ₄ C(O)SR°; -(CH ₂ )o- ₄ C(0)OSiR° ₃ ; -(CH ₂ ) ₀ - ₄ OC(O)R°; -OC(O)(CH ₂ ) ₀ - ₄ SR°-, SC(S)SR°; -(CH ₂ ) ₀ - ₄ SC(O)R°; -(CH ₂ )o- ₄ C(0)NR° ₂ ; -C(S)NR° ₂ ; -C(S)SR°; -(CH ₂ ) ₀ - ₄ OC(O)NR° ₂ ; -C(0)N(OR°)R°;

-C(0)C(0)R°; -C(0)CH ₂ C(0)R°; -C(NOR°)R°; -(CH ₂ ) ₀ - ₄ SSR°; -(CH ₂ ) ₀ - ₄ S(O) ₂ R°;

-(CH ₂ )o- ₄ S(0) ₂ OR°; -(CH ₂ ) ₀ - ₄ OS(O) ₂ R°; -S(0) ₂ NR° ₂ ; -(CH ₂ ) ₀ - ₄ S(O)R°; -N(R°)S(0) ₂ NR° ₂ ; -N(R°)S(0) ₂ R°; -N(OR°)R°; -C( H)NR° ₂ ; -P(0) ₂ R°; -P(0)R° ₂ ; -OP(0)R° ₂ ; -OP(0)(OR°) ₂ ; -SiR°3; -(Ci_ ₄ straight or branched alkylene)0-N(R°) ₂ ; or -(Ci_ ₄ straight or branched alkylene)C(0)0-N(R°) ₂ , wherein each R° may be substituted as defined below and is independently hydrogen, Ci_6 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, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0045] In some embodiments, a suitable monovalent substituent on a substitutable carbon atom of an "optionally substituted" group additionally includes -C(0)-N(R°)-S(0) ₂ -R°. [0046] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen,

-(CH ₂ ) ₀ - ₂ R ^e , -(haloR*), -(CH ₂ ) ₀ - ₂ OH, -(CH ₂ ) ₀ - ₂ OR ^e , -(CH ₂ ) ₀ - ₂ CH(OR ^e ) ₂ ; -O(haloR'), -CN, -N ₃ , -(CH ₂ ) ₀ - ₂ C(O)R ^e , -(CH ₂ )o- ₂ C(0)OH, -(CH ₂ ) ₀ - ₂ C(O)OR ^e , -(CH ₂ ) ₀ - ₂ SR ^e , -(CH ₂ ) ₀ - ₂ SH,

-(CH ₂ )o- ₂ NH ₂ , -(CH ₂ ) ₀ - ₂ NHR ^e , -(CH ₂ ) ₀ - ₂ NR ^e ₂ , -N0 ₂ , -SiR' ₃ , -OSiR' ₃ , -C(0)SR ^e -(d_ ₄ straight or branched alkylene)C(0)OR", or -SSR" wherein 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 on a saturated carbon atom of R° include =0 and =S.

[0047] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0, =S, = NR ^* ₂ , = NHC(0)R ^* , = NHC(0)OR ^* , = NHS(0) ₂ R ^* , =NR ^* , =NOR ^* , -0(C(R ^* ₂ )) ₂ _ ₃ 0-, or -S(C(R ^* ₂ )) ₂ _ ₃ S-, 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 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.

[0048] 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.

[0049] 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 ^† ,

-S(0) ₂ NR ^† ₂ , -C(S)NR ^† ₂ , -C(NH)NR ^† ₂ , or -N(R ^† )S(0) ₂ R ^† ; wherein 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.

[0050] 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.

[0051] The term "moiety" refers to a portion of a compound of this invention comprising at least one hydrogen atom and at least one carbon atom.

[0052] 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.

[0053] If, for instance, a particular enantiomer of compound of the present invention is desired, it 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. Alternatively, where 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.

[0054] Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound, as well as enantiomeric mixtures thereof. [0055] As used herein, 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.

[0056] As used herein, 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. As used herein, 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.

[0057] As used herein, the term "pharmaceutical 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.

[0058] As used herein, the term "pharmaceutically acceptable salt" refers to any

pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention which, upon administration to a subject, is capable of providing a compound of this invention or an active metabolite or residue thereof. As is known to those of skill in the art, "salts" of the compounds of the present invention may be derived from inorganic or organic acids and bases. Examples of 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, 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.

[0059] Examples of 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.

[0060] Examples of salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate,

glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of 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.

[0061] For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are

non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0062] Throughout the description, where 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.

II. Compounds

[0063] In one aspect, the invention provides a compound represented by Formula I:

(I)

or a pharmaceutically acceptable salt thereof, wherein:

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; and

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; and

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:

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 -;

any alkyl or alkylene portion of R ⁸ is optionally substituted with an appropriate alkyl or alkylene substituent other than =0;

R ⁹ is selected from hydrogen; optionally substituted -C1-C6 alkyl or

-C(R ^7f )(R ¹⁰ )-COOH, wherein: R ¹⁰ is -(C1-C5 alkylene)-R ^d , and

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;

wherein any aryl, heteroaryl, carbocyclyl, and heterocyclyl portion of the compound is optionally substituted.

[0064] In some embodiments of Formula I, 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 )-.

[0065] In some embodiments of Formula I, R ⁴ is additionally selected from

-0-[C(R ^b )(R ^b )] _n -Y-[C(R ^b )(R ^b )] _m -

[0066] In some embodiments of Formula I, 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.

[0067] In some embodiments of Formula I, R ⁸ is additionally selected from C2-C6 alkenyl. In certain other embodiments of Formula I, R ⁸ is selected from -(C0-C3 alkylene)-aryl, -(C0-C3 alkylene)-heteroaryl, -(C ₀ -C ₃ alkylene)-carbocyclyl, -(C ₀ -C ₃ alkylene)-heterocyclyl, C2-C6 alkenyl and C1-C6 alkyl, wherein: (1) 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-; and (2) any alkyl, alkenyl or alkylene portion of R ⁸ is optionally substituted with one or more substituents other than =0.

[0068] In some embodiments of Formula I, R ⁹ is additionally selected from optionally substituted cycloalkyl.

[0069] In some embodiments of Formula I, R ⁹ is further additionally selected from optionally substituted heteroaryl and optionally substituted heterocyclyl.

[0070] In some embodiments of Formula I, the C ₀ -C5 alkylene portion of R ⁵ is further optionally substituted with aryl, which may be optionally substituted.

[0071] In certain embodiments of Formula I:

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 .

[0072] In certain embodiments of Formula I:

R ^7c is selected from hydrogen and -CH ₃ ;

R ^7f is selected from hydrogen and -CH ₃ ;

-CCR' CR^-COOH ; and

R ^1U is selected from -CH ₃ , -CH ₂ -cyclohexyl, -CH ₂ OH and -(CH ₂ ) ₂ -C(0)-NH ₂ .

[0073] In certain embodiments of Formula I, 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,

0074] In certain embodiments of Formula I, R ¹ is additionally selected from:

-NH-(CH ₂ ) ₄ -OH, -N(CH ₃ )-(CH ₂ ) ₃ -OH, -NH-CH ₂ -CH(CH ₃ )OH, -NH-(CH ₂ ) ₂ -CH(CH ₃ )OH, -NH- CH ₂ ) ₂ -0-(CH ₂ ) ₂ -OH, -NH-CH ₂ -S0 ₃ H, -NH-(CH ₂ ) ₂ -S0 ₃ H, and -NH-(CH ₂ ) ₃ -S0 ₃ H.

[0075] In certain embodiments of Formula I, R ¹ is further additionally selected from:

possible, tautomers thereof.

[0076] In a more specific embodiment of Formula I, R ¹ is selected from: [0077] In another more specific embodiment of Formula I, R ¹ is selected from:

[0078] In certain embodiments of Formula I, R is selected from: -(CH ₂ ) ₃ -,

"1" represents a portion of R bound to

X. In one aspect of these embodiments, R is selected from -(CH ₂ ) ₃ -, -CH2-C(CH ₃ )2-CH2-, , , wherein "1" represents a portion of R bound to X. [0079] In certain embodiments of Formula I, R ³ is selected from -(CH ₂ )3-,

wherein "1" represents a portion of R bound to X.

[0080] In certain embodiments, R ³ is additionally selected from

[0081] In another embodiment of Formula I, R is selected from

wherein "1" represents a portion of R ³ bound to X.

[0082] In a more specific embodiment of Formula I, R ³ is

[0083] In another more specific embodiment of Formula I, R ³ is selected from

[0084] In a more specific embodiment of Formula I, X is *-C(0)-NH-, wherein "*" represents a portion of X bound to R ³ .

[0085] In another more specific embodiment of Formula I 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)-.

[0086] In certain embodiments of Formula I, Y is arene-diyl or carbocycle-diyl; and each of n and m is independently 0 or 1. In one aspect of these embodiments, Y is arene-diyl; and n is 0 or 1 ; and m is 0. In another aspect of these embodiments, R is selected from -(CH ₂ )4-,

-(benzene- 1 ,4-diyl)-, (also referred to as -CH ₂ -(benzene- 1 ,4-diyl)

(also referred to as -CH2-(cyclohexane-l,4-diyl)-†), wherein "†" represents a portion of R ⁴ bound to N(R ^7a ).

[0087] In certain embodiments of Formula I, 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

l ; and m is 0. In another aspect of these embodiments, 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 ).

[0088] In a more specific embodiment of Formula I, R is or

[0089] In certain embodiments of Formula I, 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. In one aspect of these embodiments, 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. In a more specific aspect of these embodime R ⁵ is

methylene substituted with a substituent selected from:

[0091] In a I, R ⁵ is meth lene substituted with a substituent

additionally and

[0092] In a more specific embodiment of Formula I, R is methylene substituted with a

substituent selected from

[0093] In an even more specific embodiment of Formula I, R is methylene substituted with a

substituent selected

[0094] In certain embodiments of Formula I, 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. In certain embodiment of Formula I, R ⁶ is additionally selected from heteroaryl. In a more specific aspect of these

[0096] In another more specific aspect, R ⁶ is additionally selected from:

[0097] In another more specific aspect, R ⁶ is additionally selected from

[0098] In still another more specific embodiment of Formula I, R ⁶ is selected from [ is selected from

[00100] In certain embodiments of Formula I, R ^7a , R ^7b , R ^7c , R ^7d R ^7e , and R ^7f is independently selected from methyl and hydrogen.

[00101] 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. In certain embodiments, 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 from halogen, hydroxyl, and C1-C4 alkyl for the optionally substituted heteroaryl in the definition of R ⁹ ; the optional substituents for the optionally substituted saturated or partially saturated heterocyclyl that may be formed when 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 or partially saturated heterocyclyl are independently selected from halogen, haloalkyl, haloalkoxyl, hydroxyl, C1-C4 alkoxyl, C1-C4 alkyl, C3-C6 cycloalkyl, -CO2H, amino, oxo, hydroxyalkyl, a 5-membered heteroaryl optionally substituted by alkyl, and/or a 5 or 6 membered saturated or partially saturated heterocyclic ring optionally substituted with one or two oxo groups; the optional substituents are independently selected from oxo, halogen, hydroxyl, and C1-C4 alkyl for the optionally substituted heterocyclyl in the definition of R ⁹ ; and for the further provision in the definition of Formula I that "any aryl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted" the optional substituent(s) are independently selected from halogen, haloalkyl, haloalkoxyl, hydroxyl, C1-C4 alkoxyl, Ci- C4 alkyl, -CO2H, aminoalkyl, amidoalkyl, hydroxyalkyl, cyano, amino, amido, -SCh-alkyl, and -SO ₃ H. [00102] The description above describes multiple embodiments relating to compounds of Formula I. The patent application specifically contemplates all combinations of the embodiments. For example, the invention contemplates a compound of Formula I wherein X -C(0)-NH-, R ¹ is -OH, R ^2a is hydrogen, R ^2b is hydrogen, and Y is arene-diyl.

[00103] Another aspect of the invention provides a compound represented by Formula la:

or a pharmaceutically acceptable salt thereof, wherein:

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;

each of 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; 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;

wherein any aryl, heteroaryl, carbocyclyl, and heterocyclyl portion of the compound is optionally substituted. [00104] Another aspect of the invention provides a compound of Formula lb:

, or a pharmaceutically acceptable salt thereof, wherein:

Z is CH or ;

and

R is cyclohexyl or 2-chlorobenzyl; and

R is selected from

[00105] Still another aspect of the invention provides a compound of Formula Ic

(Ic), or a pharmaceutically acceptable salt thereof, wherein:

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 ; and

at least one of a or b is 1

[00106] In some embodiments of Formula Ic, R is selected from:

[00108] In some embodiments, X' is further selected from **-N(CH ₃ )-C(0)-, wherein " ^: represents the portion of X' bound to -[CH ₂ ]b-.

[00109] 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.

[00111] Any of the compounds of Formula I, may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including ^l H, ² H (D or deuterium),

3 12 13 14

and H (T or tritium); C may be in any isotopic form, including C, C, and C; O may be in any isotopic form, including ¹⁶ 0 and ¹⁸ 0; and the like; N may be in any isotopic form, including ¹⁴ N and ¹⁵ N.

[00112] Unless otherwise indicated when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.

[00113] 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.

II. Methods of Synthesis of Compounds of the Invention

[00114] 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.

[00115] Abbreviations as used herein include

0-(7-azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU); diisopropylethylamine (DIPEA); dimethylformamide (DMF); 9-fluorenylmethoxycarbonyl (Fmoc); methanol (MeOH); methylene chloride (DCM); N-methylmorpholine (NMM);

tert-butoxycarbonyl (Boc); tert-butyl (tBu); tetrahydrofuran (THF); trifluoroacetic acid (TFA); 1,8-diazobicyclo [5.4.0]-undec-7-ene (DBU); l-hydroxy-7-azabenzotriazole (HOAt); phenyl (Ph); ethyl acetate (EA); and petroleum ether (PE). SCHEME 1.

Formula I Formula I

[00116] 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.

e

Formula I

[00117] 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.

77

Formula I

[00118] 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

Formula I

[00119] 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.

[00120] 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). III. Therapeutic Applications

[00121] 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. Such diseases include inflammatory diseases and conditions, proliferative diseases (e.g., cancer), autoimmune diseases and other disease described herein.

[00122] Increased levels of IL-17 (i.e., IL-17A) have been associated with several conditions including 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-β and TNF-a dependent and independent pathways. IL-17 stimulates secretion of other cytokines and chemokines, e.g., TNF-a, IL-Ιβ, 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 β activity (Ann Rheum Dis 2000, 59:529-32). Anti-IL-Ιβ antibody has no effect on IL-17 induced inflammation and joint damage (J Immunol 2001, 167: 1004-1013). In an SCW- induced murine arthritis model, IL-17 induced inflammatory cell infiltration and proteoglycan depletion in wild-type and IL-Ιβ 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,

171 :6173-6177).

[00123] Increased levels of IL-17-secreting cells have also been observed in the facet joints of patients suffering from ankylosing spondylitis (H Appel et al, Arthritis Res Therap 201 1, 13:R95).

[00124] Multiple sclerosis ("MS") is an autoimmune disease characterized by central nervous system ("CNS") inflammation with damage to the myelin sheath surrounding axons. A hallmark of MS is that T cells infiltrate into the CNS. Higher numbers of IL- 17

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.

[00125] In one embodiment, 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.

[00126] In another embodiment, 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.

[00127] In a more specific embodiment, 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. In one more specific embodiment, the condition is RA. In another more specific embodiment, the condition is psoriasis.

[00128] The use of the compounds of the present invention for treating or preventing of at least one of the aforementioned disorders in which IL-17 activity is detrimental or which benefits for decreased levels of bioactive IL-17 is contemplated herein. Additionally, the use of a compound of the present invention for use in the manufacture of a medicament for the treatment of at least one of the aforementioned disorders is contemplated.

[00129] In another aspect, 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.

[00130] In still another aspect, 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. In certain aspects the IL-17 chemokine or effector is one or more of IL-6, IL-8, G-CSF, TNF-a, IL-Ι β, PGE2, and IFN-γ.

[00131] Methods for determining the levels of IL-17 or any of its chemokines or effectors in a patient are well-known in the art. Typically, 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-Ι β, PGE2, and IFN-γ.

[00132] The invention also provides for combination therapy of a compound described herein and a second therapeutic agent. "Combination therapy" (or "co-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).

[00133] 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. For example, 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. Alternatively, for example, 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.) Where 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.

[00134] Accordingly, in certain instances, the method further comprises administering a therapeutically effective amount of an anti-inflammatory agent. In certain instances, 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, suprofen, tiaprofenic acid, mefenamic acid, flufenamic acid, meclofenamic acid, tolfenamic acid, phenylbutazone, ampyrone, azapropazone, clofezone, kebuzone, metamizole, mofebutazone, oxyphenbutazone, phenazone, phenylbutazone, sulfinpyrazone, celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib, prednisone, methylprednisolone, hydrocortisone, or budesonide.

[00135] In certain instances, the method further comprises administering a therapeutically effective amount of an agent for treating multiple sclerosis. In certain instances, the agent for treating multiple sclerosis is interferon beta-2, interferon beta-1, glatiramer, natalizumab, or mitoxantrone.

[00136] In certain instances, the method further comprises administering infliximab, etanercept, adalimumab, or certolizumab pegol.

[00137] In certain instances, 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, oxaprozin, pirprofen, suprofen, tiaprofenic acid, mefenamic acid, flufenamic acid,

meclofenamic acid, tolfenamic acid, phenylbutazone, ampyrone, azapropazone, clofezone, kebuzone, metamizole, mofebutazone, phenazone, sulfinpyrazone, celecoxib, etoricoxib, lumiracoxib, parecoxib, prednisone, methylprednisolone, hydrocortisone, and budesonide.

IV. Pharmaceutical Compositions and Dosing

[00138] The invention also provides pharmaceutically acceptable 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. As described in detail below, the pharmaceutical 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.

[00139] The phrase "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.

[00140] The phrase "pharmaceutically-acceptable carrier" as used herein means a

pharmaceutically-acceptable material, 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. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of 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 hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical formulations.

[00141] Wetting agents, emulsifiers and lubricants, 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.

[00142] Examples of pharmaceutically-acceptable antioxidants 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.

[00143] 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.

[00144] In certain embodiments, 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. In certain embodiments, an aforementioned formulation renders orally bioavailable a compound of the present invention.

[00145] 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. In general, 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.

[00146] 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.

[00147] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches and the like), 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 as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical 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.

[00148] 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.

[00149] The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, 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. They 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. Examples of 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.

[00150] Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, 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.

[00151] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[00152] 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.

[00153] 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.

[00154] 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.

[00155] 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.

[00156] 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.

[00157] 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.

[00158] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such 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.

[00159] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.

[00160] Pharmaceutical 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.

[00161] Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention 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. 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.

[00162] These 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

monostearate and gelatin.

[00163] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be

accomplished by the use of 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. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[00164] 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.

[00165] When 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.

[00166] Regardless of the route of administration selected, 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.

[00167] Actual dosage levels of the active ingredients in the pharmaceutical 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. [00168] 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.

[00169] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, 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.

[00170] In general, 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.

[00171] If desired, 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.

[00172] 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).

EXAMPLES

[00173] The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention. [00174] EXAMPLE 1 - Synthesis of [l-(i2-[4-(9H-Fluoren-9-ylmethoxycarbonylaminoV Phenyll-Ethylcarbamoyll-MethvD-Cvclopentyll-Acetic Acid (Intermediate 30).

[00175] Step 1: Synthesis of 4-(2-aminoethyl)-N- (tert-butoxycarbonyl) phenylamine (2). To a stirred solution of compound 1 (2.5 g, 18.38mmol) in 10% aqueous AcOH (100 ml) was added a solution of B0C2O (4.4 g, 20.2mmol) in 1,4-dioxane (200 ml) slowly at 0°C. After complete addition, resulting mixture was warmed to room temperature over the period of time and stirring continued for 20 h. Progress of the reaction was monitored by TLC. Upon completion of the reaction, mixture was diluted with ¾0 (200 ml) extracted well with diethyl ether (3 x 100 ml) and ether layer was discarded. The aqueous phase was then made basic with 2 N NaOH to pH ~14 and then extracted with copious amount of ether (3 x 200 ml). The organic phase was washed with H ₂ 0 (2 x 100 ml), dried over Na2S04, filtered and concentrated under vacuum to get the title compound 2 as yellow solid. Yield: (2.3g, 53%); 1HNMR (400 MHz, CDC13): δ ppm =7.31-7.29 (d, 2H), 7.11-7.09 (d, 1H), 2.83-2.80 (t, 2H), 2.69-2.65 (t, 2H), 1.49 (s, 9H); LC-MS: [M+H] = 236.9

[00176] Step 2: Synthesis of (l-{ [2-(4-tert-butoxycarbonylaminophenyl)-ethylcarbamoyl] - methyl}-cyclopentyl)-acetic acid (4). To a stirred solution of 2 (5.5g, 23.30mmol) in 150ml 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.

[00177] Yield: (7.8g, 82%) 1HNMR (400 MHz, DMSO): δ ppm = 12.07 (bs, 1H), 9.24 (s, 1H), 7.99-7.96 (t, 1H), 7.35-7.33 (d, 2H), 7.07-7.05 (d, 2H), 3.24-3.19 (q, 2H), 2.62-2.59 (t, 2H), 2.36 (s, 2H), 2.21 (s, 2H), 1.54-1.41 (m, 17H); LC-MS: [M+H] = 405.3

[00178] Step 3: synthesis of (l-{ [2-(4-amino-phenyl)-ethylcarbamoyl] -methylj-cyclopenyl)- acetic acid hydrochloride salt (5). To 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.

Progress of the reaction was monitored by TLC. After complete N-boc-deprotection, reaction mixture was concentrated on rotary evaporator to dryness. Crude hydrochloride salt was washed well with diethyl ether to give the title compound 5 as solid. Yield: (6.3g, 95%).

[00179] Step 4: Synthesis of [ l-( {2-[ 4-(9H-fluoren-9-ylmethoxycarbonylamino)-phenylJ- ethylcarbamoyl}-methyl)-cyclopentyl] -acetic acid (30). To a stirred suspension of 5 (6.3g, 18.50mmol) in 50ml 1,4-dioxane, was added 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. After completion of the reaction, volatile solvents were removed by rotary evaporation. The remaining aqueous solution was diluted with ethyl acetate (200ml) and then acidified with dilute HC1 solution (to a pH ~2-3). After stirring the mixture for few minutes, organic layer was separated out and aqueous phase was further extracted with ethyl acetate (3 x 200ml). Organic layers were combined and washed with copious amount of water (2 x 200ml). Organic layer was then dried over anhydrous a ₂ S0 ₄ and concentrated in vacuo to get the crude material which was subjected to silica gel (100-200 mesh) column

chromatography and eluted with 50% ethyl acetate in hexanes system to afford the desired title compound 30 as pale brown solid. Yield: (5.0 g, 51%); 1HNMR (400 MHz, DMSO): δ ppm = 12.20 (bs, 1H), 9.60 (s, 1H), 7.97-7.94 (t, 1H), 7.91-7.90 (d, 2H), 7.75-7.73 (d, 2H), 7.44-7.32 (m, 6H), 7.09-7.07 (m, 2H), 4.47-4.45 (m, 2H), 4.31-4.28 (t, 1H), 3.25-3.20 (m, 2H), 2.64-2.60 (t, 2H), 2.36 (s, 2H), 2.21 (s, 2H), 1.54-1.41 (m, 8H); LC-MS: [M+H] = 527.0; HPLC (purity): 93.82%.

[00180] EXAMPLE 2 - Synthesis of Compound 286.

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). 2-(l-(2-(4-(((9H-fluoren-9- yl)methoxy)carbonylamino)phenethylamino)-2-oxoethyl)cyclopen tyl)acetic acid (30; 3.16 g, 6.00 mmol) and -ethyl-N-isopropylpropan-2-amine ("DIEA"; 5.24 mL, 30.00 mmol) was dissolved in DCM (30 mL). The resulting solution was added to the swelled resin and agitated for 2 hours. The resin was then washed with 85: 10:5 DCM:MeOH:DIPEA (20 mL x 3); DCM (20 mL x 3), DMF (20 mL x 3), DCM (20 mL x 3). After flushing with argon and dried under vacuum, resin 31 (7.53 g) was obtained.

[00181] 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). Fmoc-2-chloro-L-phenylalanine (32; 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 ("ΝΜΜ"; 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 DMF (2 mL x 30 sec).

[00182] 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). α,α-Difluorophenylacetic acid (34; 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 30 min. The reagents were drained from the reaction vessel, and the resin was washed six times with DMF (2 mL x 30 sec). α,α-Difluorophenylacetic acid (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 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.

[00183] 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.

[00184] Crude reaction product (0.075 mmol; from the procedure described in the previous paragraph), pyrrolidine (0.031 mL, 5 equiv), and DIEA (0.13 mL, 10 equiv) was dissolved in DMF (5 mL). This solution was added to a solution containing HATU (34 mg, 0.090 mmol, 1.2 equiv) and HOAt (12 mg, 0.090 mmol, 1.2 equiv) dissolved in DMF (30 mL). After 30 minutes the volatiles were evaporated on a Genevac EZ2.2 evaporator at 50 °C. The resultant crude mixture was dissolved in DMSO and purified on a Waters HPLC. Evaporation of volatiles followed by lyophilization resulted in final product Compound 286 (15 mg, 0.022 mmol, 29% yield) as a white powder. 1H NMR (300MHz, DMSO-d6) δ 10.06 (IH, s), 9.24 (IH, d), 7.83 (IH, t), 7.51 (IH, m), 7.45 (6H, m), 7.37 (IH, dd), 7.26 (IH, dd), 7.20 (IH, td), 7.14-7.08 (3H), 4.80 (IH, q), 3.26-3.17 (6H), 2.62 (IH, t), 2.34 (2H, s), 2.22 (2H, s), 1.81 (2H, m), 1.73 (4H, m), 1.56-1.40 (8H).

[00185] EXAMPLE 3 - Synthesis of Compound 294.

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)phenethyla mino)-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, and the resin was washed with six times DMF (2 mL x 30 sec) to produce resin 41.

[00186] 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), 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 DMF (2 mL x 30 sec) to produce resin 42.

[00187] 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). α,α-Difluorophenylacetic acid (34; 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 30 min. The reagents were drained from the reaction vessel, and the resin was washed six times with DMF (2 mL x 30 sec). α,α-Difluorophenylacetic acid (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 30 min. The reagents were drained from the reaction vessel, and the resin was washed with six times DMF (2 mL x to produce resin 43.

[00188] Resin 43 (0.075 mmol, 105 mg) was treated with 5% TFA in DCM (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 was dissolved in DMSO and purified on a Waters HPLC. Evaporation of volatiles followed by lyophilization resulted in final product Compound 294 (28 mg, 0.038 mmol, 51% yield) as a white powder.

[00189] EXAMPLE 4 - Synthesis of 2-(l-(2-(2-(5-(((9H-fluoren-9- yl)methoxy)carbonylamino)pyridin-2-yl)ethylamino)-2-oxoethyl )cyclopentyl)acetic acid (Intermediate 51). The title compound was prepared by the following scheme:

[00190] 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₎ δ: 8.7-8.6 (d, 1H), 8.1 (d, 1H), 7.3-7.2 (s, 1H), 1.7-1.5 (s, 9H).

[00191] 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₎ δ: 9.5-9.4 (s, 1H), 8.6-8.5 (d, 1H), 7.7 (d, 1H), 4.2-4.1 (s, 2H).

[00192] 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 %).

[00193] 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 %). ¾ NMR (300 MHz, CDC1 ₃₎ δ: 8.1-8.0 (s, 1H), 7.0 (s, 2H), 4.0-3.8 (m, 2H), 3.1-3.0 (m, 2H), 2.9-2.8 (m, 2H), 1.9-1.7 (m, 2H).

[00194] 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 %)

[00195] 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 %). 1H NMR (300 MHz, CDC1 ₃₎ δ: 8.6-8.4 (s, 1H), 7.8-7.7 (d, 2H), 7.7-7.6 (d, 2H), 7.5-7.3 (m, 5H), 7.2-7.1 (d, 1H), 4.7-4.5 (d, 2H), 4.3-4.2 (m, 1H), 3.8-3.6 (m, 2H), 3.1-3.0 (m, 2H), 2.5-2.3 (d, 4H), 1.8-1.6 (m, 5H), 1.6-1.5 (m, 4H). LC-MS: m/z=528.4 (M+l) ⁺ .

[00196] Intermediate 51 was used in an analogous fashion to intermediate 30 in the synthesis of, e.g., Compound Nos. 384, 385, 472 and 473.

[00197]

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) and N-ethyl-N- isopropylpropan-2-amine (7.8 mL, 44.5 mmol) was dissolved in DCM (50 mL). The resulting solution was added to the swelled resin and agitated for 2 hours. The resin was then washed with 85: 10:5 DCM:MeOH:DIPEA (50 mL x 3); DCM (50 mL x 3), DMF (50 mL x 3), DCM (50 mL x 3). After flushing with argon and dried under vacuum, resin 53 (12.1 g) was obtained

[00198] 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), 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 DMF (2 mL x 30 sec) to yield 55.

[00199] 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

DMF (2 mL x 30 sec) to yield 57.

[00200] 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). Fmoc-(S)-2-amino-2-cyclohexylacetic acid (58; 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 DMF (2 mL x 30 sec) to yield 59.

[00201] 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). α,α-Difluorophenylacetic acid (34; 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 30 min.

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.

[00202] Resin 60 (0.075 mmol, 1 10 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 resultant crude mixture was dissolved in DMSO and purified on a Waters HPLC. Evaporation of volatiles followed by lyophilization resulted in final product Compound 383 (8 mg, 0.012 mmol, 16% yield) as a white powder.

[00203]

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) and 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. The resin was then washed with 85: 10:5 DCM:MeOH:DIPEA (10 mL x 3); DCM (10 mL x 3), DMF (10 mL x 3), DCM (20 niL x 3). After flushing with argon and dried under vacuum, resin 61 (0.985 g) was obtained.

[00204] 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.

[00205] 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), 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 63.

[00206] 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). α,α-Difluorophenylacetic acid (34; 0.1 M solution in DMF, 3 mL, 2 equiv, 0.30 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 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.

[00207] 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.

[00208] Crude reaction product 65 (0.150 mmol), pyrrolidine (0.062 mL, 5 equiv), and DIEA (0.26 mL, 10 equiv) was dissolved in DMF (10 mL). This solution was added to a solution containing HATU (68 mg, 0.180 mmol, 1.2 equiv) and HOAt (24 mg, 0.180 mmol, 1.2 equiv) dissolved in DMF (30 mL). After 30 minutes the volatiles were evaporated on a Genevac EZ2.2 evaporator at 50 °C. The resultant crude mixture was dissolved in DMSO and purified on a Waters HPLC. Evaporation of volatiles followed by lyophilization resulted in final product Compound 374 (47.5 mg, 0.070 mmol, 46.6% yield) as a white powder.

[00209] Other compounds of Formula I were made by a similar process as described above with the appropriate substitution for one or more of reagents 1, 3, 10, 30, 32, 34, and/or 40. Mass Spectrometry values for compounds of the invention are set forth in Table 1. ^X H NMR data for exemplary compounds is set forth in Table 2.

Table 1. Mass Spectrometry Data for Exemplary Compounds of the Invention.

( om ou it Iwacl Mass Obserx d ( om ou ii l.xacl Mass Obs n d d No. (M+l l) Mass ( M+M ) d No. ( .M+l l ) Mass (M+l l )

100 824.4598 824.8121 142 795.4333 795.28

101 866.4704 866.8226 143 782.4129 782.27

102 671.3444 671.23 144 849.4050 849.4

103 628.3023 628.21 145 747.4333 747.3

104 781.4176 781.46 146 853.4751 853.28

104 781.4176 781.46 147 799.4082 799.35

105 713.3550 713.22 148 799.4082 799.49

106 552.2710 552.21 149 782.4129 782.49

107 705.3863 705.24 150 747.4333 747.38

108 684.3761 684.24 151 671.3444 671.23

109 641.3339 641.22 152 713.3550 713.22

110 794.4492 794.32 153 795.4333 795.28

11 1 726.3866 726.23 154 795.4333 795.28

112 565.3026 565.37 155 782.4129 782.37

113 767.4020 767.26 156 820.4285 820.42

114 795.4333 795.42 157 787.4646 787.3

115 795.4333 795.28 158 797.4125 797.28

116 797.4125 797.42 159 623.3081 623.18

117 81 1.4282 811.32 160 686.3190 686.24

118 747.4333 747.3 161 686.3190 686.24

119 747.4333 747.3 162 713.3550 713.22

120 782.4129 782.42 163 699.3394 699.17

121 763.3918 763.27 164 665.3550 665.24

122 717.3652 717.21 165 749.3550 749.22

123 723.4121 723.28 166 749.3550 749.3

124 683.3808 683.21 167 775.3707 775.47

125 655.3495 655.26 168 767.3267 767.41

126 670.3604 670.27 169 686.3190 686.24

127 697.3601 697.18 170 719.4020 719.28

128 710.3917 710.26 171 787.3893 787.44

129 715.3343 715.22 172 781.3424 781.16

130 910.4602 910.1628 173 689.3350 689.27

131 685.3237 685.2 174 717.3663 717.29

132 727.3707 727.19 175 677.3914 677.29

133 755.4020 755.21 176 705.4227 705.31

134 795.4333 795.43 177 739.3318 739.24

135 723.4121 723.2 178 767.3631 767.41

136 781.4176 781.46 179 695.3820 695.27

137 787.4646 787.3 180 723.4133 723.29

138 795.4333 795.43 181 709.3976 709.24

139 767.4020 767.19 182 745.3788 745.24

140 733.4176 733.26 183 773.4101 773.33

141 781.4176 781.23 184 759.3944 759.29 m pouii hxact Mass Obsorv i-d ( om poll it Lxacl Mass Observed

(1 No. (M+l l ) Mass ( M+l l ) d No. ( M+l l ) Mass ( M+l l )

185 617.3 139 617.29 230 631.3051 631.182

186 601.3 190 601.32 231 633.2843 633.1777

187 555.2982 555.27 232 617.2894 617.21 18

188 539.3033 539.16 233 631.3295 631.2559

189 73 1.3456 731.12 234 631.3295 631.2559

190 737.3925 737.18 235 615.3346 615.2161

191 682.3240 681.96 236 645.3452 645.2264

192 700.3346 700 237 629.3503 629.2603

193 675.3 194 674.94 238 886.3349 886.2876

194 681.3663 681 239 810.3036 810.2998

195 689.3350 688.99 240 858.3036 858.3471

196 691.3 143 691.13 241 782.2723 782.2839

197 689.3350 689.13 242 604.2578 604.21

198 697.2673 696.97 243 590.2421 590.24

199 697.2673 696.97 244 618.2734 618.25

200 697.2673 696.97 245 604.2578 604.28

201 747.3 160 747.24 246 631.3051 63 1.26

202 733.3004 733.19 247 617.2894 617.29

203 727.3707 727.28 248 645.3207 645.3 1

204 713.3550 713.31 249 631.3051 63 1.26

205 743.3656 743.32 250 604.2578 604.21

206 729.3499 729.27 251 646.3160 646.27

207 699.3394 699.26 252 686.3473 686.33

208 785.3925 785.31 253 672.33 16 672.2875

209 805.4551 805.41 254 673.3156 673.25

210 835.3893 835.35 255 657.3207 657.28

21 1 849.4050 849.32 256 590.2421 590.24

212 855.4519 855.39 257 632.3003 632.3

213 685.3601 685.22 258 672.33 16 672.29

214 685.3601 685.22 259 659.3000 659.28

215 699.3757 699.26 260 643.3051 643.3 1

216 699.3757 699.26 261 606.2371 606.2019

217 615.3346 615.2161 262 620.2527 620.2468

219 771.4133 771.2621 263 608.2327 608.1978

220 715.3507 715.2288 264 622.2484 622.2462

221 746.3565 746.2022 265 633.2843 633.2568

222 601.3 190 601.1723 266 647.3000 647.3018

223 799.4082 799.2789 267 635.2800 635.2527

224 615.3346 615.29 268 649.2957 649.2977

225 615.3346 615.1422 269 640.1981 640.1 1

226 587.3033 587.2767 270 654.2137 654.1765

227 601.3 190 601.2462 271 624.2032 624.1646

228 617.3 139 617.21 18 272 638.2188 638.2095

229 647.3000 647.2221 273 667.2454 667.1868 Compouii hxact Mass Obsorvi-d ( om poll it Lxacl Mass Observed

(1 No. (M+ll) Mass (M+ll) d No. (M+ll) Mass (M+ll)

274 681.2610 681.232 318 673.3156 673.5251

275 651.2505 651.2197 319 641.2742 641.5077

276 665.2661 665.1909 320 717.3055 717.522

277 658.3160 658.32 321 711.2925 711.5325

278 688.3265 688.2794 322 581.2894 581.5413

279 701.3270 701.48 325 665.2706 665.41

280 644.3003 644.47 326 667.2862 667.46

281 693.3019 693.49 327 611.3000 611.4871

282 681.3816 681.59 328 625.3156 625.5361

283 624.3550 624.57 329 737.2917 737.4871

284 687.3313 687.43 330 745.3168 745.5471

285 673.3156 673.45 331 723.2761 723.5116

286 693.3019 693.42 332 731.3011 731.4976

287 673.3565 673.3 333 723.2761 723.5116

288 597.2843 597.4384 334 731.3011 731.4976

289 711.2925 711.5325 335 745.3168 745.5471

290 711.2925 711.5325 336 693.3019 693.4901

291 693.3019 693.4901 337 639.3313 639.5113

292 675.3113 675.5216 338 671.3000 671.5287

293 661.2957 661.4724 339 673.3156 673.5251

294 737.2917 737.4871 340 685.3520 685.5041

295 723.3125 723.5116 341 700.3629 700.5148

296 723.3125 723.5116 342 715.2898 715.4516

297 737.2917 737.4871 343 717.3055 717.522

298 722.3284 722.5502 344 729.3419 729.5011

299 679.2862 679.5146 345 651.3722 651.564

300 708.3128 708.5009 346 680.3987 680.6237

301 695.2812 695.4866 347 695.3620 695.5605

302 705.3219 705.543 348 555.3546 555.5889

303 705.3219 705.543 349 597.2843 597.5124

304 690.3222 690.5323 350 681.3583 681.51

305 704.3379 704.5817 351 681.3583 681.51

306 661.2957 661.5463 352 679.2862 679.4

307 677.2906 677.5182 353 744.3528 744.5195

308 719.3011 719.5186 354 694.4144 694.5253

309 719.3011 719.5186 355 717.3055 717.3741

310 679.2862 679.4 356 695.3620 695.4866

311 707.3175 707.5 357 681.3463 681.4373

312 659.3175 659.5 358 677.3714 677.5182

313 709.2968 709.536 359 663.3558 663.4688

314 709.2968 709.536 360 644.3538 645.5

315 736.3441 736.5997 362 621.3315 622.5

316 736.3441 736.5997 363 672.3078 673.5

317 723.3125 723.5116 364 674.2683 675.4 m pouii hxact Mass Obsorv i-d ( om poll it Lxacl Mass Observed

(1 No. (M+l l ) Mass ( M+l l ) d No. ( M+l l ) Mass ( M+l l )

365 688.2839 689.4 409 672.3487 673.4243

366 702.2996 703.4 410 716.3385 717.3695

367 716.3 152 717.4 41 1 710.2847 71 1.303

368 736.2839 737.4 412 754.2745 755.3229

369 750.2996 751.4 413 700.2410 701.09

370 626.3632 627.5 414 725.3708 726.25

371 692.2941 693.3 415 764.3152 765.3105

372 706.3097 707.4 416 679.2737 680.16

373 664.2628 665.3 417 688.2839 689.1083

374 678.2784 679.3 418 636.3487 637.25

375 655.2925 656.4 419 610.3331 61 1.28

376 701.4152 702.51 14 420 680.3385 681.19

377 736.2839 737.413 1 421 636.3487 637.25

378 657.4254 658.5 422 876.2884 877.17

379 678.2784 679.37 423 749.3156 750.1481

380 660.3242 661.29 424 636.3487 637.26

381 722.2683 723.21 425 608.3174 609.22

382 722.2683 723.21 426 652.3072 653.23

383 680.3385 681.28 427 678.2784 679.19

384 651.3596 652.34 428 722.3047 723.2881

385 693.2893 694.21 429 650.2471 651.15

386 813.2775 814.29 430 620.3129 621.1946

387 875.293 1 876.29 431 634.3286 635.2506

388 692.2941 693.25 432 674.2847 675.1998

389 678.2784 679.27 433 732.2200 733.2018

390 726.3204 727.36 434 746.2400 747.1847

391 664.2895 665.21 435 760.2500 761.2416

392 770.3 103 771.16 436 765.360 765.485

393 708.2793 709.31 437 632.418 632.439

394 678.2784 679.19 438 625.357 625.3375

395 682.2734 683.1898 439 685.357 685.3353

396 696.2890 697.1723 440 737.252 737.1377

397 710.3047 71 1.1898 441 725.308 725.29

398 710.3047 71 1.1865 442 741.303 741.27

399 696.2890 697.1723 443 687.33 1 687.33

400 710.3047 71 1.1793 444 717.342 717.15

401 708.2890 709.1575 445 733.352 733.2

402 726.2996 727.2093 446 682.316 682.15

403 616.2628 617.1998 447 658.316 658.33

404 630.2784 63 1.1817 448 644.301 644.28

405 644.2941 645.2098 449 721.283 721.14

406 717.2893 718.18 450 698.322 698.13

407 656.2941 657.2965 451 648.307 648.34

408 780.2334 781.291 452 621.321 621.34 m pouii hxact Mass Obsorv i-d ( om poll it Lxacl Mass Observed

(1 No. (M+l l ) Mass ( M+l l ) d No. ( M+l l ) Mass ( M+l l )

453 689.308 689.1 1 497 738.2872 738.2326

454 727.263 727.06 498 660.313 660.2557

455 769.298 769.181 499 674.3286 674.2494

456 785.293 785.204 500 709.264 709.2061

457 73 1.321 73 1.204 501 636.33 18 636.2862

458 761.332 761.242 502 650.3475 650.2684

459 777.342 777.23 1 503 685.2828 685.1876

460 726.306 726.204 504 709.3082 709.23 14

461 702.306 702.203 505 723.3239 723.2391

462 688.290 688.221 506 758.2592 758.2082

463 763.293 765.163 507 679.3264 679.2688

464 744.328 742.215 508 680.3217 680.2761

465 694.3 12 692.208 509 650.3475 650.3075

466 665.3 1 1 665.212 510 664.3631 664.3246

467 665.3 1 1 665.212 51 1 699.2985 699.2438

468 733.298 733.202 512 651.3427 651.304

469 771.253 771.155 513 665.3584 665.2979

470 684.336 684.226 514 700.2937 700.274

471 623.381 623.4139 515 681.3465 681.2863

472 666.306 666.3222 516 653.3152 653.3015

473 745.348 745.1872 517 779.3622 779.3079

474 690.2872 690.218 518 726.3788 726.32

475 579.3912 579.2499 519 636.33 18 636.29

476 651.3427 651.3781 520 671.2672 671.2

477 730.3849 730.3906 521 660.313 660.27

478 744.4006 744.3732 522 695.2483 695.18

479 757.264 757.1724 523 646.2973 646.27

480 665.3584 665.36 524 665.3108 665.29

481 709.3778 709.31 525 651.2951 651.27

482 669.3465 669.2814 526 675.2763 675.23

483 669.3465 669.2813 527 623.381 623.34

484 693.3021 693.24 528 609.3654 609.36

485 651.3724 651.3 529 633.3465 633.33

486 737.2919 737.2 530 743.2483 743.19

487 695.3622 695.27 531 697.3415 697.2463

488 783.4366 783.3789 532 739.2712 739.1929

489 769.421 769.681 1 533 737.2919 737.197

490 669.3465 669.2814 534 685.2828 685.1 1

491 669.3465 669.2813 535 622.3162 622.3

492 686.2781 686.2178 536 694.2973 694.28

493 650.3475 650.34 537 771.4002 771.2819

494 636.3318 636.29 538 806.3356 806.2236

495 708.3 13 708.27 539 71 1.3427 71 1.2286

496 710.2592 710.1932 540 746.2781 746.1494 Compouii hxact Mass Obsorv i-d ( om poll it Lxacl Mass Observed

(1 No. (M+l l ) Mass ( M+l l ) d No. ( M+l l ) Mass (M+l l)

541 710.2923 710.1932 585 743.2483 743.12

542 759.2433 759.0979 586 765.3465 765.1626

543 725.3584 725.2412 587 693.3654 693.2352

544 676.2904 676.1624 588 660.2624 660.1077

545 707.3577 707.2338 589 674.2781 674.1642

546 667.29 667.2099 590 686.2781 686.223

547 737.2919 737.123 591 834.3669 834.3372

548 687.2621 687.119 592 750.3094 750.2709

549 715.3343 715.224 593 727.3531 727.2092

550 741.2691 741.118 594 736.3676 736.23

551 736.3443 736.2352 595 736.3676 736.23

552 661.3082 661.2175 596 750.3833 750.27

553 680.3217 680.3045 597 692.4178 692.3033

554 680.3217 680.3785 598 678.4021 678.2975

555 752.3028 752.2896 599 678.4021 678.2877

556 752.3028 752.2896 600 723.2291 723.2141

557 780.3574 780.3292 600 597.2845 597.3298

558 751.3076 751.1788 601 799.2604 799.1951

559 751.3076 751.1797 602 721.3967 721.3646

560 785.4159 785.2863 603 769.3967 769.3057

561 761.3144 761.09 604 741.3688 741.34

562 675.3239 675.1965 605 789.3688 789.3552

563 699.2985 699.1699 606 581.2896 581.2472

564 699.2985 699.1699 607 611.3002 611.2816

565 637.3271 637.188 608 625.3158 625.2635

566 745.2276 745.11 609 637.3158 637.322

567 785.3186 785.23 610 623.3002 623.266

568 727.3531 727.28 611 651.3315 651.3041

569 727.2534 727.14 612 799.3343 799.269

570 751.2734 751.18 613 783.3393 783.2886

571 707.2674 707.16 614 674.2781 674.2381

572 736.2715 736.24 615 750.3094 750.218

573 762.2872 762.28 616 692.4178 692.3636

574 731.3622 731.2783 617 740.4178 740.3782

575 707.381 707.3079 618 636.3318 636.3603

576 721.3967 721.2906 619 636.3318 636.3603

577 669.2879 669.2073 620 650.3475 650.3425

578 664.3631 664.2507 621 750.3833 750.218

579 678.4021 678.2943 622 750.3833 750.366

580 750.3833 750.2557 623 764.3989 764.3488

581 725.2555 725.14 624 640.2904 640.2072

582 722.3286 722.28 625 654.306 654.1893

583 804.3574 804.2261 626 666.306 666.1851

584 769.3237 769.22 627 786.3635 786.3218 m pouii hxact Mass Obsorv i-d ( om poll it Lxacl Mass Observed

(1 No. (M+l l ) Mass ( M+l l ) d No. ( M+l l ) Mass ( M+l l )

628 814.3948 814.2877 672 718.3606 718.5132

629 730.3373 730.2424 673 554.2423 554.2184

630 71 1.3582 71 1.2289 674 554.2423 554.27

63 1 793.3778 793.2764 675 596.3126 596.35

632 699.2985 699.2452 676 668.2938 668.32

633 671.2672 671.2 677 732.3763 732.4095

634 736.3676 736.309 678 727.3531 727.3913

635 745.3958 745.261 1 679 690.306 690.3262

636 764.3989 764.3488 680 685.2828 685.3145

637 664.3865 664.3616 681 768.3763 768.4381

638 655.2723 655.225 682 763.3531 763.4144

639 73 1.3802 73 1.3522 683 765.3402 765.4

640 691.3013 691.2538 684 760.3171 760.39

641 676.2904 676.2354 685 833.4062 833.49

642 689.3332 689.3633 686 713.3375 713.4

643 747.3872 747.4412 687 726.306 726.3593

644 748.3824 748.403 1 688 721.2828 721.3274

645 675.3 176 675.3 144 689 768.3763 768.4415

646 697.3425 697.3536 690 763.3531 763.4189

647 773.4505 773.4838 691 726.306 726.3569

648 733.3715 733.384 692 721.2828 721.3246

649 717.3879 717.4034 693 800.3295 800.4142

650 622.3 162 622.2513 694 718.3606 718.4935

651 636.3318 636.2436 695 732.3763 732.5136

652 636.3318 636.2436 696 686.2781 686.4

653 706.3 122 706.2318 697 707.3559 707.5

654 736.3676 736.2694 698 609.3443 609.46

655 750.3833 750.2526 699 713.3375 713.4337

656 664.3865 664.357 700 790.3418 790.5002

657 671.2672 671.23 701 732.3763 732.5702

658 671.2672 671.22 702 762.3868 762.608

659 718.3606 718.29 703 746.3919 746.5533

660 790.3418 790.3 704 785.3186 785.9745

661 622.3 162 622.2612 705 791.3370 791.9666

662 609.2845 609.3 171 706 719.3559 719.9136

663 623.3002 623.3709 707 742.3418 742.1516

664 567.274 567.2961 708 732.3763 732.2049

665 662.3475 662.4333 709 756.3574 756.1877

666 707.2784 707.3415 710 790.3818 790.2221

667 749.3487 749.4327 71 1 790.3818 790.2221

668 833.4062 833.49 712 776.3661 776.1707

670 733.3715 733.4919 713 776.3661 776.171

671 691.3013 691.4348 Table 2. H NMR Data for Exemplary Compounds of the Invention.

EXAMPLE 5- EVALUATION OF BIOLOGICAL ACTIVITY

[00210] 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.

Experimental Procedures:

A. IL-17 ELISA Assay.

[00211] 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 μg/mL), 100 μΕ/well, for 30 min at 37°C followed by 5 min at 4°C. Plates were then washed in PBST (PBS/0.05%Tween-20) on a plate washer, (Biotech EL-450) blocked with protein-free blocking buffer (Thermo Scientific #37573), 250 μΕΛνεΙΙ for 30 min on shaker at room temperature and washed again. Compound dilutions prepared in PBST were added into the wells in duplicates followed by the addition of IL-17R/Fc (R&D Systems #177-IR) at a final concentration of 12 nM. Plates were then incubated for 30 min at room temperature on the shaker. Wells with no compound served as a positive "no competitor" control, while wells with no IL-17R/Fc and no compound served as a blank negative control. After an additional PBST wash, 50 ng/ml HRP -conjugated goat anti-human Fc IgG (KPL #04-10-20) was added to the plate for 30 min at room temperature, followed by PBST wash and addition of SureBlue™ TMB (KPL #52-00-03). After the sufficient color development, the reaction was fixed by the addition of 100 μΐ/ννεΐΐ 0.5 N HCl and absorbance was measured at 450 nm on Biotek plate reader. The absorbances of 'no competitor' control and blank control did not exceed 1.0 A.U. and 0.05 A.U. respectively.

[00212] Data were processed using BioAssay Enterprise vlO.1.4 (CambridgeSoft) software. Linear OD λ450 were plotted against log concentration (x) and fitted to a 4-parameter logistic equation. IC5 ₀ was calculated using positive 'no competitor' control data as an upper limit and blank control as a lower limit in each assay.

[00213] 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 μΕ/well, for 30 min at 37° C followed by 5 min at 4° C. The plate was then washed in PBST

(PBS/0.05%Tween-20) on a plate washer, (BioTek ELx450) then blocked with protein-free blocking buffer (Thermo Scientific #37573), 250 μΕΛνεΙΙ for 30 min on a shaker at room temperature and washed again. IL-17R/Fc (R&D Systems #177-IR; 10 nM in PBST, 100 μΕΛνεΙΙ) was then added to all wells. The plate was then incubated for 30 min at room temperature on the shaker.

[00214] While the receptor capture step was underway compound dilutions were prepared in PBST to a concentration of 1 μΜ in 1.5 mL tubes. After the receptor capture step the plate was washed and 50 μΐ _^ PBST was added to the wells in row B down to row H. Then 62.5 μΐ _^ of the 1 μΜ compound dilutions were added to the wells of row A. From row A 12.5 μΐ _^ of the compound solution was removed and added to row B with mixing and this process of 5-fold dilutions was continued, by row, to row G. One of the wells in row A received only PBST, 62.5 μΐ _^ and this dilution series served as the no competitor control. Then going up from row G to row A 50 μΐ, of b-IL-17 (biotinylated human IL-17, R&D Systems #317-ILB; 20 nM) was added to all wells. Row H received 50 μΐ _^ 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 μΐ. Streptavidin-Horseradish Peroxidase (SA-HRP) (KPL #14- 30-00) at 25 ng/mL in PBST was added to each well in the plate and the plate incubated for 30 min RT followed by wash and 100 μΐ. SureBlue™ TMB (KPL #52-00-03). After sufficient color development (approx 3-6 minutes), the reaction was fixed by the addition of 100 μΙ,ΛνεΙΙ 0.5 N HC1 and absorbance was measured at 450 nm on a BioTek Synergy 2 plate reader. The absorbances of 'no competitor' control and blank control should not exceed 1.5 A.U. and 0.06 A.U. respectively.

[00216] Data was processed using BioAssay Enterprise vlO.1.4 (CambridgeSoft) software. Linear OD λ450 were plotted against log concentration (x) and fitted to a 4-parameter logistic equation. IC50 was calculated using positive 'no competitor' control data as an upper limit and blank control as a lower limit in each assay.

B. Surface Plasmon Resonance (SPR) Analysis of Compound Interactions with

IL-17A

[00217] SPR analysis was carried out with a GE Healthcare (Piscataway, NJ) Biacore X100 system. Typically, the chip (NTA Biacore Biosensor chip; GE Healthcare BR-1000-34) was first conditioned by injection of 0.35 M EDTA, which also served to remove any immobilized proteins from previous runs. Before immobilization of the recombinant 6-His-tagged IL-17, the chip was washed with 0.5 mM nickel chloride in NTA buffer (10 mM HEPES buffer, 0.15 M sodium chloride, 10 μΜ 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 μΜ for 60-120 seconds, followed by a stabilization step washing with NTA + 0.5% DMSO for 120 seconds or longer.

[00218] Five 2 or 3-fold serial dilutions of test compound were injected serially onto the chip. All steps were conducted using NTA buffer containing 0.5% v/v dimethylsulfoxide (DMSO). Compounds were diluted from stock solutions of 10 mM concentration in 100% DMSO with NTA buffer to obtain 50 μΜ solutions in NTA + 0.5% DMSO. Subsequent 2x or 3x dilutions were made in NTA + 0.5% DMSO. Compound was generally injected for 180 seconds followed by washing the chip in buffer alone for 120 seconds. The rate of refractive index change (RU units/time) and the maximum extent of RU change was measured during the "on" phase of analyte injection, followed by measuring the rate during the "off phase. [00219] Kinetic parameter fits were conducted using the Biacore SPR Evaluation Program (GE Healthcare) for 1 : 1 molecular binding fits, after subtracting the baseline average of 2 or more runs in which no analyte was injected. This program then reports the best fit average for the "on" rate (k _a ), the "off rate (ka) and the dissociation constant (Ka) (Chaiken, I et al, Anal Biochem 201, 197-210 (1992)). A separate program in the Biacore SPR Evaluation Program then calculates the best fit for Ka based upon the extent of binding alone (RU units bound) at each concentration of analyte and reports the best fit Ka by best fit to a Lineweaver-Burke plot. Typically, the Ka value calculated through both means agreed within a factor of three.

[00220] The presence and activity of IL-17 on the NTA chip was routinely confirmed three ways:

1) An increase in response units (RU) upon immobilization confirms that the IL-17 was immobilized on the chip;

2) Anti-IL-17 was also injected on the chip to confirm the presence of IL-17; and

3) 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.

C. Inhibition of IL-17A Induced Secretion of IL6 in Human Rheumatoid Arthritis Synovial Fibroblast Cells

[00221] 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.

[00222] Low passage (passage 2-8) Primary human RASF cells (Asterand) were maintained in maintenance medium. Cells were detached from flasks by tryptic digestion and the cell density of the suspension determined. To each well of a 96 well culture plate was added 100 μΐ of seeding medium containing 50,000 cells/ml and the plate incubated overnight in a humidified 37°C, 5% CO ₂ incubator. The medium was replaced with fresh assay medium and cells were incubated for additional 5 hours in a humidified 37°C, 5% CO ₂ incubator prior to stimulation with recombinant human IL-17A ("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 μg/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 μΜ to 25 μΜ.

[00223] Immediately before stimulation, cells were washed once with fresh assay medium. Then 100 μΐ of the test samples was added in triplicate wells and the plates incubated for 20 hours in a humidified 37°C, 5% CO ₂ incubator. The assay medium from each well was collected and the IL-6 concentration in cell culture supernatants was determined by ELISA either immediately or after storage at -20°C.

[00224] 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.

D. HT-29 Cellular Assay

[00225] To test the ability of a compound of the invention to neutralize or antagonize an IL-17 bioactivity, the following cell-based assay was used. IL-17 can stimulate epithelial cells and other cells to secrete GROa. The ability of a compound of the invention to neutralize

IL-17 - induced GROa secretion from the human colorectal adenocarcinoma epithelial cell line HT-29 is tested in this assay.

[00226] HT-29 cells (human colorectal adenocarcinoma epithelial cells, ATCC #HTB-38), were maintained in culture/assay medium in tissue culture-treated flasks using standard techniques. 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 μΐ) 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. In a separate 96-well plate the compounds to be tested were serially diluted in Defined Keratinocyte SFM and run in triplicate in 100 μϊ _^ total volume. To these compound samples were then added 100 μϊ _^ of human IL-17 at a concentration of 20 ng/ml in Defined Keratinocyte SFM for serum- free assays. 150 μΐ _^ of the compound/IL-17 mixture was then added to the cells from which the media has previously been removed. The cells were grown for 48 hours in Defined Keratinocyte SFM in a tissue culture incubator (37°C, 5% CO ₂ ).

[00227] At the end of the incubation, 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 μg/ml. GROa is detected using biotinylated goat anti-human GROa (R+D Systems BAF275) at 200 ng/ml using TMB as a substrate. At the end of the ELISA reactions, plates are read at 450 nm on a microplate reader and compared to a standard calibration curve.

[00228] Only compound 148 was tested in the HT-29 assay and produced a value of 2.3μΜ. All subsequent cell assays were performed in RASF cells.

[00229] The results of all biochemical and cellular assays are set forth in Table 3, below. For each of the ELISA assays, "A" indicates an IC50 value of less than 100 nM; "B" an IC50 value of between 100 nM and 1 μΜ; "C" an IC50 value between greater than 1 μΜ and 10 μΜ; and "D" an IC50 value of greater than 10 μΜ. For the RASF cell assays, "A" indicates an EC50 value of less than 1 μΜ; "B" an EC50 value of between 1 μΜ and 10 μΜ; and "C" an EC50 value greater than 10 μΜ. For the SPR Biacore assay, "A" indicates a K _d value of less than 500 nM; "B" a K _d value between 500 nM and 1 μΜ; "C" a K _d value greater than 1 μΜ and less than or equal to 10 μΜ; and "D" a K _d value of over 10 μΜ. For every assay, 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.

TABLE 3— In Vitro and Cell Assay Results for Select Compounds of Formula I

E. Murine Model of Delayed Hypersensitivity

[00230] We used a murine model of fluorodinitrobenzene (DNFB)-induced ear edema to test the anti-inflammatory activity of orally dosed exemplary compounds of the invention. BALB/c mice (Harlan Sprague-Dawley, Inc., male, 6-8 weeks old) were topically treated on their shaved abdomen with 30 μΐ of 0.5% l-fluoro-2,4-dinitrobenzene (DNFB) (4: 1 acetone:olive oil) once on Day 0 and once on Day 1.

[00231] Exemplary compounds of the invention (Compound Nos. 285, 286 and 288) 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. Thirty minutes later, 20 μϊ _^ of 0.2% DNFB was applied to the right ear of animals and vehicle (DNFB: olive oil) was applied to the left ear. One and four hours after DNFB challenge, a subset of mice was exsanguinated and plasma prepared from the blood. Twenty-four hours after challenge, the remaining mice were euthanized, and their ears were removed and weighed to determine the amount of edema. Plasma was assayed for interleukin-6, and interferon-γ concentrations using commercially-available assays.

[00232] The results are summarized below in Table 4.

Table 4. Delayed Hypersensitivity Assay Results for Select Compounds of Formula I

Com pou nd Dose Reduct ion in 1 1.6 Reduct ion in Reduct ion in

No. ( m« k ^« ) (" » ) l l- V/ ( " ») r.dcnuM " ., )

285 30 10.3 3.9 6.8

286 30 67.0 73.7 59.0

10 26.0 40.7 17.2

288 30 42.0 not tested 41.7

[00233] Fig. 1 is a bar graph demonstrating that Compound 286 reduces edema, interleukin-6, and interferon-γ 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.

F. Mouse Collagen-Induced Arthritis Model

[00234] 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 μΐ 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. On study days 24-25, 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. Once a day oral treatment with 30 mg/kg Compound 286 was initiated after enrollment and continued once a day as indicated through arthritis day 10. Mice were terminated on day 1 1. Clinical scores were calculated for each of the paws (right front, left front, right rear, left rear) on arthritis days 1-11 and the results were summarized as a reduction in clinical arthritis score for all paws over the time period of dosing.

[00235] 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.

[00236] 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.

INCORPORATION BY REFERENCE

[00237] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes. E QUI VALENTS

[00238] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.