WO2010091543A1

WO2010091543A1 - Novel hydrazino-cyclobut-3-ene-1, 2-dione derivatives as cxcr2 antagonists

Info

Publication number: WO2010091543A1
Application number: PCT/CN2009/070387
Authority: WO
Inventors: Shu-Hui Chen; Hao Wu; Jingchao Dong; Shilan Liu; Yinhui Niu
Original assignee: Merck Sharp & Dohme Corp.
Priority date: 2009-02-10
Filing date: 2009-02-10
Publication date: 2010-08-19

Abstract

The present invention relates to novel hydrazino-cyclobut-3-ene-1,2-dione compounds of Formula (I) as selective CXCR2 antagonists, pharmaceutical compositions containing the novel compounds, as well as methods for treating or preventing chemokine mediated diseases or conditions in human and non-human animals using the novel compounds (I).

Description

NOVEL HYDRAZINO-CYCLOBUT-S -ENE-I, 2-DIONE DERIVATIVES AS CXCR2

ANTAGONISTS

BACKGROUND OF THE INVENTION Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T-cells, eosinophils, basophils, neutrophils and endothelial cells to sites of inflammation and tumor growth. Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved cysteine motif. At the present time, the chemokine superfamily comprises three groups exhibiting characteristic structural motifs, the CXC, CC and CX₃C families. The CXC and CC families have sequence similarity and are distinguished from one another on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues. The CX₃C family is distinguished from the other two families on the basis of having a triple amino acid insertion between the NH-proximal pair of cysteine residues.

The CXC chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (TL-8) and neutrophil-activating peptide 2 (NAP-2).

The CC chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils. Examples include human monocyte chemotactic proteins 1-3 (MCP-I, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins lα and lβ (MP-I α and MIP-I β). The CX3C chemokine (also known as fractalkine) is a potent chemoattractant and activator of microglia in the central nervous system (CNS) as well as of monocytes, T cells, NK cells and mast cells.

Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCRl, CCR2, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRI l (for the CC family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the CXC family) and CX₃CRl for the CX₃C family. These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above. There remains a need for compounds that are capable of modulating activity at

CXC-chemokine receptors. For example, conditions associated with an increase in IL-8 production (which is responsible for chemotaxis of neutrophil and T-cell subsets into the inflammatory site and growth of tumors) would benefit by compounds that are inhibitors of IL- 8 receptor binding.

SUMMARY OF THE INVENTION

The present invention relates to novel hydrazino-cyclobut-3-ene-l,2-dione compounds encompassed by Formula (I) as selective CXCR2 antagonists, pharmaceutical compositions containing the novel compounds, as well as methods for treating or preventing chemokine mediated diseases or conditions in human and non-human animals using these novel compounds:

DESCRIPTION OF THE INVENTION

The present invention describes compounds of Formula (I) and pharmaceutically acceptable salts thereof:

wherein A is selected from the group consisting of:

B is selected from the group consisting of: (1) hydrogen,

(2) Ci_-8 alkyl, optionally substituted with 1 to 3 substituents selected from the group consisting of:

(a) aryl, optionally substituted with 1 to 3 substituents selected from the group consisting of (a) C_1-8 alkyl, (b) halogen, and (c) -OR^b, and

(b) heteroaryl, optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci_-8 alkyl, (b) halogen, and (c) -OR^b,

(3) C_3-8 cycloalkyl,

(4) Ci_-8 alkoxy,

(5)

, wherein n is 0, 1, 2, or 3,

(6) aryl, optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci_-8 alkyl, (b) halogen, and (c) -OR^b, and

(7) heteroaryl, optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci_-8 alkyl, (b) halogen, and (c) -OR^b; C is selected from the group consisting of

(1) hydrogen,

(2) Ci_-8 alkyl,

(3) C_3-8 cycloalkyl,

(4) Ci_-8 alkoxy, (5) aryl, and

(6) heteroaryl;

W is selected from the group consisting of -CH₂- and -NH-;

X is selected from the group consisting of hydrogen, Ci_-8 alkyl, C_3-8 cycloalkyl, Ci_-8 alkoxy, halogen, -CN, -CF₃, and -OCF₃; Y is selected from the group consisting of hydrogen, Ci_-8 alkyl, C_3-8 cycloalkyl, Ci_-8 alkoxy, halogen, -CN, -CF₃, and -OCF₃; each occurrence of Rl and R2 is independently selected from the group consisting of:

(1) hydrogen,

(2) Ci_-8 alkyl, (3) C_3-8 cycloalkyl, and

(4) aryl, wherein each of the Ci-S alkyl, C3_8 cycloalkyl, and aryl is optionally substituted with 1 to 3 substituents selected from the group consisting of Ci_-8 alkyl, halogen, and -OR^a; or Rl or R2 taken together with the nitrogen they are attached to form an unsubstituted or substituted saturated or unsaturated 4-8 membered ring, wherein the 4-8 membered ring contains 1 nitrogen and 0 to 3 additional heteroatoms selected from the group consisting of O, S, and N; and each occurrence of R^a and R^b is independently selected from the group consisting of:

(1) hydrogen,

(2) Ci_-8 alkyl, (3) aryl, and

(4) heteroaryl, wherein each of the Ci_-8 alkyl, aryl, and heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of Ci_-8 alkyl, halogen, hydroxy, and Ci_-8 alkoxy. Unless indicated otherwise, the following definitions apply throughout the present specification and claims. These definitions apply regardless of whether a term is used by itself or in combination with other terms. For example, the definition of "alkyl" also applies to the "alkyl" portion of "alkoxy".

As used herein, the term "alkyl" means both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, Ci_-8 alkyl means branched- or straight-chain saturated aliphatic hydrocarbon groups having 1 to 8 carbon atoms. Non-limiting examples of suitable alkyl groups include methyl (Me), ethyl (Et), n-propyl (Pr), n-butyl (Bu), n-pentyl, n-hexyl, and the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu), secbutyl (s-Bu), tert-buty\ (t-Bu), isopentyl, and isohexyl.

The term "alkoxy" means an alkyl-O-group wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen.

The term "aryl" means an aromatic monocyclic or multicyclic ring system, wherein at least one ring is aromatic, comprising about 6 to about 14 carbon atoms, or more specifically, about 6 to about 10 carbon atoms, or even more specifically, about 6 to about 8 carbon atoms. Non-limiting examples of suitable aryl groups include phenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, anthracenyl, and fiuorenyl. The term "cycloalkyl" means a monocyclic saturated carbocyclic ring, having the specified number of carbon atoms, for example, 3, 4, 5, 6, 7 or 8 carbon atoms for C_3-S cycloalkyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "optionally substituted" means "unsubstituted or substituted," and therefore, the generic structural formulas described herein encompass compounds containing the specified optional substituent as well as compounds that do not contain the optional substituent. Each variable is independently defined each time it occurs within the generic structural formula definitions. The terms "halo" or "halogen" refer to fluoro, chloro, bromo and iodo unless otherwise noted. In one embodiment, the term "halogen" refers to fluoro or chloro.

The term "heteroaryl" means an aromatic monocyclic or multi cyclic ring system comprising 5 to 14 ring atoms, or more specifically, 5 to 10 ring atoms, or even more specifically, 5 to 6 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example, nitrogen, oxygen or sulfur, alone or in combination. Non-limiting examples of suitable heteroaryls contain 5 to 6 ring atoms. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[l,2-a]pyridinyl, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4- triazinyl, and benzothiazolyl.

In one embodiment of Formula I are compounds wherein A is selected from the group consisting of:

In another embodiment, A is selected from the group consisting of:

In yet another embodiment, A is . In one subset of this embodiment, X is selected from the group consisting of (a) hydrogen, (b) Ci-S alkyl, (c) C3_8 cycloalkyl, (d) Ci_-8 alkoxy, (e) halogen, (f) -CN, (g) -CF₃, and (h) -OCF₃. In another subset, X is selected from the group consisting of (a) hydrogen and (b) Ci-6 alkyl. In another subset, X is selected from the group consisting of (a) hydrogen and (b) Ci_-4 alkyl. In yet another subset, X is hydrogen. In another subset of this embodiment, Y is selected from the group consisting of

(a) hydrogen, (b) Ci_-8 alkyl, (c) C_3-8 cycloalkyl, (d) Ci_-8 alkoxy, (e) halogen, (f) -CN, (g) -CF₃, and (h) -OCF₃. In another subset, Y is selected from the group consisting of (a) hydrogen and

(b) Ci-6 alkyl. In another subset, Y is selected from the group consisting of (a) hydrogen and (b) C_1-4 alkyl. In yet another subset, Y is hydrogen. In another subset of this embodiment, each occurrence of R¹ and R² is independently selected from the group consisting of:

(1) hydrogen,

(2) Ci_-8 alkyl,

(3) C_3-8 cycloalkyl, and (4) aryl, wherein each of the Ci_-8 alkyl, C_3-8 cycloalkyl, and aryl is optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci_-8 alkyl, (b) halogen, and (c) -0R^a; or

Rl or R2 taken together with the nitrogen they are attached to form an unsubstituted or substituted saturated or unsaturated 4-8 membered ring, wherein the 4-8 membered ring contains 1 nitrogen and 0 to 3 additional heteroatoms selected from the group consisting of O, S and N.

In another subset of this embodiment, each occurrence of R¹ and R² is independently Ci_-6 alkyl. In another subset, each occurrence of R¹ and R² is independently Ci_-4 alkyl. In yet another subset, each occurrence of R¹ and R² is methyl or ethyl.

In another subset of this embodiment, R^a is selected from the group consisting of:

(1) hydrogen,

(2) Ci_-8 alkyl, (3) aryl, and

(4) heteroaryl, wherein each of the Ci_-8 alkyl, aryl, and heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci_-8 alkyl, (b) halogen, (c) hydroxy, and (d) Ci_-8 alkoxy. In another subset of this embodiment, R^a is selected from the group consisting of (a) hydrogen and (b) Ci_-6 alkyl. In another subset, R^a is selected from the group consisting of (a) hydrogen and (b) Ci_-4 alkyl. In yet another subset, R^a is hydrogen.

In one embodiment of Formula I are compounds wherein B is selected from the group consisting of: (1) hydrogen,

(a) aryl, optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci_-8 alkyl, (b) halogen, and (c) -OR^b, and (b) heteroaryl, optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci_-8 alkyl, (b) halogen, and (c) -OR^b,

(3) C_3-8 cycloalkyl,

(4)

(5)

, wherein n is 0, 1, 2, or 3, (6) aryl, optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci_-8 alkyl, (b) halogen, and (c) -OR^b, and

(7) heteroaryl, optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci_-8 alkyl, (b) halogen, and (c) -OR^b. In another embodiment, B is selected from the group consisting of:

(1) hydrogen,

(2) Ci_-6 alkyl, optionally substituted with 1 to 3 substituents selected from the group consisting of:

(a) aryl, optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci_-6 alkyl, (b) halogen, and (c) -OR^b, and

(b) heteroaryl, optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci_-6 alkyl, (b) halogen, and (c) -OR^b, O

— f H₂c-τ— c-R^b

(3) ^{v ; n} , wherein n is 0, 1, 2, or 3,

(4) aryl, optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci_-6 alkyl, (b) halogen, and (c) -OR^b, and

(5) heteroaryl, optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci_-6 alkyl, (b) halogen, and (c) -OR^b.

In another embodiment, B is selected from the group consisting of:

O c , . Il .

, i-f- H₂C-fr-C-R^b

(1) hydrogen; (2) Ci_-6 alkyl, optionally substituted with -OR^b, (3) ^{? n} , (4)

, (8) , (₉) , and (10)

^N ; wherein n is 0, 1, or 2, and wherein R is selected from the group consisting of: (a) hydrogen, (b) Ci_-6 alkyl, and (c) halogen. In one subset of this embodiment, n is 0 or 1. In another subset, R^b is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, chloro, and fiuoro. ^J , (7)

In one embodiment of Formula I are compounds wherein C is selected from the group consisting of:

(1) hydrogen,

(2) Ci_-8 alkyl, (3) C_3-8 cycloalkyl,

(4) Ci_-8 alkoxy,

(5) aryl, and

(6) heteroaryl.

In another embodiment, C is selected from the group consisting of (1) hydrogen and (2) Ci_-6 alkyl.

In yet another embodiment, C is selected from the group consisting of (1) hydrogen, (2) methyl, (3) ethyl, (4) n-propyl, and (5) n-butyl.

In still another embodiment, C is methyl or ethyl.

In one embodiment of Formula I are compounds wherein W is selected from the group consisting of -CH₂- and -NH-. In another embodiment, W is -CH₂-.

In one embodiment of Formula I are compounds wherein X is selected from the group consisting of:

(1) hydrogen,

(2) Ci_-8 alkyl, (3) C_3-8 cycloalkyl,

(4) Ci_-8 alkoxy,

(5) halogen,

(6) -CN, (7) -CF₃, and

(8) -OCF₃.

In another embodiment, X is selected from the group consisting of (1) hydrogen and (2) Ci_-6 alkyl. In yet another embodiment, X is hydrogen. In one embodiment of Formula I are compounds wherein Y is selected from the group consisting of:

(1) hydrogen,

(2) Ci_-8 alkyl,

(3) C_3-8 cycloalkyl, (4) Ci_-8 alkoxy,

(5) halogen, (6) -CN,

(7) -CF₃, and

(8) -OCF₃. In another embodiment, Y is selected from the group consisting of (1) hydrogen and (2) Ci_-6 alkyl. In yet another embodiment, Y is hydrogen.

In one embodiment of Formula I are compounds wherein each occurrence of Rl and R2 is independently selected from the group consisting of (1) hydrogen, (2) Ci_-8 alkyl, (3) C_3-8 cycloalkyl, and (4) aryl, wherein each of the Ci_-8 alkyl, C_3-8 cycloalkyl, and aryl is optionally substituted with 1 to 3 substituents selected from the group consisting of Ci_-8 alkyl, halogen, and -OR^a; or Rl or R2 taken together with the nitrogen they are attached to form an unsubstituted or substituted saturated or unsaturated 4-8 membered ring, wherein the 4-8 membered ring contains 0 to 3 heteroatoms selected from the group consisting of O, S and N.

In another embodiment, each occurrence of Rl and R2 is independently selected from the group consisting of (1) hydrogen, (2) Ci_-6 alkyl, and (3) C_3-6 cycloalkyl. In yet another embodiment, each occurrence of Rl and R2 is independently selected from the group consisting of (1) hydrogen and (2) Ci_-4 alkyl. In still another embodiment, each occurrence of Rl and R2 is independently methyl or ethyl.

In one embodiment of Formula I are compounds wherein each occurrence of R^a and R^b is independently selected from the group consisting of (1) hydrogen, (2) Ci_-8 alkyl, (3) halogen, (4) aryl, and (5) heteroaryl, wherein each of the Ci_-8 alkyl, aryl, and heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of Ci-S alkyl, halogen, hydroxy, and Ci_-8 alkoxy.

In another embodiment, each occurrence of R^a and R^b is independently selected from the group consisting of (1) hydrogen, (2) Ci_-6 alkyl, and (3) halogen. In yet another embodiment, each occurrence of R^a and R^b is independently selected from the group consisting of (1) hydrogen, (2) methyl, and (3) ethyl, (4) n-propyl, (5) chloro, and (6) fiuoro.

In one embodiment, R^a is hydrogen. In another embodiment, R^b is hydrogen, methyl, or fiuoro.

In one exemplary embodiment are compounds of Formula Ia:

wherein B is selected from the group consisting of (1) hydrogen, (2) Ci_-6 alkyl, optionally

selected from the group consisting of: (a) hydrogen, (b) Ci_-6 alkyl, and (c) halogen. In one subset of this embodiment, C is selected from the group consisting of hydrogen and Ci_-6 alkyl. In another subset, C is methyl or ethyl. In another subset of this embodiment, each occurrence of Rl and R2 is independently selected from the group consisting of (1) methyl, (2) ethyl, (3) n-propyl, and (4) n-butyl. In yet another subset of this embodiment, each occurrence of R^a and R^b is independently selected from the group consisting of (1) hydrogen, (2) Ci_-6 alkyl, and (3) halogen.

In another exemplary embodiment are compounds of Formula Ia, wherein B

group consisting of: (1) hydrogen, (2) methyl, (3) ethyl, and (4) n-propyl.

Optical Isomers - Diastereomers - Geometric Isomers - Tautomers

Compounds described herein may contain an asymmetric center and may thus exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centers, they may additionally exist as diastereomers. When bonds to the chiral carbon are depicted as straight lines in the formulas of the invention, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formulas. The present invention includes all such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers. The above Formula I is shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of Formula I and pharmaceutically acceptable salts thereof.

Diastereoisomeric pairs of enantiomers may be separated by, for example, fractional crystallization from a suitable solvent, and the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid or base as a resolving agent or on a chiral F£PLC column. Further, any enantiomer or diastereomer of a compound of the general Formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.

When compounds described herein contain olefinic double bonds, unless specified otherwise, such double bonds are meant to include both E and Z geometric isomers. Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. For example, compounds including carbonyl -CH2C(O)- groups (keto forms) may undergo tautomerism to form hydroxyl -

CH=C(OH)- groups (enol forms). Both keto and enol forms, individually as well as mixtures thereof, are included within the scope of the present invention. Salts

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts prepared from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines derived from both naturally occurring and synthetic sources. Pharmaceutically acceptable organic non-toxic bases from which salts can be formed include, for example, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, dicyclohexylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

Solvates

The present invention includes within its scope solvates of compounds of Formulas I. As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (i.e., a compound of Formula I) or a pharmaceutically acceptable salt thereof and a solvent that does not interfere with the biological activity of the solute. Examples of solvents include, but are not limited to water, ethanol, and acetic acid. When the solvent is water, the solvate is known as hydrate; hydrates include, but are not limited to, hemi-, mono, sesqui-, di- and trihydrates.

Prodrugs The present invention includes within its scope the prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various conditions described with a compound of formula I or with a compound which may not be a compound of formula I, but which converts to a compound of formula I in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985.

Utilities

Compounds of the present invention are potent antagonists of the CXCR2 receptors, and as such are useful in treating or preventing diseases, disorders or conditions mediated by the activation of CXCR2 receptors. Thus one aspect of the present invention provides a method for the treatment, control or prevention of such diseases, disorders, or conditions in a mammal which comprises administering to such mammal a therapeutically effective amount of a compound of Formula I. The term "mammal" includes human and non- human animals such as dogs and cats and the like.

The diseases, disorders or conditions for which compounds of the present invention are useful in treating or preventing include, but are not limited to, (1) asthma, (2) COPD, (3) autoimmune disease, (4) allergic rhinitis, (5) psoriasis, (6) rheumatoid arthritis, (7) cardiovascular disease, and (8) cancer.

Any suitable route of administration may be employed for providing a mammal, especially a human with an effective dosage of a compound of the present invention. For example, oral, topical, parenteral, ocular, pulmonary, and nasal may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. In one embodiment, compounds of Formula I are administered orally. The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art. When treating asthma, COPD, autoimmune disease, allergic rhinitis, psoriasis, or rheumatoid arthritis using compounds of Formula (I) alone, or in conjunction with other anti-inflammatory agents, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.01 mg to about 1000 mg, or more specifically, from about 0.01 mg to about 500 mg, or even more specifically, from about 0.01 mg to about 250 mg, according to the particular application. This dosage regimen may be adjusted to provide the optimal therapeutic response.

Another aspect of the present invention provides pharmaceutical compositions which comprises a compound of Formula I and a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention comprise a compound of Formula I or a pharmaceutically acceptable salt thereof as an active ingredient, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.

The compositions include compositions suitable for oral, intravesical, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.

In practical use, the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.01 percent of active compound. The percentage of active compound in these compositions may be varied and may conveniently be between about 0.01 percent to about 30 percent, or more specifically, about 0.05 to about 20 percent, or even more specifically, about 0.1 to about 10 percent, of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally as, for example, liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.

Compounds of Formula I may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. A compound of Formula I may be used in combination with a second active agent that is useful for the treatment of chemokines mediated diseases. Suitable second active agents include, but are not limited to, an antirheumatic agent, a nonsteroidal anti-inflammatory agent, a COX-2 selective inhibitor, a COX-I inhibitor, an immunosuppressive agent, a steroid, and a biological response modifier.

The second active agent may be administered contemporaneously or sequentially with a compound of Formula I. When a compound of Formula I is used contemporaneously with the second active agent, a pharmaceutical unit dosage form may contain the second active agent in addition to a compound of Formula I. Accordingly, pharmaceutical compositions of the present invention include those that also contain one or more of the second active agents, in addition to a compound of Formula I. The compounds of Formula I of the present invention can be prepared according to the procedures of the following Schemes and Examples using appropriate materials, and are further exemplified by the following specific examples. Moreover, by utilizing the procedures described herein, one of ordinary skill in the art can readily prepare additional compounds of the present invention claimed herein. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The Examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. The instant compounds are generally isolated in the form of their pharmaceutically acceptable salts, such as those described previously hereinabove. The free amine bases corresponding to the isolated salts can be generated by neutralization with a suitable base, such as aqueous sodium hydrogen carbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide, and extraction of the liberated amine free base into an organic solvent followed by evaporation. The amine free base isolated in this manner can be further converted into another pharmaceutically acceptable salt by dissolution in an organic solvent followed by addition of the appropriate acid and subsequent evaporation, precipitation, or crystallization. All temperatures are degrees Celsius unless otherwise noted. Mass spectra (MS) were measured by electron-spray ion-mass spectroscopy.

A variety of chromatographic techniques may be employed in the preparation of the compounds. These techniques include, but are not limited to: High Performance Liquid Chromatography (HPLC) including normal phase, reversed phase, and chiral phase HPLC; Medium Pressure Liquid Chromatography (MPLC), Super Critical Fluid Chromatography; preparative Thin Layer Chromatography (prep TLC); flash chromatography with silica gel or reversed-phase silica gel; ion-exchange chromatography; and radial chromatography. All temperatures are degrees Celsius unless otherwise noted. Throughout the application, the following terms have the indicated meanings unless otherwise noted:

Term Meaning

Ac Acyl (CH₃C(O)-)

Aq. Aqueous BBHH33--TTHHFF Borane-Tetrahydrofuran complex

Bn Benzyl

BOC 7ert-Butoxycarbonyl

BuOH n-Butanol

⁰C Degree Celsius

CaIc. or calc'd Calculated

Cbz Benzyloxycarbonyl

DBU 1 ,5 -dizzabicyclo [5.4.0]undecen-5 -ene

DCM Dichloromethane

DIAD Diisopropylazodicarboxylate

DIEA N,N-Diisopropylethylamine

DMF ΛζΛT-dimethylformamide

DMSO Dimethyl sulfoxide

EDAC (or EDC) 1 -Ethyl-3 -[3 -(dimethylamino)propyl]-carbodiimide

HCl EEqq.. oorr eeqquuiivv.. Equivalent(s)

Et3N Triethylamine Et Ethyl EtOAc Ethyl acetate

EtOH Ethanol g Gram(s) h or hr Hour(s)

HCl Hydrochloric acid

HOBt 1 -Hydroxybenzotriazole

HPLC High performance liquid chromatography

KOt-Bu Potassium tert-butoxide

L Liter

LC/MS Liquid chromatography mass spectrum

LG Leaving group

M Molar

Me Methyl

MeOH Methanol min Minute(s) mg Milligram(s) mL Milliliters) mmol Millimole(s)

Ms Methanesulfonyl

MsCl Methanesulfonyl chloride

N Normal

NaHMDS Sodium hexamethyldisiliazide

NaOAc Sodium acetate

NaOtBu Sodium tert-butoxide

NMO N-methylmorpholine N oxide

Obs. Observed

PE Petroleum ether

PhNEt₂ N,N-diethylaniline

PG Protecting group

Pd(dba)2 Bis(dibenzylideneacetone) palladium

Ph Phenyl

PhMe Toluene PPh3 Tπphenylphosphine

PMB Para-methoxyb enzyl

RT Room temperature

TBAF Tetrabutyl ammonium fluoride

TBS (or TBDMS) 7ert-butyldimethylsilyl tBu Tert-buty\

Tf Triflate

TFA Trifluoroacetic acid

THF Tetrahydrofuran

TLC Thin-layer chromatography

Ts 4-toluenesulfonyl

Reaction Schemes below illustrate the methods used in the synthesis of the compounds of Formula I. All substituents are as defined above unless indicated otherwise. The synthesis of the novel compounds of Formula I may be accomplished by one or more of several similar routes, as illustrated in more detail below.

GENERAL SCHEMES

In Scheme I, 3-(2-ethoxy-3,4-dioxocyclobut-l-enylamino)-2-hydroxy-N,N- dimethy benzamide (1-1) is commercially available or may be prepared from readily available 3,4-diethoxy-3-cyclobutene-l,2-dione(diethyl squarate) and the corresponding 3-amino-2- hydroxy-N,N-dimethylbenzamide via a substitution reaction, for example using the method as published by Dwyer et al., J. Med. Chem. 49, 7603-7606 (2006).

Using 1-1 as starting material, free hydrazine (1-2) as well as alkylated (1-4) and acylated hydrazines can be prepared under various reaction conditions as shown in Schemes 1, 2 and 3.

In Scheme 1, free hydrazine 1-2 was converted to the mono-alky lated 1-4 via a reductive amination reaction. The mono -alkylated 1-4 can be further N-alkylated (wherein R^b is an alkyl) or acylated (wherein R^b is an acyl) to give 1-5 under reaction conditions with or without a base, using a solvent that can dissolve the reactants and at a temperature between - 7O⁰C to 12O⁰C. The base can be either an inorganic or an organic base. When R^b is an alkyl, X can be Cl, Br, I, Ms, or Tosy, and the base can be an inorganic base such as K2CO3, NaCθ3, NaH, and NaOH, or an organic base such as Et₃N, DBU₅ PhNEt₂, NaOEt, and KOt-Bu. The reaction temperature can be -70⁰C to 120⁰C and suitable solvents can be EtOH, MeOH, BuOH, t-BuOH, DMSO, DMF, DCM, THE, and dioxane. When R^b is an acyl, X can be Cl, Br and F, and the base can be organic amines and pyridines such as Et₃N, DBU, PhNEt₂, and pyridine. Suitable solvents can be non-proton solvents such as DMSO, DMF, DCM, THF, dioxane, and ether.

Scheme 1

1-1 1-2

1-3

1-4 1-5

In Scheme 2, hydrazine H-I can react with 1-1 under conditions with or without a base, using a solvent that can dissolve the reactants and at a temperature between -2O⁰C to 12O⁰C. The base can be either an inorganic base such as K₂CO₃, Na₂CO₃, NaH or NaOH, or an organic base such as Et₃N, DBU, PhNEt₂, NaOEt or KOt-Bu. R can be an alkyl or aryl and R^b can be an alkyl or acyl. Suitable solvents can be EtOH, MeOH, BuOH, t-BuOH, DMSO, DMF, DCM, THF or dioxane.

Scheme 2

with or without a base

H-1

1-1 I-5

In Scheme 3, the protected (for example, Boc- or Cbz-protected) alkyl hydrazine H-2 can react with 1-1 to give 1-6 under conditions with or without a base, using a solvent that can dissolve the reactants and at a temperature between -2O⁰C to 12O⁰C. The base can be either an inorganic base or an organic base. Suitable inorganic bases include, but are not limited to, K₂CO₃, Na₂CO₃, NaH and NaO. Suitable organic bases include, but are not limited to, Et₃N, DBU, PhNEt₂, NaOEt and KOt-Bu. Suitable solvents include, but are not limited to, EtOH, MeOH, BuOH, t-BuOH, DMSO, DMF, DCM, THF or dioxane.

Then, de-protection of 1-6 followed by alkylation, acylation or sulfonylation of 1-7 can give 1-8 using well known methods. For example, when PG of 1-6 is Boc, it can be removed using, for example, HCl in Et₂O or EtOAc or 2 equivalents TFA in CH₂Cl₂, to give I- 7. When PG of 1-6 is Cbz, it can be removed by hydrogenation using palladium catalysts such as Pd/C or Pd(OH)₂/C in alcohol to give 1-7. 1-7 can be converted to 1-8 under similar conditions as those for the conversion from 1-4 to 1-7 in Scheme 1. R can be alkyl or aryl, R^b can be alkyl or acyl, and R^c can be alkyl or aryl. Suitable aryls include, but are not limited to, aromatic heterocycles.

PG protection group, such as Boc or Cbz

In some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided so that the invention can be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.

Using reaction schemes described above and general knowledge known in the art of organic synthesis, compounds in the following examples were prepared. Unless noted otherwise, the analytical data for these compounds were obtained under the following conditions. All melting points are uncorrected. ¹H and ¹³C NMR spectra were recorded on Bruker DRX 400 (9.4 T, 400.13 MHz) and Varian 300 MHz instruments, respectively, using CDCI3, CD₃COD or DMSO as solvent. Chemical shift δ is given in ppm. Electron spray low resolution Mass spectra (MS) were determined at an ionizing voltage of 7OeV.

EXAMPLE 1

Preparation of 3-r2-r2-ethylhvdrazinylV3.4-dioxocvclobut-l -enylaminoV2-hvdroxy-N.N- dimethyl benzamide

2-Hydroxy-3-nitrobenzoic acid (25 g, 137 mmol), Me₂NHHCl (12.2 g, 150 mmol), HOBt (18.5 g, 137 mmol), EDC (39.3 g, 206 mmol) and DIEA (50.5 mL, 274 mmol) were mixed with CH₂Cl₂ (500 mL) and stirred overnight. The mixture was washed with water, HCl (1 M), brine, dried over Na₂Sθ4 and concentrated in vacuo to give 2-hydroxy-N,N- dimethyl-3-nitrobenzamide (5 g, yield about 20 %).

3-Amino-2-hydroxy-N.N-dimethylbenzamide

2-Hydroxy-N,N-dimethyl-3-nitrobenzamide (6.0 g, 33.3 mmol) was dissolved in methanol (20 mL), to which Raney-Ni (1 g) was added. The reaction mixture was de-gassed and then charged with H₂ and stirred overnight. The solution was filtrated and concentrated in vacuo to give 3-amino-2-hydroxy-N,N-dimethylbenzamide (4 g, yield about 89%). ¹HNMR DMSO (400MHz) δ: 6.57 ~ 6.65 (m, 2H), 6.33 ~ 6.36 (m, IH), 2.88 (s, 6H).

Step 3 : 3 -(2-Ethoxy-3 Λ-dioxocyclobut- 1 -enylamino V2-hydroxy-N.N- dimethylbenzamide

3-Amino-2-hydroxy-N,N-dimethylbenzamide (4.2 g, 23 mmol) and 3,4- diethoxycyclobut-3-ene-l,2-dione (4.0 g, 23 mmol) were dissolved in ethanol (40 mL), and stirred overnight. The reaction product was collected with filtration to give 3-(2-ethoxy-3,4- dioxocyclobut-1 -enylamino)-2 -hydroxy -N,N-dimethylbenzamide (4.1 g, yield about 59%).

Step 4: 3-(2-Hydrazinyl-3.4-dioxocyclobut-l-enylamino)-2-hydroxy-N.N-dimethyl benzamide

3-(2-Ethoxy-3,4-dioxo-cyclobut-l -enylamino)-2-hydroxy-N,N-dimethyl- benzamide (1.0 g, 3.3 mmol) was mixed with ethanol, to which N2H4.H2O (329 mg, 6.6 mmol) was added. After stirring overnight, the solid was collected with filtration and washed with EtOH to give 3-(2-hydrazinyl-3,4-dioxo-cyclobut-l-enylamino)-2-hydroxy-N,N-dimethyl- benzamide (900 mg, yield about 94 %). 1HNMR DMSO (400MHz) δ: 8.00 (s, IH), 6.72 ~ 6.74 (m, 2H), 5.21 (brs, 2H).

Low resolution mass spectrum (LRMS) calc: 290.3 obs: 291.4 (M+l).

Step 5 : 3-(2-(2-Ethylidenehydrazinyl)-3.4-dioxocyclobut-l-enylamino)-2-hydroxy-

N.N-dimethvlbenzamide

As used herein, the wavy bond " -~>~- " represents the cis-isomer, the trans-isomer, or a mixture of the cis-isomer and the trans- isomer.

3-(2-Hydrazinyl-3,4-dioxocyclobut-l-enylamino)-2-hydroxy-N,N- dimethylbenzamide (900 mg, 3.1 mmol), acetaldehyde (409 mg, 9.3 mmol) and methanol (10 mL) were mixed and stirred overnight. The solution was concentrated in vacuo to give compound 3-(2-(2-ethylidenehydrazinyl)-3,4-dioxocyclobut-l-enylamino)-2-hydroxy-N,N- dimethylbenzamide (960 mg, yield about 98 %).

¹HNMR DMSO (400MHz) δ: 12.27 (brs, IH), 10.05 (s, IH), 9.22 (s, IH), 7.96 ~ 7.97 (m, IH), 7.48 ~ 7.51 (m, IH), 6.87 ~ 6.91 (m, IH), 6.81 ~ 6.83 (m, IH), 2.98 (s, 6H), 1.96 (d, 3 H, J = 5.6 Hz). LRMS calc: 316.3 obs: 317.5 (M+l).

Step 6: 3-(2-(2-EthylhydrazinylV3.4-dioxocyclobut-l-enylaminoV2-hydroxy-N.N- dimethyl benzamide

As used herein, the wavy bond " "^ " represents the cis-isomer, the trans-isomer, or a mixture of the cis-isomer and the trans- isomer.

3-(2-(2-Ethylidenehydrazinyl)-3,4-dioxocyclobut-l-enylamino)-2-hydroxy- N,N-dimethylbenzamide (100 mg, 0.32 mmol) was dissolved in BH₃-THF solution (1 M₁ I mL), which was stirred overnight. The solution was diluted with methanol to quench the reaction. The reaction mixture was subjected to preparative HPLC separation to give 3-(2-(2- ethylhydrazinyl)-3,4-dioxocyclobut-l-enylamino)- 2-hydroxy-N,N-dimethylbenzamide (3 mg). 1HNMR CD3COD (400MHz) δ: 8.17 ~ 8.19 (m, IH), 6.93 ~ 6.95 (m, 2H), 3.07 (s, 6H), 2.98 (q, 2H, J = 6.8 Hz), 1.19 (t, 3H, J = 6.8 Hz). LRMS calc: 318.3 obs: 319.3 (M+l).

EXAMPLE 2

Preparation of 3-(2-(2-ethyl-2-(4-fluorobenzyl)hydrazinylV3.4-dioxocyclobut-l -enylaminoV2- hvdroxy-N.N-dimethylbenzamide

3-(2-(2-Ethylhydrazinyl)-3,4-dioxocyclobut-l-enylamino)-2-hydroxy-N,N- dimethylbenzamide (100 mg, 0.31 mmol), K2CO3 (86 mg, 0.62 mmol) and 1 -Bromomethyl-4- fluoro-benzene (59 mg, 0.31 mmol) were mixed with 5 mL of dry DMF, and the mixture was stirred for 16 hours at room temperature. Then the reaction mixture was concentrated in vacuo, the crude product was purified with preparative HPLC to give 3-(2-(2-ethyl-2-(4- fluorobenzyl)hydrazinyl)-3 ,4-dioxocyclobut- 1 -enylamino)-2 -hydroxy -N,N-dimethylbenzamide (40 mg, yield about 30%).

¹HNMR CD3COD (400MHz) δ: 8.13 (d, IH, 7.8 Hz), 7.32 ~ 7.50 (m, 3H), 7.23 (t, IH, J = 8.0 Hz), 7.00 ~ 7.16 (m, 3H), 4.98 (s, 2H), 3.19 (s, 3H), 2.95 (s, 3H), 1.73 (d, 3H, J = 5.4 Hz). LRMS calc: 426.4 obs: 427.3 (M+l).

EXAMPLE 3

Preparation of 3-(2-(2-ethyl-2-(4-fluorobenzoyl)hydrazinyl)-3.4-dioxocyclobut-l -enylamino)-

2-hydroxy-N.N-dimethylbenzamide

N'-Ethyl-N'-(4-fluoro-benzoylVhvdrazinecarboxylic acid tert-butyl ester

N'-Ethyl-hydrazinecarboxylic acid tert-butyl ester (500 mg, 3.13 mmol) was dissolved in anhydrous CH₂Cl₂ (20 mL), then 4-fluoro-benzoyl chloride (500 mg 3.16 mmol) was added. Anhydrous pyridine (0.74 g, 93.7 mmol) was added at 0 ⁰C. After 30 minutes, the reaction mixture was warmed to room temperature and stirred for 4 hours successively. Then the mixture was extracted with ethyl acetate. The combined organic phases were dried over Na₂SO₄, then filtrated. The filtrate was concentrated to give N'-Ethyl-N'-(4-fiuoro-benzoyl)- hydrazinecarboxylic acid tert-butyl ester (1 g).

N-ethyl-4-fluorobenzohydrazide

N'-Ethyl-N'-(4-fiuoro-benzoyl)-hydrazinecarboxylic acid tert-butyl ester (200 mg, 0.8 mmol) was dissolved in Et₂OZHCl (5 mL, 2N), and stirred at room temperature. After 1 hour 10 mL of NaHCOs (sat.) was added to adjust pH to 10. The mixture was extracted with EtOAc (50 mL x 2). The combined organic phases were dried over Na₂SO₄, and concentrated to give compound 4-fiuoro-benzoic acid N-ethyl-hydrazide (120 mg).

¹HNMR CDC13 (400MHz) δ: 7.55 (brs, 2H), 7.03 ~ 7.18 (m, 2H), 3.61 (brs, 2H), 1.23 (t, 3H, J = 6.9 Hz). LRMS calc: 182.2 obs: 183.3 (MH-I).

Step 3 : 3-(2-(2-Ethyl-2-(4-fluorobenzoyl)hydrazinyl)-3.4-dioxocyclobut-l-enylamino)-

2-hydroxy-N.N- dimethylbenzamide

3-(2-Ethoxy-3,4-dioxo-cyclobut-l-enylamino)-2-hydroxy-N,N-dimethyl- benzamide (237 mg, 0.78 mmol), K₂CO₃ (215 mg, 1.56 mmol) and N-ethyl-4- fluorobenzohydrazide (120 mg, 0.78 mmol) were added in 5 mL of EtOH, the reaction mixture was stirred for 16 hours at room temperature. Then the reaction mixture was concentrated in vacuo. The crude product was purified with preparative HPLC to give 3-(2-(2-ethyl-2-(4- fluorobenzoyl)hydrazinyl)-3,4-dioxocyclobut-l-enylamino)-2-hydroxy-N,N- dimethylbenzamide (40 mg).

¹HNMR CD3COD (400MHz) δ: 7.70-7.52 (m, 3H), 7.28-7.15 (m, 2H), 7.05 (d, IH, 7.6 Hz), 6.94 (t, IH, 7.8 Hz), 3.86-3.70 (m, 2H), 3.07 (s, 6 H), 1.30 (t, 3H, 7.0 Hz). LRMS calc: 440.4 obs: 441.1 (M+l). EXAMPLE 4 Preparation of 3-(2-(2-ethyl-2-(4-methoxyphenyl)hvdrazinylV3.4- dioxocvclobut-1- enylaminoV2-hvdroxy-N.N-dimethylbenzamide

N-Ethyl-N-(4-methoxy-phenylVamine

After two vacuum and charging with H₂ cycles to remove air from the reaction flask, the stirred mixture of 4-methoxy-phenylamine (10 g, 81.3 mmol), 10% Pd/C (1 g) and

CH₃CN (6.2 g, 162.6 mmol) in 81 mL of MeOH was hydrogenated at 1 atmospheric pressure and room temperature for 16 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The crude product was purified with column chromatography (silica gel, 12:1 petroleum etheπEtOAc) to give N-Ethyl-N-(4-methoxy- phenyl)-amine (5.1 g). MS : 151.10

N-ethyl-N-f4-methoxyphenvD nitrous amide

A mixture of N-ethyl-N-(4-methoxy-phenyl)-amine (5 g, 30.12 mmol), 48 mL HCl (con.), and 13 g ice was placed in 50 mL three-necked flask, to which a solution OfNaNO₂

(2.08 g, 30.12 mmol) in 8.3 mL H₂O was added during the course of 10 minutes below 5 ⁰C.

After 1 hour the mixture was extracted with EtOAc (200 mL x 2). The combined organic phases were dried over Na₂SO₄, then filtrated, the filtrate was concentrated to give N-ethyl-N- (4-methoxyphenyl) nitrous amide (4.8 g), which was used directly without further purification in the next step.

Step 3 : N-Ethyl-N-(4-methoxy-phenylVhydrazine

A mixture of Zn (18 g, 277 mmol) and water (30 mL) was placed in 250 mL flask, the suspension was then stirred vigorously while a solution of N-ethyl-N-(4- methoxyphenyl)nitrous amide (4.8 g, 26.7 mmol) in 20 mL AcOH was added in a slow stream. The temperature was maintained between 10 ⁰C and 20 ⁰C. When all the amide solution had been added the mixture was stirred for an hour at room temperature and then warmed to 80 ⁰C. The hot solution was filtered from the unreacted Zn, which was washed with 5% HCl. The combined filtrate was treated with 40% NaOH solution to bring PH to 12. The mixture was extracted with EtOAc (200 mL x 2). The combined organic phases were dried over Na₂SO₄, then filtrated, the filtrate was concentrated to give N-ethyl-N-(4-methoxy-phenyl)-hydrazine (2 g).

¹HNMR (DMSO-dβ) (400MHz) δ: δl 1.10 (brs, 2H), 7.48 (d, 4H, J = 8.7 Hz), 7.05 (d, 4H, J = 8.7 Hz),3.23 (q, 2H, J = 7.2 Hz), 1.20 (t, 3H, J = 7.2 Hz). LRMS calc: 166.2 obs: 163.1 (M+l).

3-(2-(2-Ethyl-2-(4-methoxyphenyl)hydrazinyl)-3.4-dioxocyclobut-l- enylaminoV2-hydroxy-N.N-dimethylbenzamide

1 -Ethyl- l-(4-methoxyphenyl)hydrazine (55 mg, 0.33 mmol) and 3-(2-ethoxy-

3,4-dioxocyclobut- l-enylamino)-2-hydroxy-N,N-dimethylbenzamide (100 mg, 0.33 mmol) were added in 5 mL of EtOH, the reaction mixture was stirred for 16 hours at room temperature. Then the reaction mixture was concentrated in vacuo, the crude product was purified with preparative HPLC to give 40 mg (yield about 29%) of 3-(2-(2-ethyl-2-(4- methoxyphenyl)hydrazinyl)-3,4-dioxocyclobut-l-enylamino)-2-hydroxy- N,N-dimethyl benzamide.

¹HNMR CD3COD (300MHz) δ: 8.20-8.29 (m, IH), 7.23 (s, IH), 7.20 (s, IH), 7.00-6.85 (m, 4H), 3.76 (s, 3H), 3.50-3.35 (m, 2H), 3.05 (s, 6H), 1.26 (t, 7.2 Hz, 3H). LRMS calc:424.4 obs: 425.1 (M+l).

EXAMPLE 5

Preparation of 3-(2-(2-ethyl-2-(pyridin-2-yl)hydrazinyl)-3.4-dioxocyclobut-l-enylamino)-2- hydroxy-N.N- dimethylbenzamide

Preparation of N-ethyl-N-pyridin-2-yl -hydrazine

2-Fluoro-pyridine (50 mg, 0.5 mmol), ethyl-hydrazine (65 mg, 0.5 mmol) and DIEA (276 μL, 1.5 mmol) were dissolved in anhydrous dioxane (0.5 mL), then heated to 150 ⁰C with microwave for 30 min. The solution was diluted with water, and extracted with ethyl acetate. The organic phase was dried over Na₂SO₄ and concentrated in vacuo to give crude N- ethyl-N-pyridin-2-yl-hydrazine (30 mg), which was used in the next step without any further purification.

Step 2: 3-(2-(2-Ethyl-2-(pyridin-2-yl)hydrazinyl)-3.4-dioxocyclobut-l-enylamino)-2- hydroxy-N.N- dimethylbenzamide

2-(l-Ethylhydrazinyl)pyridine (138 mg, 0.66 mmol), 3-(2-ethoxy-3,4- dioxocyclobut-l-enylamino)-2- hydroxy-N,N-dimethyl benzamide (100 mg, 0.33 mmol), K₂CO₃ (91 mg, 0.66 mmol) and EtOH (1 mL) were mixed, and heated to 40 ⁰C for 16 hours. After filtration, the crude product was purified with preparative HPLC to give 3-(2-(2-ethyl-2- (pyridin-2-yl)hydrazinyl)-3 ,4-dioxocyclobut- 1 -enylamino)-2-hydroxy-N,N-dimethylbenzamide (8.4 mg, yield about 6.5%).

¹HNMR CD₃OD (400MHz) δ: 8.08 ~ 8.11 (m, 2H), 7.73 (s, IH), 7.36-7.83 (m, IH), 7.14 ~ 5.15 (m, IH), 7.04 ~ 7.06 (m, IH), 6.92 ~ 6.94 (m, IH), 3.90 (q, J = 6.9 Hz, 2H), 3.06 (s, 6H), 1.36 (t, J = 6.9 Hz, 3H). LRMS calc: 395.4 obs: 396.3 (M+l).

EXAMPLE 6

Preparation of 3 -(2-(2.2-diethylhydrazinyl)-3.4-dioxocyclobut-l-enylamino)-2 -hydroxy- N.N- dimethyl benzamide

BocHNNH₂

Step 1 : Tert-buty\ 2.2-diethylhydrazinecarboxylate

Q^LJ C H O

BOCHN NH₂ ³- ► BocHN N: )

NaBH₃CN J

Tert-buty\ hydrazinecarboxylate (1 g, 7.6 mmol) and acetaldehyde (100 mg, 2.28 mmol) were dissolved in DCM (20 mL). Acetic acid (0.05mL) and NaBCNH3 (471 mg, 7.6 mmol) were added to the reaction mixture. After stirring overnight, the mixture was washed with water (50 mL x 3). The organic layer was concentrated in vacuo, then the residue was subjected to silica gel column chromatography to give tert-buty\ 2,2- diethylhydrazinecarboxylate (0.87 g, yield about 61% ).

LRMS calc: 188.2 obs: 189.2 (M+l)

Tert-buty\ 2,2-diethylhydrazinecarboxylate (1.1 g) was dissolved in 30 mL of HCl/MeOH (4M). After 1 hour, the mixture was concentrated in vacuo to givel,l- diethylhydrazine hydrochloride (0.9 g).

LRMS calc: 88.10 obs: 89.15 (M+l)

3 -(2-(2.2-DiethylhydrazinylV3.4-dioxocyclobut-l-enylaminoV2 -hydroxy- N.N- dimethyl benzamide

1,1-Diethylhydrazine hydrochloride (100 mg, 0.8 mmol), 3-(2-ethoxy-3,4- dioxocyclobut-l-enylamino)-2 -hydroxy -N,N-dimethylbenzamide (243 mg, 0.8 mmol), and K2CO3 (215 mg, 1.56 mmol) were added in 5 mL of EtOH, the reaction mixture was stirred for 16 hours at room temperature. Then the reaction mixture was concentrated in vacuo. The crude product was purified with preparative HPLC to give 3-(2-(2,2-diethylhydrazinyl)-3,4- dioxocyclobut- 1 -enylamino)-2 -hydroxy -N,N-dimethylbenzamide(34 mg). 1H NMR (DMSO-dg) (300MHz) δ: 7.67 ~ 7.62 (m, IH), 6.85 ~ 6.91 (m, 2H),

2.92 (s, 6H), 2.58(m,4H), 1.01 (m, 6H). LRMS calc: 346.4 obs: 347.5. (M+l).

EXAMPLE 7

Preparation of 3-r2-r2-acetyl-2-ethylhvdrazinylV3.4-dioxocvclobut-l -enylaminoV2-hvdroxy- N.N- dimethyl benzamide

Tert-butyl 2-acetyl-2-ethylhvdrazinecarboxylate

Tert-butyl 2-ethylhydrazinecarboxylate (1.0 g, 6.3 mmol) was mixed with CH₂Cl₂ and pyridine (1.4 g, 19 mmol), to which AcCl (1.4 g, 19 mmol) was added at 0 ^°C. After stirring overnight, the solution was washed with HCl (aq.) (IM) (10 mL x 2). The solution was dried over Na₂SO₄, evaporated in vacuo to give tert-buty\ 2-acetyl-2- ethylhydrazinecarboxylate (400 mg, yield 31%), which was used directly without further purification.

Step 2: N-ethylacetohydrazide hydrochloride

Tert-buty\ 2-acetyl-2-ethylhydrazinecarboxylate (400 mg, 2.0 mmol) was dissolved in 20 mL of HClZEt₂O (2M) solution and stirred for one hour. The solution was concentrated in vacuo to give N-ethylacetohydrazide hydrochloride (200 mg, yield 98%).

¹H NMR CD₃OD (300MHz) δ: 3.78 (q, J = 6.9 Hz, 2H), 2.22 (s, 3H), 1.30 (t, J = 6.9 Hz, 3H).

Step 3 : 3-(2-(2-acetyl-2-ethylhydrazinylV3.4-dioxocyclobut-l-enylaminoV2-hydroxy- N.N- dimethyl benzamide

N-ethylacetohydrazide hydrochloride (200 mg, 1.46 mmol), 3-(2-ethoxy-3,4- dioxocyclobut-l-enylamino)-2 -hydroxy -N,N-dimethylbenzamide (440 mg, 1.46 mmol), and DIEA (540 μL, 2.91 mmol) were mixed and heated to 30 ^°C for 48 hours. The reaction mixture was directly purified with preparative HPLC to give 3-(2-(2-acetyl-2-ethylhydrazinyl)-3,4- dioxocyclobut-1- enylamino)-2-hydroxy -N,N- dimethyl benzamide (45 mg, yield 8.6%).

¹H NMR (DMSO-dg) (300MHz) δ: 7.66 ~ 7.69 (m, IH), 6.99 ~ 6.89 (m, 2H), 3.10(m, 2H) 2.92 (s, 6H), 1.99 (s, 2H), 1.03 - 1.11 (m, 3H). m/z: 361.1 (M+l).

EXAMPLE 8

Preparation of 3-(2-(2-ethyl-2-phenylhydrazinyl)-3.4-dioxocyclobut-l-enylamino)-2-hydroxy- N.N- dimethylbenzamide

A mixture of N-ethylaniline (3.65 g, 30.12 mmol), 48 mL HCl (con.), and 12 g ice was placed in 50 mL three-necked flask, to which a solution Of NaNO₂ (2.1 g, 30.4 mmol) in 8.3 mL H₂O was added during the course of 10 minutes below 5 ⁰C. After 1 hour, the mixture was extracted with EtOAc (200 mL x 2). The combined organic phases were dried over Na₂SO₄, then filtrated, the filtrate was concentrated to give N-ethyl-N-phenylnitrous amide (4.06 g, yield about 90%), which was used directly in the next step without further purification.

1 -Ethyl- 1 -phenylhydrazine

A mixture of Zn (18 g, 277 mmol) and water (30 mL) was placed in 250 mL flask, the suspension was then stirred vigorously while a solution of N-ethyl-N-phenylnitrous amide (4.06 g, 27 mmol) in 21 mL AcOH was added in a slow stream. The temperature was maintained between 10 ⁰C and 20 ⁰C. When all the amide solution had been added the mixture was stirred for one hour at room temperature and then warmed to 80 ⁰C. The hot solution was filtered from the un-reacted Zn, Which was washed with 5% HCl. The combined filtrate was treated with 40% NaOH solution to bring PH to 12. The mixture was extracted with EtOAc (180 mL x 2). The combined organic phases were dried over Na₂SO₄, then filtrated, the filtrate was concentrated to give 1 -ethyl- 1 -phenylhydrazine (1.47 g, yield 40.1 %).

¹H NMR (DMSO-dg) (300MHz) δ: 10.36 (brs, 2H), 7.34 ~ 7.40 (m, 2H), 7.07 ~ 7.17 (m, 3H), 3.55 (q, J = 6.9 Hz, 2H), 1.00 (t, J = 6.9 Hz, 3H).

Step 3 : 3-(2-(2-Ethyl-2-phenylhydrazinyl)-3.4-dioxocyclobut-l-enylamino)-2-hydroxy-

N.N- dimethyl benzamide

1 -Ethyl- 1 -phenylhydrazine (67.5 mg, 0.50 mmol) and 3-(2-ethoxy-3,4- dioxocyclobut-1- enylamino)-2-hydroxy-N,N-dimethylbenzamide (155 mg, 0.51 mmol) were added in 5 mL of EtOH, and stirred for 16 hours at room temperature. Then the reaction mixture was concentrated in vacuo. The residue was purified with preparative HPLC to give 3-(2-(2-ethyl-2-phenylhydrazinyl)-3,4-dioxocyclobut-l-enylamino)-2-hydroxy-N,N- dimethylbenzamide (48 mg, yield about 12.2%).

¹H NMR: CD₃OD (300MHz) δ: 8.11 (brs, 1 H), 7.32 ~ 7.37 (m, 2H), 7.18 ~ 7.20 (m, 2H), 7.05 ~ 7.07 (m, IH), 6.91 ~ 6.92 (m, 2H), 3.57 (brs, 2H), 3.03 (s, 6H), 1.30 (t, J = 6.9 Hz, 3H).

EXAMPLE 9

Preparation of 3-(2-(2-ethyl-2-(4-fluoro-phenyl)hydrazinyl)-3.4-dioxocyclobut-l -enylaminoV

2-hydroxy-N.N- dimethylbenzamide

A mixture of N-ethyl-4-fluoroaniline (4.17 g, 30. mmol), 48 mL HCl (con.), and 12 g ice were placed in 50 mL three-necked flask, to which a solution Of NaNO₂ (2.1 g, 30.4 mmol) in 8.6 mL H₂O was added during the course of 10 minutes below 5°C. After 1 hour, the mixture was extracted with EtOAc (200 mL x 2). The combined organic phases were dried over Na₂Sθ4 and then filtrated. The filtrate was concentrated to give N-ethyl-N-(4- fluorophenyl)nitrous amide (3.83 g, yield 75%), which was used directly without further purification.

Step 2: 1 -ethyl- 1 -f 4-fluorophenvDhvdrazine

A mixture of Zn (18 g, 277 mmol) and water (30 mL) was placed in 250 mL flask, the mixture was then stirred vigorously while an acid solution of N-ethyl-N-(4- fluorophenyl)nitrous amide (3.83 g, 22 mmol) in 20 mL AcOH was added in a slow stream. The temperature was maintained between 10⁰C and 20⁰C. When all the amide solution had been added, the mixture was stirred for one hour at room temperature and then warmed to 80⁰C.

The warmed solution was filtered from the un-reacted Zn, which was washed with 5% HCl.

The combined filtrate was treated with 40% NaOH solution to adjust PH to 12. The mixture was extracted with EtOAc (180 mL x 2). The combined organic phases were dried over Na₂SO₄, then filtrated, and the filtrate was concentrated to give 1 -ethyl- 1 -(4- fluorophenyl)hydrazine (1.35 g, yield 38.9 %).

¹H NMR(DMSO-ds) (300MHz) δ: 10.36 (brs, 2H), 7.40 ~ 7.21 (m, 4H), 3.45 (q, J = 7.2 Hz, 2H), 0.97 (t, J = 7.2 Hz, 3H).

Step 3: 3-(2-(2-emyl-2-(4-fluorophenvπhvdrazinylV3.4-dioxocvclobut-l- envlamino)-2-hvdroxv-N,N- dimethvlbenzamide

OEEtt

1 -Ethyl- l-(4-fluorophenyl)hydrazine (77 mg, 0.50 mmol) and 3-(2-ethoxy-3,4- dioxocyclobut-1- enylamino)-2-hydroxy-N,N- dimethylbenzamide (155 mg, 0.51 mmol) were added in 5 mL of EtOH and stirred for 16 hours at room temperature. Then the reaction mixture was concentrated in vacuo. The residue was purified with preparative HPLC to give 3 -(2-(2-ethyl-2-(4-fluorophenyl)hydrazinyl)-3,4-dioxocyclobut-l-enylamino)-2 -hydroxy -N,N- dimethylbenzamide (51.5 mg, yield 25.1%).

¹H-NMR: CD3OD (300 MHz) δ: 8.19 (brs, IH), 7.32-7.18 (m, 2H), 7.16-7.05 (m, 2H), 6.93 (s, IH), 6.92 (s, IH), 3.62-3.40 (m, 2H), 3.04 (s, 6H), 1.03 (d, 7.1 Hz, 3H). m/z: 413 (M+l).

EXAMPLE 10 Preparation of 3-(2-(l-ethylhydrazinylV3.4-dioxocyclobut-l-enylaminoV2-hydroxy-N.N - dimethylbenzamide

Step 1 : rgrt-butyl-2-(2-(3-(dimethylcarbamoylV2-hydroxyphenylaminoV3.4- dioxocyclobut-1-enylV 2 -ethyl hydrazine carboxylate

Tert-buty\ 2-ethyl hydrazinecarboxylate (106 mg, 0.66 mmol), 3-(2-ethoxy-3,4- dioxocyclobut-l-enylamino)-2 -hydroxy -N,N-dimethylbenzamide (100 mg, 0.33 mmol), K₂CO₃ (91 mg, 0.66 mmol) and EtOH (1 mL) were mixed and heated to 40 ⁰C for 16 hours. After filtration, the crude product was purified with preparative TLC to give tert-buty\ 2-(2-(3- (dimethylcarbamoyl)-2-hydroxyphenylamino)-3,4-dioxocyclobut-l -enyl)-2- ethylhydrazinecarboxylate (89 mg).

Step 2: 3-(2-(l-EthylhydrazinylV3.4-dioxocyclobut-l-enylaminoV2-hydroxy-N.N- dimethylbenzamide Tert-buty\-2-(2-(3 -(dimethyl carbamoyl)-2-hydroxyphenylamino)-3, 4- dioxocyclobut-l-enyl)-2-ethyl hydrazinecarboxylate (89 mg) was dissolved in TFA/DCM (1 :1).

After 1 hour, the mixture was concentrated in vacuo to give crude product, which was purified with preparative HPLC to give 3-(2-(l-ethylhydrazinyl)-3,4-dioxocyclobut-l-enylamino)-2- hydroxy-N,N-dimethylbenzamide (18 mg). 1H NMR CDCl₃ (300MHz) δ: 8.15 ~ 8.17 (m, IH), 6.81 ~ 6.96 (m, 2H), 3.86 ~

3.88 (m, 2H), 1.33 (t, J =6.3, 3H). m/z: 319.2 (M+l).

EXAMPLE 11

Preparation of 3-(2-(2-acetyl-l -ethylhydrazinylVSΛ-dioxocyclobut-l -enylaminoV2-hydroxy- N.N- dimethylbenzamide

3-(2-(l-Ethylhydrazinyl)-3,4-dioxocyclobut-l-enylamino)-2-hydroxy-N,N- dimethylbenzamide (30 mg, 0.09 mmol) was mixed with pyridine (1 mL). Acetyl chloride (7.3 mg, 0.09 mmol) was added to reaction at O⁰C. After 1 hour, the mixture was purified with preparative HPLC to give 3-(2-(2-acetyl-l-ethylhydrazinyl)-3,4-dioxocyclobut-l-enylamino)- 2-hydroxy-N,N-dimethylbenzamide (14 mg).

LRMS calc: 360.1 obs: 361.3 (M+l).

Using the synthetic schemes and exemplary synthetic methods described above and well known knowledge in the art, exemplary compounds of Formula II in Table 1 can be prepared:

Table 1. Exemplary compounds of Formula (II).

(II), wherein:

Using the synthetic schemes and exemplary synthetic methods described above and well known knowledge in the art, exemplary compounds of Formula (III) in Table 2 can be prepared:

Table 2. Exemplary compounds of Formula (HI).

(III), wherein:

Using the synthetic schemes and exemplary synthetic methods described above and well known knowledge in the art, exemplary compounds of Formula IV in Table 3 can be prepared:

Table 3. Exemplary compounds of Formula (IV).

(IV), wherein:

Biological Binding Assays

The novel compounds described herein were evaluated for their binding affinity according to the following assay methods.

Binding Assay Method fProtocols for CXCRl and CXCR2 Binding Assays)

Cell lines: (1) human CXCRl : stable recombinant CHOKl (clone 10) prepared internally; (2) human CXCR2: stable recombinant clonal CHOKl expressing the G-protein

G_αi6 (Euroscreen, Belgium, #ES-145-F).

Membrane preparation: Membrane was prepared by nitrogen cavitation at 800 psi for up to 30 minutes on ice followed by differential centrifugation (100Og, lOmin and 16000Og,

30 min, 4°C) in the presence of serine protease inhibitors (lOμg/mL leupeptin, aprotinin, chymostatin, ImM AEBSF).

Binding assay: Binding assay was done in a 96-well SPA-compatible incubation plate in a final volume of lOOμL containing lOOpM [¹²⁵I]IL8, 0.2mg PVT-WGA SPA beads (Amersham), plus or minus 0.5%(w/v) human serum albumin for the protein shift assay (Sigma #8763), 2μL of compound competitor (in DMSO) and approximately l-3μg membrane proteins (determined experimentally for each new membrane preparation) in assay buffer (25mM HEPES pH 7.4 (KOH), 3mM MgCl₂, 0.001% (v/v) Tween-20). Total and non-specific binding were determined in the presence of DMSO and 30μM of methyl l-[(3-{[(Z)-[(2- bromophenyl)amino](cyanoimino)methyl]amino}-6-chloro-2-hydroxyphenyl)sulfonyl]-L- prolinate, respectively. The final concentration of DMSO was 2% and kept constant throughout the plate. The incubation was conducted for Ih at room temperature with shaking and then counted for 1 minute in a Microbeta counter (Perkin Elmer). Percent residual specific binding was determined as ((cpm-average cpm for non-specific)/(average cpm for total binding-average cpm for non-specific ))*100. Compounds were tested in 10-dose titration curves (no replicates) with the reference compound tested at least once in every experiment. K₁ was calculated by Inflection Point/1 +([radioligand]/K_D). K_D was determined by saturation analysis of the radioligand specific binding for CXCRl and CXCR2.

FLIPR Assay Method fIC^ The FLIPR Assay was conducted according to the method described in the publications by Hamonmond M.E. et al, J. of Immunol., 155, 1428-1433 (1995) and Ahuja S.K et al., Nature Genet, 2 (1), 31-36. (1992).

Biological Activities of Examples 1-9 and Comparative Examples a and b Using the Biological Binding Assay methods described above, CXCRl and

CXCR2 binding inhibitions and CXCR2 FLIPR IC50 values of Examples 1-9 were determined and the results are summarized in Table 4.

Table 4. CXCRl and CXCR2 Binding Affinities and CXCR2 FLIPR IC₅₀ values of Examples 1-9 and Comparative Examples a-b

Note: 1. Results reported in Dwyer et al, J. Med. Chem.2006, 49, 7603; 2. Number "n" means the number of replicates of measurements.

As a comparison, biological activities of Comparative Examples a and b having the following chemical structures are also shown in Table 4.

As can be seen from Table 4, Comparative Example b showed CXCR2 inhibitory potency (IC50) of 15 nM and about 60-fold selectivity against CXCRl according to Dwyer et al. It can also be seen from Table 4 that Comparative Example a was about 4-fold more potent (IC₅o = 3.8 nM) against CXCR2 and about 9-fold less selective (7-fold) against CXCRl in comparison to Comparative Example b.

It can be seen from Table 4 that Example 6, a close analog of Comparative Example b having one additional nitrogen in place of a carbon, exhibited CXCR2 binding affinity Ki of 120 nM. Example 7, a close analog of Example 6 having one ethyl group replaced with an acetyl group, was found to be about 3 -fold less potent than Example 6 (Ki = 320 nM) in the binding assay. When tested in FLIPR assay, Example 6 (IC50 - 46 nM) demonstrated about 30-fold better potency than Example 7 (IC50 = 1250 nM). It was also found that the compound having the following structure was substantially inactive in the binding assay:

Data in Table 4 also indicates that Examples 5 and 8 had similar CXCR2 binding affinities (130 nM and 110 nM, respectively) as that of Example 6 (120 nM). In terms of selectivity, Examples 5 and 8, each having an ethylaryl hydrazine moiety instead of the diethyl hydrazine moiety of Example 6, showed about 40-fold selectivity, whereas Example 6 displayed about 80-fold selectivity.

The results of Examples 4 and 9 show that while including an electron donating group (-0Me) for Example 4 on the phenyl ring of Example 8 had minimal effect on CXCR2 binding activity (180 nM), addition of an electron withdrawing group (-F) for Example 9 on the same phenyl ring in Example 8 resulted in about 5 -fold reduction in CXCR2 binding affinity (55O nM).

Results in Table 4 also indicate that Example 2 (7.2 μM), an analog of Example 9 having a /7-F-Bn group replacing /7-F-Ph group of Example 9 (550 nM), had about 12-fold drop in CXCR2 binding affinity.

Example 3, which has a benzoyl moiety replacing the corresponding benzyl linker in Example 2, displayed about 28-fold enhanced binding potency (260 nM) relative to

Example 2. It is also to be noted that CXCRl selectivity for Examples 9, 4 and 3 ranged from

22 - 46 fold. While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in the responsiveness of the mammal being treated for any of the indications for the active agents used in the instant invention as indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

Claims

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:

wherein:

A is selected from the group consisting of:

B is selected from the group consisting of:

(1) hydrogen,

(2) Ci-S alkyl, optionally substituted with 1 to 3 substituents selected from the group consisting of:

(a) aryl, optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci-S alkyl, (b) halogen, and (c) -OR^b, and

(3) C_3-8 cycloalkyl,

(4) Ci_-8 alkoxy, o

— f H₂C-) — C-R^b (5) ^{v l n} , wherein n is 0, 1, 2, or 3,

(1) hydrogen,

(2) C_1-8 alkyl,

(3) C_3-8 cycloalkyl, (4) Ci_-8 alkoxy,

(5) aryl, and

(6) heteroaryl;

W is selected from the group consisting Of-CH₂- and -NH-;

X is selected from the group consisting of hydrogen, Ci_-8 alkyl, C_3-8 cycloalkyl, Ci_-8 alkoxy, halogen, -CN, -CF₃, and -OCF₃;

Y is selected from the group consisting of hydrogen, Ci_-8 alkyl, C_3-8 cycloalkyl, Ci_-8 alkoxy, halogen, -CN, -CF₃, and -OCF₃; each occurrence of Rl and R2 is independently selected from the group consisting of:

(1) hydrogen, (2) Ci_-8 alkyl,

(3) C_3-8 cycloalkyl, and

(4) aryl, wherein each of the Ci_-8 alkyl, C_3-8 cycloalkyl, and aryl is optionally substituted with 1 to 3 substituents selected from the group consisting of Ci_-8 alkyl, halogen, and -0R^a; or Rl or R2 taken together with the nitrogen they are attached to form an unsubstituted or substituted saturated or unsaturated 4-8 membered ring, wherein the 4-8 membered ring contains 1 nitrogen and 0 to 3 additional heteroatoms selected from the group consisting of O, S and N; and each occurrence of R^a and R^b is independently selected from the group consisting of: (1) hydrogen,

(2) Ci_-8 alkyl,

(3) aryl, and

(4) heteroaryl, wherein each of the Ci_-8 alkyl, aryl, and heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of Ci_-8 alkyl, halogen, hydroxy, and Ci_-8 alkoxy.

2. The compound of Claim 1 , or a pharmaceutically acceptable salt thereof,

wherein A is ° ^ORa and R¹, R², R^a, X and Y are as defined in Claim 1.

3. The compound of Claim 2, or a pharmaceutically acceptable salt thereof, wherein:

X is selected from the group consisting of hydrogen and Ci_-4 alkyl; Y is selected from the group consisting of hydrogen and Ci_-4 alkyl; each occurrence of R¹ and R² is independently Ci_-4 alkyl; and R^a is hydrogen or methyl.

4. The compound of Claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

B is selected from the group consisting of:

(1) hydrogen, (2) Ci_-6 alkyl, optionally substituted with 1 to 3 substituents selected from the group consisting of:

(b) heteroaryl, optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci_-6 alkyl, (b) halogen, and (c) -OR^b,

3,

5. The compound of Claim 4, or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of:

(1) hydrogen, (2) methyl,

(3) ethyl,

(4) n-propyl,

-1-CH₂ C-CH₃

(5)

(16) ^! ' N= =/

^ ?

(19) -N

6. The compound of Claim 1 , or a pharmaceutically acceptable salt thereof, wherein C is selected from the group consisting of: (1) hydrogen,

(2) methyl,

(3) ethyl,

(4) n-propyl, and

(5) n-butyl.

7. A compound of Formula (Ia), or a pharmaceutically acceptable salt thereof:

wherein: B is selected from the group consisting of:

(1) hydrogen,

(2) methyl,

(3) ethyl,

(4) n-propyl,

O ς I l (5) S ⁰^ ^C"CHs ,

O q Il p_\ ^~t C-CH₂CH₃

OCH,

(15) ₌/ — OC

5 \

(16) N^:

C is selected from the group consisting of:

(1) hydrogen,

(2) methyl,

(3) ethyl, and

( (44)) nn--pprrooppyyll;; each occurrence of R¹ and R² is independently selected from the group consisting of (1) methyl, (2) ethyl, (3) n-propyl, and (4) n-butyl; and

R^a is hydrogen or methyl.

8. The compound of Claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

9. A pharmaceutical composition comprising a compound of Claim 1 and a pharmaceutically acceptable carrier.

10. A method for treating or preventing a chemokine mediated disease or disorder, wherein the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Claim 1.

11. The method of Claim 10 wherein the disease or disorder is selected from the group consisting of (1) asthma, (2) COPD, (3) autoimmune disease, (4) allergic rhinitis, (5) psoriasis, (6) rheumatoid arthritis, (7) cardiovascular disease, and (8) cancer.

12. A pharmaceutical composition comprising a compound of Claim 1, a second active agent selected from the group consisting of:

(1) an antirheumatic agent,

(2) a nonsteroidal anti-inflammatory agent,

(3) a COX-2 selective inhibitor, (4) a COX-I inhibitor,

(5) an immunosuppressive agent, and

(6) a steroid; and a pharmaceutically acceptable carrier.

13. A method for treating or preventing a chemokine mediated disease or disorder, wherein the method comprises administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 12.

14. Use of the compound of Claim 1 in the manufacture of a medicament for treating or preventing a chemokine mediated disease or disorder.

15. The use of Claim 14 wherein the disease or disorder is selected from the group consisting of (1) asthma, (2) COPD, (3) autoimmune disease, (4) allergic rhinitis, (5) psoriasis, (6) rheumatoid arthritis, (7) cardiovascular disease, and (8) cancer.