HK1194384A - Derivatives of 1-amino-2-cyclobutylethylboronic acid - Google Patents

Abstract

The present invention relates to derivatives of 1-amino-2-cyclobutylethylboronic acid, provides novel compounds useful as proteasome inhibitors. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various diseases.

Description

1-amino-2-cyclobutylethylboronic acid derivatives

The application is a divisional application of an application with the application date of 2009, 9 and 25, and the application number of 200980144074.X, and the name of the invention is "1-amino-2-cyclobutyl ethyl boric acid derivative".

Technical Field

The present invention relates to boronic acid and boronic ester compounds useful as proteasome inhibitors. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

This application claims priority from U.S. provisional patent application No. 61/194,614, filed on 9/29/2008, which is incorporated herein by reference in its entirety.

Background

Boronic acid and boronic ester compounds exhibit a variety of pharmaceutically useful biological activities. U.S. Pat. No. 4,499,082 (1985) to Shenwei (Shenvi) et al discloses that peptide boronic acids are inhibitors of certain proteolytic enzymes. U.S. Pat. Nos. 5,187,157 (1993), 5,242,904 (1993) and 5,250,720 (1993) to Ketner and Shenwei (Shenvi) describe a class of peptide boronic acids that inhibit trypsin-like proteases. U.S. Pat. No. 5,169,841 (1992) to Kleeman et al discloses N-terminally modified peptide boronic acids that inhibit the action of renin (renin). U.S. Pat. No. 5,106,948 (1992) to Kinder et al discloses certain boronic acid compounds to inhibit cancer cell growth. WO07/0005991 to Bachovchin et al discloses peptide boronic acid compounds that inhibit fibroblast activation proteins.

Boronic acid and boronic ester compounds are particularly promising as inhibitors of the proteasome, a multicatalytic protease responsible for the majority of intracellular protein turnover. U.S. Pat. No. 5,780,454 (1998) to Adams et al describes peptide boronic ester and ester compounds useful as proteasome inhibitors. This reference also describes the use of borate esters and boronic acid compounds to reduce the rate of muscle protein degradation, reduce the activity of NF- κ B in cells, reduce the rate of degradation of p53 protein in cells, inhibit the degradation of cyclins (cyclins) in cells, inhibit the growth of cancer cells, and inhibit NF- κ B-dependent cell adhesion. WO02/096933 to Freit (Furet) et al, WO05/016859 to Chatteriee et al, and WO05/021558 to Bernedini (Bernadii) et al, and WO06/08660 disclose other boronic ester and acid compounds that are reported to have proteasome inhibitory activity.

Chianov (Ciechanover), Cell (Cell), 79: 13-21(1994) revealed that proteasomes are proteolytic components of the ubiquitin-proteasome pathway, where proteins are targeted for degradation by binding to multiple ubiquitin molecules. Qimanov (Ciechanover) also reveals that the ubiquitin-proteasome pathway plays a key role in a variety of important physiological processes. Livett (Rivett et al, journal of biochemistry (biochem.j.) 291: 1(1993) disclose that proteasomes exhibit trypsin peptidase activity, chymotrypsin peptidase activity and peptidyl glutamyl peptidase activity. The 20S proteasome constitutes the catalytic core of the 26S proteasome. Mackeke meiji (McCormack), et al, Biochemistry (Biochemistry) 37: 7792(1998) teaches that various peptide substrates including Suc-Leu-Leu-Val-Tyr-AMC, Z-Leu-Leu-Arg-AMC and Z-Leu-Leu-Glu-2NA, where Suc is N-succinyl, AMC is 7-amino 4-methylcoumarin and 2NA is 2-naphthylamine, are cleaved by the 20S proteasome.

Proteasome inhibition represents an important new strategy for cancer therapy. Gold (King) et al, Science 274: 1652-1659(1996) describe the important role of the ubiquitin-proteasome pathway in regulating cell cycle, neoplastic growth and metastasis. The authors teach that the ubiquitin-proteasome pathway involves cyclin and cyclin dependent kinases p21 and p27 in the cell cycle^KIP1A number of key regulatory proteins within degrade chronologically. The orderly degradation of these proteins is required for the cell to go through the cell cycle and undergo mitosis.

In addition, the ubiquitin-proteasome pathway is also required for transcriptional regulation. Palomonebar (palombellar) et al, Cell (Cell), 78: 773(1994) teaches that activation of the transcription factor NF-. kappa.B is regulated by proteasome-mediated degradation of the inhibitor protein Ikappa.B. NF-. kappa.B in turn plays an important role in the regulation of genes involved in immune and inflammatory responses. Reed (Read) et al, immunology (Immunity) 2: 493-506(1995) teaches that the ubiquitin-proteasome pathway is required for the expression of cell adhesion molecules such as E-selectin, ICAM-1 and VCAM-1. Zetter, Cancer Biology Seminars (sensiars in Cancer Biology) 4: 219-229(1993) teaches that cell adhesion molecules are involved in tumor metastasis and angiogenesis in vivo by directing tumor cell adhesion to and extravasation from blood vessels to remote tissue sites in vivo. Furthermore, berg (Beg) and Baltimore (Baltimore), Science (Science) 274: 782(1996) teaches that NF-. kappa.B is an anti-apoptotic control factor, and inhibition of NF-. kappa.B activation makes cells more sensitive to environmental stress and cytotoxic agents.

Proteasome inhibitors(bortezomib; N-2-pyrazinecarbonyl-L-phenylalanine-L-leucine boronic acid) is the first proteasome inhibitor to obtain official approval. Miqishans (Mitsiades) et al, Current Drug Targets, 7: 1341(2006) reviewed clinical studies that prompted the approval of bortezomib for the treatment of multiple myeloma patients who had received at least one therapy in advance. Fisher (Fisher), et al, journal of clinical oncology (j.clin.oncol.), 30: 4867 describes an international multicenter phase II study demonstrating the activity of bortezomib in patients with relapsed or refractory mantle cell lymphoma. Ishii et al, Anti-Cancer Agents in Medicinal Chemistry (Anti-Cancer Agents in Medicinal Chemistry), 7: 359(2007) and rocaro (Roccaro et al, current pharmaceutical biotechnology (curr. pharm. biotech.), 7: 1341(2006) discusses a number of molecular mechanisms that may contribute to the anti-tumor activity of bortezomib.

The methods described by french et al, yearbook for biochemical reviews (annu. rev. biochem.), 68: 1015(1999) reported structural analysis revealed that the 20S proteasome comprises 28 subunits, with the catalytic subunits β 1, β 2, and β 5 responsible for peptidyl glutamyl, trypsin, and chymotrypsin peptidase activities, respectively. Livitt (Rivett), et al, contemporary protein peptide science (curr. protein pept. sci.), 5: 153(2004) revealed that when proteasomes were exposed to certain cytokines including IFN- γ and TNF-a, the β 1, β 2 and β 5 subunits were replaced with alternative catalytic subunits β 1i, β 2i and β 5i, forming a variant form of the proteasome known as the immunoproteasome.

Ollo gas base (Orlowski), Hematology (Hematology) (american society for Hematology education programs (am.soc. hematosol. educ.program))220(2005) revealed that immunoproteasome is also constitutively expressed in some cells derived from hematopoietic progenitor cells. The authors suggest that immunoproteasome-specific inhibitors may allow targeted therapy against cancers arising from hematological origins, potentially protecting normal tissues such as gastrointestinal and neurological tissues from side effects.

As demonstrated by the above references, proteasomes represent an important target for therapeutic intervention. Accordingly, there remains a continuing need for new and/or improved proteasome inhibitors.

Disclosure of Invention

The present invention provides compounds that are effective inhibitors of one or more peptidase activities of the proteasome. These compounds are useful for inhibiting proteasome activity in vitro and in vivo, and are particularly useful for treating a variety of cell proliferative disorders.

The compounds of the invention have the general formula (I):

or a pharmaceutically acceptable salt or boronic acid anhydride thereof, wherein:

a is 0, 1 or 2;

p is hydrogen or an amino-capping moiety;

R^a1is C_1-6Aliphatic radical, C_1-6Fluoroaliphatic radical, - (CH)₂)_m-CH₂-R^B、-(CH₂)_m-CH₂-NHC(＝NR⁴)NH-Y、-(CH₂)_m-CH₂-CON(R⁴)₂、-(CH₂)_m-CH₂-N(R⁴)CON(R⁴)₂、-(CH₂)_m-CH(R⁶)N(R⁴)₂、-(CH₂)_m-CH(R⁵)-OR⁵Or- (CH)₂)_m-CH(R⁵)-SR⁵；

Each R^a2Independently of one another is hydrogen, C_1-6Aliphatic radical, C_1-6Fluoroaliphatic radical, - (CH)₂)_m-CH₂-R^b、-(CH₂)_m-CH₂-NHC(＝NR⁴)NH-Y、-(CH₂)_m-CH₂-CON(R⁴)₂、-(CH₂)_m-CH₂-N(R⁴)CON(R⁴)₂、-(CH₂)_m-CH(R⁶)N(R⁴)₂、-(CH₂)_m-CH(R⁵)-OR⁵Or- (CH)₂)_m-CH(R⁵)-SR⁵；

Each Y is independently hydrogen, -CN, -N0₂or-S (O)₂-R¹⁰；

Each R^BIndependently a substituted or unsubstituted monocyclic or bicyclic ring system;

each R⁴Independently hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl or heterocyclic group; or two R on the same nitrogen atom⁴Together with said nitrogen atom, form a substituted or unsubstituted 4-to 8-membered heterocyclyl ring having 0 to 2 ring heteroatoms independently selected from N, O and S in addition to said nitrogen atom;

each R⁵Independently hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl or heterocyclic group;

each R⁶Independently a substituted or unsubstituted aliphatic, aryl or heteroaryl group;

each R¹⁰Independently is C_1-6Aliphatic radical, C_6-10Aryl or-N (R)⁴)₂；

m is 0, 1 or 2;

Z¹and Z²Each independently is hydroxy, alkoxy, aryloxy, or aralkoxy; or Z¹And Z²Together forming a moiety derived from a boronic acid complexing agent.

Unless explicitly stated otherwise, the term "proteasome" means a constitutive proteasome, an immunoproteasome, or both.

The term "aliphatic" or "aliphatic group" as used herein means a substituted or unsubstituted straight, branched or cyclic C that is fully saturated or contains one or more units of unsaturation, but is not aromatic_1-12A hydrocarbon. For example, suitable aliphatic groups include substituted or unsubstituted straight, branched or cyclic alkyl, alkenyl or alkynyl groups and hybrids thereof, such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl. In various embodiments, the aliphatic group has 1 to 12, 1 to 8, 1 to 6, 1 to 4, or 1 to 3 carbons.

The terms "alkyl", "alkenyl" and "alkynyl", used alone or as part of a larger moiety, refer to straight or branched chain aliphatic groups having from 1 to 12 carbon atoms. For the purposes of the present invention, the term "alkyl" will be used when the carbon atom linking the aliphatic group to the remainder of the molecule is a saturated carbon atom. However, the alkyl group may include unsaturation at other carbon atoms. Thus, alkyl groups include, but are not limited to, methyl, ethyl, propyl, allyl, propargyl, butyl, pentyl, and hexyl.

For the purposes of the present invention, the term "alkenyl" will be used when the carbon atom linking the aliphatic group to the remainder of the molecule forms part of a carbon-carbon double bond. Alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 1-butenyl, 1-pentenyl, and 1-hexenyl.

For the purposes of the present invention, the term "alkynyl" will be used when the carbon atom linking the aliphatic group to the remainder of the molecule forms part of a carbon-carbon triple bond. Alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, 1-pentynyl, and 1-hexynyl.

The term "cycloaliphatic", used alone or as part of a larger moiety, refers to a saturated or partially unsaturated cyclic aliphatic ring system having from 3 to about 14 members, wherein the aliphatic ring system is optionally substituted. In some embodiments, the cycloaliphatic radical is a monocyclic hydrocarbon having 3 to 8 or 3 to 6 ring carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl. In some embodiments, the cycloaliphatic group is a bridged or fused bicyclic hydrocarbon having 6 to 12, 6 to 10, or 6 to 8 ring carbon atoms, wherein any individual ring in the bicyclic ring system has 3 to 8 members.

In some embodiments, two adjacent substituents on a cycloaliphatic ring, together with the intervening ring atoms therebetween, form an optionally substituted fused 5-6 membered aromatic ring or 3-8 membered non-aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N and S. Thus, the term "cycloaliphatic" includes an aliphatic ring fused to one or more aryl, heteroaryl, or heterocyclyl rings. Non-limiting examples include indanyl, 5, 6, 7, 8-tetrahydroquinoxalinyl, decahydronaphthyl, or tetrahydronaphthyl, where the groups or points of attachment are on the aliphatic ring.

The terms "aryl" and "ar", used alone or as part of a larger moiety (e.g., "aralkyl", "aralkoxy", or "aryloxyalkyl"), refer to a C group containing one to three rings each optionally substituted₆To C₁₄An aromatic hydrocarbon. Aryl is preferably C_6-10And (4) an aryl group. Aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. In some embodiments, two adjacent substituents on the aryl ring, together with intervening ring atoms therebetween, form an optionally substituted fused 5-6-membered aromatic ring or a 4-8-membered non-aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N and S. Thus, the term "aryl" as used herein includes groups in which an aryl ring is fused to one or more heteroaryl, cycloaliphatic or heterocyclyl rings, wherein the group or point of attachment is on the aromatic ring. Non-limiting examples of such fused ring systems include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranylIndazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, fluorenyl, indanyl, phenanthridinyl, tetrahydronaphthyl, indolinyl, phenoxazinyl, benzodioxanyl, and benzodioxolyl. The aryl group may be monocyclic, bicyclic, tricyclic or polycyclic, preferably monocyclic, bicyclic or tricyclic, more preferably monocyclic or bicyclic. The term "aryl" is used interchangeably with the terms "aryl group", "aryl moiety", and "aryl ring".

"aralkyl" or "arylalkyl" comprises an aryl group covalently linked to an alkyl group, either of which is independently optionally substituted. Aralkyl is preferably C_6-10Aryl radical (C)_1-6) Alkyl radical, C_6-10Aryl radical (C)_1-4) Alkyl or C_6-10Aryl radical (C)_1-3) Alkyl groups including, but not limited to, benzyl, phenethyl, and naphthylmethyl.

The terms "heteroaryl" and "heteroar", used alone or as part of a larger moiety (e.g., heteroaralkyl or "heteroaralkoxy"), refer to a compound having from 5 to 14 ring atoms, preferably having 5, 6,9, or 10 ring atoms; has 6, 10 or 14 pi electrons shared in a ring array; and groups having one to four heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen or sulfur and includes any oxidized form of nitrogen or sulfur and any quaternized form of basic nitrogen. Thus, when used in reference to a ring atom of a heteroaryl group, the term "nitrogen" includes oxidized nitrogens (as in pyridine N-oxide). As further defined below, certain nitrogen atoms of the 5-membered heteroaryl groups may also be substituted. Heteroaryl groups include, but are not limited to, groups derived from thiophene, furan, pyrrole, imidazole, pyrazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, indolizine, naphthyridine, pteridine, pyrrolopyridine, imidazopyridine, oxazolopyridine, thiazolopyridine, triazolopyridine, pyrrolopyrimidine, purine, and triazolopyrimidine. The phrase "a group derived from … …" as used herein means a monovalent group produced by removing one hydrogen group from a parent heteroaromatic ring system. A group (i.e., the point of attachment of the heteroaryl to the remainder of the molecule) can be generated at any substitutable position on any ring of the parent heteroaryl ring system.

In some embodiments, two adjacent substituents on the heteroaryl group, together with intervening ring atoms therebetween, form an optionally substituted fused 5-6-membered aromatic ring or a 4-8-membered non-aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N and S. Thus, the terms "heteroaryl" and "heteroaryl" as used herein also include groups in which one heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclic rings, wherein the group or point of attachment is on the aromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, and pyrido [2, 3-b ] -1, 4-oxazin-3 (4H) -keto. Heteroaryl groups may be monocyclic, bicyclic, tricyclic or polycyclic, preferably monocyclic, bicyclic or tricyclic, more preferably monocyclic or bicyclic. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring" or "heteroaryl group," either of which includes an optionally substituted ring. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl moieties are independently optionally substituted.

The terms "aromatic ring" and "aromatic ring system" as used herein refer to an optionally substituted monocyclic, bicyclic or tricyclic group having 0-6, preferably 0-4 ring heteroatoms and having 6, 10 or 14 pi electrons shared in the ring array. Thus, the terms "aromatic ring" and "aromatic ring system" encompass both aryl and heteroaryl groups.

The terms "heterocycle", "heterocyclyl", "heterocyclic group" and "heterocyclic ring" as used herein are used interchangeably and refer to a stable 3 to 7 membered monocyclic or fused 7 to 10 membered or bridged 6 to 10 membered bicyclic heterocyclic moiety which is a saturated or partially unsaturated moiety and which has one or more, preferably one to four, heteroatoms as defined above in addition to carbon atoms. The term "nitrogen" when used in reference to a ring atom of a heterocyclic ring includes substituted nitrogens. For example, in a heterocyclyl ring having 1-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3, 4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N-substituted pyrrolidinyl). The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any ring atom may be optionally substituted. Examples of the saturated or partially unsaturated heterocyclic group include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.

In some embodiments, two adjacent substituents on the heterocyclic ring, together with intervening ring atoms therebetween, form an optionally substituted fused 5-6-membered aromatic ring or 3-8-membered non-aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N and S. Thus, the terms "heterocycle", "heterocyclyl ring", "heterocyclyl", "heterocyclic moiety" and "heterocyclic group" are used interchangeably herein and include groups in which one heterocyclyl ring is fused to one or more aryl, heteroaryl or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl, where the group or point of attachment is on the heterocyclyl ring. The heterocyclic group may be monocyclic, bicyclic, tricyclic or polycyclic, preferably monocyclic, bicyclic or tricyclic, more preferably monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

The term "partially unsaturated" as used herein refers to a cyclic moiety that includes at least one double or triple bond between ring atoms. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

The terms "haloaliphatic", "haloalkyl", "haloalkenyl" and "haloalkoxy" refer to an aliphatic, alkyl, alkenyl or alkoxy group optionally substituted with one or more halogen atoms. The term "halogen" or "halo" as used herein means F, C1, Br, or I. The term "fluoroaliphatic group" refers to a haloaliphatic group in which the halogen is fluorine, including perfluoroaliphatic groups. Examples of fluoroaliphatic groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2, 2, 2-trifluoroethyl, 1, 2-trifluoroethyl, 1, 2, 2-trifluoroethyl, and pentafluoroethyl.

The term "linker" or "linker" means an organic moiety that links two moieties of a compound. The linking group typically comprises an atom such as oxygen or sulfur, such as-NH-, -CH₂A unit such as-C (O) -, -C (O) NH-or an atom chain such as an alkylene chain. The linker typically has a molecular mass in the range of about 14 to 200, preferably 14 to 96, and a length of up to about 6 atoms. In some embodiments, the linker is C_1-6An alkylene chain.

The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e. - (CH)₂)_x-, where x is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2 or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below with respect to substituted aliphatic groups. The alkylene chain may also be substituted at one or more positions with an aliphatic or substituted aliphatic group.

The alkylene chain may also optionally be interrupted with functional groups. When the internal methylene unit is replaced with a functional group, the alkylene chain is "interrupted" with the functional group. Suitable "heteroNon-limiting examples of "incorporative functional groups" include-C (R) -, -C.ident.C-, -O-, -S-, -S (O) -, -S (O)₂-、-S(O)₂N(R⁺)-、-N(R*)-、-N(R⁺)CO-、-N(R⁺)C(O)N(R⁺)-、-N(R⁺)C(＝NR⁺)-N(R⁺)-、-N(R⁺)-C(＝NR⁺)-、-N(R⁺)CO₂-、-N(R⁺)SO₂-、-N(R⁺)SO₂N(R⁺)-、-OC(O)-、-OC(O)O-、-OC(O)N(R⁺)-、-C(O)-、-CO₂-、-C(O)N(R⁺)-、-C(O)-C(O)-、-C(＝NR⁺)-N(R⁺)-、-C(NR⁺)＝N-、-C(＝NR⁺) -O-, -C (OR) ═ N-, -C (R °) ═ N-O-, OR-N (R) (-)⁺)-N(R⁺) -. Each R⁺Independently hydrogen or an optionally substituted aliphatic, aryl, heteroaryl or heterocyclic group, or two R on the same nitrogen atom⁺Together with the nitrogen atom, form a 5-8 membered aromatic or non-aromatic ring having 0-2 ring heteroatoms selected from N, O and S in addition to the nitrogen atom. Each R is independently hydrogen or an optionally substituted aliphatic, aryl, heteroaryl or heterocyclic group.

C "contaminated with" -O_3-6Examples of alkylene chains include, for example, -CH₂OCH₂-、-CH₂O(CH₂)₂-、-CH₂O(CH₂)₃-、-CH₂O(CH₂)₄-、-(CH₂)₂OCH₂-、-(CH₂)₂O(CH₂)₂-、-(CH₂)₂O(CH₂)₃-、-(CH₂)₃O(CH₂)-、-(CH₂)₃O(CH₂)₂-and- (CH)₂)₄O(CH₂) -. Other examples of alkylene chains "incorporating" functional groups include-CH₂ZCH₂-、-CH₂Z(CH₂)₂-、-CH₂Z(CH₂)₃-、-CH₂Z(CH₂)₄-、-(CH₂)₂ZCH₂-、-(CH₂)₂Z(CH₂)₂-、-(CH₂)₂Z(CH₂)₃-、-(CH₂)₃Z(CH₂)-、-(CH₂)₃Z(CH₂)₂-and- (CH)₂)₄Z(CH₂) -, wherein Z is one of the "hetero" functional groups listed above.

One of ordinary skill in the art will recognize that certain combinations will not be sufficiently stable for medical use when an alkylene chain having a hetero-entering group is attached to a functional group. Similarly, T¹And R^2cOr T²And R^2dCertain combinations of (a) will not be sufficiently stable for medical use. Only stable or chemically viable compounds are within the scope of the invention. A stable or chemically viable compound is one that maintains its integrity long enough to be suitable for therapeutic or prophylactic administration to a patient. Preferably, the chemical structure does not substantially change when stored for at least one week in the absence of moisture or other chemically reactive conditions at a temperature of less than-70 ℃, less than-50 ℃, less than-20 ℃, less than 0 ℃ or less than 20 ℃.

As used herein, "substituted" means that the hydrogen radical of the specified moiety is replaced with the specified substituent, provided that the substitution results in a stable or chemically feasible compound. The term "substitutable" when used in reference to an indicated atom means that a hydrogen radical which is substitutable by a radical of an appropriate substituent is attached to the atom.

The phrase "one or more substituents" as used herein refers to a number of substituents equal to one to the maximum number of substituents possible based on the number of available bonding sites, provided that the above-described conditions of stability and chemical feasibility are met. Unless otherwise specified, an optionally substituted group may have a substituent at each substitutable position of the group, and the substituents may be the same or different.

The term "independently selected" as used herein means that the same or different values may be selected for multiple instances of a given code number in a single compound.

Aryl (including aryl moieties in aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaryl moieties in heteroaralkyl and heteroaralkoxy and the like) groups may contain one or more substituents. Non-limiting examples of suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group include halo, -NO₂、-CN、-R*、-C(R*)＝C(R*)₂、-C≡C-R*、-OR*、-SR°、-S(O)R°、-SO₂R°、-SO₃R*、-SO₂N(R⁺)₂、-N(R⁺)₂、-NR⁺C(O)R*、-NR⁺C(O)N(R⁺)₂、-N(R⁺)C(＝NR⁺)-N(R⁺)₂、-N(R⁺)C(＝NR⁺)-R°、-NR⁺CO₂R°、-NR+SO₂R°、-NR+SO₂N(R⁺)₂、-O-C(O)R*、-O-CO₂R*、-OC(O)N(R⁺)₂、-C(O)R*、-CO₂R*、-C(O)-C(O)R*、-C(O)N(R⁺)₂、-C(O)N(R⁺)-OR*、-C(O)N(R⁺)C(＝NR⁺)-N(R⁺)₂、-N(R⁺)C(＝NR⁺)-N(R⁺)-C(O)R*、-C(＝NR⁺)-N(R⁺)₂、-C(＝NR⁺)-OR*、-N(R⁺)-N(R⁺)₂、-C(＝NR⁺)-N(R⁺)-OR*、-C(R°)＝N-OR*、-P(O)(R*)₂、-P(O)(OR*)₂-O-P (O) -OR and-P (O) (NR)⁺)-N(R⁺)₂Wherein R ° is an optionally substituted aliphatic, aryl or heteroaryl group, and R⁺And R is as defined above, or two adjacent substituents together with intervening atoms therebetween form a 5-to 6-membered unsaturated or partially unsaturated ring having 0-3 ring atoms selected from the group consisting of N, O and S.

The aliphatic or non-aromatic heterocyclic ring may be substituted with one or more substituents. Examples of suitable substituents on saturated carbons of aliphatic or non-aromatic heterocycles include, but are not limited to, those listed above for unsaturated carbons of aryl or heteroaryl groups andthe following: either O, S, C (R)₂、＝N-N(R*)₂、＝N-OR*、＝N-NHC(O)R*、＝N-NHCO₂R°、＝N-NHSO₂R ° or ═ N-R, where R and R ° are each as defined above.

Suitable substituents on the substitutable nitrogen atom of the heteroaryl or non-aromatic heterocycle include, but are not limited to, -R, -N (R)₂、-C(O)R*、-CO₂R*、-C(O)-C(O)R*、-C(O)CH₂C(O)R*、-SO₂R*、-SO₂N(R*)₂、-C(＝S)N(R*)₂、-C(＝NH)-N(R*)₂and-NR SO₂R is the sum of R; wherein each R is as defined above. The ring nitrogen atoms of the heteroaryl or non-aromatic heterocyclic ring may also be oxidized to form the corresponding N-hydroxy or N-oxide compounds. A non-limiting example of such a heteroaryl group having an oxidized ring nitrogen atom is an N-oxiranyl pyridyl group.

The term "about" as used herein means about, within, about, or about. When the term "about" is used in connection with a numerical range, it modifies that range by extending the limits of the stated values upward or downward. In general, the term "about" is used herein to modify a numerical value to a deviation of 10% above and below the numerical value.

The term "comprising" as used herein means "including (but not limited to)".

It will be apparent to those skilled in the art that certain compounds of the invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention. Unless otherwise indicated, the structures described herein are also intended to include all geometric (or configurational) isomers, i.e., (Z) and (E) double bond isomers and (Z) and (E) configurational isomers, as well as all stereochemical forms of the structures; i.e. the R and S configuration of each asymmetric center. Thus, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the compounds of the invention are within the scope of the invention. When a mixture is enriched in one stereoisomer relative to another, the mixture may contain, for example, an enantiomeric excess of at least 50%, 75%, 90%, 99%, or 99.5%.

Unless otherwise indicated, structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, by replacement of hydrogen by deuterium or tritium, or by carbon atoms¹³C-or¹⁴In addition to C-rich carbon substitution, compounds having the structure of the present invention are within the scope of the present invention.

In the compounds of formula (I), the symbol P is hydrogen or an amino-terminated moiety. Non-limiting examples of amino-capping moieties can be found in p.g.m. martens (p.g.m.wuts) and t.w. guillain (t.w.greene), green's Protective Groups in Organic Synthesis (fourth edition) john wiley & Sons, NJ (2007), and include, for example, acyl, sulfonyl, oxyacyl and aminoacyl Groups.

In some embodiments, P is R^c-C(O)-、R^c-O-C(O)-、R^c-N(R^4c)-C(O)-、R^c-S(O)₂-or R^c-N(R^4c)-S(O)₂-, wherein R^cSelected from the group consisting of C_1-6Aliphatic radical, C_1-6Fluoroaliphatic radical, -R^D、-T¹-R^Dand-T¹-R^2cGroup of and the code T¹、R^D、R^2cAnd R^4cHaving the values described below.

Code number R^4cIs hydrogen, C_1-4Alkyl radical, C_1-4Fluoroalkyl or C_6-10Aryl (C)_1-4Alkyl) with or without substitution of the aryl moiety. In some embodiments, R^4cIs hydrogen or C_1-4An alkyl group. In certain particular embodiments, R^4cIs hydrogen.

Code number T¹Is 0-2 independently selected R^3aOr R^3bSubstituted C_1-6An alkylene chain, wherein the alkylene chain is optionally interrupted by-C (R)⁵)＝C(R⁵) -, -C.ident.C-or-O-. Each R^3aIndependently of each otherSelected from the group consisting of: -F, -OH, -O (C)_1-4Alkyl), -CN, -N (R)⁴)₂、-C(O)(C_1-4Alkyl), -CO₂H、-CO₂(C_1-4Alkyl), -C (O) NH₂and-C (O) -NH (C)_1-4Alkyl groups). Each R^3bIndependently is optionally via R^3aOr R⁷Substituted C_1-3An aliphatic group. Each R⁷Is a substituted or unsubstituted aromatic group. In some embodiments, T¹Is C_1-4An alkylene chain.

Code number R^2cIs halo, -OR⁵、-SR⁶、-S(O)R⁶、-SO₂R⁶、-SO₂N(R⁴)₂、-N(R⁴)₂、-NR⁴C(O)R⁵、-NR⁴C(O)N(R⁴)₂、-NR⁴CO₂R⁶、-N(R⁴)SO₂R⁶、-N(R⁴)SO₂N(R⁴)₂、-O-C(O)R⁵、-OC(O)N(R⁴)₂、-C(O)R⁵、-CO₂R⁵or-C (O) N (R)⁴)₂Wherein:

each R⁴Independently hydrogen or an optionally substituted aliphatic, aryl, heteroaryl or heterocyclic group; or two R on the same nitrogen atom⁴Together with the nitrogen atom, form an optionally substituted 4-to 8-membered heterocyclyl ring having 0-2 ring heteroatoms independently selected from N, O and S in addition to the nitrogen atom;

each R⁵Independently hydrogen or an optionally substituted aliphatic, aryl, heteroaryl or heterocyclic group; and is

Each R⁶Independently an optionally substituted aliphatic, aryl or heteroaryl group.

Code number R^DIs a substituted or unsubstituted aromatic, heterocyclic, or cycloaliphatic ring, any of which is optionally fused to a substituted or unsubstituted aromatic, heterocyclic, or cycloaliphatic ring.R^DEach saturated ring carbon atom in (A) is unsubstituted, or by (H) O, R^dOr R^8dAnd (4) substitution. R^DEach unsaturated ring carbon atom in (A) is unsubstituted, or R is substituted^dOr R^8dAnd (4) substitution. R^DEach of the substitutable ring nitrogen atoms in (a) is unsubstituted or substituted by: -C (O) R⁵、-C(O)N(R⁴)₂、-CO₂R⁶、-SO₂R⁶、-SO₂N(R⁴)₂、C_1-4Aliphatic radical, substituted or unsubstituted C_6-10Aryl or C_6-10Aryl (C)_1-4) Alkyl, the aryl portion of which is substituted or unsubstituted.

In some embodiments, R^DWherein one or two saturated ring carbon atoms are substituted with ═ O; r^DFrom 0 to 2R to the remaining substitutable ring carbon atoms^dAnd 0-2R^8dSubstitution; and R is^DEach of the substitutable ring nitrogen atoms in (a) is unsubstituted or substituted by: -C (O) R⁵、-C(O)N(R⁴)₂、-CO₂R⁶、-SO₂R⁶、-SO₂N(R⁴)₂、C_1-4Aliphatic radical, substituted or unsubstituted C_6-10Aryl or C_6-10Aryl (C)_1-4) Alkyl, the aryl portion of which is substituted or unsubstituted. Each R^dIndependently selected from the group consisting of: c_1-6Aliphatic radical, C_1-6Fluoroaliphatic radical, halo radical, -R^1d、-R^2d、-T²-R^1dand-T²-R^2dWherein the code is T²、R^1d、R^2dAnd R^8dHaving the values described below.

T²Is 0-2 independently selected R^3aOr R^3bSubstituted C_1-6An alkylene chain, wherein the alkylene chain is optionally interrupted by-C (R)⁵)＝C(R⁵) -, -C.ident.C-or-O-. Code number R^3aAnd R^3bHaving the values described above.

Each R^1dIndependently is a substituted or unsubstituted aryl groupHeteroaryl, heterocyclyl or cycloaliphatic ring.

Each R^2dIndependently is-NO₂、-CN、-C(R⁵)＝C(R⁵)₂、-C≡C-R⁵、-OR⁵、-SR⁶、-S(O)R⁶、-SO₂R⁶、-SO₂N(R⁴)₂、-N(R⁴)₂、-NR⁴C(O)R⁵、-NR⁴C(O)N(R⁴)₂、-N(R⁴)C(＝NR⁴)-N(R⁴)₂、-N(R⁴)C(＝NR⁴)-R⁶、-NR⁴CO₂R⁶、-N(R⁴)SO₂R⁶、-N(R⁴)SO₂N(R⁴)₂、-O-C(O)R⁵、-OC(O)N(R⁴)₂、-C(O)R⁵、-CO₂R⁵、-C(O)N(R⁴)₂、-C(O)N(R⁴)-OR⁵、-C(O)N(R⁴)C(＝NR⁴)-N(R⁴)₂、-N(R⁴)C(＝NR⁴)-N(R⁴)-C(O)R⁵or-C (═ NR)⁴)-N(R⁴)₂。

Each R^8dIndependently selected from the group consisting of: c_1-4Aliphatic radical, C_1-4Fluoroaliphatic radical, halo, -OH, -O (C)_1-4Aliphatic group), -NH₂、-NH(C_1-4Aliphatic radical) and-N (C)_1-4Aliphatic radical)₂。

In some embodiments, R^DIs a substituted or unsubstituted monocyclic or bicyclic ring system selected from the group consisting of: furyl, thienyl, pyrrolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuryl, benzothienyl, indolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, indazolyl, purinyl, naphthyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinuclidinylAn oxinyl group, a phthalazinyl group, a naphthyridinyl group, a tetrahydroquinolyl group, a tetrahydroisoquinolyl group, a tetrahydroquinoxalyl group, and a dihydrobenzoxazinyl group. In some embodiments, R^DIs a substituted or unsubstituted monocyclic or bicyclic ring system selected from the group consisting of: phenyl, pyridyl, pyrimidinyl, pyrazinyl, naphthyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, and dihydrobenzoxazinyl.

In some embodiments, R^DWherein one or two saturated ring carbon atoms are substituted by ═ O, and R^DFrom 0 to 1R to the remaining substitutable ring carbon atoms^dAnd 0-2R^8dSubstitution, wherein:

each R^dIndependently selected from the group consisting of: c_1-6Aliphatic radical, C_1-6Fluoroaliphatic radical, halo radical, -R^1d、-R^2d、-T²-R^1dand-T²-R^2d；

T²Is unsubstituted or substituted by R^3aOr R^3bSubstituted C_1-3An alkylene chain;

each R^1dIndependently is a substituted or unsubstituted aryl, heteroaryl, heterocyclic or cycloaliphatic ring; and is

Each R^2dIndependently is-OR⁵、-SR⁶、-S(O)R⁶、-SO₂R⁶、-SO₂N(R⁴)₂、-N(R⁴)₂、-NR⁴C(O)R⁵、-NR⁴C(O)N(R⁴)₂、-O-C(O)R⁵、-OC(O)N(R⁴)₂、-C(O)R⁵、-CO₂R⁵or-C (O) N (R)⁴)₂。

In some embodiments, the code R^dHaving the formula-Q-R^EWherein Q is-O-, -NH-or-CH₂-, and R^EIs substituted or unsubstituted aryl, heteroaryl, heterocyclyl orA cycloaliphatic ring. In some embodiments, R^EIs a substituted or unsubstituted phenyl, pyridyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl or morpholinyl ring.

In some embodiments, P has the formula R^c-C (O) -, wherein R^cIs C_1-4Alkyl radical, C_1-4Fluoroalkyl or C_6-10Aryl (C)_1-4) Alkyl, the aryl portion of which is substituted or unsubstituted. In certain such embodiments, P is selected from the group consisting of acetyl, trifluoroacetyl, and phenylacetyl.

In some embodiments, P has the formula R^D-C (O) -, wherein R^DIs a substituted or unsubstituted phenyl, pyridyl, pyrazinyl, pyrimidinyl, quinolinyl or quinoxalinyl group. In certain embodiments, P has the formula R^D-C (O) -, wherein R^DIs through 0-1R^dAnd 0-2R^8dSubstituted phenyl, pyridyl, pyrazinyl, pyrimidinyl, naphthyl, quinolinyl, quinoxalinyl, benzimidazolyl or dihydrobenzoxazinyl. In certain particular embodiments, P has the formula R^D-C (O) -, wherein R^DIs of the formula-O-R^EPyridyl, pyrazinyl or pyrimidinyl substituted with the substituent of (a), and R^EIs a substituted or unsubstituted phenyl group. In certain other particular embodiments, P has the formula R^D-C (O) -, wherein R^DIs of the formula-O-R^EPhenyl substituted with the substituent of (1), and R^EIs a substituted or unsubstituted pyridyl, pyrazinyl or pyrimidinyl group.

In some other embodiments, P has the formula R^c-SO₂-, wherein R^cis-R^Dor-T⁵-R^DWherein T is¹Is C_1-4Alkylene and R^DIs through 0-1R^dAnd 0-2R^8dSubstituted phenyl, pyridyl, pyrazinyl, pyrimidinyl, naphthyl, quinolinyl, quinoxalinyl, benzimidazolyl or dihydrobenzoxazinyl. In some embodiments, P has the formula R^D-SO₂-, wherein R^DIs substituted or unsubstituted phenyl, pyridyl,Pyrazinyl, pyrimidinyl, quinolinyl, or quinoxalinyl. In certain embodiments, P has the formula R^D-SO₂-, wherein R^DIs through 0-1R^dAnd 0-2R^8dSubstituted phenyl, pyridyl, pyrazinyl, pyrimidinyl, naphthyl, quinolinyl, quinoxalinyl, benzimidazolyl or dihydrobenzoxazinyl. In certain particular embodiments, P has the formula R^D-SO₂-, wherein R^DIs of the formula-O-R^EPyridyl, pyrazinyl or pyrimidinyl substituted with the substituent of (a), and R^EIs a substituted or unsubstituted phenyl group. In certain other particular embodiments, P has the formula R^D-SO₂-, wherein R^DIs of the formula-O-R^EPhenyl substituted with the substituent of (1), and R^EIs a substituted or unsubstituted pyridyl, pyrazinyl or pyrimidinyl group.

Code number R^a1And each code number R^a2Independently is C_1-6Aliphatic radical, C_1-6Fluoroaliphatic radical, - (CH)₂)_m-CH₂-R^B、-(CH₂)_m-CH₂-NHC(＝NR⁴)NH-Y、-(CH₂)_m-CH₂-CON(R⁴)₂、-(CH₂)_m-CH₂-N(R⁴)CON(R⁴)₂、-(CH₂)_m-CH(R⁶)N(R⁴)₂、-(CH₂)_m-CH(R⁵)-OR⁵Or- (CH)₂)_m-CH(R⁵)-SR⁵Wherein the code R⁴、R⁵And R⁶Having the values described above and the code R^BAnd m has the value described below.

Each R^BIndependently a substituted or unsubstituted monocyclic or bicyclic ring system. In some embodiments, each R^BIndependently a substituted or unsubstituted phenyl, pyridyl, indolyl, benzimidazolyl, naphthyl, quinolinyl, quinoxalinyl, or isoquinolinyl ring. In certain embodiments, R^BIs a substituted or unsubstituted phenyl ring.

The code m is 0, 1 or 2. In some embodiments, m is 0 or 1.

In some embodiments, R^a1And R^a2Each independently is C_1-6Aliphatic radical, C_1-6Fluoroaliphatic radical or- (CH)₂)_m-CH₂-R^BAnd m is 0 or 1. In some such embodiments, R^BIs a substituted or unsubstituted phenyl group.

In some embodiments, R^a1Is C_1-6Aliphatic radical, - (CH)₂)_m-CH₂R^BOr- (CH)₂)_m-CH(C_1-4Alkyl) -OH. In certain embodiments, R^a1Is benzyl. In certain other embodiments, R^a1is-CH₂-CH(CH₃)-OH。

In some embodiments, R^a2Is C_1-6Aliphatic radical or- (CH)₂)_m-CH₂R^B. In certain embodiments, R^a2Is isopropyl, benzyl or phenethyl.

Code number A is 0, 1 or 2. In some embodiments, a is 0 or 1. In certain embodiments, a is 0.

In some embodiments, the invention relates to compounds of formula (I) characterized by formula (I-a):

or a pharmaceutically acceptable salt or boronic acid anhydride thereof, each of which is identified by the code P, R^a1、R^a2、A、Z¹And Z²Having the values and preferred values described above for formula (I).

In certain embodiments, the invention relates to compounds of formula (I) characterized by formula (I-B):

or a pharmaceutically acceptable salt or boronic acid anhydride thereof, each of which is identified by the code P, R^a1、R^a2、A、Z¹And Z²Having the values and preferred values described above for formula (I).

In certain particular embodiments, the invention relates to compounds of formula (I) characterized by formula (II):

or a pharmaceutically acceptable salt or boronic acid anhydride thereof, each of which is identified by the code P, Z¹And Z²Having the values and preferred values described above for formula (I).

In some embodiments, the invention relates to compounds of formula (II) wherein P has formula R^D-C (O) -, wherein R^DIs a substituted or unsubstituted phenyl, pyridyl, pyrazinyl, pyrimidinyl, quinolinyl or quinoxalinyl group. In certain embodiments, P has the formula R^D-C (O) -, wherein R^DIs through 0-1R^dAnd 0-2R^8dSubstituted phenyl, pyridyl, pyrazinyl, pyrimidinyl, naphthyl, quinolinyl, quinoxalinyl, benzimidazolyl or dihydrobenzoxazinyl. In certain particular embodiments, P has the formula R^D-C (O) -, wherein R^DIs of the formula-O-R^EPyridyl, pyrazinyl or pyrimidinyl substituted with the substituent of (a), and R^EIs a substituted or unsubstituted phenyl group. In certain other particular embodiments, P has the formula R^D-C (O) -, wherein R^DIs of the formula-O-R^EPhenyl substituted with the substituent of (1), and R^EIs a substituted or unsubstituted pyridyl, pyrazinyl or pyrimidinyl group.

In some other embodiments, the present invention relates to compounds of formula (II), wherein P isHas a formula R^c-SO₂-, wherein R^cis-R^Dor-T¹-R^DWherein T is¹Is C_1-4Alkylene and R^DIs through 0-1R^dAnd 0-2R^8dSubstituted phenyl, pyridyl, pyrazinyl, pyrimidinyl, naphthyl, quinolinyl, quinoxalinyl, benzimidazolyl or dihydrobenzoxazinyl. In some embodiments, P has the formula R^D-SO₂-, wherein R^DIs a substituted or unsubstituted phenyl, pyridyl, pyrazinyl, pyrimidinyl, quinolinyl or quinoxalinyl group. In certain embodiments, P has the formula R^D-SO₂-, wherein R^DIs through 0-1R^dAnd 0-2R^8dSubstituted phenyl, pyridyl, pyrazinyl, pyrimidinyl, naphthyl, quinolinyl, quinoxalinyl, benzimidazolyl or dihydrobenzoxazinyl. In certain particular embodiments, P has the formula R^D-SO₂-, wherein R^DIs of the formula-O-R^EPyridyl, pyrazinyl or pyrimidinyl substituted with the substituent of (a), and R^EIs a substituted or unsubstituted phenyl group. In certain other particular embodiments, P has the formula R^D-SO₂-, wherein R^DIs of the formula-O-R^EPhenyl substituted with the substituent of (1), and R^EIs a substituted or unsubstituted pyridyl, pyrazinyl or pyrimidinyl group.

Representative examples of compounds of formula (I) are shown in table 1.

Table 1: proteasome inhibitors

The compounds in table 1 above can also be identified by the following chemical names:

the term "boronic acid" as used herein means a compound containing-B (OH)₂A moiety of a compound. In some embodiments, the boronic acid compound can form an oligomeric anhydride by dehydration of the boronic acid moiety. For example, sinader (Snyder) et al, U.S.Journal of graphic chemistry association (j.am.chem.soc.) 80: 3611(1958) report on oligomeric arylboronic acids.

The term "boronic anhydride" as used herein refers to a compound formed by the combination of two or more molecules of a boronic acid compound with the loss of one or more water molecules. When mixed with water, the boronic acid anhydride compound hydrates to release the free boronic acid compound. In various embodiments, the boronic anhydride can comprise two, three, four, or more boronic acid units, and can have a cyclic or linear configuration. Non-limiting examples of oligomeric boronic acid anhydrides of the peptide boronic acid compounds of the present invention are illustrated below:

in formulae (1) and (2), the code n is an integer from 0 to about 10, preferably 0, 1, 2, 3 or 4. In some embodiments, the boronic anhydride compound comprises a cyclic trimer of formula (2) ("boroxine"), wherein n is 1. Code number W has formula (3):

wherein the code is P, R^a1And R^a2Having the values and preferred values described above for formula (I).

In some embodiments, at least 80% of the boronic acids present in the boronic anhydride compound are present as a single oligomeric anhydride. In some embodiments, at least 85%, 90%, 95%, or 99% of the boronic acids present in the boronic anhydride compound are present as a single oligomeric anhydride. In certain preferred embodiments, the boronic acid anhydride compound consists of, or consists essentially of, a boroxine having formula (3).

The boronic anhydride compound can preferably be prepared from the corresponding boronic acid by exposure to dehydration conditions (including but not limited to recrystallization, freeze drying), exposure to heat, and/or exposure to a drying agent. Non-limiting examples of suitable recrystallization solvents include ethyl acetate, dichloromethane, hexane, diethyl ether, acetonitrile, ethanol, and mixtures thereof.

In some embodiments, Z¹And Z²Together forming a moiety derived from a boronic acid complexing agent. For the purposes of the present invention, the term "boronic acid complexing agent" refers to any compound having at least two functional groups, each of which can form a covalent bond with boron. Non-limiting examples of suitable functional groups include amino, hydroxyl, and carboxyl. In some embodiments, at least one functional group is a hydroxyl group. The term "moiety derived from a boronic acid complexing agent" refers to a moiety formed by removing a hydrogen atom from two functional groups of a boronic acid complexing agent.

The term "boronate ester/boronic ester" as used herein is used interchangeably and is meant to contain-B (Z)¹)(Z²) A compound of moiety wherein Z¹Or Z²At least one of which is alkoxy, aralkyloxy or aryloxy; or Z¹And Z²Together forming moieties derived from a boronic acid complexing agent having at least one hydroxyl group.

In the compounds of the formulae (I), (I-A), (I-B) and (II), Z¹And Z²Each independently is hydroxy, alkoxy, aryloxy, or aralkoxy; or Z¹And Z²Together forming a moiety derived from a boronic acid complexing agent. In some embodiments, Z¹And Z²Each is a hydroxyl group. In some other embodiments, Z¹And Z²Together form a moiety derived from a compound having at least two hydroxyl groups separated by at least two linking atoms in a chain or ring comprising carbon atoms and optionally one or more heteroatoms which may be N, S or O, wherein in each case is bonded to boronThe attached atom is an oxygen atom.

The term "compound having at least two hydroxyl groups" as used herein refers to any compound having two or more hydroxyl groups. For the purposes of the present invention, the two hydroxyl groups are preferably separated by at least two linking atoms, preferably from about 2 to about 5 linking atoms, more preferably 2 or 3 linking atoms. For convenience, the term "dihydroxy compound" may be used to refer to compounds having at least two hydroxyl groups as defined above. Thus, the term "dihydroxy compound" as used herein is not intended to be limited to compounds having only two hydroxyl groups. The moiety derived from a compound having at least two hydroxyl groups may be attached to the boron through the oxygen atoms of any two of the hydroxyl groups. The boron atom, the oxygen atom to which boron is attached and the atom linking the two oxygen atoms preferably together form a 5-or 6-membered ring.

For the purposes of the present invention, the boric acid complexing agent is preferably pharmaceutically acceptable, i.e. suitable for administration to humans. In some preferred embodiments, the boric acid complexing agent is a sugar, as described, for example, in WO02/059131 to Plamondon et al and WO02/059130 to Gupta (Gupta) et al. The term "saccharide" includes any polyhydroxy carbohydrate moiety, including monosaccharides, disaccharides, polysaccharides, sugar alcohols, and amino sugars. In some embodiments, the sugar is a monosaccharide, disaccharide, sugar alcohol, or amino sugar. Non-limiting examples of suitable sugars include glucose, sucrose, fructose, trehalose, mannitol, sorbitol, glucosamine, and N-methylglucamine. In certain embodiments, the sugar is mannitol or sorbitol. Thus, in embodiments where the sugar is mannitol or sorbitol, Z¹And Z²Together form formula C₆H₁₂O₆Wherein the oxygen atoms of the two deprotonated hydroxyl groups form a covalent linkage with boron, thereby forming a boronic ester compound. In certain particular embodiments, Z¹And Z²Together forming a moiety derived from D-mannitol.

In some other preferred embodiments, the boric acid complexing agent is an alpha-hydroxycarboxylic acid or a beta-hydroxycarboxylic acid, as described, for example, in U.S.12/485,344, filed on 6/16/2009 by eliliott (Elliott), et al. In some such embodiments, the boric acid complexing agent is selected from the group consisting of: glycolic acid, malic acid, hexahydromandelic acid, citric acid, 2-hydroxyisobutyric acid, 3-hydroxybutyric acid, mandelic acid, lactic acid, 2-hydroxy-3, 3-dimethylbutyric acid, 2-hydroxy-3-methylbutyric acid, 2-hydroxyisocaproic acid, β -hydroxyisovaleric acid, salicylic acid, tartaric acid, benzilic acid, glucoheptonic acid, maltobionic acid, lactobionic acid, galactaric acid, embonic acid (embonic acid), 1-hydroxy-2-naphthoic acid and 3-hydroxy-2-naphthoic acid. In certain described embodiments, the boric acid complexing agent is citric acid.

General synthetic method

The compounds of formula (I) can be prepared by methods known to those skilled in the art. See, e.g., U.S. Pat. Nos. 5,780,454 to Adams (Adams), et al; international patent publication WO2005/097809 to Pickersgill et al. N-acyl-peptidyl boronic acid compounds of the invention (p ═ R)^cAn exemplary synthetic route for-C (O) -) is set forth in scheme 1 below.

Scheme 1:

coupling compound i with the N-protected amino acid (ii) followed by removal of the N-terminal protecting group forms compound iii. Examples of suitable Protecting Groups (PG) include, but are not limited to: acyl protecting groups such as formyl, acetyl (Ac), succinyl (Suc) and methoxysuccinyl; and carbamate protecting groups such as t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz) and fluorenylmethoxycarbonyl (Fmoc). Peptide coupling reactions can be carried out by first converting the carboxylic acid moiety of compound ii to an activated ester (e.g., an O- (N-hydroxysuccinimide) ester), followed by treatment with compound i. Alternatively, the activated ester may be generated in situ by contacting the carboxylic acid with a peptide coupling reagent. Examples of suitable peptide coupling reagents include (but are not limited to): carbodiimide reagents such as Dicyclohexylcarbodiimide (DCC) or 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC); phosphonium reagents, such as benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP); and urea salt reagents such as O- (1H-benzotriazol-1-yl) -N, N' -tetramethyluronium tetrafluoroborate (TBTU).

Followed by reacting the compound iii with a carboxylic acid (R)^cCO₂H) Coupling gives the compound iv. The peptide coupling conditions described above for the coupling of compound i with compound ii also apply to the coupling of compound iii with R^cCO₂H. Subsequently, the protecting group of the boronic acid moiety is deprotected to give compound v. Preferably by including borate compound iv, organic borate acceptor, lower alkanol, C_5-8And (3) performing transesterification reaction in a two-phase mixture of a hydrocarbon solvent and an inorganic acid aqueous solution to complete the step of removing the protecting group.

And (2) a flow scheme:

alternatively, the order of the coupling reaction is reversed as shown in scheme 2. Thus, first an O-protected glycine (vi) is reacted with a substituted benzoic acid (ArCO)₂H) Coupling followed by ester hydrolysis to form compound vii. Subsequently, coupling to compound i and boronic acid protecting group removal is accomplished as described above for scheme 1 to afford compound v.

Preparation of N-sulfonyl-peptidyl boronic acid compounds of the invention (P ═ R)^c-S(O)₂-) an exemplary synthetic route is set forth in scheme 3 below:

and (3) a flow path:

treatment of compound iii prepared as described above for scheme 1 with sulfonyl chloride in the presence of a base such as diisopropylethylamine affords compound vi. Subsequently, deprotection of the boronic acid moiety is accomplished as described above for scheme 1 to provide compound vii. The reaction sequence for the preparation of compound vii can also be reversed in a manner analogous to scheme 2.

Use, formulation and administration

The present invention provides compounds that are potent inhibitors of the proteasome. The ability of the compounds to inhibit proteasome-mediated peptide hydrolysis or protein degradation can be assayed in vitro or in vivo.

Thus, in another aspect, the invention provides a method of inhibiting one or more peptidase activities of a proteasome in a cell, comprising contacting a cell in need of proteasome inhibition with a compound described herein, or a pharmaceutically acceptable salt, borate, or boronic anhydride thereof.

The invention also provides a method of inhibiting cell proliferation comprising contacting a cell in need of such inhibition with a compound described herein. The phrase "inhibiting cell proliferation" is used to indicate the ability of a compound of the invention to inhibit the cell number or cell growth of a contacted cell compared to a cell not contacted with the inhibitor. Cell proliferation can be assessed by counting cells using a cell counter or by cell viability assays (e.g., MTT or WST assays). Such assessment of cell proliferation can be made when the cells are in solid growth (e.g., a solid tumor or organ), for example, by measuring growth with a caliper and comparing the scale of growth of contacted cells to non-contacted cells.

Preferably, the growth of cells contacted with the inhibitor is retarded by at least about 50% compared to the growth of non-contacted cells. In various embodiments, cell proliferation is inhibited by at least about 75%, at least about 90%, or at least about 95% in the contacted cell compared to the non-contacted cell. In some embodiments, the phrase "inhibiting cell proliferation" includes a reduction in the number of contacted cells as compared to non-contacted cells. Thus, a proteasome inhibitor that inhibits cell proliferation of a contacted cell can induce the contacted cell to undergo growth retardation, to undergo growth arrest, to undergo programmed cell death (i.e., apoptosis), or to undergo necrotic cell death.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or boronic anhydride thereof, and a pharmaceutically acceptable carrier.

If pharmaceutically acceptable salts of the compounds of the present invention are used in these compositions, the salts are preferably derived from inorganic or organic acids or bases. For a review of suitable salts, see, e.g., bellqi (Berge) et al, journal of medical science (j.pharm.sci.) 66: 1-19(1977) and Remington: pharmaceutical science and Practice (Remington: The science and Practice of Pharmacy), 20 th edition, ed.Gennaro (A.Gennaro), Leipisco Williams and Wilkins Press (Lippincott Williams & Wilkins), 2000.

Non-limiting examples of suitable acid addition salts include the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate (lucoheptanoate), glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectate, persulfate, 3-phenyl-propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.

Suitable base addition salts include (but are not limited to): an ammonium salt; alkali metal salts such as lithium salts, sodium salts, and potassium salts; alkali metal salts, such as calcium and magnesium salts; other polyvalent metal salts, such as zinc salts; with a solvent such as dicyclohexylamine, N-methyl-D-glucamine, tert-butylamine,Salts with organic bases such as ethylenediamine, ethanolamine, and choline; and salts with amino acids such as arginine, lysine, and the like. In some embodiments, the pharmaceutically acceptable salt is a base addition salt of a boronic acid compound of formula (I), wherein Z is¹And Z²Are all hydroxyl groups.

The term "pharmaceutically acceptable carrier" as used herein refers to a substance that is compatible with the recipient subject (preferably a mammal, more preferably a human) and is suitable for delivering an active agent to a target site without terminating the activity of the agent. Toxicity or adverse effects associated with the carrier, if present, are preferably commensurate with a reasonable risk/benefit ratio for the intended use of the active agent.

The terms "carrier," "adjuvant," or "vehicle" are used interchangeably herein and include any and all solvents, diluents, and other liquid vehicles, dispersants or dispersion aids, surfactants, pH adjusters, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, and the like, as appropriate for the particular desired dosage form. Remington: the pharmaceutical sciences and practices (Remington: The Science and Practice of Pharmacy), 20 th edition, ed.A. Gennaro (A.Gennaro), Leipisco Williams and Wilkins Press (Lippincott Williams & Wilkins), 2000, disclose various carriers and known techniques for their preparation for formulating pharmaceutically acceptable compositions. Unless any conventional carrier medium is incompatible with the compounds of the present invention, such as by producing any undesirable biological effect, or otherwise interacting in a deleterious manner with any other component of a pharmaceutically acceptable composition, its use is contemplated within the scope of the present invention. Some examples of materials that can be used as pharmaceutically acceptable carriers include (but are not limited to): an ion exchanger; alumina; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphates, carbonates, magnesium and aluminium hydroxides, glycine, sorbic acid or potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; no pyrogen water; salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts; colloidal silicon dioxide; magnesium trisilicate; polyvinylpyrrolidone; a polyacrylate; a wax; a polyethylene-polyoxypropylene capped polymer; lanolin; sugars such as lactose, glucose, sucrose and mannitol; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc powder; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; alginic acid; isotonic saline water; ringer's solution (Ringer's solution); alcohols such as ethanol, isopropanol, cetyl alcohol and glycerol; cyclodextrins, such as hydroxypropyl- β -cyclodextrin and sulfobutyl ether- β -cyclodextrin; lubricants such as sodium lauryl sulfate and magnesium stearate; petroleum hydrocarbons such as mineral oil and paraffin wax. Coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preserving and anti-oxidizing agents may also be present in the composition according to the judgment of the formulator.

The pharmaceutical compositions of the present invention may be manufactured by methods well known in the art, such as, inter alia, conventional granulation, mixing, dissolution, encapsulation, lyophilization, or emulsification methods. The compositions may be produced in a variety of forms including granules, precipitates or microparticles, powders (including freeze-dried powders, spin-dried powders, or spray-dried powders), amorphous powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions, or solutions.

According to a preferred embodiment, the composition of the invention is formulated for pharmaceutical administration to a mammal, preferably a human. The pharmaceutical compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implantable reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intravenously or subcutaneously. The formulations of the present invention may be designed as short-acting, fast-release or long-acting formulations. Further, the compounds may be administered locally rather than systemically, such as at the tumor site (e.g., by injection).

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, cyclodextrin, dimethylformamide; oils (especially cottonseed, groundnut, corn, germ, olive, castor and sesame oils); glycerol; tetrahydrofurfuryl alcohol; polyethylene glycol; and fatty acid esters of sorbitan; and mixtures thereof. In addition to inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a parenterally acceptable non-toxic diluent or solvent, for example as a solution in 1, 3-butanediol. Acceptable vehicles and solvents that can be used include water, ringer's solution, U.S. p. and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. Thus, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids, such as oleic acid, are used in the preparation of injectables. The injection formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents, in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injection medium prior to use. Compositions formulated for parenteral administration may be injected by bolus injection or timed bolus injection, or may be administered by continuous infusion.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one of the following: a pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or dicalcium phosphate; and/or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia; c) humectants, such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) dissolution retarders, such as paraffin; f) absorption promoters, such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glyceryl monostearate; h) absorbents such as kaolin and bentonite; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents, such as phosphates or carbonates.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose (lactose/milk sugar) and high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical compounding art. They may optionally contain opacifying agents and may also have a composition such that they release the active ingredient(s) only or preferentially in a certain portion of the intestinal tract, or optionally in a delayed manner. Examples of embedding compositions that can be used include polymers and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose (lactose/milk sugar) and high molecular weight polyethylene glycols and the like.

The active compounds may also be formulated in microencapsulated form using one or more of the above excipients. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In these solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. In normal practice, these dosage forms may also contain other substances in addition to inert diluents, for example tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, these dosage forms may also comprise buffering agents. It may optionally contain opacifying agents and may also have a composition that it releases the active ingredient only or preferentially in a certain portion of the intestinal tract, or optionally in a delayed manner. Examples of embedding compositions that can be used include polymers and waxes.

Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is combined under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives or buffers as required. Ophthalmic formulations, ear drops, and eye drops are also contemplated to be within the scope of the present invention. Furthermore, the present invention encompasses the use of transdermal patches, which have the additional advantage of providing controlled delivery of the compound to the body. These dosage forms may be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers may also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

In some embodiments, the compound of formula (I) is administered intravenously. In some such embodiments, Z is described in WO02/059131 to Plamondon et al, which is incorporated herein by reference in its entirety¹And Z²The compounds of formula (I) which together form a moiety derived from a boronic acid complexing agent may be prepared in lyophilized powder form. In some embodiments, the lyophilized powder further comprises a free boric acid complexing agent. Preferably, the free boric acid complexing agent and the compound of formula (I) are present in a ratio of about 0.5: 1 to about 100: 1. more preferably about 5: 1 to about 100: 1 rangeThe molar ratio of (a) to (b) is present in the mixture. In various embodiments, the lyophilized powder comprises a molar ratio of between about 10: 1 to about 100: 1. about 20: 1 to about 100: 1 or about 40: 1 to 100: 1 with a corresponding borate ester.

In some embodiments, the lyophilized powder comprises a boric acid complexing agent and a compound of formula (I), substantially free of other components. However, the composition may also include one or more other pharmaceutically acceptable excipients, carriers, diluents, fillers, salts, buffers, bulking agents, stabilizers, solubilizers, and other materials well known in the art. The preparation of pharmaceutically acceptable formulations containing these substances is described, for example, in remington: medical Science and practice (Remington: The Science and practice of pharmacy), 20 th edition, ed.A. Gennaro (A.Gennaro), Leipikoc Williams and Wilkins Press (Lippincott Williams & Wilkins), 2000 or The latest edition. In some embodiments, the pharmaceutical composition comprises a compound of formula (I), a bulking agent, and a buffer.

Lyophilized powders comprising the compound of formula (I) may be prepared according to the procedures described in WO02/059131 to pramonon et al. Thus, in some embodiments, a method of preparing a lyophilized powder comprises: (a) preparation of a boronic acid compound comprising formula (I) (wherein z is¹And Z²Each hydroxyl group) and a boric acid complexing agent; and (b) lyophilizing the mixture.

The lyophilized powder is preferably reconstituted by addition of an aqueous solvent suitable for pharmaceutical administration. Examples of suitable reconstitution solvents include, but are not limited to, water, saline, and Phosphate Buffered Saline (PBS). The lyophilized powder is preferably reconstituted with physiological (0.9%) saline. Upon reconstitution, an equilibrium is established between the boronic ester compound and the corresponding free boronic acid compound. In some embodiments, equilibration is achieved rapidly, e.g., within 10-15 minutes, after addition of the aqueous medium. The relative concentrations of borate and boric acid present at equilibrium depend on parameters such as the pH of the solution, the temperature, the nature of the boric acid complexing agent, and the ratio of boric acid complexing agent to borate compound present in the lyophilized powder.

The pharmaceutical compositions of the present invention are preferably formulated for administration to a patient suffering from, or at risk of developing, a proteasome-mediated disorder or experiencing a recurrence of the disorder. The term "patient" as used herein means an animal, preferably a mammal, more preferably a human. Preferred pharmaceutical compositions of the present invention are pharmaceutical compositions formulated for oral, intravenous or subcutaneous administration. However, any of the above dosage forms containing a therapeutically effective amount of a compound of the present invention are well within the scope of routine experimentation and, therefore, are also well within the scope of the present invention. In some embodiments, the pharmaceutical composition of the invention may also comprise another therapeutic agent. In some embodiments, the other therapeutic agent is a therapeutic agent that is typically administered to a patient having the disease or condition being treated.

By "therapeutically effective amount" is meant an amount sufficient to cause a detectable reduction in the severity of a proteasome activity or a proteasome-mediated disorder. The amount of proteasome inhibitor required will depend on the effectiveness of the inhibitor for a given cell type and the length of time required to treat the disorder. It will also be understood that the specific dose and treatment regimen for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex and diet of the patient, the time of administration, the rate of excretion, drug combination and the judgment of the treating physician, and the severity of the particular disease being treated. The amount of other therapeutic agent present in the compositions of the present invention will generally not exceed that normally administered using compositions that contain only the therapeutic agent as the only active agent. Preferably, the amount of the other therapeutic agent will range from about 50% to about 100% of the amount typically present in a composition comprising the agent as the sole therapeutically active agent.

In another aspect, the invention provides a method of treating a patient having, or at risk of developing, a proteasome-mediated disorder or experiencing a recurrence of the disorder. The term "proteasome-mediated disorder" as used herein includes any disorder, disease or condition resulting from or characterized by increased proteasome expression or activity, or requiring proteasome activity. The term "proteasome-mediated disorder" also includes any disorder, disease or condition in which inhibition of proteasome activity is beneficial.

For example, the compounds and pharmaceutical compositions of the invention are useful in the treatment of proteins modulated by proteasome activity (e.g., nfk B, p 27)^Kip、p21^WAF/CIP1P 53). Related disorders include inflammatory disorders (e.g., rheumatoid arthritis, inflammatory bowel disease, asthma, Chronic Obstructive Pulmonary Disease (COPD), osteoarthritis, skin diseases (e.g., atopic dermatitis, psoriasis)), vasculoproliferative disorders (e.g., atherosclerosis, restenosis), proliferative ocular disorders (e.g., diabetic retinopathy), benign proliferative disorders (e.g., hemangioma), autoimmune diseases (e.g., multiple sclerosis, tissue and organ rejection), and infection-related inflammation (e.g., immune response), neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease, motor neuron disease, neuropathic pain, trisomy repeat disorders, astrocytoma, and neurodegeneration resulting from alcoholic liver disease), ischemic injury (e.g., stroke), and cachexia (e.g., with various physiological and pathological conditions (e.g., nerve injury, nerve damage, nerve, Fasting, fever, acidosis, HIV infection, cancer affliction, and certain endocrinopathies).

The compounds and pharmaceutical compositions of the invention are particularly useful in the treatment of cancer. The term "cancer" as used herein refers to a cellular disorder characterized by unregulated or unregulated cell proliferation, reduced cell differentiation, inappropriate ability to invade surrounding tissues, and/or the ability to establish new growth at an ectopic site. The term "cancer" includes, but is not limited to, solid tumors and hematological tumors. The term "cancer" encompasses diseases of the skin, tissue, organs, bone, cartilage, blood and blood vessels. The term "cancer" also encompasses primary and metastatic cancers.

Differences in enzyme kinetics (i.e., dissociation half-lives) between the various proteasome inhibitors can result in differences in tissue distribution of the various inhibitors, which can result in differences in safety and efficacy profiles. For example, where slow reversible and irreversible inhibitors are used, a substantial proportion of the molecules may bind to proteasomes in red blood cells, vascular endothelium, and well-perfused organs such as the liver (i.e., the most "immediately available" proteasomes in the most recent compartment). These sites can effectively act as "sinks" where these agents rapidly bind to molecules and affect distribution in solid tumors.

Without wishing to be bound by theory, the inventors believe that compounds that dissociate more rapidly from the proteasome are more efficiently distributed to the tumor, resulting in improved antitumor activity. In some embodiments, the invention relates to a method of treating a patient having cancer comprising administering to the patient a compound of any one of formula (I), (I-a), (I-B), or (II), wherein the compound exhibits a dissociation half-life of less than 60 minutes. In some embodiments, the compound exhibits a dissociation half-life of less than 10 minutes.

Non-limiting examples of solid tumors that can be treated with the disclosed proteasome inhibitors include: pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent prostate cancer and androgen-independent prostate cancer; kidney cancers, including, for example, metastatic renal cell carcinoma; hepatocellular carcinoma; lung cancer including, for example, non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and lung adenocarcinoma; ovarian cancers, including, for example, progressive epithelial or primary peritoneal cancers; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, for example, phosphonium cell carcinoma of the head and neck; melanoma; neuroendocrine cancers, including metastatic neuroendocrine tumors; brain tumors, including, for example, glioma, degenerative oligodendroglioma, adult glioblastoma multiforme, and adult degenerative astrocytoma; bone cancer; and soft tissue sarcomas.

Non-limiting examples of hematological malignancies that can be treated with the disclosed proteasome inhibitors include: acute Myeloid Leukemia (AML); chronic Myelogenous Leukemia (CML), including accelerated CML and CML catastrophe (CML-BP); acute Lymphoblastic Leukemia (ALL); chronic Lymphoblastic Leukemia (CLL); hodgkin's Disease (HD); non-Hodgkin's lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma; b cell lymphoma; t cell lymphoma; multiple Myeloma (MM); waldenstrom's macroglobulinemia (Waldenstrom's macroglobulinemia); myelodysplastic syndromes (MDS) including Refractory Anemia (RA), refractory anemia with rounded basal granulocytes (RARS), refractory anemia with blastocytosis (RAEB) and transformed RAEB (RAEB-T); and myeloproliferative syndromes.

In some embodiments, a compound or composition of the invention is used to treat a patient having or at risk of developing a cancer selected from the group consisting of multiple myeloma and mantle cell lymphoma, or experiencing a recurrence of said cancer.

In some embodiments, the proteasome inhibitor of the present invention can be administered in combination with another therapeutic agent. Another therapeutic agent may also inhibit the proteasome, or may act through a different mechanism. In some embodiments, the other therapeutic agent is one that is typically administered to a patient having the disease or condition being treated. The proteasome inhibitor of the present invention can be administered with another therapeutic agent in a single dosage form or in separate dosage forms. When administered in separate dosage forms, the other therapeutic agent can be administered prior to, concurrently with, or subsequent to the administration of the proteasome inhibitor of the present invention.

In some embodiments, the proteasome inhibitor of formula (I) is administered in combination with an anti-cancer agent. The term "anti-cancer agent" as used herein refers to any agent that is administered to an individual having cancer for the purpose of treating cancer.

Non-limiting examples of DNA damaging chemotherapeutic agents include: topoisomerase I inhibitors (e.g., irinotecan (irinotecan), topotecan (topotecan), camptothecin (camptothecin) and analogs or metabolites thereof, and doxorubicin (doxorubicin)); topoisomerase II inhibitors (e.g. etoposide, teniposide and daunorubicin); alkylating agents (e.g., melphalan (melphalan), chlorambucil (chlorambucil), busulfan (busufan), thiotepa (thiotepa), ifosfamide (ifosfamide), carmustine (carmustine), lomustine (lomustine), semustine (semustine), streptozocin (streptozocin), dacarbazine (decarbazine), methotrexate (methotrexate), mitomycin c (mitomycin c), and cyclophosphamide (cyclophophamide)); DNA intercalators (e.g., cisplatin (cissplatin), oxaliplatin (oxaliplatin), and carboplatin); DNA intercalators and free radical generators, such as bleomycin (bleomycin); and nucleoside mimetics (e.g., 5-fluorouracil (5-fluorouracil), truncatorin (capecitabine), gemcitabine (gemcitabine), fludarabine (fludarabine), cytarabine (cytarabine), mercaptopurine (mercaptoprine), thioguanine (thioguanine), pentostatin (pentostatin), and hydroxyurea (hydroxyurea)).

Chemotherapeutic agents that interfere with cell replication include: paclitaxel (paclitaxel), docetaxel (docetaxel) and related analogs; vincristine (vincristine), vinblastine (vinblastin) and related analogs; thalidomide (thalidomide), lenalidomide (lenalidomide), and related analogs (e.g., CC-5013 and CC-4047); protein tyrosine kinase inhibitors (e.g., imatinib mesylate and gefitinib); proteasome inhibitors (e.g., bortezomib); NF- κ B inhibitors, including inhibitors of I κ B kinase; antibodies that bind to proteins that are overexpressed in cancer and thereby down-regulate cell replication (e.g., trastuzumab (trastuzumab), rituximab (rituximab), cetuximab (cetuximab), and bevacizumab); and other inhibitors of proteins or enzymes known to be up-regulated, over-expressed or activated in cancer, wherein inhibition of these proteins or enzymes down-regulates cell replication.

Detailed Description

In order to more fully understand the present invention, the following preparation and test examples are set forth. These examples illustrate how to prepare or test a particular compound and should not be construed in any way as limiting the scope of the invention.

Examples of the invention

Definition of

ACN acetonitrile

BOC tert-butyloxycarbonyl radical

DCM dichloromethane

DIBAL diisobutylaluminum hydride

DIEA diisopropylethylamine

DMF dimethyl formamide

EDCI N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride

EtOAc ethyl acetate

h hours

HOBt 1-hydroxybenzotriazole hydrate

homophe-OH homophenylalanine

HPLC high performance liquid chromatography

LC/MS liquid chromatography mass spectrometry

LiHMDS lithium bis (trimethylsilane) amide

min for

NMM 4-methylmorpholine

R_tResidence time from diode array spectra

TBTU tetrafluoroborate O-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium salts

THF tetrahydrofuran

TLC thin layer chromatography

Analytical LC-MS method

LCMS conditions

Boric acid was analyzed with a Waters Symmetry 3.5 μm C186 x 100 mm ID column using the following gradient: solvent A: 1% acetonitrile, 99% water, 0.1% formic acid

Solvent B: 95% acetonitrile, 5% water, 0.1% formic acid

Time of day	A[％]	B[％]	Flow rate [ ml/min ]]
				0.0	95.0	5.0	1.0
7.5	0.0	100.0	1.0
				9.8	0.0	100.0	1.0
9.8	95.0	5.0	1.0
				10.0	95.0	5.0	1.0

The spectrum of the intermediate was carried out in Hewlett-Packard HP1100 using the following conditions:

formic acid: phenominex Luna5 mu mC₁₈50X 4.6mm column, flow rate 2.5mL/min, gradient in 3 min in H₂ACN in O containing 0 to 100% 0.1% formic acid.

Ammonium acetate: phenominex Luna5 mu m C₁₈50X 4.6mm column, flow rate 2.6mL/min, gradient in 3 min in H₂ACN in O containing 0 to 100% 10mM ammonium acetate.

Example 1: (1R) -2-cyclobutyl-1- [ (3aS, 4S, 6S) -3a, 5, 5-trimethylhexahydro-4, 6-methano-1, 3, 2-benzodioxolan-2-yl)]Ethylamine C₂HO₂F₃(intermediate 4)

Step 1: (3aS, 4S, 6S) -2- (dichloromethyl) -3a, 5,5-trimethylhexahydro-4, 6-methylene-1, 3, 2-benzodioxyl Boroadole (intermediate 1)

In N₂Then, at-80 ℃ to-90 ℃ to CH₂Cl₂(80mL, 1.2mol) to a solution in THF (800mL) was added n-butyllithium (2.5M in hexane, 480mL, 1.2mol), and the reaction mixture was stirred at-80 ℃ or less for 1.5 h. Adding B (OEt) in whole portion₃(200mL, 1.2mol), and the mixture was stirred at-45 ℃ to-30 ℃ for 1 hour. An aqueous solution of HC1 (5M, 240mL, 1.2mol) was then added dropwise at a temperature below-20 ℃ and the resulting mixture was stirred at-20 ℃ for 4 hours. The organic layer was separated and washed with Et₂The aqueous layer was extracted with O (100 mL. times.2). The combined organic layers were passed over anhydrous Na₂SO₄Dried and concentrated to give an intermediate. Redissolving the intermediate in Et₂O (800mL), and pinanediol (188g, 1.1mol) was added to the solution. The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 10: 1 to 1: 1) to give intermediate 1(190g, 60% yield).

Step 2: (3aS, 4S, 6S) -2- [ (1S) -1-chloro-2-cyclobutylethyl)]-3a, 5, 5-trimethylhexahydro-4, 6-methylene -1, 3, 2-benzodioxolane (intermediate 2)

In N₂Next, DIBAL (1M in toluene, 9.1mL, 9.1mmol) was added to Mg (13.60g, 560mmol) in THF (650mL) and the mixture was stirred at room temperature for 30 min. Intermediate 2(40.6mL, 360mmol) was then added dropwise at below 40 ℃ and the reaction mixture was stirred at room temperature for 2.5 hours. After cooling to-78 ℃ in N₂The solution was transferred to a solution of intermediate 1(70g, 0.267mol) in THF (400mL) at-78 deg.C under protection and the resulting mixture was stirred for 45 min. Subsequent addition of ZnCl in portions₂(in Et)₂1M in O, 750mL, 750mmol), the mixture was allowed to warm to room temperature and stirred overnight. To the reaction mixture was added ethyl acetate (800mL) and saturated NH₄Cl (350mL), stir the mixture for 1 hour and add water (300mL), brine(300mL) the organic layer was washed with anhydrous Na₂SO₄Dried and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 20: 1 to 2: 1) to give intermediate 2(65g, 82% yield) as a colorless oil.

And step 3: n- { (1R) -2-cyclobutyl-1- [ (3aS, 4S, 6S) -3a, 5, 5-trimethylhexahydro-4, 6-methano-1, 3, 2-benzene Dioxoborolan-2-yl]Ethyl } -1, 1, 1-trimethyl-N- (trimethylsilyl) silanamine (intermediate 3)

In N₂To a solution of LiHMDS (1M in THF, 500mL, 0.5mol) in THF (500mL) at-78 ℃ under protection was added a solution of intermediate 2(130g, 0.438mol) in THF (700 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. The solvent was removed by rotary evaporation and Et at 1.0L₂O/Hex (1: 1) dissolves the residue. The solution was filtered through a pad of silica gel (300g) and Et 500mL₂O/Hex (1: 1) wash. Concentration of the solution gave intermediate 3(166g, 90%) as a colorless oil.

And 4, step 4: (1R) -2-cyclobutyl-1- [ (3aS, 4S, 6S) -3a, 5, 5-trimethylhexahydro-4, 6-methano-1, 3, 2-benzodi Oxoborolan-2-yl]Ethylamine C ₂ HO ₂ F ₃ (intermediate 4)

Intermediate 3(166g, 0.39mol) in Et at-45 deg.C₂To a solution in O (1.5L) was added TFA (92mL, 1.2mol) in Et₂Solution in O (500 mL). The mixture was allowed to warm to room temperature and stirred for 1 hour. The precipitate was collected by filtration and taken up as Et₂O (200mL × 3) wash afforded intermediate 4(103g, 71% yield) as a white solid.

Example 2: { (1R) -1- [ ((2S) -2- { [ (2S) -2- (acetylamino) -4-phenylbutyryl ] amino } -3-phenylpropionyl) amino ] -2-cyclobutylethyl } boronic acid (22)

Step 1: [ (1S) -1-benzyl-2- ({ (1R) -2-cyclobutyl-1- [ (3aS, 4S, 6S, 7aR) -3a, 5, 5-trimethylhexahydro-l -4, 6-methylene-1, 3, 2-benzodioxolan-2-yl]Ethyl } amino) -2-pendant oxyethyl group]Carbamic acid tert-butyl ester

To a single neck round bottom flask was added intermediate 4(496mg, 1.26mmol) N- (tert-butoxycarbonyl) -L-phenylalanine (0.362g, 1.36mmol), TBTU (0.640g, 1.99mmol) and N, N-dimethylformamide (10.0mL, 0.129 mol). N, N-diisopropylethylamine (1.12mL, 6.40mmol) was then added dropwise at-45 ℃. After 20 minutes the cooling bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water, then the organic layer was washed with 3 × 100mL water and 3 × 100mL brine. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. The resulting residue was purified by column chromatography in 40% EA/hex to give 0.55g (84% yield) of the product as an off-white solid.

Step 2: (2S) -2-amino-N- { (1R) -2-cyclobutyl-1- [ (3aS, 4S, 6S, 7aR) -3a, 5, 5-trimethylhexahydro-4, 6- Methylene-1, 3, 2-benzodioxolan-2-yl]Ethyl } -3-phenylpropionamide HC1

To a single neck round bottom flask were added tert-butyl [ (1S) -1-benzyl-2- ({ (1R) -2-cyclobutyl-1- [ (3aS, 4S, 6S, 7aR) -3a, 5, 5-trimethylhexahydro-4, 6-methylene-1, 3, 2-benzodioxoborolan-2-yl ] ethyl } amino) -2-lateraloxyethyl ] carbamate (0.550g, 1.05mmol), dichloromethane (6.00mL, 0.0936mol) and a 4.0M solution of hydrochloric acid in 1, 4-dioxane (6.00mL, 0.024 mol). The mixture was stirred at room temperature for 30 minutes. Removal of the solvent and HC1 in vacuo gave 0.517g (99% yield) of the desired product as a white solid.

And step 3: [ (1S) -1- ({ [ (1S) -1-benzyl-2- ({ (1R) -2-cyclobutyl-1- [ (3aS, 4S, 6S, 7aR) -3a, 5, 5-Tris-D-methyl-l-ethyl-l-methyl-l-ethyl-l-methyl- Methylhexahydro-4, 6-methylene-1, 3, 2-benzodioxolan-2-yl]Ethyl } amino) -2-oxoEthyl radical]Amino } carbonyl 3-phenylpropyl radical]Carbamic acid tert-butyl ester

To a single-necked round-bottomed flask was added successively dropwise (2S) -2-amino-N- { (1R) -2-cyclobutyl-1- [ (3aS, 4S, 6S, 7aR) -3a, 5, 5-trimethylhexahydro-4, 6-methylene-1, 3, 2-benzodioxoborolan-2-yl ] ethyl } -3-phenylpropanamide (217mg, 0.511mmol), Boc-homophe-OH (171mg, 0.614mmol), TBTU (246mg, 0.767mmol) and N, N-dimethylformamide (14.5mL, 0.187mol) at room temperature, followed by N, N-diisopropylethylamine (0.187mL, 1.07 mmol). The mixture was stirred at room temperature overnight. DMF was removed from the reaction mixture under vacuum and the resulting residue was purified by preparative TLC in 40% EtOAc/hexanes to give 298mg (85% yield) of the desired product as a white solid.

And 4, step 4: (2S) -2-amino-N- [ (1S) -1-benzyl-2- ({ (1R) -2-cyclobutyl -1- [ (3aS, 4S, 6S, 7aR) -3a, 5, 5-trimethylhexahydro-4, 6-methano-1, 3, 2-benzodioxolan-2-yl]Ethyl ammonia 2-oxo-ethyl radical]-4-phenylbutanamide HC1

To a single neck round bottom flask was added successively tert-butyl [ (1S) -1- ({ [ (1S) -1-benzyl-2- ({ (1R) -2-cyclobutyl-1- [ (3aS, 4S, 6S, 7aR) -3a, 5, 5-trimethylhexahydro-4, 6-methylene-1, 3, 2-benzodioxolan-2-yl ] ethyl } amino) -2-lateraloxyethyl ] amino } carbonyl) -3-phenylpropyl ] carbamate (298mg, 0.000434mol), dichloromethane (3.0mL, 0.047mol) and a 4.0M solution of hydrochloric acid in 1, 4-dioxane (3.0mL, 0.012 mol). The mixture was stirred at room temperature for 30 minutes, then the solvent was removed in vacuo to yield 0.243 denier (90% yield) of the desired product.

And 5: (2S) -2- (acetylamino) -N- [ (1S) -1-benzyl-2- ({ (1R) -2-cyclobutyl -1- [ (3aS, 4S, 6S, 7aR) -3a, 5, 5-trimethylhexahydro-4, 6-methano-1, 3, 2-benzodioxolan-2-yl]Ethyl ammonia 2-oxo-ethyl radical]-4-phenylbutanamide

To a 20mL scintillation vial was added (2S) -2-amino-N- [ (1S) -1-benzyl-2- ({ (1R) -2-cyclobutyl-1- [ (3aS, 4S, 6S, 7aR) -3a, 5, 5-trimethylhexahydro-4, 6-methylene-1, 3, 2-benzodioxolan-2-yl]Ethyl } amino) -2-pendant oxyethyl group]-4-phenylbutanamide HC1(52.0mg, 0.0836mmol), acetonitrile (5.20mL, 0.0996mol), acetic anhydride (8.68 μ L, 0.092mmol), N-diisopropylethylamine (36.4 μ L, 0.209mmol) and N, N-dimethylaminopyridine (0.0005g, 0.004 mmol). The mixture was stirred overnight and the precipitate was filtered and washed with Et₂O wash gave 0.028g (53% yield) of the product as a white solid.

Step 6: { (1R) -1- [ ((2S) -2- { [ (2S) -2- (acetylamino) -4-phenylbutyryl]Amino } -3-phenylpropionyl Radical) amino]-2-Cyclobutylethyl } boronic acid

To a single neck round bottom flask was added (2S) -2- (acetylamino) -N- [ (1S) -1-benzyl-2- ({ (1R) -2-cyclobutyl-1- [ (3aS, 4S, 6S, 7aR) -3a, 5, 5-trimethylhexahydro-4, 6-methylene-1, 3, 2-benzodioxolan-2-yl]Ethyl } amino) -2-pendant oxyethyl group]-4-phenylbutanamide (24.8mg, 0.0395mmol), methanol (0.237mL, 5.86mmol), hexane (0.237mL, 1.81mmol), hydrochloric acid (0.0889mmol ) and 2-methylpropylboronic acid (8.65mg, 0.0849 mmol). The mixture was stirred at room temperature overnight. By preparative TLC in 10% MeOH/CH₂Cl₂The reaction mixture was purified to give 9.90mg (51% yield) of the desired product as a white solid.¹H NMR(CD₃OD，300MHz，δ)：7.32-7.12(m，10H)；4.74(t，J＝7.94Hz，1H)；4.26(dd，J＝5.49，8.55Hz，1H)；3.14-3.05(m，2H)；2.66-2.55(m，2H)；2.48-2.41(m，1H)；2.19-2.05(m，1H)；2.04-1.89(m，8H)；1.89-1.69(m，3H)；1.58-1.36(m，3H)；1.33-1.22(m，1H)。

Example 3: d-mannitol esters of { (1R) -1- [ ((2S) -2- { [ (2S) -2- (acetylamino) -4-phenylbutyryl ] amino } -3-phenylpropionyl) amino ] -2-cyclobutylethyl } boronic acid

To the above product { (1R) -1- [ ((2S) -2- { [ (2S) -2- (acetylamino) -4-phenylbutyryl ] amino } -3-phenylpropionyl) amino ] -2-cyclobutylethyl } boronic acid (9.90mg, 0.0201mmol) were added tert-butanol (1.21mL, 0.0127mol), water (1.21mL, 0.0672mol) and D-mannitol (72.0mg, 0.395 mmol). The solution was frozen at-78 ℃ and placed on a lyophilizer for 40 hours to yield 80.1mg (97% yield) of a white powder.

Example 4: other N-acyl-peptidyl boronic acid compounds

The following boronic acid compounds were prepared by procedures analogous to those described in examples 1-2 above. All compounds were also converted to the corresponding D-mannitol esters as described in example 3.

Example 5: { (1R) -2-cyclobutyl-1- [ ((2S) -2- { [ (6-phenoxypyridin-3-yl) sulfonyl ] amino } -3-phenylpropionyl) amino ] ethyl } boronic acid (11)

Step 1: (2S) -N- { (1R) -2-cyclobutyl-1- [ (3aS, 4S, 6S, 7aR) -3a, 5, 5-trimethylhexahydro-4, 6-methano-l -1, 3, 2-benzodioxolan-2-yl]Ethyl } -2- { [ (6-phenoxypyridin-3-yl) sulfonyl]Amino } -3-phenylpropionamides

To a 20mL vial was added (2S) -2-amino-N- { (1R) -2-cyclobutyl-1- [ (3aS, 4S, 6S, 7aR) -3a, 5, 5-trimethylhexahydro-4, 6-methylene-1, 3, 2-benzodioxolan-2-yl ] ethyl } -3-phenylpropionamide HC1(46.3mg, 0.109mmol) (prepared aS described in the examples), THF (1.47mL), N-diisopropylethylamine (47.5. mu.L), and 6-phenoxy-3-pyridinesulfonyl chloride (32.4 mg). The mixture was stirred at room temperature overnight. The product was purified by preparative TLC on silica plate using 50% ethyl acetate in hexane to give 35mg of the desired product as a white solid.

Step 2: { (1R) -2-cyclobutyl-1- [ ((2S) -2- { [ (6-phenoxypyridin-3-yl) sulfonyl ] sulfonyl]Amino } -3-phenylpropane Acyl) amino]Ethyl boric acid

To a 20mL vial was added (2S) -N- { (1R) -2-cyclobutyl-1- [ (3aS, 4S, 6S, 7aR) -3a, 5, 5-trimethylhexahydro-4, 6-methylene-1, 3, 2-benzodioxolan-2-yl]Ethyl } -2- { [ (6-phenoxypyridin-3-yl) sulfonyl]Amino } -3-phenylpropionamide (31.2mg, 0.047mmol), (2-methylpropyl) boronic acid (10.4mg), 1N hydrochloric acid (0.107mmol), methanol (0.285mL) and hexane (0.285 mL). The mixture was stirred at room temperature overnight, and then the hexane layer was separated and discarded. Residual solvent was removed in vacuo and CH with 10% MeOH on silica plate by preparative TLC₂Cl₂The product was purified to give 18.4mg (74% yield) of the desired product as a white solid.¹H NMR(CD₃OD，300MHz，δ)：8.36(s，1H)；7.95-7.84(m，1H)；7.52-7.39(m，2H)；7.33-7.06(m，10H)；6.95-6.83(m，1H)；4.25-4.13(m，1H)；3.09-2.94(m，1H)；2.93-2.78(m，1H)；2.46-2.32(m，1H)；2.26-1.93(m，3H)；1.92-1.71(m，2H)；1.64-1.37(m，3H)；1.37-1.22(m，1H)。

Example 6: d-mannitol esters of { (1R) -2-cyclobutyl-1- [ ((2S) -2- { [ (6-phenoxypyridin-3-yl) sulfonyl ] amino } -3-phenylpropionyl) amino ] ethyl } boronic acid

To the above product { (1R) -2-cyclobutyl-1- [ ((2S) -2- { [ (6-phenoxypyridin-3-yl) sulfonyl group]Amino } -3-phenylpropionyl) amino]To ethyl } boronic acid (18.4mg, 0.0352mmol) were added tert-butanol (2.12mL, 0.0222mol), water (2.12mL, 0.118mol), and mannitol-D (127mg, 0.697 mmol). The solution was frozen at-78 ℃ and placed on a lyophilizer for 40 hours. 142.6mg (97% yield) of the resulting { (1R) -2-cyclobutyl-1- [ ((2S) -2- { [ (6-phenoxypyridin-3-yl) sulfonyl group are obtained as a white powder]Amino } -3-phenylpropionyl) amino]Ethyl 20[ C ] boronic acid₆H₁₄O₆]。

Example 7: other N-sulfonyl-peptidyl boronic acid compounds

The following compounds were prepared by a procedure similar to that described in example 5 above. All compounds were also converted to the corresponding D-mannitol esters.

Example 8: 20S proteasome analysis

To 1 μ L of test compound dissolved in DMSO in 384-well black microtiter plates was added 25 μ L of 37 ℃ assay buffer containing human PA28 activator (Boston Biochem, final 12nM) and Ac-WLA-AMC (β 5 selective substrate) (final 15 μ M), followed by 25 μ L of 37 ℃ assay buffer containing human 20S proteasome (Boston Biochem, final 0.25 nM). The assay buffer consisted of 20mM HEPES, 0.5mM EDTA and 0.01% BSA (pH 7.4). The reaction was then placed on a BMG Galaxy plate reader (37 ℃, excitation 380nm, emission 460nm, gain 20). Percent inhibition was calculated relative to 0% inhibition (DMSO) and 100% inhibition (10 μ M bortezomib) controls.

Compounds 1-24 and 29-32 and compounds 34-48 were tested in this assay. In this assay, compounds 1-9, 11-14, 16-32, 34-41, 43-45 and 48 show IC₅₀Values were less than 50 nM. In this assay, compounds 10, 15, 42, 46 and 47 show IC₅₀A value greater than 50nM andless than 150 nM.

Example 9: proteasome inhibition and immobilization mechanics

Enzyme kinetic parameters including dissociation constant and half-life were determined by analysis of the enzyme progress curve as follows:

proteasome inactivation measurements were obtained by monitoring individual process curves for the hydrolysis of site-specific fluorescent 7-amido-4-methylcoumarin (AMC) -labeled peptide substrates (. beta.5, Suc-LLVY-AMC.;. beta.2, Z-VLR-AMC., and. beta.1, Z-LLE-AMC) at different inhibitor concentrations. According to 460nm (lambda)_ex360nm) the cleavage of the fluorescent peptide was continuously monitored and plotted as a function of time. All assays were performed at 37. + -. 0.2 ℃ in cuvettes with 2mL50mM HEPES (pH7.5), 0.5mM EDTA with continuous stirring. Substrate concentrations from 10 to 25. mu.M (< 1/2K)_M) Are not equal. Human 20S proteasome was at a concentration of 0.25nM and activated with 0.01% SDS. Rate constant k describing the transition from initial to steady state speed_obsEstimated by non-linear least squares regression analysis of individual process curves using the equation of time dependence or slow binding inhibition:

wherein F is fluorescence, v_iAnd v_sThe initial and steady state rates of the reaction in the presence of the inhibitor, and t is the time. Obtaining the sum [ I ] from the slope of the linear fit data]Related k_obsTo obtain k_on. Apparent dissociation constant K^app _iThrough with [ I ]]Associated fractional velocity v_s/v_oIs determined by a non-linear minimum fit of, wherein v_sIs a steady state value obtained from a correlation with time or a slow combination equation and v_oInitial velocity in the absence of inhibitor:

dissociation constant K_iBy an apparent K_iCalculated using the following expression:

off rate k_offMathematically calculated from the above determined parameters using the following relationship:

then by k_offThe half-life is determined using the following relationship:

using this protocol, the dissociation half-lives of compounds 1, 2, 6, 17, 20, 35, 36, 41, 43, and 45 were determined. Compounds 1, 20, 35, 36, 41, 43 and 45 show t_1/2Less than 10 minutes. Compounds 2, 6 and 17 show T_1/2Greater than 10 minutes and less than 60 minutes.

Example 10: antiproliferative assays

HCT-116(1000) or other tumor cells in 100 μ L of appropriate cell culture medium (McCoy's 5A, Invitrogen for HCT-116) supplemented with 10% fetal bovine serum (Invitrogen) were seeded into wells of 96-well cell culture plates and incubated overnight at 37 ℃. Test compounds were added to the wells and the plates were incubated at 37 ℃ for 96 hours. MTT or WST reagents (10. mu.L, Roche) were added to each well and incubated at 37 ℃ for 4 hours as described by the manufacturer. For MTT, the metabolized dye was dissolved overnight according to the manufacturer's instructions (Roche). The optical density of each well was read using a spectrophotometer (Molecular Devices) at 595nm (dominant wavelength) and 690nm (reference wavelength) (for MTT) and at 450nm (for WST). For MTT, the reference optical density value is subtracted from the value of the principal wavelength. The percentage inhibition was calculated using the value of the DMSO control set at 100%.

Example 11: in vivo tumor efficacy model

Freshly dissociated HCT-116 (2-5X 10) in 100. mu.L RPMI-1640 medium (Sigma Aldrich) using a 1mL263/8 gauge needle (Bekton Dickinson reference number 309625)⁶)、WSU-DLCL2(2-5×10⁶) Or other tumor cells, were aseptically injected into the subcutaneous space on the right dorsal side of female CD-1 nude mice (5-8 weeks old, Charles River). Alternatively, some xenograft models (e.g., CWR22) require continuous passage of tumor fragments. In this case, a smaller section (about 1 mm) of tumor tissue is divided³) Through a No. 13 trocar (Popper, Bopp.)&Sons)7927) were implanted subcutaneously on the right dorsal side of anesthetized (3-5% isoflurane/oxygen cocktail) c.b-17/SCID mice (5-8 weeks old, charles river). Measurements were performed twice a week using a vernier caliper starting on day 7 after tumor inoculation. Standard procedure (0.5 × (length × width) was used²) Calculate tumor volume. When the tumor reaches about 200mm³At volume (v), mice were randomized into treatment groups and initially received drug treatment. The dose and time course of each experiment was determined based on previous results obtained from pharmacokinetic/pharmacodynamic and maximum tolerated dose studies. The control group will receive vehicle without any drug. Typically, test compounds (100-. Tumor size and body weight were measured twice weekly, and when control tumors reached approximately 2000mm³The study was terminated.

Although the foregoing invention has been described in some detail for purposes of clarity and understanding, these specific embodiments are to be considered in all respects only as illustrative and not restrictive. It will be understood by those skilled in the art, after reading this disclosure, that various changes in form and detail may be made without departing from the true scope of the invention, which is defined by the appended claims rather than the specific embodiments.

The patent and scientific literature referred to herein identifies the knowledge available to those skilled in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The issued patents, applications, and references cited herein are hereby incorporated by reference to the same extent as if each was specifically and individually indicated to be incorporated by reference. In case of conflict, the present disclosure, including definitions, will control.

Claims (16)

1. A compound of the formula (I),

or a pharmaceutically acceptable salt or boronic acid anhydride thereof, wherein:

a is 0, 1 or 2;

p is hydrogen or an amino-capping moiety;

R^a1is C_1-6Aliphatic radical, C_1-6Fluoroaliphatic radical, - (CH)₂)_m-CH₂-R^B、-(CH₂)_m-CH₂-NHC(＝NR⁴)NH-Y、-(CH₂)_m-CH₂-CON(R⁴)₂、-(CH₂)_m-CH₂-N(R⁴)CON(R⁴)₂、-(CH₂)_m-CH(R⁶)N(R⁴)₂、-(CH₂)_m-CH(R⁵)-OR⁵Or- (CH)₂)_m-CH(R⁵)-SR⁵；

Each R^a2Independently of one another is hydrogen, C_1-6Aliphatic radical, C_1-6Fluoroaliphatic radical, - (CH)₂)_m-CH₂-R^B、-(CH₂)_m-CH₂-NHC(＝NR⁴)NH-Y、-(CH₂)_m-CH₂-CON(R⁴)₂、-(CH₂)_m-CH₂-N(R⁴)CON(R⁴)₂、-(CH₂)_m-CH(R⁶)N(R⁴)₂、-(CH₂)_m-CH(R⁵)-OR⁵Or- (CH)₂)_m-CH(R⁵)-SR⁵；

Each Y is independently hydrogen, -CN, -NO₂or-S (O)₂-R¹⁰；

Each R^BIndependently a substituted or unsubstituted monocyclic or bicyclic ring system;

each R⁴Independently hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl or heterocyclic group; or two R4 on the same nitrogen atom together with the nitrogen atom form a substituted or unsubstituted 4-to 8-membered heterocyclyl ring having 0-2 ring heteroatoms independently selected from N, O and S in addition to the nitrogen atom;

each R⁵Independently hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl or heterocyclic group;

each R⁶Independently a substituted or unsubstituted aliphatic, aryl or heteroaryl group;

each R¹⁰Independently is C_1-6Aliphatic radical, C_6-10Aryl or-N (R)⁴)₂；

m is 0, 1 or 2;

Z¹and Z²Each independently is hydroxy, alkoxy, aryloxy, or aralkoxy; or Z¹And Z²Together forming a moiety derived from a boronic acid complexing agent.

2. The compound of claim 1, wherein P is R^c-C(O)-、R^c-O-C(O)-、R^c-N(R^4c)-C(O)-、R^c-S(O)₂-or R^c-N(R^4c)-S(O)₂-；

R^cSelected from the group consisting of C_1-6Aliphatic radical, C_1-6Fluoroaliphatic radical, -R^D、-T¹-R^Dand-T¹-R^2cA group of compounds;

T¹is 0-2 independently selected R^3aOr R^3bSubstituted C_1-6An alkylene chain, wherein the alkylene chain is optionally interrupted by-C (R)⁵)＝C(R⁵) -, -C.ident.C-or-O-;

R^Dis a substituted or unsubstituted monocyclic or bicyclic ring system;

R^2cis halo, -OR⁵、-SR⁶、-S(O)R⁶、-SO₂R⁶、-SO₂N(R⁴)₂、-N(R⁴)₂、-NR⁴C(O)R⁵、-NR⁴C(O)N(R⁴)₂、-NR⁴CO₂R⁶、-N(R⁴)SO₂R⁶、-N(R⁴)SO₂N(R⁴)₂、-O-C(O)R⁵、-OC(O)N(R⁴)₂、-C(O)R⁵、-CO₂R⁵or-C (O) N (R)⁴)₂；

Each R^3aIndependently selected from the group consisting of: -F, -OH, -O (C)_1-4Alkyl), -CN, -N (R)⁴)₂、-C(O)(C_1-4Alkyl), -CO₂H、-CO₂(C_1-4Alkyl), -C (O) NH₂and-C (O) -NH (C)_1-4Alkyl groups);

each R^3bIndependently is a warp R^3aOr R⁷Substituted or unsubstituted C_1-3An aliphatic group;

each R⁷Is a substituted or unsubstituted aromatic group; and is

R^4cIs hydrogen, C_1-4Alkyl radical, C_1-4Fluoroalkyl or C_6-10Aryl (C)_1-4Alkyl) in which said C is_6-10Aryl (C)_1-4Alkyl) is substituted or unsubstituted.

3. The compound according to claim 2, characterized by formula (I-B):

or a pharmaceutically acceptable salt or boronic anhydride thereof.

4. The compound of claim 3, wherein A is 0.

5. A compound according to claim 3, wherein R^a1And R^a2Each independently is C_1-6Aliphatic radical, C_1-6Fluoroaliphatic radical or- (CH)₂)_m-CH₂-R^BAnd m is 0 or 1.

6. The compound of claim 5, wherein R^BIs a substituted or unsubstituted phenyl group.

7. The compound of claim 6, wherein R^a1is-CH₂-R^BAnd R is^BIs phenyl.

8. A compound according to claim 3, wherein R^a1Is- (CH)₂)_m-CH(C_1-4Alkyl) -OH.

9. A compound according to claim 3, wherein R^DBy 0-2R on an optionally substituted ring carbon atom^dAnd 0-2R^8dSubstitution;

each R^dIndependently selected from the group consisting of: c_1-6Aliphatic radical, C_1-6Fluoroaliphatic radical, halo radical, -R^1d、-R^2d、-T²-R^1d、-T²-R^2d，

T²Is 0-2 independently selected R^3aOr R^3bSubstituted C_1-6An alkylene chain, wherein the alkylene chain is optionally interrupted by-C (R)⁵)＝C(R⁵) -, -C.ident.C-or-O-;

each R^1dIndependently is a substituted or unsubstituted aryl, heteroaryl, heterocyclic or cycloaliphatic ring;

each R^2dIndependently is-NO₂、-CN、-C(R⁵)＝C(R⁵)₂、-C≡C-R⁵、-OR⁵、-SR⁶、-S(O)R⁶、-SO₂R⁶、-SO₂N(R⁴)₂、-N(R⁴)₂、-NR⁴C(O)R⁵、-NR⁴C(O)N(R⁴)₂、-N(R⁴)C(＝NR⁴)-N(R⁴)₂、-N(R⁴)C(＝NR⁴)-R⁶、-NR⁴CO₂R⁶、-N(R⁴)SO₂R⁶、-N(R⁴)SO₂N(R⁴)₂、-O-C(O)R⁵、-OC(O)N(R⁴)₂、-C(O)R⁵、-CO₂R⁵、-C(O)N(R⁴)₂、-C(O)N(R⁴)-OR⁵、-C(O)N(R⁴)C(＝NR⁴)-N(R⁴)₂、-N(R⁴)C(＝NR⁴)-N(R⁴)-C(O)R⁵or-C (═ NR)⁴)-N(R⁴)₂；

Each R^3aIndependently selected from the group consisting of: -F, -OH, -O (C)_1-4Alkyl), -CN, -N (R)⁴)₂、-C(O)(C_1-4Alkyl), -CO₂H、-CO₂(C_1-4Alkyl), -C (O) NH₂and-C (O) NH (C)_1-4Alkyl groups);

each R^3bIndependently is a warp R^3aOr R⁷Substituted or unsubstituted C_1-3Aliphatic radicals, or two substituents R on the same carbon atom^3dTogether with the carbon atom to which they are attached form a 3-to 6-membered cyclic aliphatic ring;

each R⁷Independently is a substituted or unsubstituted aryl or heteroaryl ring;

each R^8dIndependently selected from the group consisting of: c_1-4Aliphatic radical, C_1-4Fluoroaliphatic radical, halo, -OH, -O (C)_1-4Aliphatic group), -NH₂、-NH(C_1-4Aliphatic radical) and-N (C)_1-4Aliphatic radical)₂(ii) a And is

R^DEach of the substitutable ring nitrogen atoms in (a) is unsubstituted or substituted by: -C (O) R⁵、-C(O)N(R⁴)₂、-CO₂R⁶、-SO₂R⁶、-SO₂N(R⁴)₂、C_1-4Aliphatic radical, substituted or unsubstituted C_6-10Aryl or C_6-10Aryl (C)_1-4) Alkyl radical, wherein said C_6-10Aryl (C)_1-4) The aryl portion of the alkyl group may be substituted or unsubstituted.

10. A compound according to claim 3, wherein:

R^Deach saturated ring carbon atom in (A) is unsubstituted or substituted by (H) O, R^dOr R^8dSubstitution;

R^Deach unsaturated ring carbon atom in (A) being unsubstituted or substituted by R^dOr R^8dSubstitution;

each R^dIndependent of each otherIs selected from the group consisting of: c_1-6Aliphatic radical, C_1-6Fluoroaliphatic radical, halo radical, -R^1d、-R^2d、-T²-R^1d、-T²-R^2d，

T²Is 0-2 independently selected R^3aOr R^3bSubstituted C_1-6An alkylene chain, wherein the alkylene chain is optionally interrupted by-C (R)⁵)＝C(R⁵) -, -C.ident.C-or-O-;

each R^1dIndependently is a substituted or unsubstituted aryl, heteroaryl, heterocyclic or cycloaliphatic ring;

each R^2dIndependently is-NO₂、-CN、-C(R⁵)＝C(R⁵)₂、-C≡C-R⁵、-OR⁵、-SR⁶、-S(O)R⁶、-SO₂R⁶、-SO₂N(R⁴)₂、-N(R⁴)₂、-NR⁴C(O)R⁵、-NR⁴C(O)N(R⁴)₂、-N(R⁴)C(＝NR⁴)-N(R⁴)₂、-N(R⁴)C(＝NR⁴)-R⁶、-NR⁴CO₂R⁶、-N(R⁴)SO₂R⁶、-N(R⁴)SO₂N(R⁴)₂、-O-C(O)R⁵、-OC(O)N(R⁴)₂、-C(O)R⁵、-CO₂R⁵、-C(O)N(R⁴)₂、-C(O)N(R⁴)-OR⁵、-C(O)N(R⁴)C(＝NR⁴)-N(R⁴)₂、-N(R⁴)C(＝NR⁴)-N(R⁴)-C(O)R⁵or-C (═ NR)⁴)-N(R⁴)₂；

Each R^3aIndependently selected from the group consisting of: -F, -OH, -O (C)_1-4Alkyl), -CN, -N (R)⁴)₂、-C(O)(C_1-4Alkyl), -CO₂H、-CO₂(C_1-4Alkyl), -C (O) NH₂and-C (O) NH (C)_1-4Alkyl groups);

each R^3bIndependently is a warp R^3aOr R⁷Substituted or unsubstituted C_1-3Aliphatic radicals, or two substituents R on the same carbon atom^3dTogether with the carbon atom to which they are attached form a 3-to 6-membered cyclic aliphatic ring;

each R⁷Independently is a substituted or unsubstituted aryl or heteroaryl ring;

each R^8dIndependently selected from the group consisting of: c_1-4Aliphatic radical, C_1-4Fluoroaliphatic radical, halo, -OH, -O (C)_1-4Aliphatic group), -NH₂、-NH(C_1-4Aliphatic radical) and-N (C)_1-4Aliphatic group) 2; and R is^DEach of the substitutable ring nitrogen atoms in (a) is unsubstituted or substituted by: -C (O) R⁵、-C(O)N(R⁴)₂、-CO₂R⁶、-SO₂R⁶、-SO₂N(R⁴)₂、C_1-4Aliphatic radical, substituted or unsubstituted C_6-10Aryl or C_6-10Aryl (C)_1-4) Alkyl radical, wherein said C_6-10Aryl (C)_1-4) The aryl portion of the alkyl group may be substituted or unsubstituted.

11. The compound of claim 7, wherein R^DIs a substituted or unsubstituted monocyclic or bicyclic ring system selected from the group consisting of: phenyl, pyridyl, pyrimidinyl, pyrazinyl, naphthyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, and dihydrobenzoxazinyl.

12. The compound of claim 7, characterized by formula (II):

or a pharmaceutically acceptable salt or boronic acid anhydride thereof, wherein:

p has the formula R^D-SO₂-or R^D-C(O)-；

R^DIs a substituted or unsubstituted monocyclic or bicyclic ring system selected from the group consisting of: phenyl, pyridyl, pyrimidinyl, pyrazinyl, naphthyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, and dihydrobenzoxazinyl;

R^Deach saturated ring carbon atom in (A) is unsubstituted or substituted by (H) O, R^dOr R^8dSubstitution;

R^Deach unsaturated ring carbon atom in (A) being unsubstituted or substituted by R^dOr R^8dSubstitution;

each R^dIndependently selected from the group consisting of-R^1d、-R^2d、-T²-R^1dand-T²-R^2dA group of compounds;

T²is unsubstituted or substituted by R^3aOr R^3bSubstituted C_1-3An alkylene chain;

each R^1dIndependently is a substituted or unsubstituted aryl, heteroaryl, heterocyclic or cycloaliphatic ring;

each R^2dIndependently is-OR⁵、-SR⁶、-S(O)R⁶、-SO₂R⁶、-SO₂N(R⁴)₂、-N(R⁴)₂、-NR⁴C(O)R⁵、-NR⁴C(O)N(R⁴)₂、-O-C(O)R⁵、-OC(O)N(R⁴)₂、-C(O)R⁵、-CO₂R⁵or-C (O) N (R)⁴)₂(ii) a And is

Each R^8dIndependently selected from the group consisting of: c_1-4Aliphatic radical, C_1-4Fluoroaliphatic radical, halo, -OH, -O (C)_1-4Aliphatic group), -NH₂、-NH(C_1-4Aliphatic radical) and-N (C)_1-4Aliphatic radical)₂。

13. The compound of claim 12, wherein R^dHaving the formula-Q-R^E；

Q is-O-, -NH-or-CH₂-; and is

R^EIs a substituted or unsubstituted aryl, heteroaryl, heterocyclic or cycloaliphatic ring.

14. The compound of claim 12, wherein R^DIs of the formula-O-R^EPhenyl, pyridyl, pyrazinyl or pyrimidinyl substituted with the substituents of (A), and R^EIs a substituted or unsubstituted phenyl, pyridyl, pyrazinyl or pyrimidinyl group.

15. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

16. A method of treating cancer comprising administering to a patient in need of such treatment a pharmaceutical composition of claim 15.