KR20140098185A - Derivatives of n-(arylamino) sulfonamides including polymorphs as inhibitors of mek as well as compositions, methods of use and methods for preparing the same - Google Patents

Abstract

The present invention relates to N- (2-arylamino) arylsulfonamide compounds which are inhibitors of MEK, including crystalline polymorphic forms exhibiting a specific powder x-ray diffraction profile and / or a unique differential scanning calorimetric profile. The present invention also relates to pharmaceutical compositions comprising the compounds described herein and to methods of using the compounds and compositions described herein, including for use in the treatment and / or prevention of cancer, hyperproliferative diseases and inflammatory conditions . The present invention also relates to methods of making the compounds and compositions described herein.

Description

TECHNICAL FIELD [0001] The present invention relates to derivatives and compositions of N- (arylamino) sulfonamides as inhibitors of MEK, including polymorphs, methods of use, and methods of preparing the same. BACKGROUND OF THE INVENTION OF USE AND METHODS FOR PREPARING THE SAME}

Cross-reference to related application

This application claims the benefit of US Provisional Application No. 61 / 044,886, filed April 14, 2008, 61 / 034,466, filed March 6, 2008, and 61 / 034,464, filed March 6, , Each of which is incorporated herein by reference in its entirety. This application is also a continuation in part of U.S. Provisional Application No. 60 / 833,886, filed July 28, 2006, and in July 2007, filed July 21, 2006, which claims the benefit of International Application No. PCT / US2006 / 028326, filed July 21, U.S. Application Serial No. 11 / 830,733, filed on March 30, 2007, each of which is incorporated herein by reference in its entirety. The International Application No. PCT / US2006 / 028326 also discloses a method and apparatus for the treatment of cancer, as described in U.S. Provisional Application No. 60 / 701,814, filed July 21, 2005, 60 / 706,719, filed August 8, 2005, 60 / 731,633, filed on even date herewith, each of which is incorporated herein by reference in its entirety.

Field of the Invention

The present invention relates to N- (2-arylamino) arylsulfonamide compounds which are inhibitors of MEK, including crystalline polymorphic forms exhibiting a specific powder x-ray diffraction profile and / or a unique differential scanning calorimetric profile. The present invention also relates to pharmaceutical compositions comprising the compounds described herein and to methods of using the compounds and compositions described herein, including for use in the treatment and / or prevention of cancer, hyperproliferative diseases and inflammatory conditions . The present invention also relates to methods of making the compounds and compositions described herein.

Oncogenes (genes that cause cancer) are typically mutated forms of certain genes in normal cells ("oncogene"). Tumor genes often code for abnormal versions of signal pathway components, such as receptor tyrosine kinases, serine-threonine kinases, or downstream signaling molecules. The central downstream signaling molecule is the Ras protein, which is immobilized on the inner surface of the cytoplasmic membrane and hydrolyzes bound guanosine triphosphate (GTP) to guanosine diphosphate (GDP). The growth factor receptor initiates a chain reaction that activates the guanine nucleotide exchange activity of Ras upon activation by growth factors. Ras alternates between an active "active" state in which GTP is bound (hereinafter "Ras.GTP") and an inert "non- Ras.GTP, in its active "working" state, binds to and activates proteins that control cell growth and differentiation.

For example, in "Protein kinases are activated by a mitogen (m itogen- a ctivated p rotein kinase) (MAP kinase) cascades", Ras.GTP induces the activation of the serine / threonine kinase cascades. One of several families of kinases known to require Ras.GTP for activation is the Raf class. Raf proteins "MEK1" and "MEK2" [short for active kinases ERK- (m itogen-activated E RK k inase-activating) activated by a mitogen (wherein, ERK is a protein kinase that is regulated by extracellular signal cells , Another name for MAPK). MEK1 and MEK2 are dual acting serine / threonine and tyrosine protein kinases and are also known as MAP kinase kinases. Thus, Ras.GTP activates Raf, which activates MEK1 and MEK2, which activate MAP kinase (MAPK). Activation of MAP kinase by mitogen is considered to be essential for proliferation, and the constitutive activation of the kinase is sufficient to induce cell transformation. For example, blockade of downstream Ras signaling using the dominant negative Raf-1 protein can completely suppress mitosis, whether derived from cell surface receptors or from oncogenic gene Ras mutants.

The interaction of Raf and Ras is a key regulatory step in the control of cell proliferation. Until now, the substrate of MEK other than MAPK has not been confirmed, but in recent reports it has been shown that MEK can also be activated by other upstream signal proteins such as MEK kinase or MEKK1 and PKC. Activated MAPKs are upregulated and accumulate in the nucleus, where phosphorylation and activation of transcription factors such as Elk-1 and Sapla can be promoted to promote the expression of genes such as genes for c-fos.

When Raf and other kinases, once activated, they are for high phosphorylate MEK on two adjacent serine residues, MEK-1 it shall be phosphorylated at S ²¹⁸ and S ^222. This phosphorylation is necessary for the activation of MEK as a kinase. Then, MEK phosphorylates MAP kinase at two amino acid residues, tyrosine Y ¹⁸⁵ and threonine T ¹⁸³ , with one amino acid. MEK appears to bind strongly to MAP kinase prior to phosphorylating MAP kinase suggesting that strong pre-interaction between these two proteins may be required for phosphorylation of MAP kinase by MEK. Two factors (the unique specificity of MEK and the need for strong interaction of MEK and MAP kinase prior to phosphorylation) suggest that the mechanism of action of MEK is sufficiently different from the mechanism of other protein kinases so that selective inhibitors of MEK enable It is possible. Possibly, such inhibitors will operate through an allosteric mechanism, rather than through a more common mechanism involving blockade of the ATP binding site.

Thus, MEK1 and MEK2 are valid and acceptable targets for anti-proliferative therapy, even when the oncogene mutation does not affect the MEK structure or expression. See, for example, United States Patent Publication 2003/0149015 (Barrett et al.) And 2004/0029898 (Boyle et al.).

Several examples of 1-substituted-2 (p-substituted-phenylamino) -aryl inhibitors of MEK have been reported. U.S. Pat. Nos. 6,440,966 and 6,750,217 and corresponding disclosures WO 00/42003 describe the preparation of carboxylic acid and hydrate of sulfonamide-substituted-2 (4-iodophenylamino) -benzoic acid ester and N-substituted benzamide The lockstock ester and N-substituted amide derivatives are described as acting as MEK inhibitors. The sulfonamide may also be N-substituted.

U.S. Patent No. 6,545,030 and corresponding disclosure WO 00/42029 disclose 1-heterocyclyl-2 (4-iodophenylamino) -benzene wherein the heterocycle is a 5 membered nitrogen-containing ring such as pyrazole, triazole, Sol, isoxazole, and isoxazolidinone). More recent US Patent Publication 2005/004186 discloses that the 4-iodo substituent of the '030 patent is an alkyl, alkoxy, acyloxy, alkenyl, carbamoyl, carbamoylalkyl, carboxyl, ≪ / RTI > sulfonamido, and the like.

U.S. Patent 6,469,004 and corresponding disclosure WO 00/42022 disclose the use of heterocyclo-condensed phenylene compounds, i.e., carboxylic acids and hydroxides of groups such as benzimidazole, benzoxazole, benzothiazole, benzothiadiazole, quinazoline, Describe the lock acid ester. The heterocycle is 7-F-6- (4-iodo-phenylamino) -5-carboxylic acid ester, carboxylic acid amide or hydroxamic acid ester. More recent publication US 2005/0026970 describes analogous compounds in which the 4-iodo substituent is replaced by a very broad group of structures. Related compounds are described in patent publications WO 03/077855, WO 03/77914 and US 2005/0554701. Additional examples of 2- (4-iodophenylamino) -phenylhydroxamic acid esters reported to be useful as MEK inhibitors can be found in WO 2005/028426.

Patent Publication No. WO 02/06213 and corresponding US Application No. 10 / 333,399 (US 2004/0054172) disclose the hydroxy-substitution of 1-oxacan-2 (4-halophenylamino) -3,4-difluorobenzene Gt; acid ester < / RTI > U.S. Patent No. 6,891,066 and corresponding disclosure WO 03/62191 describe similar compounds in which the 4-halo substituent is replaced by a very broad group of structures. Substituents at the 4-position are especially methyl, ethyl, ethynyl and 2-hydroxyethyl. Specific related compounds are described in U.S. Patent No. 6,770,778.

Patent Publication WO 04/083167, published on September 30, 2004 (in Japan), discloses that more than 2000 1- (N-substituted sulfonylurea) -2 (2,4-dihalophenylamino) -Difluorobenzene (but only provides NMR data for only 400 species), suggesting that these are useful as MEK inhibitors. Data showing inhibition of MEK are presented for only 12 subgroups. All of these 12 compounds contained, in addition to the secondary or tertiary amines, one of the following groups: N, N-disubstituted sulfonylureas, N-piperazinesulfonamides, N-piperidine sulfonamides Or N-pyrrolidine sulfone amide.

MEK cascades are also associated with inflammatory diseases and disorders. See U.S. Application Publication No. 2006/0030610 (Koch et al.), U.S. Published Application 2006/0140872 (Furue et al.). This includes both acute inflammatory disorders and chronic inflammatory disorders. Examples of such disorders are diseases and disorders associated with allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, psoriasis, multiple sclerosis, asthma, diabetic complications, and cardiovascular inflammatory complications, For example, acute coronary syndrome. Inflammatory bowel disease is particularly Crohn's disease and ulcerative colitis.

MEK1 and MEK2 are valid and acceptable targets for anti-proliferative therapy, even when tumor gene mutations do not affect MEK structure or expression. See, for example, United States Patent Publication 2003/0149015 (Barrett et al.) And 2004/0029898 (Boyle et al.).

SUMMARY OF THE INVENTION

In this application, there is provided a compound of formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof,

(I)

In this formula,

Z is H or F,

X is _{F, Cl, CH 3, CH} 2 OH, CH 2 F, CHF 2 or CF _3,

Y is I, Br, Cl, CF _3, C ₁ -C ₃ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl, cyclopropyl, OMe, OEt, SMe, phenyl or Het, where the Het is a saturated, olefinic or aromatic 5 to 10 membered monocyclic or bicyclic heterocyclic group containing 1 to 5 ring heteroatoms independently selected from N, O and S,

All of said phenyl or Het group F, Cl, Br, I, acetyl, methyl, CN, NO _2, CO ₂ H, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl, -C _{(= O) -, C 1} -C 3 alkyl, -C (= S) -, C 1 -C 3 alkoxy group -C (= S) -, C 1 -C 3 alkyl, -C (= O) O-, C ₁ -C ₃ alkyl, -O- (C = O) -, C 1 -C 3 alkyl, -C (= O) NH-, C 1 -C 3 alkyl, -C (= NH) NH-, C 1 -C 3 alkyl, -NH- (C = O) -, di -C ₁ -C ₃ alkyl, -N- (C = O) -, C 1 -C 3 alkyl, -C (= O) N (C 1 -C 3 alkyl) -, C ₁ -C ₃ alkyl-S (= O) ₂ NH- or trifluoromethyl,

All of the methyl, ethyl, C ₁ -C ₃ alkyl or cyclopropyl group is optionally substituted by OH,

     Wherein all of said methyl groups are optionally substituted with one, two or three F atoms,

R ⁰ is H, F, Cl, Br, I, CH 3 NH-, (CH 3) 2 N-, C 1 -C 6 alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, phenyl, monosubstituted phenyl, O (C ₁ -C ₄ alkyl), OC (= O) ( C 1 -C 4 alkyl) or C (= O) O (C ₁ -C ₄ alkyl), wherein,

     The group of said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl and phenyl is optionally substituted with one to three groups independently selected from F, Cl, Br, I, OH, CN, cyanomethyl, nitro, phenyl and trifluoromethyl Optionally substituted with a substituent,

The group of C ₁ -C ₆ alkyl and C ₁ -C ₄ alkoxy is also optionally substituted with OCH ₃ or OCH ₂ CH ₃ ,

G is G ₁ , G ₂ , R _1a , R _1b , R _1c , R _1d , R _1e , Ar ₁ , Ar ₂ or Ar ₃ ,

G ₁ is C ₁ -C ₆ alkyl optionally substituted by one amino, C ₁ -C ₃ alkylamino, or a group of dialkylamino containing two C ₁ -C ₄ alkyl groups which may or may not be the same Or

G ₁ is a C ₃ -C ₈ diaminoalkyl group,

G ₂ contains 1 to 3 ring heteroatoms independently selected from N, O and S and is selected from the group consisting of F, Cl, OH, O (C ₁ -C ₃ alkyl), OCH ₃ , OCH ₂ CH ₃ , CH ₃ C (= O) group of _{NH, CH 3 C (= O} ) O, CN, CF 3, and N, O and clicking a 5-membered aromatic heterocyclic containing 1 to 4 ring heteroatoms independently selected from S Unsaturated or aromatic 5 or 6 membered ring optionally substituted with one to three substituents independently selected from H,

_Wherein R _1a is methyl optionally substituted by 1 to 3 fluorine atoms or 1 to 3 chlorine atoms or OH, cyclopropoxy or C ₁ -C ₃ alkoxy, wherein said cyclopropoxy group or said C ₁ The C ₁ -C ₃ alkyl portion of the -C ₃ alkoxy group is optionally substituted with one hydroxy or methoxy group and wherein all C ₃ -alkyl groups within the C ₁ -C ₄ alkoxy are optionally further substituted with a second OH group And,

R _1b is CH (CH ₃₎ -C _{1 - 3} alkyl, or independently from C ₃ -C ₆ cycloalkyl, said alkyl and cycloalkyl, where the group F, Cl, Br, I, OH, OCH _3, and CN Optionally substituted with one to three substituents selected from < RTI ID = 0.0 >

R _1c is (CH ₂ ) _n O _m R '

          m is 0 or 1,

              when m is 0, n is 1 or 2,

              when m is 1, n is 2 or 3,

R 'is C ₁ -C ₆ alkyl optionally substituted with ₁ to 3 substituents independently selected from F, Cl, OH, OCH ₃ , OCH ₂ CH ₃ and C ₃ -C ₆ cycloalkyl,

R _1d is C (A) (A ') (B) -,

And ₄ alkyl, _- B is H, or is C ₁ groups with one or two OH optionally substituted

A and A 'are independently H, or is one or two OH groups optionally substituted by C _{1 - 4} alkyl or, or

          A and A 'together with the carbon atom to which they are attached form a 3- to 6-membered saturated ring,

이고, 이때,R _1e is

Lt; / RTI >

          q is 1 or 2,

R ₂ and R ₃ are each independently selected from the group consisting of H, F, Cl, Br, CH ₃ , CH ₂ F, CHF ₂ , CF ₃ , OCH ₃ , OCH ₂ F, OCHF ₂ , OCF ₃ , Propyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl or methylsulfonyl,

R ₄ is selected from the group consisting of H, F, Cl, Br, CH ₃ , CH ₂ F, CHF ₂ , CF ₃ , OCH ₃ , OCH ₂ F, OCHF ₂ , OCF ₃ , ethyl, Butyl, tert-butyl, methylsulfonyl, nitro, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1,3,4-oxadiazole Methyl-1,3,4-oxadiazole, 1,3,4-thiadiazole, 5-methyl-1,3,4-thiadiazole, 1H-tetrazolyl, N- Morpholylcarbonylamino, N-morpholylsulfonyl and N-pyrrolidinylcarbonylamino,

R < ₅ > is H, F, Cl or methyl,

R < ₆ > is H, F, Cl or methyl,

이고, 이때,Ar ₁ is

Lt; / RTI >

U and V are independently N, CR ₂ or CR ₃ ,

R ₂ , R ₃ and R ₄ are independently H, F, Cl, Br, CH ₃ , CH ₂ F, CHF ₂ , CF ₃ , OCH ₃ , OCH ₂ F, OCHF ₂ , OCF ₃ , , Isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, Methyl-1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 5-methyl-1,3,4-thiadiazolyl, 1H-tetrazolyl, N-morpholylcarbonylamino, N-morpholysulfonyl, N-pyrrolidinylcarbonylamino and methylsulfonyl,

R ₅ and R ₆ are independently H, F, Cl or methyl,

이고, 이때,Ar ₂ is

Lt; / RTI >

          The broken line represents an alternative structural position for the second ring double bond,

           U is -S-, -O- or -N =

               When U is -O- or -S-, V is -CH =, -CCl = or -N =

               When U is -N =, V is -CH =, -CCl = or -N =

R < ₇ > is H or methyl,

R ₈ is H, acetamido, methyl, F or Cl,

이고, 이때,Ar ₃ is

Lt; / RTI >

U is -NH-, -NCH ₃ - or -O-, and,

R ₇ and R ₈ are independently H, F, Cl or methyl.

In some embodiments, the invention provides a compound of formula I selected from:

로부터 선택되며, 여기서의 2-OH 탄소는 R 배위로 존재하는 화학식 I의 화합물을 제공한다.In some embodiments,

, Wherein the 2-OH carbon is present in the R configuration.

로부터 선택되며, 여기서의 2-OH 탄소는 S 배위로 존재하는 화학식 I의 화합물을 제공한다.In some embodiments,

, Wherein the 2-OH carbon is present in the S configuration.

In some embodiments, the invention provides a composition comprising a compound of formula I, wherein the 2-OH carbon is present in the R configuration and is substantially free of the S isomer, wherein the 2-OH carbon is present in the R configuration.

In some embodiments, the present invention provides a composition comprising a compound of formula I, wherein the 2-OH carbon is present in the S configuration and wherein the R isomer is substantially absent,

In some embodiments, the present invention provides a compound of formula I wherein Y is phenyl, pyridyl or pyrazolyl. In another subclass embodiment, the present invention provides a compound of formula I wherein Y is substituted phenyl, pyridyl or pyrazolyl. In another subclass embodiment, the present invention provides a compound of formula I wherein Y is Br or I. In one subclass embodiment, the invention provides a compound of formula I wherein G is 1-piperidyl, 2-piperidyl, 3-piperidyl or 4-piperidyl. In another subclass embodiment, the present invention provides a compound of formula I wherein G is 1-piperazinyl or 2-piperazinyl. In another subclass embodiment, the invention provides a compound of formula I wherein G is morpholyl. In another subclass embodiment, the present invention provides a compound of formula I wherein G is N-methyl-2-aminoethyl. In one subclass embodiment, the invention provides a compound of formula I wherein G is N-methyl-3-amino-n-propyl. In another subclass embodiment, the invention relates to compounds of formula I wherein G is (CH ₃ ) ₂ N-CH ₂ CH ₂ -NH- (CH ₂ ) _n -, wherein n is 1, 2 or 3 . In yet another embodiment of the subclass, the present invention G is _{(CH 3 CH 2) 2 N} -CH 2 CH 2 -NH- (CH 2) n - , and where n is the compound of formula I wherein 1 or 2 . In a more particular subclass embodiment, the present invention provides a compound of formula I wherein G is 1-piperidyl, 2-piperidyl, 3-piperidyl or 4-piperidyl and R ⁰ is H, halo or methoxy, Wherein X is F and Y is I. In another more particular subclass embodiment, the invention provides a compound of formula I wherein G is 1-piperazinyl or 2-piperazyl, R ⁰ is H, halo or methoxy, X is F and Y is I ≪ / RTI > In another more particular subclass embodiment, the present invention provides a compound of formula I wherein G is morpholyl, R < ⁰ > is H, halo or methoxy, X is F and Y is I. In another more particular subclass embodiment, the present invention provides a compound of formula I wherein G is N-methyl-2-aminoethyl and R ⁰ is H, halo or methoxy, X is F and Y is I . In another more particular subclass embodiment, the present invention provides a compound of formula I wherein G is N-methyl-3-amino-n-propyl, R ⁰ is H, halo or methoxy, X is F, I < / RTI > In another further embodiment of the specific subclass, the present invention G is _{(CH 3) 2 N-CH} 2 CH 2 -NH- (CH 2) n - , and and wherein the n is 1, 2 or 3, R ⁰ is H, halo or methoxy, X is F, and Y is I. In another further embodiment of the specific subclass, the present invention G is _{(CH 3 CH 2) 2 N} -CH 2 CH 2 -NH- (CH 2) n - and is, of where n is 1 or 2, R ⁰ is H, halo or methoxy, X is F, and Y is I.

In some embodiments, the invention provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.

로부터 선택된 화합물 또는 그의 제약상 허용가능한 염, 용매화물, 다형체, 에스테르, 호변이성질체 또는 전구약물을 포함하는 제약 조성물을 제공한다. 일부 실시양태에서, 상기 제약 조성물은 1종 이상의 제약상 허용가능한 담체를 추가로 포함한다. 일부 실시양태에서, 상기 화합물은 R 배위로 존재한다. 일부 실시양태에서, 상기 화합물은 R 배위로 존재하고, S 이성질체는 실질적으로 없다. 일부 실시양태에서, 상기 화합물은 S 배위로 존재한다.In some embodiments,

Or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier. In some embodiments, the compound is in the R configuration. In some embodiments, the compound is in the R configuration and is substantially free of the S isomer. In some embodiments, the compound is in the S configuration.

이다. 일부 실시양태에서, 상기 화합물은

이다.In some embodiments, the compound is in the S configuration and is substantially free of the R isomer. In some embodiments, the compound is

to be. In some embodiments, the compound is

to be.

. 일부 실시양태에서, 상기 분말 x선 회절 패턴은 도 5에 나타낸 피크의 50％ 이상을 함유한다. 일부 실시양태에서, 상기 분말 x선 회절 패턴은 도 5에 나타낸 피크의 70％ 이상을 함유한다. 일부 실시양태에서, 상기 분말 x선 회절 패턴은 도 5에 나타낸 피크의 90％ 이상을 함유한다. 일부 실시양태에서, 상기 분말 x선 회절 패턴은 도 5에 나타낸 분말 x선 회절 패턴과 실질적으로 동일하다. 화합물 A는 2급 알콜에서 R 및 S-MTPA 에스테르를 생성하고 양성자 화학적 이동(chemical shift) 차이를 비교하여 "S" 이성질체인 것으로 특징규명된 바 있다. 예를 들어, 문헌 [Dale, J.A.; Mosher, H.S., J. Am. Chem. Soc., 1973, 95, 512] 및 [Ohtani et al., J. Am. Chem. Soc., 1991, 113, 4092]을 참조한다.The present invention also provides N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6- methoxyphenyl) (Also referred to herein as "compound A" and "N - (-) - (3,4-difluoro) 2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide "Lt; / RTI >

. In some embodiments, the powder x-ray diffraction pattern contains at least 50% of the peaks shown in Fig. In some embodiments, the powder x-ray diffraction pattern contains at least 70% of the peaks shown in Fig. In some embodiments, the powder x-ray diffraction pattern contains at least 90% of the peak shown in Fig. In some embodiments, the powder x-ray diffraction pattern is substantially the same as the powder x-ray diffraction pattern shown in Fig. Compound A has been characterized as an "S" isomer by producing R and S-MTPA esters in secondary alcohols and comparing the differences in chemical shifts. See, for example, Dale, JA; Mosher, HS, J. Am. Chem. Soc., 1973, 95, 512] and [Ohtani et al., J. Am. Chem. Soc., 1991, 113, 4092).

. 화합물 B는 2급 알콜에서 R 및 S-MTPA 에스테르를 생성하고 양성자 화학적 이동 차이를 비교하여 "R" 이성질체인 것으로 특징규명된 바 있다. 예를 들어, 문헌 [Dale, J.A.; Mosher, H.S., J. Am. Chem. Soc., 1973, 95, 512] 및 [Ohtani et al., J. Am. Chem. Soc., 1991, 113, 4092]을 참조한다.The present invention also provides a process for the preparation of N- (R) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) (Also referred to herein as "compound B" and "N - (+) - (3,4-difluoro-2- (2- Amino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide "

. Compound B has been characterized as being the "R" isomer by producing R and S-MTPA esters in secondary alcohols and comparing differences in proton chemical shifts. See, for example, Dale, JA; Mosher, HS, J. Am. Chem. Soc., 1973, 95, 512] and [Ohtani et al., J. Am. Chem. Soc., 1991, 113, 4092).

. 일부 실시양태에서, 상기 시차 주사 열량법 패턴은 도 6에 나타낸 시차 주사 열량법 패턴과 실질적으로 동일하다.The present invention also provides N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6- methoxyphenyl) -1- (2, 3-dihydroxypropyl) cyclopropane-1-sulfonamide < / RTI >

. In some embodiments, the differential scanning calorimetric pattern is substantially the same as the differential scanning calorimetric pattern shown in Fig.

The present invention also relates to the use of an effective amount of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) - dihydroxypropyl) cyclopropane-1-sulfonamide and a pharmaceutically acceptable carrier or vehicle.

In some embodiments, the N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6- Dihydroxypropyl) cyclopropane-1-sulfonamide is useful for treating or preventing cancer or inflammatory diseases. In addition, the present invention provides an effective amount of N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- , 3-dihydroxypropyl) cyclopropane-1-sulfonamide to a subject in need of treatment or prevention of a cancer or inflammatory disease. ≪ / RTI >

In another aspect, the invention relates to a pharmaceutical composition comprising an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. Such compositions may contain adjuvants, excipients and preservatives, agents that delay absorption, fillers, binders, adsorbents, buffers, disintegrants, solubilizers, other carriers, and other sodium alginate components. Methods of formulating such compositions are well known in the art.

In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. In some embodiments, the pharmaceutical composition is in a form suitable for oral administration. In a further or additional embodiment, the pharmaceutical composition is in the form of tablets, capsules, pills, powders, sustained release formulations, solutions, suspensions, parenteral injections such as sterile solutions, suspensions or emulsions For topical administration such as ointments or creams, or for rectal administration such as suppositories. In a further or additional embodiment, the pharmaceutical composition is in unit dosage form suitable for single administration of precise dosages. In further or additional embodiments, the amount of the compound of formula I ranges from about 0.001 to about 1000 mg / kg body weight per day. In further or additional embodiments, the amount of compound of formula I ranges from about 0.5 to about 50 mg / kg / day. In further or additional embodiments, the amount of compound of formula I is from about 0.001 to about 7 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.002 to about 6 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.005 to about 5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.01 to about 5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.02 to about 5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.05 to about 2.5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.1 to about 1 g / day.

In further or additional embodiments, dosage levels below the lower limit of the aforementioned range may be more appropriate. In further or additional embodiments, dosage levels above the upper limit of the above range may be required. In a further or additional embodiment, the compound of formula I is administered in a single administration once a day. In a further or additional embodiment, the compound of formula I is administered in multiple doses more than once per day. In a further or additional embodiment, the compound of formula I is administered twice a day. In a further or additional embodiment, the compound of formula I is administered three times per day. In a further or additional embodiment, the compound of formula I is administered four times per day. In a further or additional embodiment, the compound of formula I is administered more than 4 times per day.

In some embodiments, the pharmaceutical composition is for administration to a mammal. In a further or additional embodiment, the mammal is a human.

In a further or additional embodiment, the pharmaceutical composition further comprises a pharmaceutical carrier, excipient and / or adjuvant. In a further or additional embodiment, the pharmaceutical composition further comprises at least one therapeutic agent. In a further or additional embodiment, the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenic agents and anti-neoplastic agents. In further or additional embodiments, the anti-neoplastic agent is selected from the group consisting of an alkylating agent, an anti-metabolite, an epipidolipid, an anti-neoplastic enzyme, a topoisomerase inhibitor, a procarbazine, a mitoxantrone, Complexes, biological response modifiers and growth inhibitors, hormone / anti-hormone therapeutics, and hematopoietic growth factors. In a further or additional embodiment, the therapeutic agent is Taxol, Bortezomib, or both. In a further or additional embodiment, the pharmaceutical composition is administered in combination with additional therapy. In further or additional embodiments, the additional therapy is radiation therapy, chemotherapy, surgery, or any combination thereof. In a further or additional embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of formula (I).

로부터 선택된 화합물을 포함하는 조성물 및 그의 사용 방법이 제공된다. 일부 실시양태에서, 상기 화합물의 2-OH 탄소는 R 배위로 존재한다. 일부 실시양태에서, 상기 화합물의 2-OH 탄소는 S 배위로 존재한다. 일부 실시양태에서, 상기 조성물에는 상기 화합물의 S 이성질체가 실질적으로 없다. 일부 실시양태에서, 상기 조성물에는 상기 화합물의 R 이성질체가 실질적으로 없다. 일부 실시양태에서, 상기 화합물은 그의 S 이성질체를 10％ 미만으로 함유한다. 일부 실시양태에서, 상기 화합물은 그의 R 이성질체를 10％ 미만으로 함유한다. 일부 실시양태에서, 상기 화합물은 그의 S 이성질체를 5％ 미만으로 함유한다. 일부 실시양태에서, 상기 화합물은 그의 R 이성질체를 5％ 미만으로 함유한다. 일부 실시양태에서, 상기 화합물은 그의 S 이성질체를 1％ 미만으로 함유한다. 일부 실시양태에서, 상기 화합물은 그의 R 이성질체를 1％ 미만으로 함유한다.In the present application,

≪ / RTI > and methods of use thereof are provided. In some embodiments, the 2-OH carbon of the compound is in the R configuration. In some embodiments, the 2-OH carbon of the compound is present in the S configuration. In some embodiments, the composition is substantially free of the S isomer of the compound. In some embodiments, the composition is substantially free of the R isomer of the compound. In some embodiments, the compound contains less than 10% of its S isomer. In some embodiments, the compound contains less than 10% of its R isomer. In some embodiments, the compound contains less than 5% of its S isomer. In some embodiments, the compound contains less than 5% of its R isomer. In some embodiments, the compound contains less than 1% of its S isomer. In some embodiments, the compound contains less than 1% of its R isomer.

In addition, To about 100 mg of a compound having the structure of formula (I), and a method of treating cancer or inflammation using the composition. In some embodiments, the composition allows for modified release of the compound. In some embodiments, the composition allows sustained release of the compound. In some embodiments, the composition allows delayed release of the compound. In some embodiments, the compound is present in an amount of about 1 to 50 mg. In some embodiments, the compound is present in an amount of about 1 to 10 mg. In some embodiments, the compound is present in an amount of about 10 to 20 mg. In some embodiments, the compound is present in an amount of about 20 to 40 mg. In some embodiments, the compound is present in an amount of about 40 to 50 mg.

의 구조를 갖는 화합물 약 1 내지 50 mg을 포함하고 상기 약물의 변형 방출을 허용하는 조성물 및 상기 조성물을 사용하여 암 또는 염증을 치료하는 방법이 제공된다. 일부 실시양태에서, 상기 조성물은 미세결정질 셀룰로스를 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 크로스카르멜로스 나트륨을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 나트륨 라우릴 술페이트를 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 스테아르산마그네슘을 추가로 포함한다.In addition,

To about 50 mg of a compound having the structure of formula (I), wherein the compound is capable of allowing the modified release of the drug, and a method of treating cancer or inflammation using the composition. In some embodiments, the composition further comprises microcrystalline cellulose. In some embodiments, the composition further comprises croscarmellose sodium. In some embodiments, the composition further comprises sodium lauryl sulfate. In some embodiments, the composition further comprises magnesium stearate.

의 구조를 갖는 화합물 약 1 mg을 포함하는 조성물이 제공된다. 일부 실시양태에서, 상기 조성물은 미세결정질 셀룰로스 약 222.2 mg을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 크로스카르멜로스 나트륨 약 12.0 mg을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 나트륨 라우릴 술페이트 약 2.4 mg을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 스테아르산마그네슘 약 2.4 mg을 추가로 포함한다. In addition,

Lt; RTI ID = 0.0 > 1 mg < / RTI > In some embodiments, the composition further comprises about 222.2 mg of microcrystalline cellulose. In some embodiments, the composition further comprises about 12.0 mg of croscarmellose sodium. In some embodiments, the composition further comprises about 2.4 mg of sodium lauryl sulfate. In some embodiments, the composition further comprises about 2.4 mg of magnesium stearate.

의 구조를 갖는 화합물 약 10 mg을 포함하는 조성물 및 상기 조성물을 사용하여 암 또는 염증을 치료하는 방법이 제공된다. 일부 실시양태에서, 상기 조성물은 미세결정질 셀룰로스 약 213.2 mg을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 크로스카르멜로스 나트륨 약 12.0 mg을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 나트륨 라우릴 술페이트 약 2.4 mg을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 스테아르산마그네슘 약 2.4 mg을 추가로 포함한다. In addition,

To about 10 mg of a compound having the structure of Formula I and a method of treating cancer or inflammation using the composition. In some embodiments, the composition further comprises about 213.2 mg of microcrystalline cellulose. In some embodiments, the composition further comprises about 12.0 mg of croscarmellose sodium. In some embodiments, the composition further comprises about 2.4 mg of sodium lauryl sulfate. In some embodiments, the composition further comprises about 2.4 mg of magnesium stearate.

의 구조를 갖는 화합물 약 20 mg을 포함하는 조성물 및 상기 조성물을 사용하여 암 또는 염증을 치료하는 방법이 제공된다. 일부 실시양태에서, 상기 조성물은 미세결정질 셀룰로스 약 203.2 mg을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 크로스카르멜로스 나트륨 약 12.0 mg을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 나트륨 라우릴 술페이트 약 2.4 mg을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 스테아르산마그네슘 약 2.4 mg을 추가로 포함한다. In addition,

To about 20 mg of a compound having the structure < RTI ID = 0.0 > of formula I < / RTI > and a method of treating cancer or inflammation using the composition. In some embodiments, the composition further comprises about 203.2 mg of microcrystalline cellulose. In some embodiments, the composition further comprises about 12.0 mg of croscarmellose sodium. In some embodiments, the composition further comprises about 2.4 mg of sodium lauryl sulfate. In some embodiments, the composition further comprises about 2.4 mg of magnesium stearate.

의 구조를 갖는 화합물 약 40 mg을 포함하는 조성물 및 상기 조성물을 사용하여 암 또는 염증을 치료하는 방법이 제공된다. 일부 실시양태에서, 상기 조성물은 미세결정질 셀룰로스 약 183.2 mg을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 크로스카르멜로스 나트륨 약 12.0 mg을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 나트륨 라우릴 술페이트 약 2.4 mg을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 스테아르산마그네슘 약 2.4 mg을 추가로 포함한다.In addition,

To about 40 mg of a compound having the structure of Formula I and a method of treating cancer or inflammation using the composition. In some embodiments, the composition further comprises about 183.2 mg of microcrystalline cellulose. In some embodiments, the composition further comprises about 12.0 mg of croscarmellose sodium. In some embodiments, the composition further comprises about 2.4 mg of sodium lauryl sulfate. In some embodiments, the composition further comprises about 2.4 mg of magnesium stearate.

의 구조를 갖는 화합물 약 0.4 중량％, 및 제약상 허용가능한 담체 또는 비히클 약 99.6 중량％를 포함하는 조성물 및 상기 조성물을 사용하여 암 또는 염증을 치료하는 방법이 제공된다. 일부 실시양태에서, 상기 제약상 허용가능한 담체 또는 비히클은 미세결정질 셀룰로스를 포함한다. 일부 실시양태에서, 상기 미세결정질 셀룰로스는 조성물의 약 92.6 중량％이다. 일부 실시양태에서, 상기 조성물은 약 5 중량％의 크로스카르멜로스 나트륨을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 약 1 중량％의 나트륨 라우릴 술페이트를 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 약 1 중량％의 스테아르산마그네슘을 추가로 포함한다. In addition,

And about 99.6% by weight of a pharmaceutically acceptable carrier or vehicle, and a method of treating cancer or inflammation using the composition. In some embodiments, the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose. In some embodiments, the microcrystalline cellulose is about 92.6% by weight of the composition. In some embodiments, the composition further comprises about 5% by weight of croscarmellose sodium. In some embodiments, the composition further comprises about 1% by weight of sodium lauryl sulfate. In some embodiments, the composition further comprises about 1 wt% magnesium stearate.

의 구조를 갖는 화합물 약 4.2 중량％, 및 제약상 허용가능한 담체 또는 비히클 약 95.8 중량％를 포함하는 조성물 및 상기 조성물을 사용하여 암 또는 염증을 치료하는 방법이 제공된다. 일부 실시양태에서, 상기 제약상 허용가능한 담체 또는 비히클은 미세결정질 셀룰로스를 포함한다. 일부 실시양태에서, 상기 미세결정질 셀룰로스는 조성물의 약 88.8 중량％이다. 일부 실시양태에서, 상기 조성물은 약 5 중량％의 크로스카르멜로스 나트륨을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 약 1 중량％의 나트륨 라우릴 술페이트를 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 약 1 중량％의 스테아르산마그네슘을 추가로 포함한다. In addition,

About 4.2% by weight of a compound having the structure of Formula I, and about 95.8% by weight of a pharmaceutically acceptable carrier or vehicle, and a method of treating cancer or inflammation using the composition. In some embodiments, the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose. In some embodiments, the microcrystalline cellulose is about 88.8% by weight of the composition. In some embodiments, the composition further comprises about 5% by weight of croscarmellose sodium. In some embodiments, the composition further comprises about 1% by weight of sodium lauryl sulfate. In some embodiments, the composition further comprises about 1 wt% magnesium stearate.

의 구조를 갖는 화합물 약 2 내지 약 10 중량％ 및 제약상 허용가능한 담체 또는 비히클 약 98 내지 약 90 중량％를 포함하는 조성물 및 상기 조성물을 사용하여 암 또는 염증을 치료하는 방법이 제공된다. 일부 실시양태에서, 상기 제약상 허용가능한 담체 또는 비히클은 미세결정질 셀룰로스를 추가로 포함한다. 일부 실시양태에서, 상기 미세결정질 셀룰로스는 조성물의 약 85 내지 약 95 중량％이다. 일부 실시양태에서, 상기 조성물은 약 1 내지 약 6 중량％의 크로스카르멜로스 나트륨을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 약 0.1 내지 약 2 중량％의 나트륨 라우릴 술페이트를 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 약 0.25 내지 약 1.5 중량％의 스테아르산마그네슘을 추가로 포함한다. In addition,

To about 10% by weight of a compound having the structure of formula (I) and about 98 to about 90% by weight of a pharmaceutically acceptable carrier or vehicle, and a method of treating cancer or inflammation using the composition. In some embodiments, the pharmaceutically acceptable carrier or vehicle further comprises microcrystalline cellulose. In some embodiments, the microcrystalline cellulose is from about 85% to about 95% by weight of the composition. In some embodiments, the composition further comprises about 1 to about 6 weight percent croscarmellose sodium. In some embodiments, the composition further comprises about 0.1 to about 2 weight percent sodium lauryl sulfate. In some embodiments, the composition further comprises from about 0.25 to about 1.5 weight percent magnesium stearate.

의 구조를 갖는 화합물 약 1 mg을 포함하는 조성물 및 상기 조성물을 사용하여 암 또는 염증을 치료하는 방법이 제공된다. 일부 실시양태에서, 상기 조성물은 미세결정질 셀룰로스 약 222.2 mg을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 크로스카르멜로스 나트륨 약 12.0 mg을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 나트륨 라우릴 술페이트 약 2.4 mg을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 스테아르산마그네슘 약 2.4 mg을 추가로 포함한다.In addition,

, And a method of treating cancer or inflammation using the composition. In some embodiments, the composition further comprises about 222.2 mg of microcrystalline cellulose. In some embodiments, the composition further comprises about 12.0 mg of croscarmellose sodium. In some embodiments, the composition further comprises about 2.4 mg of sodium lauryl sulfate. In some embodiments, the composition further comprises about 2.4 mg of magnesium stearate.

의 구조를 갖는 화합물 약 10 mg을 포함하는 조성물 및 상기 조성물을 사용하여 암 또는 염증을 치료하는 방법이 제공된다. 일부 실시양태에서, 상기 조성물은 미세결정질 셀룰로스 약 213.2 mg을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 크로스카르멜로스 나트륨 약 12.0 mg을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 나트륨 라우릴 술페이트 약 2.4 mg을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 스테아르산마그네슘 약 2.4 mg을 추가로 포함한다.In addition,

To about 10 mg of a compound having the structure of Formula I and a method of treating cancer or inflammation using the composition. In some embodiments, the composition further comprises about 213.2 mg of microcrystalline cellulose. In some embodiments, the composition further comprises about 12.0 mg of croscarmellose sodium. In some embodiments, the composition further comprises about 2.4 mg of sodium lauryl sulfate. In some embodiments, the composition further comprises about 2.4 mg of magnesium stearate.

의 구조를 갖는 화합물 약 20 mg을 포함하는 조성물 및 상기 조성물을 사용하여 암 또는 염증을 치료하는 방법이 제공된다. 일부 실시양태에서, 상기 조성물은 미세결정질 셀룰로스 약 203.2 mg을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 크로스카르멜로스 나트륨 약 12.0 mg을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 나트륨 라우릴 술페이트 약 2.4 mg을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 스테아르산마그네슘 약 2.4 mg을 추가로 포함한다.In addition,

To about 20 mg of a compound having the structure < RTI ID = 0.0 > of formula I < / RTI > and a method of treating cancer or inflammation using the composition. In some embodiments, the composition further comprises about 203.2 mg of microcrystalline cellulose. In some embodiments, the composition further comprises about 12.0 mg of croscarmellose sodium. In some embodiments, the composition further comprises about 2.4 mg of sodium lauryl sulfate. In some embodiments, the composition further comprises about 2.4 mg of magnesium stearate.

의 구조를 갖는 화합물 약 40 mg을 포함하는 조성물 및 상기 조성물을 사용하여 암 또는 염증을 치료하는 방법이 제공된다. 일부 실시양태에서, 상기 조성물은 미세결정질 셀룰로스 약 183.2 mg을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 크로스카르멜로스 나트륨 약 12.0 mg을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 나트륨 라우릴 술페이트 약 2.4 mg을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 스테아르산마그네슘 약 2.4 mg을 추가로 포함한다.In addition,

To about 40 mg of a compound having the structure of Formula I and a method of treating cancer or inflammation using the composition. In some embodiments, the composition further comprises about 183.2 mg of microcrystalline cellulose. In some embodiments, the composition further comprises about 12.0 mg of croscarmellose sodium. In some embodiments, the composition further comprises about 2.4 mg of sodium lauryl sulfate. In some embodiments, the composition further comprises about 2.4 mg of magnesium stearate.

의 구조를 갖는 화합물 약 0.4 중량％, 및 제약상 허용가능한 담체 또는 비히클 약 99.6 중량％를 포함하는 조성물 및 상기 조성물을 사용하여 암 또는 염증을 치료하는 방법이 제공된다. 일부 실시양태에서, 상기 제약상 허용가능한 담체 또는 비히클은 미세결정질 셀룰로스를 포함한다. 일부 실시양태에서, 상기 미세결정질 셀룰로스는 조성물의 약 92.6 중량％이다. 일부 실시양태에서, 상기 조성물은 약 5 중량％의 크로스카르멜로스 나트륨을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 약 1 중량％의 나트륨 라우릴 술페이트를 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 약 1 중량％의 스테아르산마그네슘을 추가로 포함한다. In addition,

And about 99.6% by weight of a pharmaceutically acceptable carrier or vehicle, and a method of treating cancer or inflammation using the composition. In some embodiments, the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose. In some embodiments, the microcrystalline cellulose is about 92.6% by weight of the composition. In some embodiments, the composition further comprises about 5% by weight of croscarmellose sodium. In some embodiments, the composition further comprises about 1% by weight of sodium lauryl sulfate. In some embodiments, the composition further comprises about 1 wt% magnesium stearate.

의 구조를 갖는 화합물 약 4.2 중량％ 및 제약상 허용가능한 담체 또는 비히클 약 95.8 중량％를 포함하는 조성물 및 상기 조성물을 사용하여 암 또는 염증을 치료하는 방법이 제공된다. 일부 실시양태에서, 상기 제약상 허용가능한 담체 또는 비히클은 미세결정질 셀룰로스를 포함한다. 일부 실시양태에서, 상기 미세결정질 셀룰로스는 조성물의 약 88.8 중량％이다. 일부 실시양태에서, 상기 조성물은 약 5 중량％의 크로스카르멜로스 나트륨을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 약 1 중량％의 나트륨 라우릴 술페이트를 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 약 1 중량％의 스테아르산마그네슘을 추가로 포함한다. In addition,

To about 95% by weight of a pharmaceutically acceptable carrier or vehicle, and a method of treating cancer or inflammation using the composition. In some embodiments, the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose. In some embodiments, the microcrystalline cellulose is about 88.8% by weight of the composition. In some embodiments, the composition further comprises about 5% by weight of croscarmellose sodium. In some embodiments, the composition further comprises about 1% by weight of sodium lauryl sulfate. In some embodiments, the composition further comprises about 1 wt% magnesium stearate.

의 구조를 갖는 화합물 약 2 내지 약 10 중량％ 및 제약상 허용가능한 담체 또는 비히클 약 98 내지 약 90 중량％를 포함하는 조성물 및 상기 조성물을 사용하여 암 또는 염증을 치료하는 방법이 제공된다. 일부 실시양태에서, 상기 제약상 허용가능한 담체 또는 비히클은 미세결정질 셀룰로스를 포함한다. 일부 실시양태에서, 상기 미세결정질 셀룰로스는 조성물의 약 85 내지 약 95 중량％이다. 일부 실시양태에서, 상기 조성물은 약 1 내지 약 6 중량％의 크로스카르멜로스 나트륨을 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 약 0.1 내지 약 2 중량％의 나트륨 라우릴 술페이트를 추가로 포함한다. 일부 실시양태에서, 상기 조성물은 약 0.25 내지 약 1.5 중량％의 스테아르산마그네슘을 추가로 포함한다. In addition,

To about 10% by weight of a compound having the structure of formula (I) and about 98 to about 90% by weight of a pharmaceutically acceptable carrier or vehicle, and a method of treating cancer or inflammation using the composition. In some embodiments, the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose. In some embodiments, the microcrystalline cellulose is from about 85% to about 95% by weight of the composition. In some embodiments, the composition further comprises about 1 to about 6 weight percent croscarmellose sodium. In some embodiments, the composition further comprises about 0.1 to about 2 weight percent sodium lauryl sulfate. In some embodiments, the composition further comprises from about 0.25 to about 1.5 weight percent magnesium stearate.

Further, in the present application, it is to be understood that in the present invention, N - (-) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide The crystalline polymorph Form A and the compound Is provided. In some embodiments, the crystalline polymorph Form A exhibits a powder x-ray diffraction pattern comprising at least 70% of the peaks identified in the powder x-ray diffraction pattern shown in Fig. In some embodiments, the powder x-ray diffraction pattern comprises at least 90% of the peaks identified in the powder x-ray diffraction pattern shown in Fig. In some embodiments, the powder x-ray diffraction pattern is substantially the same as the powder x-ray diffraction pattern shown in Fig. In some embodiments, the crystalline polymorph has a melting point initiation point measured by differential scanning calorimetry of about 143 ° C. In some embodiments, the crystalline polymorph is substantially free of water. In some embodiments, the crystalline polymorph is substantially free of solvent.

Further, in the present application, it is to be understood that the present invention is not limited to the specific examples of N - (-) - (3,4-difluoro-2- (2- - iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide and a composition comprising such a compound. In some embodiments, the crystalline polymorph has a melting point initiation point measured by differential scanning calorimetry of about 143 ° C. In some embodiments, the crystalline polymorph of claim 67 or 68 is substantially free of water. In some embodiments, the crystalline polymorph of any of claims 67-69 is substantially free of solvent.

Also, in the present application, amorphous N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3- (2-fluoro-4-iodophenylamino) -6- (trifluoromethyl) propyl) cyclopropane-1-sulfonamide was prepared by a method comprising crystallizing N- Methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide and a composition comprising such a compound. In some embodiments, the crystallization step comprises crystallizing from a mixture of ethyl acetate and heptane. In some embodiments, the mixture of ethyl acetate and heptane is a ratio of about 1 to 4 parts of ethyl acetate to about 2 to 10 parts of heptane. In some embodiments, the mixture of ethyl acetate and heptane is a ratio of about 2 parts ethyl acetate to about 5 parts heptane.

Also provided herein is a method of inhibiting a MEK enzyme, comprising contacting the compound or composition described herein with a MEK enzyme, wherein the compound is present in an amount sufficient to inhibit the enzyme by 25% or more do. In some embodiments, the MEK enzyme is a MEK kinase. In some embodiments, the contacting occurs within a cell.

Also provided herein are methods of treating such disorders in an individual suffering from a MEK mediated disorder, comprising administering an effective amount of a compound or composition described herein to a subject suffering from a MEK mediated disorder. In some embodiments, the MEK inhibitor is administered in combination with additional therapy. In some embodiments, the additional therapy is radiation therapy, non-MEK kinase inhibitor therapy, chemotherapy, surgery, glucocorticoid, methotrexate, biological response modifier, or any combination thereof. In some embodiments, the MEK mediated disorder is selected from the group consisting of inflammatory diseases, infections, autoimmune disorders, stroke, ischemia, cardiac disorders, neurological disorders, fibrogenetic disorders, proliferative disorders, hyperproliferative disorders, , Cancer, carcinoma, metabolic disease, and malignant disease. In some embodiments, the MEK mediated disorder is an overt disease. In some embodiments, the MEK mediated disorder is cancer, tumor, leukemia, neoplasm, or carcinoma. In some embodiments, the MEK mediated disorder is an inflammatory disease. In some embodiments, the inflammatory disease is rheumatoid arthritis or multiple sclerosis.

Also provided herein is a method of treating or preventing a proliferative disease in an individual, comprising administering to the subject an effective amount of a compound or composition as described herein. In some embodiments, the proliferative disease is cancer, psoriasis, restenosis, disease or atherosclerosis. In some embodiments, the proliferative disease is cancer. In some embodiments, the cancer is selected from the group consisting of brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, colorectal cancer, leukemia, myeloid leukemia, glioblastoma, follicular lymphoma, pre- , Chronic lymphocytic B-leukemia, stomach cancer, mesothelioma or small cell lung cancer. In some embodiments, the method further comprises administering one or more therapeutic agents. In some embodiments, such a step comprises the administration of one or more additional cancer therapies. In some embodiments, the additional therapy is radiation therapy, non-MEK kinase inhibitor therapy, chemotherapy, surgery, glucocorticoid, methotrexate, biological response modifier, or any combination thereof.

Also provided herein is a method of treating or preventing an inflammatory disease in a subject, comprising administering to the subject an effective amount of a composition comprising a compound described herein. In some embodiments, the inflammatory disease is rheumatoid arthritis or multiple sclerosis.

Also provided herein is a method of treating cancer cells, comprising contacting an cancer cell with an effective amount of a compound or composition of the invention described herein that inhibits cancer cell degradation, inhibits cancer cell growth, or kills cancer cells, Or to kill cancer cells. In some embodiments, the cancer cells include cancer cells of the brain, breast, lung, ovary, pancreas, prostate, kidney, stomach or colon rectum.

Also provided herein are methods of treating a subject suffering from a disease or condition, comprising administering to the subject an effective amount of a compound or composition described herein to inhibit an increase in the size of the tumor, decrease the size of the tumor, decrease tumor growth, or prevent tumor growth. Methods of inhibiting the increase in size of a tumor, reducing the size of the tumor, reducing tumor proliferation, or preventing tumor proliferation are provided. In some embodiments, the tumor occurs in the brain, breast, lung, ovary, pancreas, prostate, kidney, stomach, colon or rectum.

Also provided herein are methods of treating or preventing ankylosing spondylitis, gout, tendonitis, sciatica or sciatica, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) There is provided a method of treating or preventing bursitis or sciatica:

(I)

In this formula,

Z is H or F,

X is _{F, Cl, CH 3, CH} 2 OH, CH 2 F, CHF 2 or CF _3,

Y is I, Br, Cl, CF _3, C ₁ -C ₃ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl, cyclopropyl, OMe, OEt, SMe, phenyl or Het, where the Het is a saturated, olefinic or aromatic 5 to 10 membered monocyclic or bicyclic heterocyclic group containing 1 to 5 ring heteroatoms independently selected from N, O and S,

All of said phenyl or Het group F, Cl, Br, I, acetyl, methyl, CN, NO _2, CO ₂ H, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl, -C _{(= O) -, C 1} -C 3 alkyl, -C (= S) -, C 1 -C 3 alkoxy group -C (= S) -, C 1 -C 3 alkyl, -C (= O) O-, C ₁ -C ₃ alkyl, -O- (C = O) -, C 1 -C 3 alkyl, -C (= O) NH-, C 1 -C 3 alkyl, -C (= NH) NH-, C 1 -C 3 alkyl, -NH- (C = O) -, di -C ₁ -C ₃ alkyl, -N- (C = O) -, C 1 -C 3 alkyl, -C (= O) N (C 1 -C 3 alkyl) -, C ₁ -C ₃ alkyl-S (= O) ₂ NH- or trifluoromethyl,

All of the methyl, ethyl, C ₁ -C ₃ alkyl or cyclopropyl group is optionally substituted by OH,

     Wherein all of said methyl groups are optionally substituted with one, two or three F atoms,

R ⁰ is H, F, Cl, Br, I, CH 3 NH-, (CH 3) 2 N-, C 1 -C 6 alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, phenyl, monosubstituted phenyl, O (C ₁ -C ₄ alkyl), OC (= O) ( C 1 -C 4 alkyl) or C (= O) O (C ₁ -C ₄ alkyl), wherein,

     The group of said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl and phenyl is optionally substituted with one to three groups independently selected from F, Cl, Br, I, OH, CN, cyanomethyl, nitro, phenyl and trifluoromethyl Optionally substituted with a substituent,

The group of C ₁ -C ₆ alkyl and C ₁ -C ₄ alkoxy is also optionally substituted with OCH ₃ or OCH ₂ CH ₃ ,

G is G ₁ , G ₂ , R _1a , R _1b , R _1c , R _1d , R _1e , Ar ₁ , Ar ₂ or Ar ₃ ,

G ₁ is C ₁ -C ₆ alkyl optionally substituted by one amino, C ₁ -C ₃ alkylamino, or a group of dialkylamino containing two C ₁ -C ₄ alkyl groups which may or may not be the same Or

G ₁ is a C ₃ -C ₈ diaminoalkyl group,

G ₂ contains 1 to 3 ring heteroatoms independently selected from N, O and S and is selected from the group consisting of F, Cl, OH, O (C ₁ -C ₃ alkyl), OCH ₃ , OCH ₂ CH ₃ , CH ₃ C (= O) group of _{NH, CH 3 C (= O} ) O, CN, CF 3, and N, O and clicking a 5-membered aromatic heterocyclic containing 1 to 4 ring heteroatoms independently selected from S Unsaturated or aromatic 5 or 6 membered ring optionally substituted with one to three substituents independently selected from H,

_Wherein R _1a is methyl optionally substituted by 1 to 3 fluorine atoms or 1 to 3 chlorine atoms or OH, cyclopropoxy or C ₁ -C ₃ alkoxy, wherein said cyclopropoxy group or said C ₁ The C ₁ -C ₃ alkyl portion of the -C ₃ alkoxy group is optionally substituted with one hydroxy or methoxy group and wherein all C ₃ -alkyl groups within the C ₁ -C ₄ alkoxy are optionally further substituted with a second OH group And,

R _1b is CH (CH ₃₎ -C _{1 - 3} alkyl, or independently from C ₃ -C ₆ cycloalkyl, said alkyl and cycloalkyl, where the group F, Cl, Br, I, OH, OCH _3, and CN Optionally substituted with one to three substituents selected from < RTI ID = 0.0 >

R _1c is (CH ₂ ) _n O _m R '

          m is 0 or 1,

              when m is 0, n is 1 or 2,

              when m is 1, n is 2 or 3,

R 'is C ₁ -C ₆ alkyl optionally substituted with ₁ to 3 substituents independently selected from F, Cl, OH, OCH ₃ , OCH ₂ CH ₃ and C ₃ -C ₆ cycloalkyl,

R _1d is C (A) (A ') (B) -,

And ₄ alkyl, _- B is H, or is C ₁ groups with one or two OH optionally substituted

A and A 'are independently H, or is one or two OH groups optionally substituted by C _{1 - 4} alkyl or, or

          A and A 'together with the carbon atom to which they are attached form a 3- to 6-membered saturated ring,

이고, 이때,R _1e is

Lt; / RTI >

          q is 1 or 2,

R ₂ and R ₃ are each independently selected from the group consisting of H, F, Cl, Br, CH ₃ , CH ₂ F, CHF ₂ , CF ₃ , OCH ₃ , OCH ₂ F, OCHF ₂ , OCF ₃ , Propyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl or methylsulfonyl,

R ₄ is selected from the group consisting of H, F, Cl, Br, CH ₃ , CH ₂ F, CHF ₂ , CF ₃ , OCH ₃ , OCH ₂ F, OCHF ₂ , OCF ₃ , ethyl, Butyl, tert-butyl, methylsulfonyl, nitro, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1,3,4-oxadiazole Methyl-1,3,4-oxadiazole, 1,3,4-thiadiazole, 5-methyl-1,3,4-thiadiazole, 1H-tetrazolyl, N- Morpholylcarbonylamino, N-morpholylsulfonyl and N-pyrrolidinylcarbonylamino,

R < ₅ > is H, F, Cl or methyl,

R < ₆ > is H, F, Cl or methyl,

이고, 이때,Ar ₁ is

Lt; / RTI >

U and V are independently N, CR ₂ or CR ₃ ,

R ₂ , R ₃ and R ₄ are independently H, F, Cl, Br, CH ₃ , CH ₂ F, CHF ₂ , CF ₃ , OCH ₃ , OCH ₂ F, OCHF ₂ , OCF ₃ , , Isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, Methyl-1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 5-methyl-1,3,4-thiadiazolyl, 1H-tetrazolyl, N-morpholylcarbonylamino, N-morpholysulfonyl, N-pyrrolidinylcarbonylamino and methylsulfonyl,

R ₅ and R ₆ are independently H, F, Cl or methyl,

이고, 이때,Ar ₂ is

Lt; / RTI >

          The broken line represents an alternative structural position for the second ring double bond,

           U is -S-, -O- or -N =

               When U is -O- or -S-, V is -CH =, -CCl = or -N =

               When U is -N =, V is -CH =, -CCl = or -N =

R < ₇ > is H or methyl,

R ₈ is H, acetamido, methyl, F or Cl,

이고, 이때,Ar ₃ is

Lt; / RTI >

U is -NH-, -NCH ₃ - or -O-, and,

R ₇ and R ₈ are independently H, F, Cl or methyl.

In some embodiments, the compound is

로부터 선택된다. 일부 실시양태에서, 상기 화합물은

로부터 선택되며, 여기서의 2-OH 탄소는 R 배위로 존재한다. 일부 실시양태에서, 화학식 I의 화합물 또는 그의 제약 염은

로부터 선택되며, 여기서의 2-OH 탄소는 S 배위로 존재한다. 일부 실시양태에서, 상기 화합물은

이다. 일부 실시양태에서, 상기 화합물은

이다.

. In some embodiments, the compound is

Where the 2-OH carbon is present in the R configuration. In some embodiments, the compound of formula I, or a pharmaceutical salt thereof,

, Where the 2-OH carbon is present in the S configuration. In some embodiments, the compound is

to be. In some embodiments, the compound is

to be.

Also provided herein are methods of treating gastric cancer by administering a therapeutically effective amount of a compound or composition described herein. Also provided herein are methods of treating a leukemia, melanoma or liver tumor by administering a therapeutically effective amount of a compound or composition described herein.

Also provided herein are methods of treating a non-small cell lung cancer by administering a therapeutically effective amount of a compound or composition described herein. Also provided herein is a method of treating a colon cancer by administering a therapeutically effective amount of a compound or composition described herein. Also provided herein are methods of treating a CNS cancer by administering a therapeutically effective amount of a compound or composition described herein. Also provided herein are methods of treating ovarian cancer by administering a therapeutically effective amount of a compound or composition described herein. Also provided herein is a method of treating a renal cancer by administering a therapeutically effective amount of a compound or composition described herein. Also provided herein are methods of treating a prostate cancer by administering a therapeutically effective amount of a compound or composition described herein. Also provided herein is a method of treating a breast cancer by administering a therapeutically effective amount of a compound or composition described herein. In various embodiments, the methods further comprise administering one or more additional therapeutic agents. In some embodiments, one or more additional cancer therapies are performed. In some embodiments, the additional cancer therapy is radiation therapy, chemotherapy, surgery, or any combination thereof.

Also provided herein are methods of treating or preventing psoriasis by administering a therapeutically effective amount of a compound or composition described herein in a topical dosage form.

In various embodiments, the composition is administered orally. In some embodiments, the composition is administered once a day or twice a day. In some embodiments, the composition is administered once a day for at least one week.

In some embodiments, the T _max of the compound is achieved between 1 hour and 3 hours after oral administration of the composition to the subject of fasting. In some embodiments, the compound reaches a C _max of between about 0.01 μg / mL and about 1.0 μg / mL on day 1 upon administration to the subject. In some embodiments, the compound reaches a C _max of between about 0.01 μg / mL and about 0.8 μg / mL on day 1 upon administration to the subject. In some embodiments, the compound reaches a C _max of between about 0.03 μg / mL and about 0.5 μg / mL on day 1 upon administration to the subject. In some embodiments, the compound has an AUC from about 0 μg · hr / mL to about 5.0 μg · hr / mL from time 0 to time 12. In some embodiments, the AUC of the compound is from about 0.1 μg · hr / mL to about 4.0 μg · hr / mL. In some embodiments, the AUC of the compound is from about 0.5 μg · hr / mL to about 3.0 μg · hr / mL. In some embodiments, the _Tmax of the compound is 0.5 hours to 5.0 hours. In some embodiments, the _Tmax of the compound is from 1.0 hour to 3.0 hours. In some embodiments, the _Tmax of the compound is from 1.0 hour to 2.5 hours. In some embodiments, the compound has a plasma concentration of greater than about 0.01 mg / mL after 5 hours of single administration. In some embodiments, the compound has a plasma concentration of greater than about 0.01 mg / mL after 10 hours of single administration. In some embodiments, the compound has a plasma concentration of greater than about 0.01 mg / mL after 15 hours of single administration.

In some embodiments, the compound reaches a mean C _max between about 0.01 μg / mL and about 1.0 μg / mL on day 1 upon administration to a group of 10 subjects. In some embodiments, the compound reaches a mean C _max between about 0.01 μg / mL and about 0.8 μg / mL on day 1 upon administration to a group of 10 subjects. In some embodiments, the compound reaches a mean C _max of between about 0.03 μg / mL and about 0.5 μg / mL on day 1 upon administration to a group of 10 subjects. In some embodiments, the compound has an average AUC of from about 0.1 μg · hr / mL to about 5.0 μg · hr / mL. In some embodiments, the compound has an average AUC of from about 0.1 μg · hr / mL to about 4.0 μg · hr / mL. In some embodiments, the compound has an average AUC of from about 0.5 μg · hr / mL to about 3.0 μg · hr / mL. In some embodiments, the compound has an average _Tmax of 0.5 hours to 5.0 hours. In some embodiments, the compound has an average _{Tmax of} from 1.0 hour to 3.0 hours. In some embodiments, the compound has an average _Tmax between 1.0 h and 2.5 h.

Also provided herein are methods of reducing the tumor volume by administering the compounds and compositions described herein. In some embodiments, after daily administration of the drug for 5 days, the tumor is reduced in volume by about 25% or more. In some embodiments, after daily administration of the drug for 5 days, the tumor is reduced in volume by more than about 50%. In some embodiments, after daily administration of the drug for 5 days, the tumor is reduced in volume by about 20% to 70% or more. In some embodiments, after daily administration of the drug for 15 days, the tumor is reduced in volume by more than about 25%. In some embodiments, after daily administration of the drug for 15 days, the tumor is reduced in volume by more than about 50%. In some embodiments, after daily administration of the drug for 15 days, the tumor is reduced in volume by about 20% to 70% or more. In some embodiments, after daily administration of the drug for 30 days, the tumor is reduced in volume by more than about 25%. In some embodiments, after administration of the drug for 30 days daily, the tumor is reduced in volume by more than about 50%. In some embodiments, after daily administration of the drug for 30 days, the tumor is reduced in volume by about 20% to 70% or more.

Also provided herein are methods of inhibiting tumor growth by administering the compounds and compositions described herein. In some embodiments, tumor growth is inhibited by about 20% or more after administration of the drug. In some embodiments, tumor growth is inhibited by greater than about 40% after administration of the drug. In some embodiments, tumor growth is inhibited by about 60% or more after administration of the drug. In some embodiments, tumor growth is inhibited by greater than about 80% after administration of the drug. In some embodiments, tumor growth is inhibited from about 20% to about 100% after administration of the drug. In some embodiments, tumor growth is substantially inhibited after administration of the drug.

In some embodiments, the composition is administered twice daily. In some embodiments, the composition is administered once a day.

In some embodiments, the MEK inhibitor does not inhibit co-administration of the second tumor suppressor.

In some embodiments, the compositions are in the form of tablets, capsules, gel capsules, caplets, pellets, or beads. In some embodiments, the composition is in the form of a capsule or tablet, with a total weight of from about 50 mg to about 1000 mg. In some embodiments, the composition is in the form of a capsule or tablet and has a total weight of 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg and 500 mg ≪ / RTI > In some embodiments, the composition is in the form of a capsule or tablet and has a total weight of about 240 mg.

In some embodiments, the composition is selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, lactose, compressible sugar, xylitol, sorbitol, mannitol, pregelatinized starch, maltodextrin, calcium phosphate, One or more fillers selected from calcium carbonate, starch and calcium silicate.

In some embodiments, the composition further comprises at least one disintegrant selected from sodium croscarmellose, sodium starch glycolate, crospovidone, methylcellulose, alginic acid, sodium alginate, starch derivatives, bentonite, and veegum .

In some embodiments, the composition further comprises at least one lubricant selected from magnesium stearate, metallic stearate, talc, sodium stearyl fumarate and stearic acid.

In some embodiments, the composition is selected from the group consisting of sodium lauryl sulfate, glycerol, sorbitan oleate, sorbitan stearate, polyoxyethylene sorbitan laurate, palmitate, stearate, oleate or hexaoleate, Ethylene stearyl alcohol and sorbitan monolaurate. ≪ Desc / Clms Page number 7 >

In the present application, a composition in the form of a capsule or tablet is provided, wherein the capsule or tablet is prepared by using a USP (US Pharmacopeia) Apparatus II at 50 rpm and dissolving 1% When sodium lauryl sulfate is used, it releases more than 60% of the drug within 30 minutes. In some embodiments, the composition is in the form of a capsule or tablet, and the capsule or tablet is prepared by mixing 1% sodium lauryl sulfate in water as a dissolution medium using USP Applarase II at 50 rpm The drug releases about 60% to 100% of the drug within 30 minutes of use. In some embodiments, the composition is in the form of a capsule or tablet, and the capsule or tablet is prepared by mixing 1% sodium lauryl sulfate in water as a dissolution medium using USP Applarase II at 50 rpm The drug releases about 60% to 90% of the drug within 30 minutes of use. In some embodiments, the composition is in the form of a capsule or tablet, and the capsule or tablet is prepared by mixing 1% sodium lauryl sulfate in water as a dissolution medium using USP Applarase II at 50 rpm The drug releases about 60% to 80% of the drug within 30 minutes of use.

Also provided herein are batches of capsules or tablets each containing about 1 to about 50 mg of the compound described herein and having a USP acceptable value of less than about 15 for content uniformity.

Treatment method

The present invention is directed to a method of treating or preventing cancer, comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of a pharmaceutical composition comprising a compound of Formula I as described herein. In various embodiments, the compounds and compositions useful in this method are as set forth in one subgroup or class of compounds of formula I or in formula I and exemplified throughout this application.

The present invention is directed to a method of treating or preventing an inflammatory disease, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of Formula I as described herein. In various embodiments, the compounds and compositions useful in this method are as set forth in one subgroup or class of compounds of formula I or in formula I and exemplified throughout this application.

In some embodiments, the invention includes administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of Formula I as described herein, in need of treating or preventing ankylosing spondylitis, gout, tendinitis, bursitis or sciatica Ankylosing spondylitis, gout, tendinitis, bursitis, or sciatica. In various embodiments, the compounds and compositions useful in this method are as set forth in one subgroup or class of compounds of formula I or in formula I and exemplified throughout this application.

In some aspects, the invention also includes administering to a subject suffering from the disease an effective amount of a composition comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, To a method of treating a disease in an individual suffering from the disease.

In another aspect, the invention provides a method of treating a disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof ≪ / RTI >

In another aspect, the invention provides a method of treating a disorder in a mammal comprising administering to a human a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof ≪ / RTI >

In another aspect, the present invention provides a method of treating a mammal, including a human, comprising administering to a mammal comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, To a method of treating an hyperproliferative disorder in a mammal comprising said mammal.

In another aspect, the invention provides a method of treating a mammal, including a human, comprising administering to a mammal, including a human, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. The present invention relates to a method of treating an inflammatory disease, condition, or disorder in a mammal.

In another aspect, the invention provides a method of treating a mammal, including a human, comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof, of a MEK cascade. To a method of treating a disorder or condition mediated by a MEK cascade in a mammal, including a human. Appropriate dosages for a particular patient may be determined by those skilled in the art according to known methods.

MEK  Inhibition of enzymes

In another aspect, the present invention relates to a method of inhibiting MEK enzyme. In some embodiments, the method comprises contacting the MEK enzyme with a composition in an amount sufficient to inhibit the enzyme, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, Such that the enzyme is inhibited. In a further or additional embodiment, the enzyme is inhibited by at least about 1%. In a further or additional embodiment, the enzyme is inhibited by at least about 2%. In a further or additional embodiment, the enzyme is inhibited by at least about 3%. In a further or additional embodiment, the enzyme is inhibited by at least about 4%. In a further or additional embodiment, the enzyme is inhibited by at least about 5%. In a further or additional embodiment, the enzyme is inhibited by at least about 10%. In a further or additional embodiment, the enzyme is inhibited by at least about 20%. In a further or additional embodiment, the enzyme is inhibited by at least about 25%. In a further or additional embodiment, the enzyme is inhibited by at least about 30%. In a further or additional embodiment, the enzyme is inhibited by at least about 40%. In a further or additional embodiment, the enzyme is inhibited by at least about 50%. In a further or additional embodiment, the enzyme is inhibited by at least about 60%. In a further or additional embodiment, the enzyme is inhibited by at least about 70%. In a further or additional embodiment, the enzyme is inhibited by at least about 75%. In a further or additional embodiment, the enzyme is inhibited by at least about 80%. In further or additional embodiments, the enzyme is inhibited by greater than about 90%. In a further or additional embodiment, the enzyme is essentially completely inhibited. In a further or additional embodiment, the MEK enzyme is a MEK kinase. In a further or additional embodiment, the MEK enzyme is MEKl. In a further or additional embodiment, the MEK enzyme is MEK2. In further or additional embodiments, the contacting occurs within the cell. In a further or additional embodiment, the cell is a mammalian cell. In a further or additional embodiment, the mammalian cell is a human cell. In a further or additional embodiment, the MEK enzyme is inhibited by a composition comprising a pharmaceutically acceptable salt of a compound of formula (I).

MEK  Mediated disorder

In another aspect, the invention provides a method of treating a mammal suffering from a MEK mediated disorder comprising administering to a subject suffering from a MEK mediated disorder an effective amount of a composition comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof A method for treating a MEK mediated disorder in an individual suffering from a MEK mediated disorder. In some embodiments, a composition comprising a compound of Formula I is administered orally, duodenally, parenterally (e.g., intravenously, subcutaneously, intramuscularly, by intravascular or infusion), topically or rectally. In some embodiments, the pharmaceutical composition is in a form suitable for oral administration. In a further or additional embodiment, the pharmaceutical composition is in the form of tablets, capsules, pills, powders, sustained release formulations, solutions, suspensions, parenteral injections such as sterile solutions, suspensions or emulsions For topical administration such as ointments or creams, or for rectal administration such as suppositories. In a further or additional embodiment, the pharmaceutical composition is in unit dosage form suitable for single administration of precise dosages. In a further or additional embodiment, the pharmaceutical composition further comprises a pharmaceutical carrier, excipient and / or adjuvant.

In further or additional embodiments, the amount of the compound of formula I ranges from about 0.001 to about 1000 mg / kg body weight per day. In further or additional embodiments, the amount of compound of formula I ranges from about 0.5 to about 50 mg / kg / day. In further or additional embodiments, the amount of compound of formula I is from about 0.001 to about 7 g / day. In further or additional embodiments, the amount of the compound of formula I is from about 0.01 to about 7 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.02 to about 5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.05 to about 2.5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.1 to about 1 g / day. In further or additional embodiments, dosage levels below the lower limit of the aforementioned range may be more appropriate. In further or additional embodiments, dosage levels above the upper limit of the above range may be required.

In a further or additional embodiment, the compound of formula I is administered in a single administration once a day. In a further or additional embodiment, the compound of formula I is administered in multiple doses more than once per day. In a further or additional embodiment, the compound of formula I is administered twice a day. In a further or additional embodiment, the compound of formula I is administered three times per day. In a further or additional embodiment, the compound of formula I is administered four times per day. In a further or additional embodiment, the compound of formula I is administered more than 4 times per day. In some embodiments, the subject suffering from a MEK mediated disorder is a mammal. In further or additional embodiments, the subject is a human.

In some embodiments, a composition comprising a compound of formula I is administered in combination with additional therapy. In further or additional embodiments, the additional therapy is radiation therapy, chemotherapy, surgery, or any combination thereof. In a further or additional embodiment, a composition comprising a compound of formula I is administered in combination with one or more therapeutic agents. In a further or additional embodiment, the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenic agents and anti-neoplastic agents. In further or additional embodiments, the anti-neoplastic agent is selected from the group consisting of an alkylating agent, an anti-metabolite, an epipidolipid, an anti-neoplastic enzyme, a topoisomerase inhibitor, a procarbazine, a mitoxantrone, Complexes, biological response modifiers and growth inhibitors, hormone / anti-hormone therapeutics, and hematopoietic growth factors. In a further or additional embodiment, the therapeutic agent is selected from Taxol, Bortezomib, or both.

In some embodiments, the MEK mediated disorder is selected from the group consisting of inflammatory diseases, infections, autoimmune disorders, stroke, ischemia, cardiac disorders, neurological disorders, fibrotic disorders, proliferative disorders, hyperproliferative disorders, non- Atherosclerosis, rheumatoid arthritis, osteoarthritis, heart failure, chronic pain, neuropathic pain, dry eye (including, but not limited to, ), Right occlusive glaucoma and wide angle glaucoma. In a further or additional embodiment, the MEK mediated disorder is an inflammatory disease. In a further or additional embodiment, the MEK mediated disorder is an overt disease. In a further or additional embodiment, the MEK mediated disorder is selected from the group consisting of tumors, leukemias, neoplasms, cancers, carcinomas and malignancies. In a further or additional embodiment, the cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, kidney cancer, colorectal cancer or leukemia. In a further or additional embodiment, the fibrogenic disorder is skin sclerosis, multiple myositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis. In an additional or additional embodiment, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of Formula I is administered.

Achieved effect

In another aspect, the invention provides a method for treating a variety of conditions in a patient, comprising administering to the patient an effective amount of a composition comprising a compound of Formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof Cancer, immune diseases and inflammatory diseases. ≪ Desc / Clms Page number 2 > In some embodiments, the effect is inhibition of various cancers. In a further or additional embodiment, the effect is inhibition of an immune disease. In a further or additional embodiment, the effect is inhibition of inflammatory disease.

In some embodiments, a composition comprising a compound of formula I is administered in combination with additional therapy. In further or additional embodiments, the additional therapy is radiation therapy, chemotherapy, surgery, or any combination thereof. In a further or additional embodiment, a composition comprising a compound of formula I is administered in combination with one or more therapeutic agents.

In some embodiments, the compositions are administered orally, intraduodenally, parenterally (e.g., intravenously, subcutaneously, intramuscularly, by intravascular or infusion), topically or rectally. In further or additional embodiments, the amount of the compound of formula I ranges from about 0.001 to about 1000 mg / kg body weight per day. In further or additional embodiments, the amount of compound of formula I ranges from about 0.5 to about 50 mg / kg / day. In further or additional embodiments, the amount of compound of formula I is from about 0.001 to about 7 g / day. In further or additional embodiments, the amount of the compound of formula I is from about 0.01 to about 7 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.02 to about 5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.05 to about 2.5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.1 to about 1 g / day. In further or additional embodiments, dosage levels below the lower limit of the aforementioned range may be more appropriate. In further or additional embodiments, dosage levels above the upper limit of the above range may be required.

In a further or additional embodiment, the compound of formula I is administered in a single administration once a day. In a further or additional embodiment, the compound of formula I is administered in multiple doses more than once per day. In a further or additional embodiment, the compound of formula I is administered twice a day. In a further or additional embodiment, the compound of formula I is administered three times per day. In a further or additional embodiment, the compound of formula I is administered four times per day. In a further or additional embodiment, the compound of formula I is administered more than 4 times per day. In some embodiments, the individual suffering from cancer is a mammal. In further or additional embodiments, the subject is a human. In an additional or additional embodiment, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of Formula I is administered.

In another aspect, the present invention provides a method of treating cancer cells, comprising the steps of dissolving or inhibiting the growth of cancer cells, or inhibiting the growth of cancer cells, including, but not limited to, compounds of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof Or inhibiting the growth of cancer cells or killing cancer cells, comprising contacting the cancer cells with an effective amount of a composition that kills the cancer cells. In some embodiments, the cancer cells include cancer cells of the brain, breast, lung, ovary, pancreas, prostate, kidney or colon rectum. In a further or additional embodiment, the composition is administered with one or more therapeutic agents. In a further or additional embodiment, the therapeutic agent is Taxol, Bortezomib, or both. In a further or additional embodiment, the therapeutic agent is selected from the group consisting of a cytotoxic agent, an anti-angiogenic agent and an anti-neoplastic agent. In further or additional embodiments, the anti-neoplastic agent is selected from the group consisting of an alkylating agent, an anti-metabolite, an epipidolipid, an anti-neoplastic enzyme, a topoisomerase inhibitor, a procarbazine, a mitoxantrone, Complexes, biological response modifiers and growth inhibitors, hormone / anti-hormone therapeutics, and hematopoietic growth factors. In some embodiments, cancer cells are degraded. In a further or additional embodiment, 1% of cancer cells are degraded. In a further or additional embodiment, 2% of cancer cells are degraded. In a further or additional embodiment, 3% of cancer cells are degraded. In a further or additional embodiment, 4% of the cancer cells are degraded. In a further or additional embodiment, 5% of the cancer cells are degraded. In a further or additional embodiment, 10% of the cancer cells are degraded. In a further or additional embodiment, 20% of the cancer cells are degraded. In a further or additional embodiment, 25% of the cancer cells are degraded. In a further or additional embodiment, 30% of the cancer cells are degraded. In a further or additional embodiment, 40% of the cancer cells are degraded. In a further or additional embodiment, 50% of the cancer cells are degraded. In a further or additional embodiment, 60% of cancer cells are degraded. In a further or additional embodiment, 70% of the cancer cells are degraded. In a further or additional embodiment, 75% of the cancer cells are degraded. In a further or additional embodiment, 80% of the cancer cells are degraded. In a further or additional embodiment, 90% of the cancer cells are degraded. In a further or additional embodiment, 100% of the cancer cells are degraded. In a further or additional embodiment, essentially all cancer cells are degraded. In various embodiments, the above mentioned degradation occurs within 1 day, 5 days, 10 days, 1 month, 2 months, 6 months or 1 year.

In some embodiments, the cancer cells are killed. In a further or additional embodiment, 1% of the cancer cells are killed. In a further or additional embodiment, 2% of cancer cells are killed. In a further or additional embodiment, 3% of the cancer cells are killed. In a further or additional embodiment, 4% of the cancer cells are killed. In a further or additional embodiment, 5% of the cancer cells are killed. In a further or additional embodiment, 10% of the cancer cells are killed. In a further or additional embodiment, 20% of the cancer cells are killed. In a further or additional embodiment, 25% of the cancer cells are killed. In a further or additional embodiment, 30% of the cancer cells are killed. In a further or additional embodiment, 40% of the cancer cells are killed. In a further or additional embodiment, 50% of the cancer cells are killed. In a further or additional embodiment, 60% of the cancer cells are killed. In a further or additional embodiment, 70% of the cancer cells are killed. In a further or additional embodiment, 75% of the cancer cells are killed. In a further or additional embodiment, 80% of the cancer cells are killed. In a further or additional embodiment, 90% of the cancer cells are killed. In a further or additional embodiment, 100% of the cancer cells are killed. In a further or additional embodiment, essentially all cancer cells are killed. In various embodiments, the above-mentioned cancer cell death occurs within 1 day, 5 days, 10 days, 1 month, 2 months, 6 months or 1 year.

In further or additional embodiments, the growth of cancer cells is inhibited. In further or additional embodiments, the growth of cancer cells is inhibited by about 1%. In further or additional embodiments, the growth of cancer cells is inhibited by about 2%. In further or additional embodiments, the growth of cancer cells is inhibited by about 3%. In further or additional embodiments, the growth of cancer cells is inhibited by about 4%. In a further or additional embodiment, the growth of cancer cells is inhibited by about 5%. In a further or additional embodiment, the growth of cancer cells is inhibited by about 10%. In additional or additional embodiments, the growth of cancer cells is inhibited by about 20%. In a further or additional embodiment, the growth of cancer cells is inhibited by about 25%. In further or additional embodiments, the growth of cancer cells is inhibited by about 30%. In further or additional embodiments, the growth of cancer cells is inhibited by about 40%. In further or additional embodiments, the growth of cancer cells is inhibited by about 50%. In a further or additional embodiment, the growth of cancer cells is inhibited by about 60%. In further or additional embodiments, the growth of cancer cells is inhibited by about 70%. In a further or additional embodiment, the growth of cancer cells is inhibited by about 75%. In further or additional embodiments, the growth of cancer cells is inhibited by about 80%. In a further or additional embodiment, the growth of cancer cells is inhibited by about 90%. In a further or additional embodiment, the growth of cancer cells is inhibited by about 100%. In various embodiments, the above-mentioned inhibition occurs within 1 day, 5 days, 10 days, 1 month, 2 months, 6 months or 1 year.

In another aspect, the invention provides a method of treating a tumor in a subject, comprising administering to the subject an effective amount of a composition comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, Or inhibiting tumor growth, or reducing tumor proliferation or preventing tumor proliferation. In some embodiments, the size of the tumor is reduced. In a further or additional embodiment, the size of the tumor is reduced by 1% or more. In a further or additional embodiment, the size of the tumor is reduced by 2% or more. In a further or additional embodiment, the size of the tumor is reduced by 3% or more. In a further or additional embodiment, the size of the tumor is reduced by 4% or more. In a further or additional embodiment, the size of the tumor is reduced by 5% or more. In a further or additional embodiment, the size of the tumor is reduced by at least 10%. In additional or additional embodiments, the size of the tumor is reduced by 20% or more. In a further or additional embodiment, the size of the tumor is reduced by at least 25%. In a further or additional embodiment, the size of the tumor is reduced by 30% or more. In a further or additional embodiment, the size of the tumor is reduced by at least 40%. In a further or additional embodiment, the size of the tumor is reduced by 50% or more. In a further or additional embodiment, the size of the tumor is reduced by 60% or more. In a further or additional embodiment, the size of the tumor is reduced by 70% or more. In a further or additional embodiment, the size of the tumor is reduced by at least 75%. In a further or additional embodiment, the size of the tumor is reduced by 80% or more. In a further or additional embodiment, the size of the tumor is reduced by at least 85%. In a further or additional embodiment, the size of the tumor is reduced by 90% or more. In a further or additional embodiment, the size of the tumor is reduced by at least 95%. In a further or additional embodiment, the tumor is eradicated. In some embodiments, the size of the tumor does not increase. In various embodiments, the above-mentioned effect on tumor size occurs within 1 day, 5 days, 10 days, 1 month, 2 months, 6 months or 1 year.

In some embodiments, tumor growth is reduced. In some embodiments, tumor growth is reduced by 1% or more. In some embodiments, tumor growth is reduced by 2% or more. In some embodiments, tumor growth is reduced by 3% or more. In some embodiments, tumor growth is reduced by 4% or more. In some embodiments, tumor growth is reduced by 5% or more. In some embodiments, tumor growth is reduced by 10% or more. In some embodiments, tumor growth is reduced by 20% or more. In some embodiments, tumor growth is reduced by 25% or more. In some embodiments, tumor growth is reduced by 30% or more. In some embodiments, tumor growth is reduced by 40% or more. In some embodiments, tumor growth is reduced by 50% or more. In some embodiments, tumor growth is reduced by 60% or more. In some embodiments, tumor growth is reduced by 70% or more. In some embodiments, tumor growth is reduced by 75% or more. In some embodiments, tumor growth is reduced by 75% or more. In some embodiments, tumor growth is reduced by 80% or more. In some embodiments, tumor growth is reduced by 90% or more. In some embodiments, tumor growth is reduced by 95% or more. In some embodiments, tumor growth is inhibited. In various embodiments, the above-mentioned effect on cell proliferation occurs within 1 day, 5 days, 10 days, 1 month, 2 months, 6 months or 1 year.

In some embodiments, a composition comprising a compound of formula I is administered in combination with additional therapy. In further or additional embodiments, the additional therapy is radiation therapy, chemotherapy, surgery, or any combination thereof. In a further or additional embodiment, a composition comprising a compound of formula I is administered in combination with one or more therapeutic agents. In a further or additional embodiment, the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenic agents and anti-neoplastic agents. In further or additional embodiments, the anti-neoplastic agent is selected from the group consisting of an alkylating agent, an anti-metabolite, an epipidolipid, an anti-neoplastic enzyme, a topoisomerase inhibitor, a procarbazine, a mitoxantrone, Complexes, biological response modifiers and growth inhibitors, hormone / anti-hormone therapeutics, and hematopoietic growth factors. In a further or additional embodiment, the therapeutic agent is selected from Taxol, Bortezomib, or both.

In some embodiments, the compositions are administered orally, intraduodenally, parenterally (e.g., intravenously, subcutaneously, intramuscularly, by intravascular or infusion), topically or rectally. In further or additional embodiments, the amount of the compound of formula I ranges from about 0.001 to about 1000 mg / kg body weight per day. In further or additional embodiments, the amount of compound of formula I ranges from about 0.5 to about 50 mg / kg / day. In further or additional embodiments, the amount of compound of formula I is from about 0.001 to about 7 g / day. In further or additional embodiments, the amount of the compound of formula I is from about 0.01 to about 7 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.02 to about 5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.05 to about 2.5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.1 to about 1 g / day. In further or additional embodiments, dosage levels below the lower limit of the aforementioned range may be more appropriate. In further or additional embodiments, dosage levels above the upper limit of the above range may be required.

In a further or additional embodiment, the compound of formula I is administered in a single administration once a day. In a further or additional embodiment, the compound of formula I is administered in multiple doses more than once per day. In a further or additional embodiment, the compound of formula I is administered twice a day. In a further or additional embodiment, the compound of formula I is administered three times per day. In a further or additional embodiment, the compound of formula I is administered four times per day. In a further or additional embodiment, the compound of formula I is administered more than 4 times per day. In some embodiments, the individual suffering from cancer is a mammal. In further or additional embodiments, the subject is a human. In an additional or additional embodiment, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of Formula I is administered.

Proliferative disease

In another aspect, the invention provides a method of proliferating a subject in a subject, comprising administering to the subject an effective amount of a composition comprising a compound of Formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, To a method of treating or preventing a sexually transmitted disease. In some embodiments, the proliferative disease is cancer, psoriasis, restenosis, autoimmune disease or atherosclerosis. In a further or additional embodiment, the proliferative disorder is an hyperproliferative disorder. In a further or additional embodiment, the proliferative disease is selected from the group consisting of a tumor, leukemia, neoplasm, cancer, carcinoma and malignant disease. In a further or additional embodiment, the cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, colorectal cancer, gastric cancer, head and neck cancer or leukemia. In a further or additional embodiment, the fibrogenic disorder is skin sclerosis, multiple myositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis. In a further or additional embodiment, the cancer is gastric cancer, brain cancer, breast cancer, lung cancer, non-small cell lung cancer, ovarian cancer, pancreatic cancer, liver cancer, prostate cancer, kidney cancer, colorectal cancer or leukemia. In a further or additional embodiment, the cancer is brain cancer or adrenocortical carcinoma. In a further or additional embodiment, the cancer is breast cancer. In a further or additional embodiment, the cancer is an ovarian cancer. In a further or additional embodiment, the cancer is pancreatic cancer. In a further or additional embodiment, the cancer is prostate cancer. In a further or additional embodiment, the cancer is kidney cancer. In a further or additional embodiment, the cancer is colorectal cancer. In a further or additional embodiment, the cancer is myelogenous leukemia. In a further or additional embodiment, the cancer is glioblastoma. In a further or additional embodiment, the cancer is follicular lymphoma. In a further or additional embodiment, the cancer is Global-B acute leukemia. In a further or additional embodiment, the cancer is chronic lymphocytic B-leukemia. In a further or additional embodiment, the cancer is mesothelioma. In a further or additional embodiment, the cancer is a small cell lung cancer. In a further embodiment, the cancer is gastric cancer.

In some embodiments, a composition comprising a compound of formula I is administered in combination with additional therapy. In further or additional embodiments, the additional therapy is radiation therapy, chemotherapy, surgery, or any combination thereof. In a further or additional embodiment, a composition comprising a compound of formula I is administered in combination with one or more therapeutic agents. In a further or additional embodiment, the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenic agents and anti-neoplastic agents. In further or additional embodiments, the anti-neoplastic agent is selected from the group consisting of an alkylating agent, an anti-metabolite, an epipidolipid, an anti-neoplastic enzyme, a topoisomerase inhibitor, a procarbazine, a mitoxantrone, Complexes, biological response modifiers and growth inhibitors, hormone / anti-hormone therapeutics, and hematopoietic growth factors.

In a further or additional embodiment, the therapeutic agent is selected from Taxol, Bortezomib, or both. In some embodiments, the compositions are administered orally, intraduodenally, parenterally (e.g., intravenously, subcutaneously, intramuscularly, by intravascular or infusion), topically or rectally.

In further or additional embodiments, the amount of the compound of formula I ranges from about 0.001 to about 1000 mg / kg body weight per day. In further or additional embodiments, the amount of compound of formula I ranges from about 0.5 to about 50 mg / kg / day. In further or additional embodiments, the amount of compound of formula I is from about 0.001 to about 7 g / day. In further or additional embodiments, the amount of the compound of formula I is from about 0.01 to about 7 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.02 to about 5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.05 to about 2.5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.1 to about 1 g / day. In further or additional embodiments, dosage levels below the lower limit of the aforementioned range may be more appropriate. In further or additional embodiments, dosage levels above the upper limit of the above range may be required.

In a further or additional embodiment, the compound of formula I is administered in a single administration once a day. In a further or additional embodiment, the compound of formula I is administered in multiple doses more than once per day. In a further or additional embodiment, the compound of formula I is administered twice a day. In a further or additional embodiment, the compound of formula I is administered three times per day. In a further or additional embodiment, the compound of formula I is administered four times per day. In a further or additional embodiment, the compound of formula I is administered more than 4 times per day. In some embodiments, the subject suffering from a proliferative disease is a mammal. In further or additional embodiments, the subject is a human. In an additional or additional embodiment, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of Formula I is administered.

Inflammatory disease

In another aspect, the present invention provides a method of treating inflammation in a subject, comprising administering to the subject an effective amount of a composition comprising a compound of Formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, To a method of treating or preventing a disease. In a further or additional embodiment, the inflammatory disease is selected from the group consisting of chronic inflammatory diseases, rheumatoid arthritis, rheumatoid arthritis, spondylarthosis, gouty arthritis, osteoarthritis, inflammatory arthritis, acute rheumatoid arthritis, intestinal arthritis, neuropathic arthritis, Inflammatory bowel disease, irritable bowel syndrome, ulcerative colitis, reflux esophagitis, Crohn's disease, gastritis, asthma, allergies, respiratory distress syndrome, pancreatitis, chronic obstructive pulmonary disease (COPD), psoriatic arthritis, pyogenic arthritis, atherosclerosis, systemic lupus erythematosis , Pulmonary fibrosis, psoriasis, eczema or scleroderma.

In some embodiments, a composition comprising a compound of formula I is administered in combination with additional therapy. In a further or additional embodiment, a composition comprising a compound of formula I is administered in combination with one or more therapeutic agents.

In some embodiments, the compositions are administered orally, intraduodenally, parenterally (e.g., intravenously, subcutaneously, intramuscularly, by intravascular or infusion), topically or rectally. In further or additional embodiments, the amount of the compound of formula I ranges from about 0.001 to about 1000 mg / kg body weight per day. In further or additional embodiments, the amount of compound of formula I ranges from about 0.5 to about 50 mg / kg / day. In further or additional embodiments, the amount of compound of formula I is from about 0.001 to about 7 g / day. In further or additional embodiments, the amount of the compound of formula I is from about 0.01 to about 7 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.02 to about 5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.05 to about 2.5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.1 to about 1 g / day. In further or additional embodiments, dosage levels below the lower limit of the aforementioned range may be more appropriate. In further or additional embodiments, dosage levels above the upper limit of the above range may be required.

In a further or additional embodiment, the compound of formula I is administered in a single administration once a day. In a further or additional embodiment, the compound of formula I is administered in multiple doses more than once per day. In a further or additional embodiment, the compound of formula I is administered twice a day. In a further or additional embodiment, the compound of formula I is administered three times per day. In a further or additional embodiment, the compound of formula I is administered four times per day. In a further or additional embodiment, the compound of formula I is administered more than 4 times per day. In some embodiments, the subject suffering from an inflammatory disease is a mammal. In further or additional embodiments, the subject is a human. In an additional or additional embodiment, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of Formula I is administered.

cancer

In another aspect, the present invention provides a method of treating cancer in a subject, comprising administering to the subject an effective amount of a composition comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. ≪ / RTI > In a further or additional embodiment, the cancer is brain cancer, breast cancer, stomach cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, colorectal cancer or leukemia. In a further or additional embodiment, the fibrogenic disorder is skin sclerosis, multiple myositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis. In a further or additional embodiment, the cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, gastric cancer, colorectal cancer or leukemia. In a further or additional embodiment, the cancer is brain cancer or adrenocortical carcinoma. In a further or additional embodiment, the cancer is breast cancer. In a further or additional embodiment, the cancer is an ovarian cancer. In a further or additional embodiment, the cancer is pancreatic cancer. In a further or additional embodiment, the cancer is prostate cancer. In a further or additional embodiment, the cancer is kidney cancer. In a further or additional embodiment, the cancer is colorectal cancer. In a further or additional embodiment, the cancer is myelogenous leukemia. In a further or additional embodiment, the cancer is glioblastoma. In a further or additional embodiment, the cancer is follicular lymphoma. In a further or additional embodiment, the cancer is Global-B acute leukemia. In a further or additional embodiment, the cancer is chronic lymphocytic B-leukemia. In a further or additional embodiment, the cancer is mesothelioma. In a further or additional embodiment, the cancer is a small cell lung cancer. In some embodiments, the cancer is gastric cancer.

In some embodiments, a composition comprising a compound of formula I is administered in combination with additional therapy. In further or additional embodiments, the additional therapy is radiation therapy, chemotherapy, surgery, or any combination thereof. In a further or additional embodiment, a composition comprising a compound of formula I is administered in combination with one or more therapeutic agents. In a further or additional embodiment, the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenic agents and anti-neoplastic agents. In further or additional embodiments, the anti-neoplastic agent is selected from the group consisting of an alkylating agent, an anti-metabolite, an epipidolipid, an anti-neoplastic enzyme, a topoisomerase inhibitor, a procarbazine, a mitoxantrone, Complexes, biological response modifiers and growth inhibitors, hormone / anti-hormone therapeutics, and hematopoietic growth factors. In a further or additional embodiment, the therapeutic agent is selected from Taxol, Bortezomib, or both.

In some embodiments, the compositions are administered orally, intraduodenally, parenterally (e.g., intravenously, subcutaneously, intramuscularly, by intravascular or infusion), topically or rectally. In further or additional embodiments, the amount of the compound of formula I ranges from about 0.001 to about 1000 mg / kg body weight per day. In further or additional embodiments, the amount of compound of formula I ranges from about 0.5 to about 50 mg / kg / day. In further or additional embodiments, the amount of compound of formula I is from about 0.001 to about 7 g / day. In further or additional embodiments, the amount of the compound of formula I is from about 0.01 to about 7 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.02 to about 5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.05 to about 2.5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.1 to about 1 g / day. In further or additional embodiments, dosage levels below the lower limit of the aforementioned range may be more appropriate.

In further or additional embodiments, dosage levels above the upper limit of the above range may be required. In a further or additional embodiment, the compound of formula I is administered in a single administration once a day. In a further or additional embodiment, the compound of formula I is administered in multiple doses more than once per day. In a further or additional embodiment, the compound of formula I is administered twice a day. In a further or additional embodiment, the compound of formula I is administered three times per day. In a further or additional embodiment, the compound of formula I is administered four times per day. In a further or additional embodiment, the compound of formula I is administered more than 4 times per day. In some embodiments, the individual suffering from cancer is a mammal. In further or additional embodiments, the subject is a human. In an additional or additional embodiment, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of Formula I is administered.

Include references

All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual disclosure or patent application was specifically and individually indicated to be incorporated by reference.

The novel features of the invention are set forth with particularity in the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS The features and advantages of the present invention will become better understood with reference to the following detailed description of an illustrative embodiment thereof, taken in conjunction with the accompanying drawings, in which:
Figure 1 shows a graph of the average tumor volume over time (days) in mice transplanted with A375 melanoma, Colo205 colon tumor, A431 breast tumor or HT-29 colon tumor cells. Mice were orally administered once daily (25 mg / kg, 50 mg / kg or 100 mg / kg) for 14 days.
Figure 2 shows a graph of tumor growth inhibition (%) (% TGI) in A375 xenografted mice treated with 50 mg / kg QD, 25 mg / kg BID, 50 mg / kg QD and 12.5 mg / kg BID.
Figure 3 shows a graph of plasma concentration (log nM) versus pERK inhibition (%) in female nu / nu mice transplanted with Colo205 tumor cells. Mice received a single dose of 2.5, 5, 10 or 25 mg / kg.
Figure 4 shows plasma concentrations (ng / ml) for time after administration of 2 mg (2 x 1 mg capsules), 4 mg (4 x 1 mg capsules) or 6 mg (6 x 1 mg capsules) mL).
FIG. 5 is a graph showing the spectra of N (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6 -Methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide Form A powder X-ray diffraction (PXRD) pattern. The graph shows the intensity of the peak < RTI ID = 0.0 > Plot the diffraction angle 2 &thetas; (DEG).
FIG. 6 is a graphical representation of the synthesis of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) 6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide Modified differential scanning calorimetry (DSC) thermal analysis of Form A is also a graph. The graph shows the standardized heat flow rates vs. watt / gram (W / g) units. Plot the measured sample temperature (占 폚).
FIG. 7 is a graph showing the results of NMR spectra of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6- Phenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide Form A (upper) and N- (S) - (3,4- difluoro-2- -4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide amorphous (lower) PXRD pattern. The graph shows the intensity of the peak < RTI ID = 0.0 > Plot the diffraction angle 2 &thetas; (DEG).
FIG. 8 is a graph showing the spectra of the N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6- (DVS (Dynamic Vapor Sorption / Desorption)) isotherm of Form A in the presence of a catalyst.
9 is a graphical representation of the synthesis of N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6- Phenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulphonamide Form A A thermogravimetric analysis (TG) thermal analysis of Form A is shown.
FIGS. 10A and 10B show the synthesis of N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- -Dihydroxypropyl) cyclopropane-1-sulfonamide was used at increasing concentrations to show that the growth of these cells was arrested when exposed to splitting A375 cells at the exponential phase. The cells were analyzed for ATP content. 100% growth was terminated by incubation with 1 μM N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) 3-dihydroxypropyl) cyclopropane-1-sulfonamide.
Figure 11 shows a 48 hour AK assay in A375 cells. A375 cells in the great-numbered cleavage were treated with N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- , 3-dihydroxypropyl) cyclopropane-1-sulfonamide and PD-325901 for 48 hours and analyzed for AK release.
Figures 12A-12C illustrate the preparation of N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6- methoxyphenyl) (A) human colon rectal carcinoma Colo205 cells (GI ₅₀ = 11 nM), (B) A375 cells expressing no growth arrest induced by 1- (2,3-dihydroxypropyl) cyclopropane- cells (GI ₅₀ = 22 nM) and (C) N- (S) of MDA-MB231 cells (3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -6 Methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide.
Figure 13A shows growth inhibition of human colon carcinoma Colo205 cells with GI ₅₀ values of 6 nM and 11 nM, respectively.
Figure 13B shows the inhibition of growth of A375 cells with GI ₅₀ values of 5 nM and 22 nM.
FIGS. 14A and 14B are graphs showing the results of the synthesis of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -Dihydroxypropyl) cyclopropane-1-sulfonamide on the cell cycle progression and A375 cells were treated with N- (S) - (3,4-difluoro-2- (2- Exposure to 4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide resulted in depletion of cells in both G2 and S phases Lt; RTI ID = 0.0 > G1 < / RTI >
FIGS. 15A and 15B are cross-sectional views illustrating the synthesis of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) (Dihydroxypropyl) cyclopropane-1-sulfonamide on gastric cancer cell line AGS after 3 days (Fig. 15A) and 6 days (Fig. 15B). The y-axis is the number of cells for the vehicle and the x-axis is the number of cells of the N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) - (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide.
Figure 16 is a graphical representation of the concentration of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2 mg / kg, once a day, po; 10 mg / kg, once a day, po; and 50 mg / kg, once a day) were administered intraperitoneally , And po).
17 is a graph showing the effect of N - (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2 mg / kg, once a day, po; 10 mg / kg, once a day, po; and 50 mg / kg, once a day) were administered intraperitoneally , And po).
FIG. 18 is a graph showing the change in the amount of the N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) Hydroxypropyl) cyclopropane-1-sulfonamide treatment (2 mg / kg, 10 mg / kg and 50 mg / kg).
Figure 19 shows the inhibition of Hs746t cell proliferation versus cell number (vehicle value) vs. 2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) Cyclopropane-1-sulfonamide. ≪ / RTI >
FIG. 20A is a graph showing the effect of N - (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6- methoxyphenyl) -1- (2, 3-dihydroxypropyl) cyclopropane-1-sulfonamide was treated at increasing concentrations on day 5 at each of the levels of apoptosis.
Figure 20B is a graph showing the activity of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6- methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide was treated at increasing concentrations on day 5,
Figure 20C is a graphical representation of the activity of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6- methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide was treated at increasing concentrations at day 6,
20D is a graph showing the fluorescence intensity of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6- methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide was treated at increasing concentrations on day 5,
Fig. 20E is a graph showing the fluorescence intensity of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) 3-dihydroxypropyl) cyclopropane-1-sulfonamide were each treated at increasing concentrations.
Figure 20F is a graphical representation of the effect of the compound of the present invention on the ability of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) 3-dihydroxypropyl) cyclopropane-1-sulfonamide was treated at increasing concentrations on day 6 of treatment.
FIG. 20G is a graph showing the results of the cytotoxicity of N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- 2,3-dihydroxypropyl) cyclopropane-1-sulfonamide was treated at increasing concentrations on day 5 of treatment.
20H is a graph showing the results of a method for the production of N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) 2,3-dihydroxypropyl) cyclopropane-1-sulfonamide was treated at increasing concentrations on day 5 of each test.
Fig. 20I shows that glioma D37 cells were cultured in the presence of N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) , ≪ / RTI > 3-dihydroxypropyl) cyclopropane-1-sulfonamide was treated at increasing concentrations on day 5 at each level of apoptosis.
Figure 21 shows the selectivity of compound A for MEK1 and MEK2 against a 205 enzyme pan of 10 [mu] M. The cell lines were Colo205, A375, A431 and HT-29.
Figure 22 shows that in the rat Carrageenan foot edema model, rats were treated with 6, 20, 60 and 200 mg / kg of N- (S) - (3,4-difluoro-2- (Iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide was administered followed by the increase in foot volume in each treatment group, This is a graph showing the decrease in edema of the liver.
23A is a graph showing the effect of 2, 6 and 20 mg / kg of N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide in rats.
Figure 23B is a graph showing the effect of 2, 6 and 20 mg / kg of N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide.
24 is a graph showing the concentration of 1, 3 and 10 mg / kg of N- (S) - (3,4-difluoro-2- (2- fluoro-4- iodophenylamino) -6- The results show the mean arthritis score in collagen-antibody induced arthritis (CAIA) mice treated with QD of 1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide.

The section headings used herein are for organizational purposes only and are not to be construed as limiting the disclosure. All documents or documents referred to in this application, including but not limited to patents, patent applications, articles, literature, manuals and articles, are hereby expressly incorporated by reference in their entirety for any purpose.

Specific Chemical Terminology

Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Unless otherwise stated, all patents, patent applications, and publications cited throughout this disclosure are incorporated by reference in their entirety. Where there are multiple definitions for the term herein, the definitions in this section shall take precedence. If a URL or other such identification mark or address is mentioned, such identification mark may be changed and certain information on the Internet may or may not exist, but searching the Internet or other appropriate reference source may provide equivalent information It should be understood. A reference to this indicates the availability and publicity of such information.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. In the present application, the use of the singular includes the plural, unless specifically stated otherwise. As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is also to be understood that the use of "or" means "and / or" unless stated otherwise. In addition, the use of the terms "comprises" and other forms such as "comprises, ", " including,"

The definition of standard chemical terms is described in Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 ^TH ED." Vols. A (2000) and B (2001), Plenum Press, New York]. Unless otherwise stated, conventional methods of mass spectrometry, NMR, HPLC, IR and UV / Vis spectroscopy and pharmacology are used within the skill in the art. Where no specific definition is provided, nomenclature used in connection with the analytical chemistry, synthetic organic chemistry, and pharmaceutical and pharmaceutical chemistry arts described herein and experimental procedures and techniques in the art are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical formulations, formulation and delivery, and in the treatment of patients. The reaction and purification techniques can be carried out, for example, using a kit of the manufacturer's specifications, as commonly practiced in the art, or as described herein. The techniques and procedures can generally be performed according to conventional methods known in the art and as described in various general and more specific references discussed and discussed throughout this specification. As used herein, the groups and substituents thereof may be selected by those skilled in the art to provide stable moieties and compounds.

When the general formula of a substituent is specified from left to right, such a substituent equally encompasses chemically identical substituents described in the right-to-left structure thereof. As a non-limiting example, -CH ₂ O- is equivalent to -OCH ₂ -.

Unless otherwise stated, the use of general chemical terms including, but not limited to, "alkyl", "amine", "aryl" is equivalent to any of its substituted forms. For example, "alkyl" includes optionally substituted alkyl as used herein.

The compounds provided herein may have one or more stereogenic centers and each center may be in the R or S configuration, or a combination thereof. Likewise, the compounds provided herein may have one or more double bonds, each of which may be in the E (trans) or Z (cis) configuration, or a combination thereof. It is to be understood that the presentation of one particular stereoisomer, regioisomer, diastereoisomer, enantiomer or epimer is understood to include all possible stereoisomers, positional isomers, diastereoisomers, enantiomers or epimers, and mixtures thereof. Thus, the compounds provided herein include not only all of the separate coordinating stereoisomers, positional isomers, diastereoisomers, enantiomers and epimeric forms, but also their corresponding mixtures. The presentation of one particular chemical structure or chemical name for a compound containing one or more chiral centers but not of a particular stereochemistry is intended to encompass mixtures of all possible stereoisomers, pure forms of one particular stereoisomer or substantially pure Quot; encompasses all possible stereoisomers including forms and substantially pure forms of the pure stereoisomers, as well as pure stereoisomers. Techniques for reversing or changing specific stereogenic centers and techniques for dividing a mixture of stereoisomers are well known in the art, and it is within the ability of one of ordinary skill in the art to choose a method that is appropriate for the particular situation. VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5 ^TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816 and Heller, Acc. Chem. Res. 1990, 23, 128).

As used herein, the terms "residue", "chemical moiety", "group" and "chemical group" refer to a specific segment or functional group of a molecule. Chemical residues are often found in the molecule or as a chemical moiety attached to it.

The term " bond "or" single bond "refers to a chemical bond between two atoms or between two residues in the case where the atoms connected by the bond are considered to be part of a larger sub-structure.

The term "arbitrary" or " optionally "means that the event or circumstance described thereafter may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" In addition, the optionally substituted group may be unsubstituted (e.g., -CH ₂ CH ₃ ), completely substituted (eg, -CF ₂ CF ₃ ), monosubstituted , -CH ₂ CH ₂ F), or fully substituted with any level between substituted and monosubstituted _{(e.g., -CH 2 CHF 2, -CH 2} CF 3, -CF 2 CH 3, -CFHCHF 2 , etc.) . With respect to any group containing one or more substituents, those skilled in the art will appreciate that any substitution or substitution pattern (s) in which such groups are not sterically feasible and / or not feasible in synthesis (e.g., substituted alkyls are optionally substituted cycloalkyl groups , Which is again defined as including an optionally substituted alkyl group and is potentially defined in this way infinitely). Thus, any of the substituents described will generally have a maximum molecular weight of about 1,000 daltons, more typically up to about 500 daltons (e.g., when macromolecular substituents such as polypeptides, polysaccharides, polyethylene glycols, DNA, RNA, etc. are explicitly intended Except for the following).

Unless otherwise stated, common chemical terms including, but not limited to, for example, "alkyl", "amine", "aryl"

As used herein, C ₁ -C _x comprises C ₁ -C ₂ , C ₁ -C ₃ ... C ₁ -C _x . By way of example only, a group designated "C ₁ -C ₄ " means that there are one to four carbon atoms in the residue, i.e., one carbon atom, two carbon atoms, three carbon atoms, Represents not only groups containing carbon atoms but also groups in the range of C ₁ -C ₂ and C ₁ -C ₃ . Thus, by way of example only, "C ₁ -C ₄ alkyl" means that there are 1 to 4 carbon atoms in the alkyl group, i.e., the alkyl group is methyl, ethyl, propyl, iso- , Iso-butyl, sec-butyl and t-butyl. When a numerical range such as "1 to 10" is described herein, it refers to each integer within a given range - for example, "1 to 10 carbon atoms" means that the group contains one carbon atom, , Three carbon atoms, four carbon atoms, five carbon atoms, six carbon atoms, seven carbon atoms, eight carbon atoms, nine carbon atoms, or ten carbon atoms.

As used herein, the terms "A and A " together with the carbon atom to which they are attached form a 3 to 6 membered saturated ring" refers to the following structure in compounds of formula (I).

As used herein, the term "heteroatom" or "hetero ", whether alone or in combination, refers to an atom other than carbon or hydrogen. Hetero atoms may be independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but are not limited to these atoms. In embodiments wherein more than one heteroatom is present, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different from each other.

As used herein, the term "alkyl ", whether alone or in combination, refers to a straight or branched chain saturated hydrocarbon mono radical having from 1 to about 10 carbon atoms, or from 1 to 6 carbon atoms. Examples are methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, Butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer chain alkyl groups such as heptyl, octyl and the like. "C ₁ -C ₆ alkyl" or "C _{1 - 6} alkyl" and the case that the numerical ranges disclosed herein, such as, which is the alkyl group having 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, Lt; / RTI > may be composed of five carbon atoms or six carbon atoms. In one embodiment, "alkyl" is substituted. Unless otherwise indicated, "alkyl" is not substituted.

As used herein, the term "alkenyl ", whether alone or in combination, is a straight or branched chain hydrocarbon radical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, or from 2 to about 6 carbon atoms, Quot; refers to a branched hydrocarbon mono radical. It is to be understood that the groups may be in the cis or trans form around the double bond (s) and include both of the two isomers. Examples include but are not limited to ethenyl (-CH = CH ₂ ), 1-propenyl (-CH ₂ CH = CH ₂ ), isopropenyl [-C (CH ₃ ) = CH ₂ ], butenyl, Nyl, and the like. "C ₂ -C ₆ alkenyl" or "C _{2 - 6} alkenyl" and if the value range described herein, which the alkenyl group is 2, 5 carbon atoms, 3 carbon atoms, 4 carbon atoms, such as Carbon atom or 6 carbon atoms. In one embodiment, "alkenyl" is substituted. Unless otherwise indicated, "alkenyl" is not substituted.

As used herein, the term "alkynyl ", whether alone or in combination, is a straight or branched chain hydrocarbon radical having one or more carbon-carbon triple bonds and having from 2 to about 10 carbon atoms, or from 2 to about 6 carbon atoms, Quot; refers to a branched hydrocarbon mono radical. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadienyl, and the like. "C ₂ -C ₆ alkynyl" or "C _{2 - 6} alkynyl" and the numerical range is described herein if, this is the alkynyl group is 2, 5 carbon atoms, 3 carbon atoms, 4 carbon atoms, such as Carbon atom or 6 carbon atoms. In one embodiment, "alkynyl" is substituted. Unless otherwise indicated, "alkynyl" is not substituted.

As used herein, the terms "heteroalkyl "," heteroalkenyl ", and "heteroalkynyl ", alone or in combination, refer to one or more main chain carbon atoms (and any bonded hydrogen atoms Each independently represent a heteroatom (i.e., including but not limited to an atom other than carbon, such as oxygen, nitrogen, sulfur, silicon, phosphorus, tin or a combination thereof) or -OO-, -SS-, OS-, -SO-, = NN =, -N = N-, -N = N-NH-, -P (O) 2 -, -OP (O) 2 -, -P (O) 2 -O- and the like include, but are replaced by hetero but not limited magnetic, alkyl, alkenyl and alkynyl structures respectively, as described above -, -S (O) -, -S (O) 2 -, -SnH 2 Quot;

As used herein, the terms "haloalkyl "," haloalkenyl ", and "haloalkynyl ", alone or in combination, signifies substitution of at least one hydrogen atom with a fluorine, chlorine, bromine or iodine atom, Quot; refers to each of the alkyl, alkenyl, and alkynyl structures as defined above. In some embodiments, two or more hydrogen atoms may be replaced by the same halogen atom (e.g., difluoromethyl), and in another embodiment, two or more hydrogen atoms may be replaced by halogen atoms that are not all identical to each other For example, 1-chloro-1-fluoro-1-iodoethyl). Non-limiting examples of haloalkyl groups are fluoromethyl, chloromethyl, and bromoethyl. A non-limiting example of a haloalkenyl group is bromoethenyl. A non-limiting example of a haloalkynyl group is chloroethynyl.

As used herein, the term "carbon chain", whether alone or in combination, refers to any alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl group that is linear, cyclic, Lt; / RTI > When the chain is part of a linker and the linker comprises more than one ring as part of the core backbone, the "chain" in calculating the chain length is the number of carbon atoms constituting the lower or upper (but not both) Atoms, and if the lengths of the top and bottom of the ring (s) are not equal, a shorter length is used to determine the chain length. If the chain contains a heteroatom as part of the main chain, these atoms are not counted as part of the carbon chain length.

As used herein, the terms "cycle", "cyclic", "ring" and "ring", whether alone or in combination, refer to alicyclic, heterocyclic, aromatic, Refers to a structure closed with any covalent bond, including fused polycyclic or non-fused ring systems. The ring may be optionally substituted. The rings may form part of a fused ring system. The term "to" is intended to indicate the number of backbone atoms that make up the ring. Thus, by way of example only, cyclohexane, pyridine, pyran and pyrimidine are six-membered rings, and cyclopentane, pyrrole, tetrahydrofuran and thiophene are five-membered rings.

As used herein, the term "fused ", alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.

등의 잔기를 포함하지만 이에 제한되지 않는다.As used herein, the term "cycloalkyl ", whether alone or in combination, refers to a saturated hydrocarbon mono-radical ring containing from 3 to about 15 ring carbon atoms or from 3 to about 10 ring carbon atoms, Of the non-cyclic carbon atom as a substituent (for example, methylcyclopropyl). When a numerical range such as "C ₃ -C ₆ cycloalkyl" or "C _3-6 cycloalkyl" is described herein, this means that the cycloalkyl group has three carbon atoms, four carbon atoms, Cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl or cycloalkyl. The term includes fused radicals, unfused radicals, bridged radicals and spiro radicals. The fused cycloalkyl may contain from two to four fused rings wherein the attachment ring is a cycloalkyl ring and the other individual ring is an alicyclic, heterocyclic, aromatic, heteroaromatic, or any of these Lt; / RTI > Examples include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, decalinyl, and bicyclo [2.2.1] heptyl and adamantyl ring systems. An example of this is

But are not limited thereto.

In one embodiment, "cycloalkyl" is substituted. Unless otherwise indicated, "cycloalkyl" is not substituted.

등을 포함한다.As used herein, the terms "non-aromatic heterocyclyl" and "heteroalicyclic", whether alone or in combination, contain 3 to about 20 ring atoms and wherein at least one ring atom is oxygen, nitrogen, sulfur Refers to saturated, partially unsaturated or fully unsaturated non-aromatic cyclic mono radicals that are atoms other than carbon which are independently selected from, but not limited to, phosphorus, silicon, selenium and tin. In embodiments wherein more than one heteroatom is present in the ring, said two or more heteroatoms may be the same as each other, or some or all of the above two or more heteroatoms may be different from one another. The term includes fused radicals, unfused radicals, bridged radicals and spiro radicals. Fused non-aromatic heterocyclic radicals may contain from two to four fused rings wherein the attachment ring is a non-aromatic heterocycle and the other individual rings are alicyclic, heterocyclic, aromatic, hetero Aromatic, or any combination of these. The fused ring system may be a single bond or a double bond and also a fused bond between a carbon-carbon, carbon-heteroatom or heteroatom-heteroatom bond. The term also includes radicals having 3 to about 12 backbone ring atoms and also radicals having 3 to about 10 backbone ring atoms. Attachment of a non-aromatic heterocyclic subunit to its parent molecule may be via a heteroatom or carbon atom. Likewise, further substitution can be via a heteroatom or a carbon atom. By way of non-limiting example, the imidazolidine non-aromatic heterocycle may be attached to the parent molecule via its N atom (imidazolidin-1-yl or imidazolidin-3-yl) 2-yl, imidazolidin-4-yl or imidazolidin-5-yl). In certain embodiments, the non-aromatic heterocycle contains one or more groups of carbonyl or thiocarbonyl, such as oxo- and thio-containing groups. Examples are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, Thiazinyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6 Pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, thiazolyl, Imidazolidinyl, imidazolidinyl, 3-aza-bicyclo [3.1.0] hexanyl, 3-aza-bicyclopentadienyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, But are not limited to, [4.1.0] heptanyl, 3H-indolyl and quinolizinyl. Examples of heterocycloalkyl groups, also referred to as non-aromatic heterocycles,

And the like.

The term also includes all-ring carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In one embodiment, "non-aromatic heterocyclyl" or "heteroalicyclic" is substituted. Unless otherwise indicated, "non-aromatic heterocyclyl" or "heteroalicyclic"

As used herein, the term "aryl ", whether alone or in combination, refers to an aromatic hydrocarbon radical of 6 to about 20 ring carbon atoms and includes fused aryl rings and non-fused aryl rings. The fused aryl ring radical contains 2 to 4 fused rings wherein the attachment ring is an aryl ring and the other individual rings are alicyclic, heterocyclic, aromatic, heteroaromatic, or any combination thereof . In addition, the term aryl includes fused and non-fused rings containing from 6 to about 12 ring carbon atoms and fused and non-fused rings containing from 6 to about 10 ring carbon atoms do. By way of non-limiting example, a single ring aryl group includes phenyl, the fused ring aryl group includes naphthyl, phenanthrenyl, anthracenyl, azulenyl, and the unfused bi-aryl group includes biphenyl . In one embodiment, "aryl" is substituted. Unless otherwise indicated, "aryl" is not substituted.

등의 잔기를 포함한다.As used herein, the term "heteroaryl", whether alone or in combination, contains about 5 to about 20 backbone ring atoms, wherein one or more ring atoms are replaced by oxygen, nitrogen, sulfur, phosphorus, silicon, Quot; refers to an aromatic mono radical that is a heteroatom independently selected from but not limited to these atoms, but wherein the ring of the group does not contain two adjacent O or S atoms. In embodiments wherein more than one heteroatom is present in the ring, said two or more heteroatoms may be the same as each other, or some or all of the above two or more heteroatoms may be different from one another. The term heteroaryl includes fused heteroaryl radicals having one or more heteroatoms and non-fused heteroaryl radicals. The term heteroaryl also includes fused heteroaryl having 5 to about 12 backbone ring atoms and unfused heteroaryl and also fused heteroaryl having 5 to about 10 backbone ring atoms and unfused heteroaryl, . The bond to the heteroaryl group may be through a carbon atom or a hetero atom. Thus, as a non-limiting example, an imidazole group can have any of its carbon atoms (imidazol-2-yl, imidazol-4-yl or imidazol- Yl or imidazol-3-yl). Likewise, a heteroaryl group may be further substituted through any or all of its carbon atoms, and / or any or all of its heteroatoms. The fused heteroaryl radical may contain from two to four fused rings wherein the attachment ring is a heteroaromatic ring and the other ring is an alicyclic, heterocyclic, aromatic, heteroaromatic, or any of these . ≪ / RTI > Non-limiting examples include monocyclic heteroaryl groups include pyridyl, fused ring heteroaryl groups include benzimidazolyl, quinolinyl, acridinyl, and non-fused bi-heteroaryl groups include bipyridyl, Dynyl. Further examples of heteroaryls include furanyl, thienyl, oxazolyl, acridinyl, phenazinyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzothiophenyl, benz Wherein the heterocyclic ring is selected from the group consisting of oxadiazolyl, benzotriazolyl, imidazolyl, indolyl, isoxazolyl, isoquinolinyl, indolizinyl, isothiazolyl, isoindolyloxadiazolyl, indazolyl, pyridyl, , Pyrazinyl, pyrrolyl, pyrazinyl, pyrazolyl, purinyl, phthalazinyl, phthiridinyl, quinolinyl, quinazolinyl, quinoxalinyl, triazolyl, tetrazolyl, thiazolyl, And the like, and the oxides thereof, for example, pyridyl-N-oxide. Examples of heteroaryl groups include, but are not limited to,

And the like.

In one embodiment, "heteroaryl" is substituted. Unless otherwise indicated, "heteroaryl" is unsubstituted.

As used herein, the term "heterocyclyl ", alone or in combination, refers to a group of heteroalicyclic and heteroaryl groups. In the present application, when the number of carbon atoms in the heterocycle is indicated (e. G., A C ₁ -C ₆ heterocycle), one or more non-carbon atoms (heteroatoms) must be present in the ring. An indication such as "C ₁ -C ₆ heterocycle" refers to only the number of carbon atoms in the ring and does not indicate the total number of atoms in the ring. An indication such as "4 to 6 membered heterocycle" indicates the total number of atoms contained in the ring (i.e., at least one atom is a carbon atom and at least one atom is a heteroatom and the remaining 2 to 4 atoms are carbon A 4-membered, 5-membered or 6-membered ring which is an atom or a hetero atom). In the case of a heterocycle having two or more heteroatoms, the above two or more heteroatoms may be the same or different from each other. The non-aromatic heterocyclic group includes groups having only 3 atoms in the ring, but the aromatic heterocyclic group should have at least 5 atoms in the ring. The bond to the heterocycle (i. E. Attachment to the parent molecule or further substitution) can be via a heteroatom or a carbon atom. In one embodiment, "heterocyclyl" is substituted. Unless otherwise indicated, "heterocyclyl" is unsubstituted.

As used herein, the term "halogen", "halo" or "halide", whether alone or in combination, refers to fluoro, chloro, bromo and / or iodo.

As used herein, the term "amino ", alone or in combination, refers to a mono radical -NH ₂ .

As used herein, the term "alkylamino ", alone or in combination, refers to a mono radical -NH (alkyl), wherein alkyl is as defined herein.

As used herein, the term "dialkylamino ", alone or in combination, signifies a mono radical-N (alkyl) (alkyl) wherein each alkyl may be the same or different and is as defined herein The same).

As used herein, the term "diaminoalkyl ", whether alone or in combination, refers to an alkyl group containing two amine groups, wherein the amine group is an alkyl group that may be an amino, alkylamino or dialkylamino group (H or alkyl or alkylene-) (H (alkylene) -) alkylene-N (H or alkyl or alkylene-), where one or both of the amine groups form part of the alkyl chain, Or alkyl or alkylene-).

As used herein, the term "hydroxy ", alone or in combination, refers to a mono radical-OH.

As used herein, the term "cyano ", alone or in combination, refers to a mono radical -CN.

As used herein, the term "cyano-methyl" refers to a mono-radical -CH ₂ CN between alone or in combination for anything.

As used herein, the term "nitro", whether alone or in combination, refers to a mono radical -NO ₂ .

As used herein, the term "oxy", whether alone or in combination, refers to a diradical -O-.

As used herein, the term "oxo ", alone or in combination, refers to a diradical = O.

As used herein, the term "carbonyl", whether alone or in combination, refers to a diradical-C (= O) - (which may be described as -C (O) -).

As used herein, the term "carboxy" or "carboxyl ", alone or in combination, refers to the residue -C (O) OH (which may be described as -COOH).

As used herein, the term "alkoxy", whether alone or in combination, refers to an alkyl ether radical, -O-alkyl, such as the groups -O-aliphatic and -O-carbocyclyl, And carbocyclyl groups may optionally be substituted and the term alkyl, aliphatic and carbocyclyl are as defined herein. Non-limiting examples of alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.

As used herein, the term "sulfinyl ", alone or in combination, refers to a diradical-S (= O) -.

As used herein, the term "sulfonyl", whether alone or in combination, refers to a diradical -S (= O) ₂ -.

As used herein, the terms "sulfonamide "," sulfonamido ", and "sulfonamidyl ", whether alone or in combination, refer to the radicals -S (= O) ₂ -NH- and -NH-S = O) ₂ -.

As used herein, the terms "sulfamido "," sulfamido ", and "sulfamidyl ", whether alone or in combination, refer to the radical -NH-S (= O) ₂ -NH- of the diradical.

As used herein, the term "reactant" refers to the nucleophile or electrophile used to form the covalent linkage.

When two or more radicals are used in series to define a substituent attached to the structure, it should be understood that the first named radical is considered to be the terminal and the last named radical is to be attached to that structure. Thus, for example, the radical arylalkyl is attached to the structure by an alkyl group.

Specific pharmaceutical term

As used herein, the term "MEK inhibitor" refers to a compound having an IC _{50 in} relation to MEK activity of less than or equal to about 100 μM, or less than about 50 μM, as measured by the Mek1 kinase assay as generally described herein. "IC ₅₀ " is the concentration of inhibitor that reduces the activity of the enzyme (eg, MEK) to half the maximum level. The compounds described herein were found to exhibit inhibition against MEK. The compounds of the present invention preferably have an IC ₅₀ associated with MEK of less than or equal to about 10 μM, more preferably less than or equal to about 5 μM, even more preferably less than or equal to about 1 μM, as measured by the Mek1 kinase assay described herein Preferably about 200 nM or less.

As used herein, the term "subject," "patient, " or" subject "as used in reference to an individual suffering from a disorder or the like includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the following mammalian classes: human, non-human primates such as chimpanzees, and other apes and monkey species, livestock animals such as cows, horses, sheep, goats Rabbits, dogs and cats, laboratory animals such as rodents such as rats, mice and guinea pigs. Examples of non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

As used herein, the terms " treating ", "treating ", or" treating ", and other grammatically equivalent expressions refer to the alleviation, attenuation or amelioration of a disease or condition symptom, the prevention of further symptoms, Reduction of a disease or condition, reduction of a disease or condition, reduction of a disease or condition, reduction of a disease or condition, reduction of a condition caused by a disease or condition, , And includes prevention. The term further encompasses achieving a therapeutic benefit and / or a prophylactic benefit. Therapeutic benefits mean eradication or improvement of the underlying disorder to be treated. In addition, the therapeutic benefit may be achieved by eradication or amelioration of one or more physiological symptoms associated with the underlying disorder, such that the improvement is observed in the patient even though the patient may still be suffering from the underlying disorder. For prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease or to a patient who may not have been diagnosed with the disease, but who complain of one or more physiological symptoms of the disease.

The term "effective amount "," therapeutically effective amount ", or "pharmaceutically effective amount" as used herein refers to a dosage of one or more agents or compounds sufficient to treat or prevent a particular disease or condition. The result may be a reduction and / or alleviation of the signs, symptoms or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is an amount required for a composition comprising a compound as disclosed herein to provide a clinically significant reduction in the disease. The appropriate "effective" amount in any individual case can be determined, for example, by techniques such as dose-increasing studies.

As used herein, the terms "substantially free of water" and "substantially free of solvent" include water or solvents each containing less than 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, Crystalline < / RTI > polymorphic form.

As used herein, the term " substantially the same as "refers to a powder x-ray diffraction pattern or a differential scanning calorimetric pattern that may not be the same as that shown herein, but which is within the limits of experimental error .

As used herein, the terms "administer," "administer," "administer," and the like refer to a method that can be used to enable a compound or composition to be delivered to a desired biological site of action. Such methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular, intravenous or by injection), topical and rectal administration. As discussed in, for example, Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed. Pergamon and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. Are familiar with the administration techniques in which the compounds and methods described herein may be used. In a preferred embodiment, the compounds and compositions described herein are administered orally.

As used herein, the term "acceptable " with respect to a formulation, composition or ingredient means that it does not have a persistent adverse effect on the general health of the subject being treated.

The term "pharmaceutically acceptable" as used herein refers to a relatively non-toxic substance, such as a carrier or diluent, without eliminating the biological activity or properties of the compounds described herein, Can be administered to a subject without causing undesirable biological effects or interacting in a detrimental manner with any of the ingredients contained within the composition.

As used herein, the term "pharmaceutical composition" includes one or more pharmaceutically acceptable chemical components including, but not limited to, carriers, stabilizers, diluents, dispersants, suspending agents, thickening agents and / Refers to a biologically active compound that is optionally mixed.

As used herein, the term "carrier" refers to a relatively non-toxic chemical compound or agent that facilitates incorporation of the compound into cells or tissues.

As used herein, the term "agonist" refers to a molecule, such as a compound, drug, enzyme activator or hormone modifier that enhances the activity of another molecule or receptor site.

As used herein, the term "antagonist" refers to a molecule, such as a compound, drug, enzyme inhibitor or hormone modulator, that attenuates or inhibits the action of another molecule or receptor site.

As used herein, the term "modulate" means directly or indirectly interacting with a target to alter the activity of the target, including but not limited to enhancing activity of the target or inhibiting activity of the target Or to limit the activity of the target or to extend the activity of the target.

As used herein, the term "modulator" refers to a molecule that interacts directly or indirectly with a target. Such interactions include, but are not limited to, interactions of agonists and antagonists.

As used herein, the term "pharmaceutically acceptable derivative or prodrug" refers to a compound of formula I, which upon administration to a recipient can provide, either directly or indirectly, a compound of the invention or a pharmaceutical active metabolite or moiety thereof Refers to any pharmaceutically acceptable salt, ester, salt of ester or other derivative. Particularly advantageous derivatives or prodrugs are those that increase the bioavailability of the compound when the compound of the present invention is administered to the patient (e. G., Allowing the orally administered compound to be more readily absorbed into the blood) (E. G., The brain or lymphatic system).

As used herein, "prodrug" is a compound that can be converted under physiological conditions or by solvolysis to a pharmaceutically acceptable salt of such compound. Prodrugs include amino acid residues, or compounds wherein the polypeptide chain of two or more amino acid residues is covalently linked to the free amino, hydroxy or carboxylic acid group of the compound of formula I through an amide or ester bond. The amino acid residues contemplated include, but are not limited to, 20 naturally occurring amino acids. Other suitable amino acids are 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline,? -Alanine,? -Aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone . Additional types of prodrugs are known in the art.

Pharmaceutically acceptable prodrugs of the compounds described herein include esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich ) Bases, Schiff bases, amino acid conjugates, phosphate esters, metal salts and sulfonate esters. Various forms of prodrugs are known in the art. See, for example, Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985, Method in Enzymology, Widder, K. et al., Ed .; Academic, 1985, vol. &Quot; Design and Application of Prodrugs "in Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p.113-191 and Bundgaard , H., Advanced Drug Delivery Review, 1992, 8, 1-38), each of which is incorporated herein by reference. Prodrugs described herein include, but are not limited to, the following groups and combinations of these groups:

Amine-derived prodrugs:

The hydroxy prodrugs include, but are not limited to, acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, and disulfide-containing esters.

As used herein, the term "pharmaceutically acceptable salts" includes those salts which retain the biological effectiveness of the free acids and bases of the specified compounds and which are not biologically or otherwise undesirable. Because the described compounds may possess acidic or basic groups, they can react with any of a number of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts are the salts prepared by reacting the compounds described herein with an inorganic or organic acid or inorganic base such as, for example, acetate, acrylate, adipate, alginate, aspartate, benzoate, But are not limited to, nitrate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chloride, chlorobenzoate, chloride, citrate, cyclopentane Propionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, Phosphate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma -hydroxybutyrate But are not limited to, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate , Methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, phamoate, pectinate, persulfate, phenylacetate, phenyl Propionate, phthalate, phenylbutyrate, propanesulfonate, pyrophosphate, pyruvate, pyruvate, pyruvate, pyruvate, pyruvate, propionate, Salicylate, succinate, sulphate, sulphite, succinate, sulberate, sebacate, sulphate Sulfonates, sulfonates, phosphates, phosphates, tartrates, thiocyanates, tosylates, undeconates and xylenesulfonates. Although other acids such as oxalic acid are not in themselves pharmaceutically acceptable, they can be used to prepare salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts (see, for example, Berge et al., J. Pharm. Sci., 1977, 66, 1-19). In addition, the compounds described herein which may include groups of the free acid are, for example, a suitable base such as a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, ammonia, Lt; RTI ID = 0.0 > primary, < / RTI > secondary or tertiary amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like. Examples of the base are sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N ⁺ _- and the like (C _{1 4} alkyl) _4. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It is to be understood that the compounds described herein also include quaternization of any basic nitrogen-containing groups that they may contain. Water-soluble or oil-soluble or dispersible products can be obtained with this quaternization. See, for example, Berge et al., Supra). These salts may be prepared in situ during the final isolation and purification of the compounds of the present invention or may be prepared by reacting the purified compound in free base form with a suitable organic or inorganic acid separately and isolating the salt thus formed.

As used herein, the term "enhancing" or "enhancing" means increasing or extending a desired effect in a potency or duration. Thus, in the context of enhancing the efficacy of a therapeutic agent, the term "enhancing " refers to the ability to increase or prolong the effect of another therapeutic agent on the system, either in its potency or duration. As used herein, an "enhancement-effective amount" refers to an amount sufficient to promote the effectiveness of another therapeutic agent in the desired system.

As used herein, the term " pharmaceutical combination ", "administering additional therapy "," administering additional therapeutic agent ", etc. refer to pharmaceutical therapies produced by mixing or combining more than one active ingredient And both fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one of the compounds described herein and one or more co-agents to a patient in the form of a single agent or dosage form. The term "non-fixed combination" refers to the sequential administration of one or more of the compounds described herein, and one or more co-agents, as separate entities to the patient, simultaneously, jointly, or at various time intervals, Administration provides an effective level of two or more compounds in the body of a patient. They can also be applied to cocktail therapy, for example, administration of three or more active ingredients.

As used herein, the terms "co-administration "," administered in combination with ", and other grammatically equivalent expressions thereof are meant to include administration of the selected therapeutic agent to a single patient, Route of administration, or treatment regimes administered at the same or different times. In some embodiments, the compounds described herein will be co-administered with other agents. The term includes administration of two or more agents to an animal such that both of these two agents and / or their metabolites are simultaneously present in the animal. This includes administration at the same time as separate compositions, administration at different times as separate compositions, and / or administration with a composition in which both of the two agents are present. Thus, in some embodiments, the compounds of the present invention and other agonist (s) are administered in a single composition. In some embodiments, the compounds of the present invention and other agonist (s) are mixed in a composition.

As used herein, the term "metabolite" refers to a derivative of a compound formed when a compound is metabolized.

As used herein, the term "active metabolite" refers to a biologically active derivative of a compound formed when a compound is metabolized.

As used herein, the term "metabolism" refers collectively to processes in which a particular substance is altered by an organism, including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes. Thus, enzymes can produce structural changes that are unique to the compound. For example, cytochrome P450 catalyzes a variety of oxidation and reduction reactions, but the uridine diphosphate glucuronyltransferase is a compound in which the activated glucuronic acid molecule is reacted with an aromatic alcohol, an aliphatic alcohol, a carboxylic acid, As shown in FIG. Further information on metabolism can be found in The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996).

compound

In the present application, compounds of formula (I), and pharmaceutically acceptable salts, solvates, polymorphs, esters, amides, tautomers or prodrugs thereof,

(I)

In this formula,

Z is H or F,

X is _{F, Cl, CH 3, CH} 2 OH, CH 2 F, CHF 2 or CF _3,

Y is I, Br, Cl, CF _3, C ₁ -C ₃ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl, cyclopropyl, OMe, OEt, SMe, phenyl or Het, where the Het is a saturated, olefinic or aromatic 5 to 10 membered monocyclic or bicyclic heterocyclic group containing 1 to 5 ring heteroatoms independently selected from N, O and S,

All of said phenyl or Het group F, Cl, Br, I, acetyl, methyl, CN, NO _2, CO ₂ H, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl, -C _{(= O) -, C 1} -C 3 alkyl, -C (= S) -, C 1 -C 3 alkoxy group -C (= S) -, C 1 -C 3 alkyl, -C (= O) O-, C ₁ -C ₃ alkyl, -O- (C = O) -, C 1 -C 3 alkyl, -C (= O) NH-, C 1 -C 3 alkyl, -C (= NH) NH-, C 1 -C 3 alkyl, -NH- (C = O) -, di -C ₁ -C ₃ alkyl, -N- (C = O) -, C 1 -C 3 alkyl, -C (= O) N (C 1 -C 3 alkyl) -, C ₁ -C ₃ alkyl-S (= O) ₂ NH- or trifluoromethyl,

All of the methyl, ethyl, C ₁ -C ₃ alkyl or cyclopropyl group is optionally substituted by OH,

     Wherein all of said methyl groups are optionally substituted with one, two or three F atoms,

R ⁰ is H, F, Cl, Br, I, CH 3 NH-, (CH 3) 2 N-, C 1 -C 6 alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, phenyl, monosubstituted phenyl, O (C ₁ -C ₄ alkyl), OC (= O) ( C 1 -C 4 alkyl) or C (= O) O (C ₁ -C ₄ alkyl), wherein,

     The group of said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl and phenyl is optionally substituted with one to three groups independently selected from F, Cl, Br, I, OH, CN, cyanomethyl, nitro, phenyl and trifluoromethyl Optionally substituted with a substituent,

The group of C ₁ -C ₆ alkyl and C ₁ -C ₄ alkoxy is also optionally substituted with OCH ₃ or OCH ₂ CH ₃ ,

G is G ₁ , G ₂ , R _1a , R _1b , R _1c , R _1d , R _1e , Ar ₁ , Ar ₂ or Ar ₃ ,

G ₁ is C ₁ -C ₆ alkyl optionally substituted by one amino, C ₁ -C ₃ alkylamino, or a group of dialkylamino containing two C ₁ -C ₄ alkyl groups which may or may not be the same Or

G ₁ is a C ₃ -C ₈ diaminoalkyl group,

G ₂ contains 1 to 3 ring heteroatoms independently selected from N, O and S and is selected from the group consisting of F, Cl, OH, O (C ₁ -C ₃ alkyl), OCH ₃ , OCH ₂ CH ₃ , CH ₃ C (= O) group of _{NH, CH 3 C (= O} ) O, CN, CF 3, and N, O and clicking a 5-membered aromatic heterocyclic containing 1 to 4 ring heteroatoms independently selected from S Unsaturated or aromatic 5 or 6 membered ring optionally substituted with one to three substituents independently selected from H,

_Wherein R _1a is methyl optionally substituted by 1 to 3 fluorine atoms or 1 to 3 chlorine atoms or OH, cyclopropoxy or C ₁ -C ₃ alkoxy, wherein said cyclopropoxy group or said C ₁ The C ₁ -C ₃ alkyl portion of the -C ₃ alkoxy group is optionally substituted with one hydroxy or methoxy group and wherein all C ₃ -alkyl groups within the C ₁ -C ₄ alkoxy are optionally further substituted with a second OH group And,

R _1b is CH (CH ₃₎ -C _{1 - 3} alkyl, or independently from C ₃ -C ₆ cycloalkyl, said alkyl and cycloalkyl, where the group F, Cl, Br, I, OH, OCH _3, and CN Optionally substituted with one to three substituents selected from < RTI ID = 0.0 >

R _1c is (CH ₂ ) _n O _m R '

          m is 0 or 1,

              when m is 0, n is 1 or 2,

              when m is 1, n is 2 or 3,

R 'is C ₁ -C ₆ alkyl optionally substituted with ₁ to 3 substituents independently selected from F, Cl, OH, OCH ₃ , OCH ₂ CH ₃ and C ₃ -C ₆ cycloalkyl,

R _1d is C (A) (A ') (B) -,

And ₄ alkyl, _- B is H, or is C ₁ groups with one or two OH optionally substituted

A and A 'are independently H, or is one or two OH groups optionally substituted by C _{1 - 4} alkyl or, or

          A and A 'together with the carbon atom to which they are attached form a 3- to 6-membered saturated ring,

이고, 이때,R _1e is

Lt; / RTI >

          q is 1 or 2,

R ₂ and R ₃ are each independently selected from the group consisting of H, F, Cl, Br, CH ₃ , CH ₂ F, CHF ₂ , CF ₃ , OCH ₃ , OCH ₂ F, OCHF ₂ , OCF ₃ , Propyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl or methylsulfonyl,

R ₄ is selected from the group consisting of H, F, Cl, Br, CH ₃ , CH ₂ F, CHF ₂ , CF ₃ , OCH ₃ , OCH ₂ F, OCHF ₂ , OCF ₃ , ethyl, Butyl, tert-butyl, methylsulfonyl, nitro, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1,3,4-oxadiazole Methyl-1,3,4-oxadiazole, 1,3,4-thiadiazole, 5-methyl-1,3,4-thiadiazole, 1H-tetrazolyl, N- Morpholylcarbonylamino, N-morpholylsulfonyl and N-pyrrolidinylcarbonylamino,

R < ₅ > is H, F, Cl or methyl,

R < ₆ > is H, F, Cl or methyl,

이고, 이때,Ar ₁ is

Lt; / RTI >

U and V are independently N, CR ₂ or CR ₃ ,

R ₂ , R ₃ and R ₄ are independently H, F, Cl, Br, CH ₃ , CH ₂ F, CHF ₂ , CF ₃ , OCH ₃ , OCH ₂ F, OCHF ₂ , OCF ₃ , , Isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, Methyl-1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 5-methyl-1,3,4-thiadiazolyl, 1H-tetrazolyl, N-morpholylcarbonylamino, N-morpholysulfonyl, N-pyrrolidinylcarbonylamino and methylsulfonyl,

R ₅ and R ₆ are independently H, F, Cl or methyl,

이고, 이때,Ar ₂ is

Lt; / RTI >

          The broken line represents an alternative structural position for the second ring double bond,

           U is -S-, -O- or -N =

               When U is -O- or -S-, V is -CH =, -CCl = or -N =

               When U is -N =, V is -CH =, -CCl = or -N =

R < ₇ > is H or methyl,

R ₈ is H, acetamido, methyl, F or Cl,

이고, 이때,Ar ₃ is

Lt; / RTI >

U is -NH-, -NCH ₃ - or -O-, and,

R ₇ and R ₈ are independently H, F, Cl or methyl.

In addition to the definitions provided herein for groups of G, R < ⁰ >, X, Y and Z, further substitutions that may be considered by those skilled in the chemical and pharmaceutical arts are included.

In some embodiments, the invention provides a compound of formula I wherein G is G ₁ or G ₂ . In another embodiment, G is G < _{1 &} gt ;. In further or additional embodiments, G is G < _{2 &} gt ;.

In some embodiments, the invention provides a compound of G is _{R 1a, R 1b, R 1c} , R 1d, R 1e, Ar 1, Ar 2 or Ar ₃ in formula I. In further or additional embodiments, G is R _1a , R _1b , R _1c , R _1d or R _1e . In further or additional embodiments, G is R &_lt; _{1a &} gt ;. In further or additional embodiments, G is R < _{1b &} gt ;. In further or additional embodiments, G is R < _{1c &} gt ;. In further or additional embodiments, G is R < _{1d &} gt ;. In further or additional embodiments, G is R < _{1e &} gt ;. In further or additional embodiments, G is Ar ₁ , Ar ₂ or Ar ₃ . In further or additional embodiments, G is Ar < _{1 &} gt ;. In further or additional embodiments, G is Ar < _{2 &} gt ;. In further or additional embodiments, G is Ar < _{3 &} gt ;.

In some embodiments, there is provided a compound of formula I, or a pharmaceutically acceptable salt thereof. In a further or additional embodiment, there is provided herein a compound of formula I, or a solvate thereof. In a further or additional embodiment, there is provided herein a compound of formula I, or a polymorph thereof. In a further or additional embodiment, there is provided herein a compound of formula I, or an ester thereof. In a further or additional embodiment, there is provided herein a compound of formula I, or an amide thereof. In a further or additional embodiment, there is provided herein a compound of formula I, or a tautomer thereof. In a further or additional embodiment, there is provided herein a compound of formula I or a prodrug thereof.

In some embodiments, Z is H. In some embodiments, Z is F. In some embodiments, X is F. In some embodiments, X is Cl. In some embodiments, X is CH _3. In some embodiments, X is CH ₂ OH. In some embodiments, X is CH ₂ F. In some embodiments, X is CHF ₂ . In some embodiments, X is CF _3. In some embodiments, X is F, Cl or CH _3.

In some embodiments, G is G ₁ or G _2, X is F, Cl or CH _3, and, Y is I, Br, Cl, CF _3, C ₁ -C ₃ alkyl, phenyl, pyridyl, pyrrolyl or pyrazolyl, and the phenyl, pyridyl, pyrrolyl and pyrazolyl groups F, Cl, Br, I, acetyl, _{methyl, CN, NO 2, CO 2} H, C 1 -C 3 alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl, -C (= O) -, C 1 -C 3 alkyl, -C (= S) -, C 1 -C 3 alkoxy group -C (= S) -, C 1 -C 3 alkyl -C (= O) O-, C 1 -C 3 alkyl, -O- (C = O) -, C 1 -C 3 alkyl, -C (= O) NH-, C 1 -C 3 alkyl, -C (= NH) NH-, C ₁ -C ₃ alkyl, -NH- (C = O) -, di -C ₁ -C ₃ alkyl, -N- (C = O) -, C 1 -C 3 alkyl, -C (= O ) N (C ₁ -C ₃ alkyl) -, C ₁ -C ₃ alkyl-S (= O) ₂ NH- or trifluoromethyl, and Z is H or F. In a further or additional embodiment G is G ₁ or G ₂ and R ⁰ is F, Cl, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy, said C ₁ -C ₄ alkyl group and said C The C ₁ -C ₄ alkyl residue of the ₁ -C ₄ alkoxy group is optionally substituted with F, Cl, OCH ₃ or OCH ₂ CH ₃ . In a further or additional embodiment, G is G ₁ or G ₂ and R ⁰ is H, F, Cl, C ₁ -C ₄ alkyl, methoxy, ethoxy or 2-methoxy-ethoxy.

In some embodiments, G < ₁ > is N-methyl-2-aminoethyl. In a further or additional embodiment, G ₁ is (CH ₃ ) ₂ N-CH ₂ CH ₂ -NH- (CH ₂ ) _n -, wherein n is 1, 2 or 3. In a further or additional embodiment, G ₁ is (CH ₃ ) ₂ N-CH ₂ CH ₂ -NH- (CH ₂ ) _n -, wherein n is 1, 2 or 3 and X is F. In a further or additional embodiment, G ₁ is (CH ₃ ) ₂ N-CH ₂ CH ₂ -NH- (CH ₂ ) _n -, wherein n is 1, 2 or 3, X is F, Z is F.

In some embodiments, G ₂ is 1-piperidyl, 2-piperidyl, 3-piperidyl, or 4-piperidyl. In further or additional embodiments, G ₂ is morpholyl, 1-piperazyl, or 2-piperazinyl.

In some embodiments, G is R _1a , R _1b , R _1c , R _1d , R _1e , Ar ₁ , Ar _2, or Ar ₃ ; and X is F, Cl, or CH ₃ . In a further or additional embodiments, G is _{R 1a, R 1b, R 1c} , R 1d, R 1e, and Ar _1, Ar ₂ or Ar _3, X is F, Cl or CH _3, Y is I, Br, it is Cl, CF ₃ or C ₁ -C ₃ alkyl. In a further or additional embodiments, G is _{R 1a, R 1b, R 1c} , R 1d, R 1e, and Ar _1, Ar ₂ or Ar _3, X is F, Cl or CH _3, Y is I, is Br, Cl, CF ₃ or C ₁ -C ₃ alkyl, Z is H or F.

In a further or additional embodiments, G is _{R 1a, R 1b, R 1c} , and _{R 1d, R 1e, Ar 1} , Ar 2 or Ar _3, R ⁰ is F, Cl, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy, wherein the C ₁ -C ₄ alkyl group and the C ₁ -C ₄ alkyl residue of the C ₁ -C ₄ alkoxy group are optionally substituted with F, Cl, OCH ₃ or OCH ₂ CH ₃ . In a further or additional embodiments, G is _{R 1a, R 1b, R 1c} , R 1d, R 1e, Ar 1, and Ar ₂ or Ar _3, R ⁰ is _{H, F, Cl, C 1} -C 4 Alkyl, methoxy, ethoxy or 2-methoxy-ethoxy.

In some embodiments, G is R &_lt; _1a > In further or additional embodiments, G is R _1a , wherein R _1a is CH ₃ , R ⁰ is H, and Y is Br, I, CF _3, or CH ₃ . In some embodiments, G is R < ₁ > _b and Z is F. In a further or additional embodiments, G is R _1b, and Z is F, R ⁰ is H, F or OCH _3. In further or additional embodiments, G is R _1b , Z is F, R ⁰ is H, F, or OCH ₃ , and X is F or CH ₃ . In further or additional embodiments, G is R _1b , Z is F, R ⁰ is H, F or OCH ₃ , X is F or CH ₃ , and Y is Br, I or CH ₃ . In further or additional embodiments, G is R _1b , wherein R _1b is C ₃ -C ₆ cycloalkyl. In further or additional embodiments, G is R _1b , wherein R _1b is substituted C ₃ -C ₆ cycloalkyl. In further or additional embodiments, G is R _1b , wherein R _1b is unsubstituted C ₃ -C ₆ cycloalkyl. In further or additional embodiments, G is R _1b , wherein R _1b is unsubstituted C ₃ -C ₆ cycloalkyl, and R ⁰ is H. In further or additional embodiments, G is R _1b , wherein R _1b is isopropyl or cyclopropyl.

In some embodiments, G is R _1c and Y is I, Br, CH _3, or CF ₃ . In a further or additional embodiments, G is R _1c, Y is I, Br, CH ₃ or CF _3, Z is F. In a further or additional embodiments, G is R _1c, Y is I, Br, CH ₃ or CF _3, and, Z is F, m is zero.

In some embodiments, G is R _1d and R ⁰ is selected from the group consisting of fluoro, chloro, methyl, ethyl, propyl, isopropyl, sec-butyl, iso-butyl, tert- butyl, cyclopropyl, cyclobutyl, Methoxy, fluoromethoxy, methylamino or dimethylamino. In further or additional embodiments G is R _1d and R ⁰ is selected from the group consisting of fluoro, chloro, methyl, ethyl, propyl, isopropyl, sec-butyl, iso-butyl, tert- butyl, cyclopropyl, fluoro, and methyl, methoxy, difluoromethoxy, methylamino or dimethylamino, X is F, Cl, CH _3, or a mono-, di- or tri-fluoro methyl. In further or additional embodiments G is R _1d and R ⁰ is selected from the group consisting of fluoro, chloro, methyl, ethyl, propyl, isopropyl, sec-butyl, iso-butyl, tert- butyl, cyclopropyl, fluoro, and methyl, methoxy, difluoromethoxy, methylamino or dimethylamino, X is F, Cl, CH _3, or mono-, di-or tri-a-fluoro, Y is I, Br, Cl, or mono- , Di- or tri-fluoromethyl. In further or additional embodiments G is R _1d and R ⁰ is selected from the group consisting of fluoro, chloro, methyl, ethyl, propyl, isopropyl, sec-butyl, iso-butyl, tert- butyl, cyclopropyl, fluoro, and methyl, methoxy, difluoromethoxy, methylamino or dimethylamino, X is F, Cl, CH _3, or mono-, di-or tri-and fluoromethyl, Y is I, Br, Cl, or mono- , Di- or tri-fluoromethyl, and Z is H or F. In a further or additional embodiment, G is R _1d and R ⁰ is F, Cl, methyl, ethyl, methoxy, ethoxy or 2-methoxy-ethoxy.

In a further or additional embodiments, G is R _1d, R ⁰ is F, Cl, methyl, ethyl, methoxy, ethoxy or 2-methoxy-a-ethoxy, X is F, Cl or CH ₃ . In further or additional embodiments, G is R _1d and R ⁰ is F, Cl, methyl, ethyl, methoxy, ethoxy or 2-methoxy-ethoxy and X is F, Cl or CH ₃ , Y is I, Br, Cl or mono-, di- or tri-fluoromethyl. In a further or additional embodiments, G is R _1d and, R ⁰ is F, Cl, methyl, ethyl, methoxy, ethoxy or 2-methoxy-and ethoxymethyl, X is F, Cl or CH ₃ and , Y is I, Br, Cl or mono-, di- or tri-fluoromethyl, and Z is H or F. In further or additional embodiments, G is R _1d , R ⁰ is H, and X is F, Cl, CH ₃ or mono-, di- or tri-fluoromethyl. In a further or additional embodiments, G is R _1d, and an R ⁰ is H, X is F, Cl, CH _3, or mono-, di-or tri-a-fluoro, Y is I, Br, Cl Or mono-, di- or tri-fluoromethyl. In a further or additional embodiment, G is R _1d , R ⁰ is H, X is F, Cl, CH ₃ or mono-, di- or tri-fluoromethyl and Y is I, Br, Cl Or mono-, di- or tri-fluoromethyl, and Z is H or F.

In further or additional embodiments, G is R _1d and C (A) (A ') of R _1d is C ₁ -C ₆ cycloalkyl. In further or additional embodiments, G is R _1d , and C (A) (A ') of R _1d is C ₁ -C ₆ cycloalkyl and B is H. In a further or additional embodiment, G is R _1d , C (A) (A ') of R _1d is C ₁ -C ₆ cycloalkyl and B is methyl, ethyl, 2-hydroxyethyl, , 3-hydroxypropyl, 2,3-dihydroxypropyl, 3,4-dihydroxybutyl, isopropyl, 1-methyl-2-hydroxyethyl, n-butyl, sec- -Hydroxymethyl-3-hydroxypropyl. ≪ / RTI >

In a further or additional embodiment, G is R _1d , C (A) (A ') of R _1d is C ₁ -C ₆ cycloalkyl and B is 2,3-dihydroxypropyl or 3,4- Dihydroxybutyl. In a further or additional embodiment, G is R _1d , C (A) (A ') of R _1d is C ₁ -C ₆ cycloalkyl and B is 2,3-dihydroxypropyl or 3,4- Dihydroxybutyl, wherein the chiral carbon of B is present in the R configuration. In a further or additional embodiment, G is R _1d , C (A) (A ') of R _1d is C ₁ -C ₆ cycloalkyl and B is 2,3-dihydroxypropyl or 3,4- Dihydroxybutyl, wherein the chiral carbon of B is present in the S configuration. In further or additional embodiments, G is R _1d , C (A) (A ') of R _1d is C ₁ -C ₆ cycloalkyl and B is methyl optionally substituted with one OH group or 1 or 2 OH group of the optionally substituted C ₂ -C ₄ alkyl. In a further or additional embodiment, G is R _1d , C (A) (A ') of R _1d is C ₁ -C ₆ cycloalkyl and R ⁰ is fluoro, chloro, methyl, Isopropyl, sec-butyl, iso-butyl, tert-butyl, cyclopropyl, cyclobutyl, fluoromethyl, methoxy, fluoromethoxy, methylamino or dimethylamino. In a further or additional embodiment, G is R _1d , C (A) (A ') of R _1d is C ₁ -C ₆ cycloalkyl and R ⁰ is F, Cl, methyl, ethyl, methoxy, Ethoxy or 2-methoxy-ethoxy. C (A) (A ') of R _1d is C ₁ -C ₆ cycloalkyl, R ⁰ is H, and X is F, Cl, CH ₃ , and the like. In a further or additional embodiment, G is R _1d , Or mono-, di- or tri-fluoromethyl.

In a further or additional embodiment, the invention relates to compounds of formula _I wherein G is R _1d , C (A) (A ') of R _1d is C ₁ -C ₆ cycloalkyl and B is 2,3-dihydroxypropyl or 3 , 4-dihydroxybutyl, wherein the chiral carbon of B is present in the R configuration and is substantially free of the S isomer. In a further or additional embodiment, the invention relates to compounds of formula (I) wherein G is R _1d , C (A) (A ') of R _1d is C ₁ -C ₆ cycloalkyl, B is 2,3-dihydroxypropyl, Wherein the chiral carbon of B is present in the R configuration and is substantially free of the S isomer. In a further or additional embodiment, the invention relates to compounds of formula (I) wherein G is R _1d , C (A) (A ') of R _1d is C ₁ -C ₆ cycloalkyl, B is 3,4-dihydroxybutyl, Wherein the chiral carbon of B is present in the R configuration and is substantially free of the S isomer. In a further or additional embodiment, the invention relates to compounds of formula _I wherein G is R _1d , C (A) (A ') of R _1d is C ₁ -C ₆ cycloalkyl and B is 2,3-dihydroxypropyl or 3 , 4-dihydroxybutyl, wherein the chiral carbon of B is present in the S configuration and is substantially free of the R isomer. In a further or additional embodiment, the invention relates to compounds of formula (I) wherein G is R _1d , C (A) (A ') of R _1d is C ₁ -C ₆ cycloalkyl, B is 2,3-dihydroxypropyl, Wherein the chiral carbon of B is present in the S configuration and is substantially free of the R isomer. In a further or additional embodiment, the invention relates to compounds of formula (I) wherein G is R _1d , C (A) (A ') of R _1d is C ₁ -C ₆ cycloalkyl, B is 3,4-dihydroxybutyl, Wherein the chiral carbon of B is present in the S configuration and is substantially free of the R isomer.

In further or additional embodiments, G is R _1d and C (A) (A ') of R _1d is cyclopropyl. In a further or additional embodiment, G is R _1d , C (A) (A ') of R _1d is cyclopropyl and B is H. In a further or additional embodiment, G is R _1d , C (A) (A ') of R _1d is cyclopropyl and B is methyl, ethyl, 2-hydroxyethyl, Propyl, 2,3-dihydroxypropyl, 3,4-dihydroxybutyl, isopropyl, 1-methyl-2-hydroxyethyl, n-butyl, sec-butyl, isobutyl or 2- Hydroxypropyl. In a further or additional embodiment, G is R _1d , C (A) (A ') of R _1d is cyclopropyl and B is 2,3-dihydroxypropyl or 3,4-dihydroxybutyl . In a further or additional embodiment, G is R _1d , C (A) (A ') of R _1d is cyclopropyl, and B is 2,3-dihydroxypropyl or 3,4-dihydroxybutyl , Wherein the chiral carbon of B is present in the R configuration. In a further or additional embodiment, G is R _1d , C (A) (A ') of R _1d is cyclopropyl, and B is 2,3-dihydroxypropyl or 3,4-dihydroxybutyl , Wherein the chiral carbon of B is present in the S configuration. In a further or additional embodiment, G is R _1d , C (A) (A ') of R _1d is cyclopropyl and B is methyl optionally substituted with one OH group or optionally substituted with one or two OH groups C ₂ -C ₄ alkyl. In a further or additional embodiment, G is R _1d , C (A) (A ') of R _1d is cyclopropyl, and R ⁰ is fluoro, chloro, methyl, ethyl, Butyl, iso-butyl, tert-butyl, cyclopropyl, cyclobutyl, fluoromethyl, methoxy, fluoromethoxy, methylamino or dimethylamino. In a further or additional embodiment, G is R _1d , C (A) (A ') of R _1d is cyclopropyl, and R ⁰ is F, Cl, methyl, ethyl, methoxy, ethoxy or 2- Methoxy-ethoxy. In a further or additional embodiment, G is R _1d , C (A) (A ') of R _1d is cyclopropyl, R ⁰ is H, X is F, Cl, CH ₃ or mono-, di - or tri-fluoromethyl.

In a further or additional embodiment, the present invention provides a compound of _{formula I} wherein G is R _1d , C (A) (A ') of R _1d is cyclopropyl and B is 2,3-dihydroxypropyl or 3,4- Wherein the chiral carbon of B is present in the R configuration and is substantially free of the S isomer. In a further or additional embodiment, the present invention provides a compound of formula I, wherein G is R _1d , C (A) (A ') of R _1d is cyclopropyl and B is 2,3-dihydroxypropyl, The carbon is present in the R configuration and is substantially free of the S isomer. In a further or additional embodiment, the present invention provides a compound of _{formula I} wherein G is R _1d , C (A) (A ') of R _1d is cyclopropyl and B is 3,4-dihydroxybutyl, The carbon is present in the R configuration and is substantially free of the S isomer. In a further or additional embodiment, the present invention provides a compound of _{formula I} wherein G is R _1d , C (A) (A ') of R _1d is cyclopropyl and B is 2,3-dihydroxypropyl or 3,4- R < 1 > is hydrogen, R < 2 > is butyl, the chiral carbon of B is present in the S configuration and is substantially free of the R isomer. In a further or additional embodiment, the present invention provides a compound of formula I, wherein G is R _1d , C (A) (A ') of R _1d is cyclopropyl and B is 2,3-dihydroxypropyl, The carbon is present in the S configuration and the R isomer is substantially absent. In a further or additional embodiment, the present invention provides a compound of _{formula I} wherein G is R _1d , C (A) (A ') of R _1d is cyclopropyl and B is 3,4-dihydroxybutyl, The carbon is present in the S configuration and the R isomer is substantially absent.

In some embodiments, G is R < _1e >, and n is 1. In a further or additional embodiments, G is R _1e is, and R ⁰ is H, and R _{4 -6} is H, R ₂ and R ₃ are independently H, F, Cl, Br, CH _3, CH ₂ F, CHF _2, CF _3, OCH _3, OCH ₂ F, OCHF _2, OCF _3, ethyl, n- propyl, isopropyl, cyclopropyl, isobutyl, sec- butyl, tert- butyl and methyl sulfonyl, X Is F, and Y is I.

이며, 이때의 R₂ 및 R₃은 독립적으로 H, F, Cl, CH₃, CF₃, OCH₃이다. 추가의 또는 부가적인 실시양태에서, G는 Ar₁이고, 여기서의 Ar₁은

이고, 이때의 R₂ 및 R₃은 독립적으로 H, F, Cl, CH₃, CF₃, OCH₃이고, X는 F 또는 CH₃이고, Y는 I, Br 또는 Cl이며, Z는 F이다. 추가의 또는 부가적인 실시양태에서, G는 Ar₁이고, 여기서의 Ar₁은 페닐 또는 일치환된 페닐이다. 추가의 또는 부가적인 실시양태에서, G는 Ar₁이고, 여기서의 Ar₁은 페닐 또는 일치환된 페닐이고, X는 F 또는 CH₃이고, Y는 I, Br 또는 Cl이고, Z는 F이며, R⁰은 F, 메틸, 에틸, 메톡시 또는 2-메톡시-에톡시이다. 추가의 또는 부가적인 실시양태에서, G는 Ar₁이고, 여기서의 U는 N 또는 CR₂이고 V는 N이다. 추가의 또는 부가적인 실시양태에서, G는 Ar₁이고, 여기서의 U는 N 또는 CR₂이고 V는 CR이다. 추가의 또는 부가적인 실시양태에서, G는 Ar₁이고, 여기서의 U는 N 또는 CR₂이고 V는 CR이고, R⁰은 H이고, X는 F, Cl 또는 메틸이며, Y는 Br, I, CF₃, C₁-C₃알킬, C₂-C₃알케닐, C₂-C₃알키닐, 시클로프로필, OCH₃, OCH₂CH₃ 또는 SCH₃이다.In some embodiments, G is Ar ₁ , wherein Ar ₁ is acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1,3,4-oxadiazole Methyl-1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 5-methyl-1,3,4-thiadiazolyl, 1H-tetrazolyl, N- to know polril carbonylamino, N- know Paul rilsul sulfonyl, N- pyrrolidinyl-carbonyl-amino and methylsulfonyl groups optionally substituted with one F, 1 to 3 substituents independently selected from Cl and CH ₃ selected from Optionally substituted phenyl. In further or additional embodiments, G is Ar ₁ , wherein Ar ₁ is acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1,3,4 Methyl-1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 5-methyl-1,3,4-thiadiazolyl, 1H-tetra pyridazinyl, N- know polril carbonylamino, N- know Paul rilsul sulfonyl, N- pyrrolidinyl-carbonyl-amino and methylsulfonyl one group selected from the sulfonyl is optionally substituted and 1 independently selected from F, Cl and CH ₃ to is optionally substituted phenyl to 3 substituents, R and ⁰ is H, X is F, Cl or a methyl, Y is _{Br, I, CF 3, C} 1 -C 3 alkyl, C ₂ -C ₃ alkenyl, C _2- C ₃ alkynyl, cyclopropyl, OCH ₃ , OCH ₂ CH ₃ or SCH ₃ . In some embodiments, G is Ar ₁ , wherein Ar ₁ is

, Wherein R ₂ and R ₃ are independently H, F, Cl, CH ₃ , CF ₃ , OCH ₃ . In further or additional embodiments, G is Ar ₁ , wherein Ar ₁ is

Wherein R ₂ and R ₃ are independently H, F, Cl, CH ₃ , CF ₃ , OCH ₃ , X is F or CH ₃ , Y is I, Br or Cl, and Z is F. In further or additional embodiments, G is Ar ₁ , wherein Ar ₁ is phenyl or monosubstituted phenyl. In additional or additional embodiments, G is Ar ₁ , wherein Ar ₁ is phenyl or monosubstituted phenyl, X is F or CH ₃ , Y is I, Br or Cl, Z is F, R ⁰ is F, methyl, ethyl, methoxy or 2-methoxy-ethoxy. In further or additional embodiments, G is Ar ₁ , wherein U is N or CR ₂ and V is N. In further or additional embodiments, G is Ar ₁ , wherein U is N or CR ₂ and V is CR. In a further or additional embodiment, G is Ar ₁ , wherein U is N or CR ₂ , V is CR, R ⁰ is H, X is F, Cl or methyl, Y is Br, I, CF ₃ , C ₁ -C ₃ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl, cyclopropyl, OCH ₃ , OCH ₂ CH ₃ or SCH ₃ .

이고, 이때의 R₇은 H 또는 메틸이며 R₈은 H, 아세트아미도, 메틸, F 또는 Cl이다. 추가의 또는 부가적인 실시양태에서, G는 Ar₂이고, 여기서의 Ar₂는

이고, 이때의 R₇은 H 또는 메틸이며 R₈은 H, 아세트아미도, 메틸, F 또는 Cl이고, R⁰은 H이고, X는 F, Cl 또는 메틸이고, Y는 Br, I, CF₃, C₁-C₃알킬, C₂-C₃알케닐, C₂-C₃알키닐, 시클로프로필, OCH₃, OCH₂CH₃ 또는 SCH₃이며, Z는 F이다. 추가의 또는 부가적인 실시양태에서, G는 Ar₂이고, 여기서의 Ar₂는

이고, 이때의 U는 S 또는 O이고 V는 CH=이고 R₈은 H 또는 CH₃이고 R₇은 H 또는 메틸이고 R₈은 H, 아세트아미도, 메틸, F 또는 Cl이고, R⁰은 H이고, X는 F, Cl 또는 메틸이고, Y는 Br, I, CF₃, C₁-C₃알킬, C₂-C₃알케닐, C₂-C₃알키닐, 시클로프로필, OCH₃, OCH₂CH₃ 또는 SCH₃이며, Z는 F이다. 추가의 또는 부가적인 실시양태에서, R⁰은 H이다. 추가의 또는 부가적인 실시양태에서, R⁰은 H이고, X는 F 또는 Cl이며, Y는 Br, I, CH₂CH₃ 또는 SCH₃이다.In some embodiments, G is Ar ₂ , wherein Ar ₂ is

Wherein R ₇ is H or methyl and R ₈ is H, acetamido, methyl, F or Cl. In further or additional embodiments, G is Ar ₂ , wherein Ar ₂ is

And, wherein the R ₇ is H or methyl and R ₈ is H, and acetamido, methyl, F or Cl, and R ⁰ is H, X is F, Cl or methyl, Y is Br, I, CF ₃ , C ₁ -C ₃ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl, cyclopropyl, OCH ₃ , OCH ₂ CH ₃ or SCH ₃ , and Z is F. In further or additional embodiments, G is Ar ₂ , wherein Ar ₂ is

, Wherein U is S or O, V is CH =, R ₈ is H or CH ₃ , R ₇ is H or methyl and R ₈ is H, acetamido, methyl, F or Cl and R ⁰ is H , X is F, Cl or methyl, Y is _{Br, I, CF 3, C} 1 -C 3 alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl, cyclopropyl, OCH _3, OCH ₂ CH ₃ or SCH ₃ , and Z is F. In further or additional embodiments, R < ⁰ > In further or additional embodiments, R ⁰ is H, X is F or Cl, and Y is Br, I, CH ₂ CH _3, or SCH ₃ .

In some embodiments, G is Ar ₃ , wherein U is -O-.

In a further or additional embodiments, G is R _1a, R _1a, where a is defined as above. In further or additional embodiments, G is R &_lt; _1a &_gt; and R < ⁰ > is H, wherein R < _1a > In a further or additional embodiments, G is R _1a and, R ⁰ are as defined above other than H, wherein the R _1a is as defined above. In further or additional embodiments, G is R _1a , wherein R _1a is methyl, monohalomethyl, C ₁ -C ₃ alkoxymethyl or cyclopropoxymethyl. In further or additional embodiments, G is R _1a , wherein R _1a is methyl, monohalomethyl, C ₁ -C ₃ alkoxymethyl or cyclopropoxymethyl and R ⁰ is F, Cl, C ₁ C ₃ alkyl, monochloroC ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, trifluoromethoxy or 2-methoxy-ethoxy.

In a further or additional embodiments, G is R _1b, R _1b, where a is defined as above. In a further or additional embodiments, G is and R _1b, R ⁰ is H, R _1b, where a is defined as above. In a further or additional embodiment, G is R < _1b &_gt;, R < ⁰ > is H and Z is F, wherein R < _1b > In a further or additional embodiments, G is R _1b, R ⁰ are as defined above other than H, wherein the R _1b is as defined above. In a further or additional embodiment, G is R _1b , wherein R _1b is isopropyl, 2-butyl, 2-pentyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, OH and OCH < ₃ > and Y is Br, I, methyl or trifluoromethyl. In a further or additional embodiment, G is R _1b , wherein R _1b is isopropyl, 2-butyl, 2-pentyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, is optionally substituted from OCH ₃ with one or two substituents independently selected, Y is Br, I, and methyl, methyl or trifluoromethyl, R ⁰ is F, Cl, C ₁ -C ₃ alkyl, mono-chloro-C ₁ - C ₃ alkyl, C ₁ -C ₃ alkoxy, trifluoromethoxy or 2-methoxy-ethoxy. In a further or additional embodiment, G is R _1b , wherein R _1b is isopropyl, 2-butyl, 2-pentyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, Optionally substituted with one or two OH groups, and Y is Br, I, methyl or trifluoromethyl. In a further or additional embodiment, G is R _1b , wherein R _1b is isopropyl, 2-butyl, 2-pentyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, group with one or two OH is optionally substituted, Y is Br, I, and methyl, methyl or trifluoromethyl, R ⁰ is F, Cl, C ₁ -C ₃ alkyl, mono-chloro-C ₁ -C ₃ alkyl, C ₁ C ₃ alkoxy, trifluoromethoxy or 2-methoxy-ethoxy.

In a further or additional embodiments, G is R _1c, R _1c, where a is defined as above. In a further or additional embodiments, G is R _1c is, R ⁰ is H, R _1c, where a is defined as above. In a further or additional embodiments, G is R _1c is, R ⁰ are as defined above other than H, wherein the R _1c are as defined above. If further or additional embodiments, G is R _1c, and an R ⁰ is H, R _1c here is _{(CH 2) n O m R} ' , and m at this time is 0 or 1 and m is 1 Wherein n is 2 or 3 and m is 0, n is 1 or 2 and R 'is selected from F, Cl, OH, OCH ₃ , OCH ₂ CH ₃ and C ₃ -C ₆ cycloalkyl to an optionally substituted C ₁ -C ₆ alkyl with 3 substituents. In yet another more particular subclass embodiment, m is 0, n is 1 or 2, and R 'is optionally substituted C ₁ -C ₄ alkyl as described above. In another more particular subclass embodiment, m is 1, n is 2 or 3, and R 'is optionally substituted C ₁ -C ₄ alkyl as described above. In a more specific subclass embodiment, m is 0, n is 1 or 2, and R 'is C ₁ -C ₄ alkyl optionally substituted with one to three groups selected from OH, OCH ₃ , Cl and cyclopropyl to be.

In a further or additional embodiments, G is R _1d, R _1d, where a is defined as above. In further or additional embodiments, G is R _1d and R ⁰ is H, wherein R _1d is defined as above. In a further or additional embodiments, G is R _1d and, R ⁰ are as defined above other than H, wherein the R _1d are defined as above. In further or additional embodiments, G is R _1d and R ⁰ is H, wherein R _1d is C (A) (A ') (B) -, wherein B, A, and A' forming, or ₄ alkyl, or a and a 'is a saturated ring of 3 to 6 together with the carbon atom to which they are attached, _- independently, is H, or is one or two OH groups or halogen atoms, an optionally substituted C ₁ Which ring optionally contains one or two heteroatoms independently selected from O, N and S and is optionally substituted with one or two groups independently selected from methyl, ethyl, fluoro, chloro, bromo and iodo Lt; / RTI >

In a further or additional embodiments, G is R _1e, R _1e herein, is defined as above. In a further or additional embodiments, G is R _1e is, R ⁰ is H, R _1e herein, is defined as above. In a further or additional embodiments, G is R _1e is, R ⁰ are as defined above other than H, wherein the R _1e is as defined above.

In further or additional embodiments, G is Ar ₁ , wherein Ar ₁ is defined as above. In further or additional embodiments, G is Ar ₁ and R ⁰ is H, wherein Ar ₁ is defined as above. In a further or additional embodiments, G is Ar _1, R ⁰ is as defined above other than H, is Ar ₁ here is defined as above.

In further or additional embodiments, G is Ar ₂ , wherein Ar ₂ is defined as above. In further or additional embodiments, G is Ar ₂ and R ⁰ is H, wherein Ar ₂ is defined as above. In further or additional embodiments, G is Ar ₂ and R ⁰ is as defined above except H, wherein Ar ₂ is defined as above.

In a further or additional embodiments, X is F, Cl or CH _3, Y is I, Br, Cl, CF ₃ or C ₁ -C ₃ alkyl, Z is H or F. In a further or additional embodiments, X is F, Cl or CH _3, and, Y is I, Br, Cl, CF ₃ or a C ₁ -C ₃ alkyl, Z is H or F, R ⁰ is halogen, C ₁ -C ₆ alkyl, mono halo C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, phenyl, monosubstituted phenyl, OR ₃ , OC (= O) R _4, or C (= O) OR ₅ . In a further or additional embodiments, X is F, Cl or CH _3, and, Y is I, Br, Cl, CF ₃ or a C ₁ -C ₃ alkyl, Z is H or F, R ⁰ is furyl, Thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl or pyrazolyl. In a further or additional embodiment, X is F, Cl or a CH _3, and, Y is I, Br, Cl, CF ₃ or a C ₁ -C ₃ alkyl, Z is H or F, R ⁰ is F, is ethoxy - Cl, C ₁ -C ₄ alkyl, C ₁ -C ₃ alkoxy, trifluoromethoxy or 2-methoxyethyl.

In another more specific subclass embodiment, R _1d is cycloalkyl or 1-alkyl-cycloalkyl, wherein the 1-alkyl group is optionally substituted with one or two OH groups or one or two halogen atoms.

In another more particular subclass embodiment, R ⁰ is selected from the group consisting of halogen, C ₁ -C ₆ alkyl, mono halo C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, phenyl, monosubstituted _{phenyl, oR 3, OC (= O} ) R 4 or C (= O), and oR _5, R _1d is cycloalkyl or 1-alkyl- cycloalkyl, in which the The 1-alkyl group is optionally substituted with one or two OH groups or one or two halogen atoms.

In another more specific subclass embodiment, R ⁰ is a furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, or pyrazolyl, R _1d is cycloalkyl or 1-alkyl- Cycloalkyl, wherein the 1-alkyl group is optionally substituted with one or two OH groups or one or two halogen atoms.

In another more particular subclass embodiment, R _1d is cycloalkyl or 1-alkyl-cycloalkyl, wherein the 1-alkyl group is optionally substituted with one or two OH groups, Y is Br, I, methyl or Trifluoromethyl. In another more particular subclass embodiment, R _1d is cycloalkyl or 1-alkyl-cycloalkyl, wherein the 1-alkyl group is optionally substituted with one or two fluorine or chlorine atoms, Y is Br, I, Methyl or trifluoromethyl. In another more particular subclass embodiment, R _1d is cycloalkyl or (1-alkyl) -cycloalkyl, wherein the 1-alkyl group is optionally substituted with one or two OH groups, and R ⁰ is F, Cl , C ₁ -C ₃ alkyl, monochloroC ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, trifluoromethoxy or 2-methoxy-ethoxy. In another more particular subclass embodiment, R _1d is tetrahydrofuryl, tetrahydrothienyl, pyrrolidyl, piperidyl, piperazinyl or morpholyl, each of which is optionally substituted as described above, Y is Br, I, methyl or trifluoromethyl. In another more particular subclass embodiment, R _1d is selected from the group consisting of oxazolidinyl, thiazolidinyl, isoxazolidinyl, isothiazolidinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidyl, piperidyl, Each of which is optionally substituted as defined above, and Y is Br, I, methyl or trifluoromethyl. In another more particular subclass embodiment, R _1d is cyclopropyl or 1-alkyl-cyclopropyl, wherein the 1-alkyl group is optionally substituted with one or two OH groups, and R ⁰ is F, Cl, methyl , Ethyl, chloromethyl, C ₁ -C ₂ alkoxy, trifluoromethoxy or 2-methoxy-ethoxy. In a still more specific embodiment, R _1d is 1- (monohydroxyalkyl) cycloalkyl. In another more particular embodiment, R _1d is 1- (monohydroxyalkyl) cycloalkyl and R ⁰ is F, Cl, methyl, ethyl, chloromethyl, C ₁ -C ₂ alkoxy, trifluoromethoxy, or 2 -Methoxy-ethoxy. ≪ / RTI > In a still more specific embodiment, R _1d is 1- (dihydroxyalkyl) cycloalkyl. In another more specific embodiment, R _1d is 1- (dihydroxyalkyl) cycloalkyl and R ⁰ is F, Cl, methyl, ethyl, chloromethyl, C ₁ -C ₂ alkoxy, trifluoromethoxy, or 2 -Methoxy-ethoxy. ≪ / RTI >

In a more specific subclass embodiment, U is CR < ₂ > and V is N. In yet another more specific subclass embodiment, U and V are both N. In a more specific subclass embodiment, U is CR < ₂ > and V is CR < _{3 &} gt ;.

In a more particular subclass embodiment, the present invention provides a compound of formula _I wherein G is Ar ₁ , wherein Ar ₁ is phenyl or monosubstituted phenyl and R ⁰ is F, methyl, ethyl, C ₁ -C ₃ alkoxy, trifluoromethoxy, ethoxy or 2-methoxy-ethoxy and X is F, Cl or CH _3, Y is I, provides compounds of formula I wherein Z is F. In another subclass embodiment, the invention provides a compound of formula _I wherein G is Ar ₁ , wherein Ar ₁ is phenyl or monosubstituted phenyl, and R ⁰ is halogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl , C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, and all such alkyl, cycloalkyl, alkenyl and alkynyl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, OH, CN, cyanomethyl, nitro, phenyl and trifluoromethyl optionally substituted with one to three substituents selected independently of the other, it is from, or R ⁰ is a phenyl, oR _3, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl or pyrazolyl formula I < / RTI > In a further embodiment of a specific sub-class of embodiments, the invention where A is Ar _1, Ar ₁ is wherein the phenyl or monosubstituted phenyl, R ⁰ is F, Cl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, 2-methoxyethoxy, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl, trifluoromethyl, phenyl, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl , Pyrrolyl or pyrazolyl, X is F, Cl or methyl, Y is I, Br, Cl, CF ₃ or C ₁ -C ₃ alkyl and Z is F.

In another more particular subclass embodiment, the present invention provides a compound of formula _I wherein G is Ar ₁ , wherein Ar ₁ is phenyl or monosubstituted phenyl, R ⁰ is H, X is F, Cl or CH ₃ , Y ≪ / RTI > is Br or I, and Z is F.

In another subclass embodiment, the invention provides a compound of formula I wherein G is Ar ₂ , wherein Ar ₂ is selected from 2-thienyl, 2-furyl, 3-thienyl, 3- furyl, , All of which are optionally substituted by methoxycarbonyl, methylcarbamoyl, acetamido, acetyl, methyl, ethyl, trifluoromethyl or halogen. In a more particular subclass embodiment, the invention provides a compound of formula I wherein G is Ar ₂ , wherein Ar ₂ is selected from the group consisting of ₂ -thienyl, 2-furyl, 3-thienyl, 3- furyl, Wherein all are optionally substituted with methoxycarbonyl, methylcarbamoyl, acetamido, acetyl, methyl, ethyl, trifluoromethyl or halogen and R ⁰ is other than H and X is F, Cl or CH ₃ , Y is I, Br, Cl, CF ₃ or C ₁ -C ₃ alkyl, and Z is H or F. In another subclass embodiment, the invention provides a compound of formula I wherein G is Ar ₂ , wherein Ar ₂ is selected from 2-thienyl, 2-furyl, 3-thienyl, 3- furyl, and, both the methoxycarbonyl, methylcarbamoyl, acetamido, acetyl, methyl, ethyl, trifluoromethyl, and optionally substituted with methyl or halogen, R ⁰ is F, Cl, C ₁ -C ₃ alkyl, mono chloro C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, trifluoromethoxy, methyloxy-methoxy or 2-methoxy-and ethoxymethyl, X is F, Cl or CH _3, and, Y is I, Br , and Cl, CF ₃ or C ₁ -C ₃ alkyl, and Z is provided a compound of formula I, H or F. In another subclass embodiment, the invention provides a compound of formula I wherein G is Ar ₂ , wherein Ar ₂ is selected from 2-thienyl, 2-furyl, 3-thienyl, 3- furyl, and, both the methoxycarbonyl, methylcarbamoyl, acetamido, acetyl, methyl, ethyl, tri optionally substituted with methyl or halogen, fluoroalkyl, and R ⁰ is H, X is F, Cl or CH ₃ and , Y is I, Br, Cl, CF ₃ or C ₁ -C ₃ alkyl, and Z is provided a compound of formula I, H or F. In another subclass embodiment, the present invention provides compounds of Formula I wherein G is Ar ₂ , wherein Ar ₂ is thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl or pyrazolyl, all of which are methoxycarbonyl , methylcarbamoyl, acetamido, optionally substituted with acetyl, methyl, ethyl, methyl, or halogen trifluoromethyl, and R ⁰ is H or methoxy, wherein X is F, Cl or CH _3, Y is I, It is Br, Cl, CF ₃ or C ₁ -C ₃ alkyl, and Z is provided a compound of formula I, H or F.

In some embodiments, the compound of formula I, or a pharmaceutical salt thereof,

로부터 선택된다.

.

로부터 선택되며, 여기서의 2-OH 탄소는 R 배위로 존재하는 화학식 I의 화합물 또는 그의 제약 염을 제공한다.In some embodiments,

, Wherein the 2-OH carbon is present in the R configuration, or a pharmaceutical salt thereof.

로부터 선택되며, 여기서의 2-OH 탄소는 S 배위로 존재하는 화학식 I의 화합물 또는 그의 제약 염을 제공한다.In some embodiments,

, Wherein the 2-OH carbon is present in the S configuration, or a pharmaceutical salt thereof.

이다.In a further or additional embodiment, the compound of formula I, or a pharmaceutical salt thereof,

to be.

이다.In a further or additional embodiment, the compound of formula I, or a pharmaceutical salt thereof,

to be.

In some embodiments, the invention provides a composition comprising a compound of formula I, wherein the 2-OH carbon is present in the R configuration and is substantially free of the S isomer, wherein the 2-OH carbon is present in the R configuration.

In some embodiments, the present invention provides a composition comprising a compound of formula I, wherein the 2-OH carbon is present in the S configuration and wherein the R isomer is substantially absent,

In some embodiments, the present invention provides a compound of formula I wherein Y is phenyl, pyridyl or pyrazolyl. In another subclass embodiment, the present invention provides a compound of formula I wherein Y is substituted phenyl, pyridyl or pyrazolyl. In another subclass embodiment, the present invention provides a compound of formula I wherein Y is Br or I. In one subclass embodiment, the invention provides a compound of formula I wherein G is 1-piperidyl, 2-piperidyl, 3-piperidyl or 4-piperidyl. In another subclass embodiment, the present invention provides a compound of formula I wherein G is 1-piperazinyl or 2-piperazinyl. In another subclass embodiment, the invention provides a compound of formula I wherein G is morpholyl. In another subclass embodiment, the present invention provides a compound of formula I wherein G is N-methyl-2-aminoethyl. In one subclass embodiment, the invention provides a compound of formula I wherein G is N-methyl-3-amino-n-propyl. In another subclass embodiment, the invention relates to compounds of formula I wherein G is (CH ₃ ) ₂ N-CH ₂ CH ₂ -NH- (CH ₂ ) _n -, wherein n is 1, 2 or 3 . In yet another embodiment of the subclass, the present invention G is _{(CH 3 CH 2) 2 N} -CH 2 CH 2 -NH- (CH 2) n - , and where n is the compound of formula I wherein 1 or 2 . In a more particular subclass embodiment, the present invention provides a compound of formula I wherein G is 1-piperidyl, 2-piperidyl, 3-piperidyl or 4-piperidyl and R ⁰ is H, halo or methoxy, X is F, and Y is I. In another more particular subclass embodiment, the invention provides a compound of formula I wherein G is 1-piperazinyl or 2-piperazyl, R ⁰ is H, halo or methoxy, X is F and Y is I ≪ / RTI > In another more particular subclass embodiment, the present invention provides a compound of formula I wherein G is morpholyl, R < ⁰ > is H, halo or methoxy, X is F and Y is I. In another more particular subclass embodiment, the present invention provides a compound of formula I wherein G is N-methyl-2-aminoethyl and R ⁰ is H, halo or methoxy, X is F and Y is I . In another more particular subclass embodiment, the present invention provides a compound of formula I wherein G is N-methyl-3-amino-n-propyl, R ⁰ is H, halo or methoxy, X is F, I < / RTI > In another further embodiment of the specific subclass, the present invention G is _{(CH 3) 2 N-CH} 2 CH 2 -NH- (CH 2) n - , and and wherein the n is 1, 2 or 3, R ⁰ is H, halo or methoxy, X is F, and Y is I. In another further embodiment of the specific subclass, the present invention G is _{(CH 3 CH 2) 2 N} -CH 2 CH 2 -NH- (CH 2) n - and is, of where n is 1 or 2, R ⁰ is H, halo or methoxy, X is F, and Y is I.

In some embodiments, the invention provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof. In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.

로부터 선택된 화합물 또는 그의 제약상 허용가능한 염, 용매화물, 다형체, 에스테르, 아미드, 호변이성질체 또는 전구약물을 포함하는 제약 조성물을 제공한다. 일부 실시양태에서, 상기 제약 조성물은 1종 이상의 제약상 허용가능한 담체를 추가로 포함한다. 일부 실시양태에서, 상기 화합물은 R 배위로 존재한다. 일부 실시양태에서, 상기 화합물은 R 배위로 존재하고, S 이성질체는 실질적으로 없다. 일부 실시양태에서, 상기 화합물은 S 배위로 존재한다. 일부 실시양태에서, 상기 화합물은 S 배위로 존재하고, R 이성질체는 실질적으로 없다. 일부 실시양태에서, 상기 화합물은

이다. 일부 실시양태에서, 상기 화합물은

이다. 일부 실시양태에서, 상기 화합물은

이다. 일부 실시양태에서, 상기 화합물은

이다.In some embodiments,

Or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof. In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier. In some embodiments, the compound is in the R configuration. In some embodiments, the compound is in the R configuration and is substantially free of the S isomer. In some embodiments, the compound is in the S configuration. In some embodiments, the compound is in the S configuration and is substantially free of the R isomer. In some embodiments, the compound is

to be. In some embodiments, the compound is

to be. In some embodiments, the compound is

to be. In some embodiments, the compound is

to be.

A table showing non-limiting examples of compounds of formula (I)

The following table shows examples of individual compounds provided or considered in the present invention. These examples should not be considered to be limiting.

Table 1 below shows compounds of formula I wherein R ⁰ is as defined herein and G is R _1a , wherein R _1a is as defined in the table below, and X, Y and Z are as defined in the following table Lt; RTI ID = 0.0 > of: < / RTI >

<Table 1>

Table 2 below shows the compounds of formula I wherein R ⁰ is as defined herein and G is R _1b , wherein R _1b is as defined in the following table and X, Y and Z are as defined in the following table Lt; RTI ID = 0.0 &gt; of: &lt; / RTI &gt;

<Table 2>

Table 3 below shows compounds of formula I wherein R ⁰ is as defined herein and G is R _1c , wherein R _1c is as defined in the table below and X, Y and Z are as defined in the following table Lt; RTI ID = 0.0 &gt; of: &lt; / RTI &gt;

<Table 3>

Tables 4a and 4b below illustrate embodiments of the present invention wherein G = R _1d , Z is F, X is F, and R _1d and R ⁰ are compounds of formula I as defined in the following table. Each row in the table corresponds to four different species only at position Y:

<Table 4a>

<Table 4b>

Table 5a below shows an embodiment of the present invention wherein G is Ar ₁ , Ar ₂ or R _1d , R ⁰ is H, Z is F and G and X are as defined in the following table . Each row in the table and only position Y only correspond to different five kinds (Y _a, Y _b, Y _c, Y _d, and Y _{e), wherein, Y a = SCH 3, Y} b = Br, Y c = I , Y _d = Cl, Y _e = CH ₃ :

<Table 5a>

Table 5b below shows an embodiment of the invention wherein G is Ar ₁ , Ar ₂ or R _1d , R ⁰ is H, Z is F and G and X are as defined in the following table . Each row in the table and only the position corresponding to Y only five kinds of different (Y _a, Y _b, Y _c, Y _d, and Y _e), where, Y = _a phenyl, Y _b = 3- substituted phenyl, Y _c = 3-pyridyl, Y _d = 4-pyridyl, 3-pyrazolyl:

<Table 5b>

Synthesis procedure

In yet another aspect, a method of synthesizing a compound described herein is provided. In some embodiments, the compounds described herein may be prepared by the following method. The following procedures and examples are intended to illustrate such methods. Neither of these procedures or examples should be construed as limiting the invention in any way. The compounds described herein may be synthesized using standard synthetic techniques known to those skilled in the art, or methods known in the art, in combination with the methods described herein. In addition, the solvent, temperature, and other reaction conditions set forth herein may vary depending upon the practice and knowledge of those skilled in the art.

Starting materials for the synthesis of compounds as described herein are commercially available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis.), Sigma Chemical Co. (St. Louis, Lewis), or a starting material may be synthesized. The compounds described herein, and other related compounds having different substituents, are described, for example, in March, ADVANCED ORGANIC CHEMISTRY 4 ^th Ed., (Wiley 1992), Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 ^th Ed. (Wiley 1999)], all of which are incorporated herein by reference in their entirety), as described in, for example, Vols. A and B (Plenum 2000, 2001) and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 ^rd Ed. Can be synthesized using techniques and materials known to those skilled in the art. General methods for preparing compounds as disclosed herein may be derived from reactions known in the art and the reactions may be carried out in a manner suitable for introduction of the various moieties present in the formulas as provided herein, Can be modified using reagents and conditions.

With the invitation itself Nucleophile  Formation of covalent bond by reaction

The compounds described herein can be modified with the use of various electrophiles or nucleophiles to form new functional groups or substituents. The following table entitled " Covalent Coupling Connections and Examples of its Precursors "presents selected examples of covalent linkages and the precursor functionalities that produce them, and can be used as a guide for the various combinations of electrophiles and nucleophiles available. The precursor functional groups were represented as electrophilic and nucleophilic groups.

Use of Protector

In the reactions described, it may be necessary to protect these reactive functional groups, such as groups of hydroxy, amino, imino, thio or carboxy, in the final product, to avoid unwanted participation in the reaction. A protecting group is used to block some or all of the reactive moieties and to prevent these groups from participating in the chemical reaction until removal of the protecting group. In some embodiments, each protecting group is removable by different means. Protectors that are cleaved under completely heterogeneous reaction conditions meet the requirements of differential elimination. The protecting group may be removed by acid, base and hydrolysis. Groups such as trityl, dimethoxytrityl, acetal, and t-butyldimethylsilyl are acid-labile and can be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with a Cbz group removable by hydrolytic cleavage, The Fmoc group is base-labile. The carboxylic acid and hydroxy reactive moieties may be cleaved in the presence of an acid which is blocked with an acid-labile group, such as t-butyl carbamate or carbamate (stable, but hydrolytically removable at both the acid and the base) Ethyl, and acetyl. &Lt; / RTI &gt;

The carboxylic acid and hydroxy reactive moieties may also be blocked with a hydrolytically removable protecting group, such as a benzyl group, and the amine group capable of hydrogen bonding with an acid may be blocked with a base-labile group such as Fmoc. The carboxylic acid reactive moiety may be protected through conversion to a simple ester compound as exemplified herein or may be blocked with a protecting group removable by oxidation such as 2,4-dimethoxybenzyl, Can be blocked with a fluorine-labile silyl carbamate.

Allylblockers are useful in the presence of acid- and base-protecting groups because they are stable and can subsequently be removed by metal or pi-acid catalysts. For example, the allyl-blocked carboxylic acid can be deprotected with a Pd-catalyzed reaction in the presence of an acid-labile t-butyl carbamate or a base-labile acetate amine protecting group. Another type of protecting group is a resin to which a compound or an intermediate can be attached. As long as the residue is attached to the resin, the functional group is blocked and can not react. Once the functional group is released from the resin, it can be used for the reaction.

The protector or breaker

로부터 선택될 수 있다.

Lt; / RTI &gt;

Detailed descriptions of techniques applicable to the formation of other protecting groups and protecting groups and their removal can be found in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd ed., John Wiley &amp; Sons, New York, , Protective Groups, Thieme Verlag, New York, NY, 1994), which is incorporated herein by reference in its entirety.

Preparation of compounds of formula (I)

The compounds of the present invention can be prepared by various methods. The following procedure is intended to illustrate this method, and the examples given are intended to illustrate the scope of the invention. None of these methods or examples should be construed as limiting the invention in any way.

I. The preparation of compounds of formula (VI) is summarized below:

<Reaction Scheme I>

Scheme I illustrates a method for preparing a sulfonamide derivative of formula VI. The 1,2-diamine derivative (Formula IV) can be readily prepared in two steps from the desired nitro derivative (Formula I). The compound of formula (IV) can be reacted with a sulfonyl chloride derivative (formula V, see the following scheme) to form the desired sulfonamide. Alternatively, the 1,2-diamine derivative IV may be protected to form imidazolidone VII, followed by reaction with the corresponding sulfonyl chloride. The 1,2-diamine VIII is deprotected under basic conditions to give the desired material VI.

II. The general route for synthesizing compounds of formula V is summarized below:

<Reaction Scheme II>

Scheme II shows an example of preparing a complex sulfonyl chloride. Compound XX can be synthesized from IX and can be alkylated to convert it to the potassium salt XII. The salt is treated with SOCl ₂ or POCl ₃ to give the desired compound. Other more specific procedures for preparing the unique sulfonyl chloride derivatives are reported in the Experimental section.

III. The general route of synthesizing the compound of formula (XIII) is summarized in Scheme III:

<Reaction Scheme III>

Scheme III illustrates the preparation of the sulfonamide derivative of formula XIII. For example, the compound can be readily obtained by reacting compound VI with a boronic acid using a palladium catalyst under Suzuki conditions.

IV. The general route for synthesizing compounds of formula (XV) is summarized in Scheme IV:

<Reaction Scheme IV>

Scheme IV illustrates the preparation of the sulfonamide derivative of formula (XV). The vinylsulfonamide (XIV) is reacted with an amine to form a derivative of formula XV.

Additional forms of compounds of formula (I)

The isomer of the compound of formula (I)

The compounds described herein may exist as geometric isomers. The compounds described herein may have one or more double bonds. The compounds provided herein include all cis, trans, syn, anti, entgegen (E) and zusammen (Z) isomers as well as their corresponding mixtures. In some circumstances, the compound may exist as a tautomer. The compounds described herein include all possible tautomers within the formulas described herein. The compounds described herein may have one or more chiral centers, and each center may be present in the R or S configuration. The compounds described herein include not only all diastereoisomeric, enantiomeric, and epimeric forms, but also their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures, combinations, or interconversions of enantiomers and / or diastereoisomers resulting from a single preparation step may also be useful for the applications described herein. The compounds described herein are prepared by reacting a racemic mixture of the above compounds with an optically active resolving agent to form a pair of diastereoisomeric compounds and separating the diastereomers to recover the optically pure enantiomer, . The resolution of the enantiomers can be performed using covalent diastereomeric derivatives of the compounds described herein, or a dissociable complex may be used (e. G., A crystalline diastereomeric salt). The diastereomers have inherent physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and can be readily separated using these differences. The diastereomers can be separated by chiral chromatography or by separation / resolution techniques based on differences in solubility. The optically pure enantiomer is then recovered with the resolving agent through any useful means that does not cause racemization. A more detailed description of the applicable techniques for separating the stereoisomers of the compound from its racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley And Sons, Inc., 1981, which is incorporated herein by reference in its entirety.

&Lt; RTI ID = Labeled  compound

Also described herein are methods of treating isotopically-labeled compounds and disorders of Formula &lt; RTI ID = 0.0 &gt; I. &lt; / RTI &gt; For example, the present invention provides a method of treating a disease by administering an isotopically-labeled compound of formula (I). The isotopically-labeled compounds of formula I may be administered as pharmaceutical compositions. The compounds of formula (I) are thus also identical to those mentioned hereinbefore, but the fact that one or more of the atoms has been replaced by an atom having an atomic weight or mass number different from the atomic mass or mass number of an atom normally present in nature, . Examples of isotopes that can be incorporated in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as isotopes of ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl. The compounds described herein containing the above-mentioned isotopes and / or other isotopes of other atoms, the pharmaceutically acceptable salts thereof, are within the scope of the present invention. Compounds incorporating certain isotopically-labeled compounds of formula I, such as radioactive isotopes such as ³ H and ¹⁴ C, are useful for drug and / or substrate tissue distribution assays. Tritium, i.e., ³ H and carbon-14, i.e., ¹⁴ C, isotopes are often readily prepared and detectable. In addition, substitution with heavier isotopes such as deuterium, i.e., ² H, may provide certain therapeutic advantages due to increased metabolic stability, for example increased in vivo half-life or reduced dosage requirements, Which may be desirable in some situations. The isotopically-labeled compounds and their pharmaceutically acceptable salts can be prepared by carrying out the procedures described herein using readily available isotopically labeled reagents instead of reagents that are not generally labeled with isotopes.

The compounds described herein may be labeled by other means including, but not limited to, the use of chromophore or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Compounds of formula I Pharmaceutical image  Acceptable salt

Also described herein are methods of treating pharmaceutically acceptable salts and disorders of compounds of formula (I). For example, the present invention provides a method of treating a disease by administering a pharmaceutically acceptable salt of a compound of formula (I). Pharmaceutically acceptable salts of the compounds of formula I may be administered as pharmaceutical compositions.

Thus, the compounds described herein are prepared by replacing the acidic proton present in the parent compound with a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion, or a pharmaceutically acceptable salt formed with an organic base . The base addition salts may also be prepared by reacting the free acid form of the compounds described herein with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like, or with an aqueous base such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, With inorganic or organic bases such as, but not limited to, inorganic bases such as sodium hydroxide and the like. In addition, the salt forms of the disclosed compounds can be prepared using salts of the starting materials or intermediates.

In addition, the compounds described herein may be prepared by reacting the free base forms of the above compounds with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid and the like and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, malonic acid, malonic acid, maleic acid, fumaric acid, Q-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, Methanesulfonic acid, ethanesulfonic acid, 1,2-ethane disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2] oct- Acid, glucoheptonic acid, 4,4'-methylenebis- (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiarybutylacetic acid, laurylsulfuric acid, gluconic acid , Glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. Including an organic acid, but can be prepared as a pharmaceutically acceptable salt formed by a pharmaceutically acceptable inorganic or organic acid and the reaction is not limited to this.

Solvates of compounds of formula (I)

Also described herein are methods of treating solvates and disorders of compounds of formula (I). For example, the present invention provides a method of treating a disease by administering a solvate of a compound of formula (I). Solvates of the compounds of formula I may be administered as pharmaceutical compositions.

The solvate contains a stoichiometric or non-stoichiometric amount of solvent and may be formed during the crystallization process using a pharmaceutically acceptable solvent such as water, ethanol, and the like. The hydrate is formed when the solvent is water, or the alcoholate is formed when the solvent is alcohol. Solvates of the compounds described herein may conveniently be prepared or formed during the process described herein. By way of example only, the hydrates of the compounds described herein may conveniently be prepared via recrystallization from aqueous / organic solvent mixtures using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol . In addition, the compounds provided herein may exist in unsolvated as well as solvated forms. For purposes of the compounds and methods provided herein, solvated forms are generally regarded as equivalent to unsolvated forms.

Compounds of formula I Polymorph

Also described herein are methods of treating polymorphs and disorders of the compounds of formula (I). For example, the present invention provides a method of treating a disease by administering a polymorph of a compound of formula (I). Polymorphs of the compounds of formula I may be administered as pharmaceutical compositions.

Thus, the compounds described herein include all crystalline forms thereof known to be polymorphs. Polymorphs include different crystal packing alignments of compounds having the same elemental composition. The polymorph may differ in x-ray diffraction pattern, infrared spectrum, melting point, density, hardness, crystalline form, optical and electrical properties, stability and solubility. Various factors such as recrystallization solvent, rate of crystallization and storage temperature may predominate the single crystal form.

N- (S) - (3,4- difluoro-2- (2-fluoro-4-iodo-phenylamino) -6-methoxy-phenyl) - 1 - (2,3-dihydroxypropyl) Crystalline polymorph form of cyclopropane-1-sulfonamide

. 일부 실시양태에서, 상기 분말 x선 회절 패턴은 도 5에 나타낸 피크의 약 50％ 이상을 함유한다. 일부 실시양태에서, 상기 분말 x선 회절 패턴은 도 5에 나타낸 피크의 약 70％ 이상을 함유한다. 일부 실시양태에서, 상기 분말 x선 회절 패턴은 도 5에 나타낸 피크의 약 90％ 이상을 함유한다. 일부 실시양태에서, 상기 분말 x선 회절 패턴은 도 5에 나타낸 분말 x선 회절 패턴과 실질적으로 동일하다.The present invention also provides N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6- methoxyphenyl) -1- (2, 3-dihydroxypropyl) cyclopropane-1-sulfonamide &lt; / RTI &gt;

. In some embodiments, the powder x-ray diffraction pattern contains at least about 50% of the peaks shown in Fig. In some embodiments, the powder x-ray diffraction pattern contains at least about 70% of the peaks shown in Fig. In some embodiments, the powder x-ray diffraction pattern contains at least about 90% of the peaks shown in Fig. In some embodiments, the powder x-ray diffraction pattern is substantially the same as the powder x-ray diffraction pattern shown in Fig.

The present invention also provides N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6- methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide. In some embodiments, the specific differential scanning calorimetric pattern is substantially the same as the differential scanning calorimetric pattern shown in Fig. In some embodiments, the crystalline polymorph Form A has a melting point initiation point measured by differential scanning calorimetry of about 143 ° C.

The present invention also relates to amorphous N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) (S) - (3,4-difluoro-2- (2-fluoro-4-trifluoromethylphenyl) propionic acid prepared by a process comprising crystallizing N- - iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide. The present invention also relates to amorphous N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) Dihydroxypropyl) cyclopropane-1-sulfonamide from a mixture of hexane and ethyl acetate to give N- (S) - (3,4-difluoro-2- -Fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide.

The present invention also relates to the use of an effective amount of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) - dihydroxypropyl) cyclopropane-1-sulfonamide and a pharmaceutically acceptable carrier or vehicle. Another aspect of the invention relates to a pharmaceutical composition comprising crystalline polymorph Form A and one or more excipients or carriers.

2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) Crystalline polymorph Form A of cyclopropane-1-sulfonamide is useful for treating or preventing cancer or inflammatory diseases. Additionally, the present invention provides a method for treating or preventing a cancer or inflammatory disease comprising administering to a subject in need thereof an effective amount of N- (S) - (3,4-difluoro-2- (2-fluoro-4- ) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide in the form of a crystalline polymorph Form A, &Lt; / RTI &gt; Another aspect of the invention relates to a method of treating or preventing an inflammatory disease, comprising administering an effective amount of the crystalline polymorph to a subject in need of treatment or prevention of the inflammatory disease. A further aspect of the invention relates to a method of treating or preventing a proliferative disease, comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of the crystalline polymorph.

Compounds of formula I Prodrug drug

Also described herein are methods of treating prodrugs and disorders of compounds of formula (I). For example, the present invention provides a method of treating a disease by administering a prodrug of a compound of formula (I). Prodrugs of the compounds of formula I may be administered as pharmaceutical compositions.

Generally, prodrugs are drug precursors that are converted to active or more active species through several processes, such as conversion by metabolic pathways after administration to a subject and absorption. Some prodrugs include chemical groups that make the prodrug less active and / or impart solubility or some other property to the drug. Once the chemical groups are cleaved and / or modified from the prodrug, the active drug is produced. Prodrugs are often useful in some situations because prodrugs may be easier to administer than parent drugs. For example, they may be bioavailable by oral administration, but not the parent drug. Prodrugs can also improve solubility in pharmaceutical compositions over parent drug. Non-limiting examples of prodrugs are those that are administered as esters ("prodrugs") that facilitate delivery across cell membranes having a water solubility disadvantageous to portability, but once inside the cell with beneficial water solubility, Is hydrolyzed metabolically by a carboxylic acid. A further example of a prodrug may be a short peptide (polyamino acid) attached to an acid group and metabolized to reveal an active moiety.

Prodrugs can be designed as reversible drug derivatives for use as modifiers to enhance drug delivery to site-specific tissues. To date, the design of prodrugs has been to increase the effective solubility of the therapeutic compound in order to target the area where water is the predominant solvent. (Fedorak et al., Am. J. Physiol., 269: G210-218 (1995), McLoed et al., Gastroenterol, 106: 405-413 (J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987)], J. Larsen et al., Int , J. Pharm., 47, 103 (1988)], Sinkula et al., J. Pharm. Sci., 64: 181-210 (1975), ACS Symposium Series See, for example, T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, Everyone is covered by the full text.

In addition, prodrug derivatives of the compounds described herein can be prepared by methods known to those skilled in the art (see, for example, Saulnier et al., (1994) Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). By way of example only, suitable prodrugs can be prepared by reacting the non-derivatized compound of formula I with a suitable carbamylate, including but not limited to 1,1-acyloxyalkylcarbanocloridate, para-nitrophenyl carbonate, And then reacting with a base. Prodrug forms of the compounds described herein that are metabolized in vivo to produce derivatives as described herein are included in the claims. Indeed, some of the compounds described herein may be prodrugs for another derivative or active compound.

In some embodiments, the prodrug may be an amino acid residue, or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues is linked via an amide or ester linkage to the free amino, A compound covalently bonded to a group of a hydroxy or carboxylic acid. Such amino acid residues include, but are not limited to, 20 naturally occurring amino acids, typically represented by the three letter designation, and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, Valine, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also included.

Compounds of formula (I) having a free amino, amido, hydroxy or carboxyl group can be converted into prodrugs. For example, the free carboxyl group may be derivatized with an amide or alkyl ester. As summarized in Advanced Drug Delivery Reviews 1996, 19, 115, the free hydroxy groups are protected using groups including, but not limited to, hemi-succinate, phosphate esters, dimethylaminoacetate and phosphoryloxymethyloxycarbonyl Can be derivatized. Also included are carbamate prodrugs of hydroxy groups and amino groups, as well as carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.

(Acyloxy) ethyl ether wherein the acyl group may be an alkyl ester optionally substituted with a group including but not limited to an ether, an amine and a carboxylic acid functional group, or wherein the acyl group is substituted with a group as defined above Lt; / RTI &gt; is the same amino acid ester). Prodrugs of this type are described in J. Med. Med. Chem. 1996, 39, 10]. In addition, free amines can be derivatized with amides, sulfonamides or phosphonamides. All these prodrug moieties may incorporate groups including, but not limited to, ethers, amines, and carboxylic acid functionality.

Incorporation of suitable substituents into the aromatic ring structure may reduce, minimize or eliminate such metabolic pathways, as the moiety of the aromatic ring moiety in the compounds of formula I may be susceptible to a variety of metabolic reactions.

Pharmaceutical composition

The present application describes pharmaceutical compositions. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate or derivative thereof and at least one pharmaceutically acceptable Carrier. In some embodiments, the pharmaceutical composition is for treating a disorder. In some embodiments, the pharmaceutical composition is for treating a disorder in a mammal. In some embodiments, the pharmaceutical composition is for treating a disorder in a human.

In a further aspect, the invention relates to a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. Such compositions may contain adjuvants, excipients and preservatives, agents that delay absorption, fillers, binders, adsorbents, buffers, disintegrants, solubilizers, other carriers, and other inert ingredients. Methods of formulating such compositions are well known in the art.

In some embodiments, the pharmaceutical composition is in a form suitable for oral administration. In a further or additional embodiment, the pharmaceutical composition is in the form of tablets, capsules, pills, powders, sustained release formulations, solutions, suspensions, parenteral injections such as sterile solutions, suspensions or emulsions For topical administration such as ointments or creams, or for rectal administration such as suppositories.

In a further or additional embodiment, the pharmaceutical composition is in unit dosage form suitable for single administration of precise dosages. In further or additional embodiments, the amount of the compound of formula I ranges from about 0.001 to about 1000 mg / kg body weight per day. In further or additional embodiments, the amount of compound of formula I ranges from about 0.5 to about 50 mg / kg / day. In further or additional embodiments, the amount of compound of formula I is from about 0.001 to about 7 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.002 to about 6 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.005 to about 5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.01 to about 5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.02 to about 5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.05 to about 2.5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.1 to about 1 g / day. In further or additional embodiments, dosage levels below the lower limit of the aforementioned range may be more appropriate. In further or additional embodiments, dosage levels above the upper limit of the above range may be required.

In a further or additional embodiment, the compound of formula I is administered in a single administration once a day. In a further or additional embodiment, the compound of formula I is administered in multiple doses more than once per day. In a further or additional embodiment, the compound of formula I is administered twice a day. In a further or additional embodiment, the compound of formula I is administered three times per day. In a further or additional embodiment, the compound of formula I is administered four times per day. In a further or additional embodiment, the compound of formula I is administered more than 4 times per day. In some embodiments, the pharmaceutical composition is for administration to a mammal. In a further or additional embodiment, the mammal is a human.

In a further or additional embodiment, the pharmaceutical composition further comprises a pharmaceutical carrier, excipient and / or adjuvant. In a further or additional embodiment, the pharmaceutical composition further comprises at least one therapeutic agent. In a further or additional embodiment, the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenic agents and anti-neoplastic agents. In further or additional embodiments, the anti-neoplastic agent is selected from the group consisting of an alkylating agent, an anti-metabolite, an epipidolipid, an anti-neoplastic enzyme, a topoisomerase inhibitor, a procarbazine, a mitoxantrone, Complexes, biological response modifiers and growth inhibitors, hormone / anti-hormone therapeutics, and hematopoietic growth factors. In a further or additional embodiment, the therapeutic agent is Taxol, Bortezomib, or both. In a further or additional embodiment, the pharmaceutical composition is administered in combination with additional therapy. In further or additional embodiments, the additional therapy is radiation therapy, chemotherapy, surgery, or any combination thereof. In a further or additional embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of formula (I).

를 포함하는 조성물에 관한 것이다. 일부 실시양태에서, 상기 화합물의 2-OH 탄소는 R 배위로 존재한다. 일부 실시양태에서, 상기 조성물에는 상기 화합물의 S 이성질체가 실질적으로 없다. 일부 실시양태에서, 상기 화합물은 그의 S 이성질체를 10％ 미만으로 함유한다. 일부 실시양태에서, 상기 화합물은 그의 S 이성질체를 5％ 미만으로 함유한다. 일부 실시양태에서, 상기 화합물은 그의 S 이성질체를 1％ 미만으로 함유한다. 일부 실시양태에서, 상기 화합물은 R 배위로 존재한다.The present invention also

&Lt; / RTI &gt; In some embodiments, the 2-OH carbon of the compound is in the R configuration. In some embodiments, the composition is substantially free of the S isomer of the compound. In some embodiments, the compound contains less than 10% of its S isomer. In some embodiments, the compound contains less than 5% of its S isomer. In some embodiments, the compound contains less than 1% of its S isomer. In some embodiments, the compound is in the R configuration.

In some embodiments, the 2-OH carbon of the compound is present in the S configuration. In some embodiments, the composition is substantially free of the R isomer of the compound. In some embodiments, the compound contains less than 10% of its R isomer. In some embodiments, the compound contains less than 5% of its R isomer. In some embodiments, the compound contains less than 1% of its R isomer. In some embodiments, the compound is in the S configuration.

In some embodiments, the composition contains at least about 50% of a compound exhibiting a powder x-ray diffraction pattern comprising at least 50% of the peaks identified in the powder x-ray diffraction pattern shown in Fig. In some embodiments, the powder x-ray diffraction pattern comprises at least 70% of the peaks identified in the powder x-ray diffraction pattern shown in Fig. In some embodiments, the powder x-ray diffraction pattern comprises at least 90% of the peaks identified in the powder x-ray diffraction pattern shown in Fig. In some embodiments, the powder x-ray diffraction pattern is substantially the same as the powder x-ray diffraction pattern shown in Fig.

In some embodiments, the composition contains at least about 75% of a compound exhibiting a powder x-ray diffraction pattern comprising at least 50% of the peaks identified in the powder x-ray diffraction pattern shown in Fig. In some embodiments, the powder x-ray diffraction pattern comprises at least 70% of the peaks identified in the powder x-ray diffraction pattern shown in Fig. In some embodiments, the powder x-ray diffraction pattern comprises at least 90% of the peaks identified in the powder x-ray diffraction pattern shown in Fig. In some embodiments, the powder x-ray diffraction pattern is substantially the same as the powder x-ray diffraction pattern shown in Fig.

In some embodiments, the composition contains about 90% or more of a compound exhibiting a powder x-ray diffraction pattern comprising at least 50% of the peaks identified in the powder x-ray diffraction pattern shown in Fig. In some embodiments, the powder x-ray diffraction pattern comprises at least 70% of the peaks identified in the powder x-ray diffraction pattern shown in Fig. In some embodiments, the powder x-ray diffraction pattern comprises at least 90% of the peaks identified in the powder x-ray diffraction pattern shown in Fig. In some embodiments, the powder x-ray diffraction pattern is substantially the same as the powder x-ray diffraction pattern shown in Fig.

In some embodiments, substantially all of the compounds in the composition exhibit a powder x-ray diffraction pattern comprising at least 50% of the peaks identified in the powder x-ray diffraction pattern shown in Fig. In some embodiments, the powder x-ray diffraction pattern comprises at least 70% of the peaks identified in the powder x-ray diffraction pattern shown in Fig. In some embodiments, the powder x-ray diffraction pattern comprises at least 90% of the peaks identified in the powder x-ray diffraction pattern shown in Fig. In some embodiments, the powder x-ray diffraction pattern is substantially the same as the powder x-ray diffraction pattern shown in Fig.

In some embodiments, the crystalline polymorph present in the composition has a melting point initiation point measured by differential scanning calorimetry of about 143 ° C. In some embodiments, the crystalline polymorph is substantially free of water. In some embodiments, the crystalline polymorph is substantially free of solvent.

In some embodiments, the composition contains about 50% or more of a compound exhibiting a differential scanning calorimetric pattern substantially the same as the differential scanning calorimetric pattern shown in Fig. In some embodiments, the crystalline polymorph has a melting point initiation point measured by differential scanning calorimetry of about 143 ° C. In some embodiments, the crystalline polymorph is substantially free of water. In some embodiments, the crystalline polymorph is substantially free of solvent.

In some embodiments, the composition contains about 75% or more of a compound exhibiting a differential scanning calorimetric pattern substantially the same as the differential scanning calorimetric pattern shown in Fig. In some embodiments, the crystalline polymorph has a melting point initiation point measured by differential scanning calorimetry of about 143 ° C. In some embodiments, the crystalline polymorph is substantially free of water. In some embodiments, the crystalline polymorph is substantially free of solvent.

In some embodiments, the composition contains about 90% or more of a compound exhibiting a differential scanning calorimetric pattern substantially the same as the differential scanning calorimetric pattern shown in Fig. In some embodiments, the crystalline polymorph has a melting point initiation point measured by differential scanning calorimetry of about 143 ° C. In some embodiments, the crystalline polymorph is substantially free of water. In some embodiments, the crystalline polymorph is substantially free of solvent.

In some embodiments, substantially all of the compounds in the composition exhibit a differential scanning calorimetric pattern substantially identical to the differential scanning calorimetric pattern shown in Fig. In some embodiments, the crystalline polymorph has a melting point initiation point measured by differential scanning calorimetry of about 143 ° C. In some embodiments, the crystalline polymorph is substantially free of water. In some embodiments, the crystalline polymorph is substantially free of solvent.

In some embodiments, amorphous N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3- (2-fluoro-4-iodophenylamino) -6- (trifluoromethyl) propyl) cyclopropane-1-sulfonamide was prepared by a method comprising crystallizing N- Methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide are provided. In some embodiments, the crystallization step comprises crystallizing from a mixture of ethyl acetate and heptane, for example, a mixture of ethyl acetate and heptane, in a ratio of about 1 to 4 parts of ethyl acetate to about 2 to 10 parts of heptane, Specifically about 2 parts of ethyl acetate to about 5 parts of heptane.

In some embodiments, the compound is formulated such that it is released rapidly. In some embodiments, the compound is formulated such that it is sustained release. In another embodiment, the compound is formulated such that it is prolonged release.

In some embodiments, the composition is in tablet form. In another embodiment, the composition is in a capsule dosage form. The compositions may be prepared in capsule or tablet dosage form, a wide range of alternative compositions and manufacturing approach of the range may be used (References: (1) [Remington, The Science and Practice of Pharmacy, 20 th Edition, 2000 (2) [Pharmaceutical Dosage Forms Tablets Volumes 1-3, 1989] and (3) [Modern Pharmaceuticals 4 ^th Edition, 2002]). A range of manufacturing approaches may be employed including dry blending, wet granulation, roller pressing, extrusion, spheronization, coating and spray drying processes. Soft gel formulations and manufacturing approaches are also possible.

In some embodiments, the composition comprises a filler or diluent. In various embodiments, the filler or diluent is selected from microcrystalline cellulose, silicified microcrystalline cellulose, lactose, mannitol, compressed sugar, calcium phosphate, calcium sulfate, calcium carbonate, calcium silicate and starch. In another embodiment, the filler or diluent is microcrystalline cellulose.

In some embodiments, the composition comprises a disintegrant. In various embodiments, the disintegrant is selected from sodium croscarmellose, sodium starch glycolate, crospovidone, methylcellulose, alginic acid, sodium alginate, starch derivatives, bentonites and beages. In some embodiments, the disintegrant is croscarmellose sodium.

In some embodiments, the composition comprises a lubricant. In various embodiments, the lubricant is selected from magnesium stearate, metallic stearate, talc, sodium stearyl fumarate and stearic acid. In some embodiments, the lubricant is magnesium stearate.

In some embodiments, the composition comprises a wetting agent or a surfactant. In various embodiments, the wetting agent or surfactant is selected from the group consisting of sodium lauryl sulfate, glycerol, sorbitan oleate, sorbitan stearate, polyoxyethylene sorbitan laurate, palmitate, stearate, oleate or hexaoleate , Polyoxyethylene stearyl alcohol, and sorbitan monolaurate. In some embodiments, the humectant or surfactant is sodium lauryl sulfate.

Additional excipients such as lubricants, flavors, and coloring agents may be added. Additional alternative excipients can be found in The Handbook of Pharmaceutical Excipients, 5 ^th Edition, 2005 and the FDA Inactive Ingredient database.

The present invention also

rescue (As defined in any of the above embodiments) of about 1 mg,

About 222.2 mg of microcrystalline cellulose,

About 12.0 mg of croscarmellose sodium,

About 2.4 mg of sodium lauryl sulfate, and

Magnesium stearate Approximately 2.4 mg

&Lt; / RTI &gt;

The present invention also

(임의의 상기 실시양태에서 정의한 바와 같음)의 화합물 약 10 mg,rescue

(As defined in any of the above embodiments), about 10 mg,

About 213.2 mg of microcrystalline cellulose,

About 12.0 mg of croscarmellose sodium,

About 2.4 mg of sodium lauryl sulfate, and

Magnesium stearate Approximately 2.4 mg

&Lt; / RTI &gt;

The present invention also

(임의의 상기 실시양태에서 정의한 바와 같음)의 화합물 약 20 mg,rescue

(As defined in any of the above embodiments), about 20 mg,

About 203.2 mg of microcrystalline cellulose,

About 12.0 mg of croscarmellose sodium,

About 2.4 mg of sodium lauryl sulfate, and

Magnesium stearate Approximately 2.4 mg

&Lt; / RTI &gt;

The present invention also

(임의의 상기 실시양태에서 정의한 바와 같음)의 화합물 약 40 mg,rescue

(As defined in any of the above embodiments) of about 40 mg,

About 183.2 mg of microcrystalline cellulose,

About 12.0 mg of croscarmellose sodium,

About 2.4 mg of sodium lauryl sulfate, and

Magnesium stearate Approximately 2.4 mg

&Lt; / RTI &gt;

(임의의 상기 실시양태에서 정의한 바와 같음)의 화합물 약 0.4 중량％, 및 제약상 허용가능한 담체 또는 비히클 약 99.6 중량％를 포함하는 조성물에 관한 것이다. 일부 실시양태에서, 상기 제약상 허용가능한 담체 또는 비히클은 미세결정질 셀룰로스를 포함한다. 추가의 또는 부가적인 실시양태에서, 상기 미세결정질 셀룰로스는 조성물의 약 92.6 중량％이다. 추가의 또는 부가적인 실시양태에서, 상기 조성물은 크로스카르멜로스 나트륨 약 5 중량％, 나트륨 라우릴 술페이트 약 1 중량％, 및 스테아르산마그네슘 약 1 중량％를 추가로 포함한다.The invention also relates to

About 0.4% by weight of a compound of formula (as defined in any of the above embodiments), and about 99.6% by weight of a pharmaceutically acceptable carrier or vehicle. In some embodiments, the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose. In a further or additional embodiment, the microcrystalline cellulose is about 92.6% by weight of the composition. In a further or additional embodiment, the composition further comprises about 5% by weight of croscarmellose sodium, about 1% by weight of sodium lauryl sulfate, and about 1% by weight of magnesium stearate.

(임의의 상기 실시양태에서 정의한 바와 같음)의 화합물 약 4.2 중량％, 및 제약상 허용가능한 담체 또는 비히클 약 95.8 중량％를 포함하는 조성물에 관한 것이다. 일부 실시양태에서, 상기 제약상 허용가능한 담체 또는 비히클은 미세결정질 셀룰로스를 포함한다. 추가의 또는 부가적인 실시양태에서, 상기 미세결정질 셀룰로스는 조성물의 약 88.8 중량％이다. 추가의 또는 부가적인 실시양태에서, 상기 조성물은 크로스카르멜로스 나트륨 약 5 중량％, 나트륨 라우릴 술페이트 약 1 중량％, 및 스테아르산마그네슘 약 1 중량％를 추가로 포함한다.The invention also relates to

About 4.2% by weight of a compound of formula (as defined in any of the above embodiments), and about 95.8% by weight of a pharmaceutically acceptable carrier or vehicle. In some embodiments, the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose. In a further or additional embodiment, the microcrystalline cellulose is about 88.8% by weight of the composition. In a further or additional embodiment, the composition further comprises about 5% by weight of croscarmellose sodium, about 1% by weight of sodium lauryl sulfate, and about 1% by weight of magnesium stearate.

(임의의 상기 실시양태에서 정의한 바와 같음)의 화합물 약 2 내지 약 10 중량％, 및 제약상 허용가능한 담체 또는 비히클 약 98 내지 약 90 중량％를 포함하는 조성물에 관한 것이다. 일부 실시양태에서, 상기 제약상 허용가능한 담체 또는 비히클은 미세결정질 셀룰로스를 포함한다. 추가의 또는 부가적인 실시양태에서, 상기 미세결정질 셀룰로스는 조성물의 약 85 내지 약 95 중량％이다. 추가의 또는 부가적인 실시양태에서, 상기 조성물은 크로스카르멜로스 나트륨 약 1 내지 약 6 중량％, 나트륨 라우릴 술페이트 약 0.1 내지 약 2 중량％, 및 스테아르산마그네슘 약 0.25 내지 약 1.5 중량％를 추가로 포함한다. 일부 실시양태에서, 상기 제약상 허용가능한 담체 또는 비히클은 미세결정질 셀룰로스를 포함한다. 추가의 또는 부가적인 실시양태에서, 상기 미세결정질 셀룰로스는 조성물의 약 85 내지 약 95 중량％이다. 추가의 또는 부가적인 실시양태에서, 상기 조성물은 크로스카르멜로스 나트륨 약 1 내지 약 6 중량％, 및 스테아르산마그네슘 약 0.25 내지 약 1.5 중량％를 추가로 포함한다.The invention also relates to

About 2 to about 10% by weight of a compound of formula (as defined in any of the above embodiments), and from about 98 to about 90% by weight of a pharmaceutically acceptable carrier or vehicle. In some embodiments, the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose. In further or additional embodiments, the microcrystalline cellulose is from about 85% to about 95% by weight of the composition. In a further or additional embodiment, the composition further comprises about 1 to about 6 weight percent sodium croscarmellose, about 0.1 to about 2 weight percent sodium lauryl sulfate, and about 0.25 to about 1.5 weight percent magnesium stearate . In some embodiments, the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose. In further or additional embodiments, the microcrystalline cellulose is from about 85% to about 95% by weight of the composition. In further or additional embodiments, the composition further comprises about 1 to about 6% by weight of croscarmellose sodium, and about 0.25 to about 1.5% by weight of magnesium stearate.

The present invention also

의 화합물 약 1 mg,rescue

About 1 mg,

About 222.2 mg of microcrystalline cellulose,

About 12.0 mg of croscarmellose sodium,

About 2.4 mg of sodium lauryl sulfate, and

Magnesium stearate Approximately 2.4 mg

&Lt; / RTI &gt;

The present invention also

의 화합물 약 10 mg,rescue

About 10 mg,

About 213.2 mg of microcrystalline cellulose,

About 12.0 mg of croscarmellose sodium,

About 2.4 mg of sodium lauryl sulfate, and

Magnesium stearate Approximately 2.4 mg

&Lt; / RTI &gt;

The present invention also

의 화합물 약 20 mgrescue

A mixture of about 20 mg

About 203.2 mg of microcrystalline cellulose,

About 12.0 mg of croscarmellose sodium,

About 2.4 mg of sodium lauryl sulfate, and

Magnesium stearate Approximately 2.4 mg

&Lt; / RTI &gt;

The present invention also

의 화합물 약 40 mg,rescue

&Lt; / RTI &gt; about 40 mg,

About 183.2 mg of microcrystalline cellulose,

About 12.0 mg of croscarmellose sodium,

About 2.4 mg of sodium lauryl sulfate, and

Magnesium stearate Approximately 2.4 mg

&Lt; / RTI &gt;

의 화합물 약 0.4 중량％, 및 제약상 허용가능한 담체 또는 비히클 약 99.6 중량％를 포함하는 조성물에 관한 것이다. 일부 실시양태에서, 상기 제약상 허용가능한 담체 또는 비히클은 미세결정질 셀룰로스를 포함한다. 추가의 또는 부가적인 실시양태에서, 상기 미세결정질 셀룰로스는 조성물의 약 92.6 중량％이다. 추가의 또는 부가적인 실시양태에서, 상기 조성물은 크로스카르멜로스 나트륨 약 5 중량％, 나트륨 라우릴 술페이트 약 1 중량％, 및 스테아르산마그네슘 약 1 중량％를 추가로 포함한다.The invention also relates to

About 0.4% by weight of a compound of formula I, and about 99.6% by weight of a pharmaceutically acceptable carrier or vehicle. In some embodiments, the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose. In a further or additional embodiment, the microcrystalline cellulose is about 92.6% by weight of the composition. In a further or additional embodiment, the composition further comprises about 5% by weight of croscarmellose sodium, about 1% by weight of sodium lauryl sulfate, and about 1% by weight of magnesium stearate.

의 화합물 약 4.2 중량％, 및 제약상 허용가능한 담체 또는 비히클 약 95.8 중량％를 포함하는 조성물에 관한 것이다. 일부 실시양태에서, 상기 제약상 허용가능한 담체 또는 비히클은 미세결정질 셀룰로스를 포함한다. 추가의 또는 부가적인 실시양태에서, 상기 미세결정질 셀룰로스는 조성물의 약 88.8 중량％이다. 추가의 또는 부가적인 실시양태에서, 상기 조성물은 크로스카르멜로스 나트륨 약 5 중량％, 나트륨 라우릴 술페이트 약 1 중량％, 및 스테아르산마그네슘 약 1 중량％를 추가로 포함한다.The invention also relates to

About 4.2% by weight of a compound of formula I, and about 95.8% by weight of a pharmaceutically acceptable carrier or vehicle. In some embodiments, the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose. In a further or additional embodiment, the microcrystalline cellulose is about 88.8% by weight of the composition. In a further or additional embodiment, the composition further comprises about 5% by weight of croscarmellose sodium, about 1% by weight of sodium lauryl sulfate, and about 1% by weight of magnesium stearate.

의 화합물 약 2 내지 약 10 중량％, 및 제약상 허용가능한 담체 또는 비히클 약 98 내지 약 90 중량％를 포함하는 조성물에 관한 것이다. 일부 실시양태에서, 상기 제약상 허용가능한 담체 또는 비히클은 미세결정질 셀룰로스를 포함한다. 추가의 또는 부가적인 실시양태에서, 상기 미세결정질 셀룰로스는 조성물의 약 85 내지 약 95 중량％이다. 추가의 또는 부가적인 실시양태에서, 상기 조성물은 크로스카르멜로스 나트륨 약 1 내지 약 6 중량％, 나트륨 라우릴 술페이트 약 0.1 내지 약 2 중량％, 및 스테아르산마그네슘 약 0.25 내지 약 1.5 중량％를 추가로 포함한다. 일부 실시양태에서, 상기 제약상 허용가능한 담체 또는 비히클은 미세결정질 셀룰로스를 포함한다. 추가의 또는 부가적인 실시양태에서, 상기 미세결정질 셀룰로스는 조성물의 약 85 내지 약 95 중량％이다. 추가의 또는 부가적인 실시양태에서, 상기 조성물은 크로스카르멜로스 나트륨 약 1 내지 약 6 중량％, 및 스테아르산마그네슘 약 0.25 내지 약 1.5 중량％를 추가로 포함한다.The invention also relates to

From about 2 to about 10 weight percent of a compound of Formula I, and from about 98 to about 90 weight percent of a pharmaceutically acceptable carrier or vehicle. In some embodiments, the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose. In further or additional embodiments, the microcrystalline cellulose is from about 85% to about 95% by weight of the composition. In a further or additional embodiment, the composition further comprises about 1 to about 6 weight percent sodium croscarmellose, about 0.1 to about 2 weight percent sodium lauryl sulfate, and about 0.25 to about 1.5 weight percent magnesium stearate . In some embodiments, the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose. In further or additional embodiments, the microcrystalline cellulose is from about 85% to about 95% by weight of the composition. In further or additional embodiments, the composition further comprises about 1 to about 6% by weight of croscarmellose sodium, and about 0.25 to about 1.5% by weight of magnesium stearate.

The present invention also

의 화합물 약 1 mg,rescue

About 1 mg,

About 222.2 mg of microcrystalline cellulose,

About 12.0 mg of croscarmellose sodium,

About 2.4 mg of sodium lauryl sulfate, and

Magnesium stearate Approximately 2.4 mg

&Lt; / RTI &gt;

The present invention also

의 화합물 약 10 mg, rescue

Gt; About 10 mg ,

About 213.2 mg of microcrystalline cellulose,

About 12.0 mg of croscarmellose sodium,

About 2.4 mg of sodium lauryl sulfate, and

Magnesium stearate Approximately 2.4 mg

&Lt; / RTI &gt;

The present invention also

의 화합물 약 20 mg,rescue

About 20 mg of a compound of formula &lt;

About 203.2 mg of microcrystalline cellulose,

About 12.0 mg of croscarmellose sodium,

About 2.4 mg of sodium lauryl sulfate, and

Magnesium stearate Approximately 2.4 mg

&Lt; / RTI &gt;

The present invention also

의 화합물 약 40 mg,rescue

&Lt; / RTI &gt; about 40 mg,

About 183.2 mg of microcrystalline cellulose,

About 12.0 mg of croscarmellose sodium,

About 2.4 mg of sodium lauryl sulfate, and

Magnesium stearate Approximately 2.4 mg

&Lt; / RTI &gt;

의 화합물 약 0.4 중량％, 및 제약상 허용가능한 담체 또는 비히클 약 99.6 중량％를 포함하는 조성물에 관한 것이다. 일부 실시양태에서, 상기 제약상 허용가능한 담체 또는 비히클은 미세결정질 셀룰로스를 포함한다. 추가의 또는 부가적인 실시양태에서, 상기 미세결정질 셀룰로스는 조성물의 약 92.6 중량％이다. 추가의 또는 부가적인 실시양태에서, 상기 조성물은 크로스카르멜로스 나트륨 약 5 중량％, 나트륨 라우릴 술페이트 약 1 중량％, 및 스테아르산마그네슘 약 1 중량％를 추가로 포함한다.The invention also relates to

About 0.4% by weight of a compound of formula I, and about 99.6% by weight of a pharmaceutically acceptable carrier or vehicle. In some embodiments, the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose. In a further or additional embodiment, the microcrystalline cellulose is about 92.6% by weight of the composition. In a further or additional embodiment, the composition further comprises about 5% by weight of croscarmellose sodium, about 1% by weight of sodium lauryl sulfate, and about 1% by weight of magnesium stearate.

의 화합물 약 4.2 중량％, 및 제약상 허용가능한 담체 또는 비히클 약 95.8 중량％를 포함하는 조성물에 관한 것이다. 일부 실시양태에서, 상기 제약상 허용가능한 담체 또는 비히클은 미세결정질 셀룰로스를 포함한다. 추가의 또는 부가적인 실시양태에서, 상기 미세결정질 셀룰로스는 조성물의 약 88.8 중량％이다. 추가의 또는 부가적인 실시양태에서, 상기 조성물은 크로스카르멜로스 나트륨 약 5 중량％, 나트륨 라우릴 술페이트 약 1 중량％, 및 스테아르산마그네슘 약 1 중량％를 추가로 포함한다.The invention also relates to

About 4.2% by weight of a compound of formula I, and about 95.8% by weight of a pharmaceutically acceptable carrier or vehicle. In some embodiments, the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose. In a further or additional embodiment, the microcrystalline cellulose is about 88.8% by weight of the composition. In a further or additional embodiment, the composition further comprises about 5% by weight of croscarmellose sodium, about 1% by weight of sodium lauryl sulfate, and about 1% by weight of magnesium stearate.

의 화합물 약 2 내지 약 10 중량％, 및 제약상 허용가능한 담체 또는 비히클 약 98 내지 약 90 중량％를 포함하는 조성물에 관한 것이다. 일부 실시양태에서, 상기 제약상 허용가능한 담체 또는 비히클은 미세결정질 셀룰로스를 포함한다. 추가의 또는 부가적인 실시양태에서, 상기 미세결정질 셀룰로스는 조성물의 약 85 내지 약 95 중량％이다. 추가의 또는 부가적인 실시양태에서, 상기 조성물은 크로스카르멜로스 나트륨 약 1 내지 약 6 중량％, 나트륨 라우릴 술페이트 약 0.1 내지 약 2 중량％, 및 스테아르산마그네슘 약 0.25 내지 약 1.5 중량％를 추가로 포함한다. 일부 실시양태에서, 상기 제약상 허용가능한 담체 또는 비히클은 미세결정질 셀룰로스를 포함한다. 추가의 또는 부가적인 실시양태에서, 상기 미세결정질 셀룰로스는 조성물의 약 85 내지 약 95 중량％이다. 추가의 또는 부가적인 실시양태에서, 상기 조성물은 크로스카르멜로스 나트륨 약 1 내지 약 6 중량％, 및 스테아르산마그네슘 약 0.25 내지 약 1.5 중량％를 추가로 포함한다.The invention also relates to

From about 2 to about 10 weight percent of a compound of Formula I, and from about 98 to about 90 weight percent of a pharmaceutically acceptable carrier or vehicle. In some embodiments, the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose. In further or additional embodiments, the microcrystalline cellulose is from about 85% to about 95% by weight of the composition. In a further or additional embodiment, the composition further comprises about 1 to about 6 weight percent sodium croscarmellose, about 0.1 to about 2 weight percent sodium lauryl sulfate, and about 0.25 to about 1.5 weight percent magnesium stearate . In some embodiments, the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose. In further or additional embodiments, the microcrystalline cellulose is from about 85% to about 95% by weight of the composition. In further or additional embodiments, the composition further comprises about 1 to about 6% by weight of croscarmellose sodium, and about 0.25 to about 1.5% by weight of magnesium stearate.

In addition, An effective amount of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) Propyl) cyclopropane-1-sulfonamide. &Lt; / RTI &gt; In some embodiments, the pharmaceutical composition comprises an effective amount of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) - (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide, and one or more pharmaceutically acceptable carriers. In some embodiments, the pharmaceutical composition is for treating a disorder. In some embodiments, the pharmaceutical composition is for treating a disorder in a mammal. In some embodiments, the pharmaceutical composition is for treating a disorder in a human. In some embodiments, the pharmaceutical composition is for treating or preventing an inflammatory disease. In some embodiments, the pharmaceutical composition is for treating or preventing a proliferative disease.

Polymorph  &Lt; / RTI &gt; and methods of using the compositions.

In another aspect, the invention provides a method of treating a patient suffering from various cancers, including cancer, comprising administering to the patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof, Inhibition of immune diseases and inflammatory diseases. In some embodiments, the compound or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof is administered as a component of a composition that additionally comprises a pharmaceutically acceptable carrier or vehicle. In some embodiments, the effect is inhibition of various cancers. In a further or additional embodiment, the effect is inhibition of an immune disease. In a further or additional embodiment, the effect is inhibition of inflammatory disease.

Any of the compositions described and claimed herein may be used in the methods provided in this section.

In some embodiments, a composition comprising a compound of formula I is administered in combination with additional therapy. In further or additional embodiments, the further therapy is radiation therapy, chemotherapy or surgery, or any combination thereof. In a further or additional embodiment, a composition comprising a compound of formula I is administered in combination with one or more therapeutic agents.

In some embodiments, the compositions are administered orally, intraduodenally, parenterally (e.g., intravenously, subcutaneously, intramuscularly, by intravascular or infusion), topically or rectally. In further or additional embodiments, the amount of the compound of formula I ranges from about 0.001 to about 1000 mg / kg body weight per day. In further or additional embodiments, the amount of compound of formula I ranges from about 0.5 to about 50 mg / kg / day. In further or additional embodiments, the amount of compound of formula I is from about 0.001 to about 7 g / day. In further or additional embodiments, the amount of the compound of formula I is from about 0.01 to about 7 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.02 to about 5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.05 to about 2.5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.1 to about 1 g / day. In further or additional embodiments, dosage levels below the lower limit of the aforementioned range may be more appropriate. In further or additional embodiments, dosage levels above the upper limit of the above range may be required.

의 군에서 선택된다.In some embodiments of the compositions and methods provided herein, there is provided a MEK protein kinase inhibitor further comprising a compound of formula I wherein the compound of formula I is present in an amount from about 0.1 mg to about 200 mg. In another embodiment, the MEK protein kinase inhibitor comprises a compound of Formula I, wherein the compound is present in an amount from about 0.2 mg to about 100 mg. In another embodiment, the MEK protein kinase inhibitor comprises a compound of formula I, wherein the compound is present in an amount from about 0.3 mg to about 90 mg. In another embodiment, the MEK protein kinase inhibitor comprises a compound of formula I, wherein the compound is present in an amount from about 0.4 mg to about 80 mg. In another embodiment, the MEK protein kinase inhibitor comprises a compound of formula I, wherein the compound is present in an amount from about 0.5 mg to about 70 mg. In another embodiment, the MEK protein kinase inhibitor comprises a compound of formula I, wherein the compound is present in an amount from about 0.4 mg to about 80 mg. In another embodiment, the MEK protein kinase inhibitor comprises a compound of formula I, wherein the compound is present in an amount from about 0.5 mg to about 70 mg. In another embodiment, the MEK protein kinase inhibitor comprises a compound of formula I, wherein the compound is present in an amount from about 1 mg to about 60 mg. In another embodiment, the MEK protein kinase inhibitor comprises a compound of formula I, wherein the compound is present in an amount from about 1.5 mg to about 50 mg. In another embodiment, the MEK protein kinase inhibitor comprises a compound of formula I, wherein the compound is present in an amount from about 2 mg to about 45 mg. In another embodiment, the MEK protein kinase inhibitor comprises a compound of Formula I, wherein the compound is present in an amount from about 2.5 mg to about 40 mg. In a further embodiment, the compounds of formula I present in the doses provided herein,

&Lt; / RTI &gt;

의 군에서 선택된다.In some embodiments of the compositions and methods provided herein, the compound of formula I is further comprised of about 0.1 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.4 mg, About 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4.0 mg, about 4.5 about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, A MEK protein kinase inhibitor is present in an amount of about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, and / or about 13 mg, about 14 mg, or about 15 mg. In a further embodiment, the compounds of formula I present in the doses provided herein,

&Lt; / RTI &gt;

의 군에서 선택된다.In some embodiments of the compositions and methods provided herein, the compound of formula I is further comprised of about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, About 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 175 mg, about 180 mg, about 190 mg, MEK protein kinase inhibitors are provided. In a further embodiment, the compounds of formula I present in the doses provided herein,

&Lt; / RTI &gt;

In a further or additional embodiment, the compound of formula I is administered in a single administration once a day. In a further or additional embodiment, the compound of formula I is administered in multiple doses more than once per day. In a further or additional embodiment, the compound of formula I is administered twice a day. In a further or additional embodiment, the compound of formula I is administered three times per day. In a further or additional embodiment, the compound of formula I is administered four times per day. In a further or additional embodiment, the compound of formula I is administered more than 4 times per day. In some embodiments, the individual suffering from cancer is a mammal. In further or additional embodiments, the subject is a human. In an additional or additional embodiment, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of Formula I is administered.

In some aspects, the invention includes administering to an individual suffering from a disease, an effective amount of a composition comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, , A method of treating a disease in an individual suffering from the disease.

In another aspect, the invention provides a method of treating a disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof &Lt; / RTI &gt;

In another aspect, the invention provides a method of treating a disorder in a mammal comprising administering to a human a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof &Lt; / RTI &gt;

MEK  Adjusted diseases and disorders

Also described herein are methods of modulating MEK activity by contacting MEK with a compound of formula I in an amount sufficient to modulate the activity of MEK. The modulation may be inhibition or activation of the MEK activity. In some embodiments, the present invention provides a method of inhibiting MEK activity by contacting MEK with a compound of Formula I in an amount sufficient to inhibit the activity of MEK. In some embodiments, the present invention provides a method of inhibiting MEK activity in a solution by contacting a solution containing MEK with a compound of formula I in an amount sufficient to inhibit the activity of MEK in the solution. In some embodiments, the invention provides a method of inhibiting MEK activity in a cell by contacting the cell containing the MEK with a compound described herein in an amount sufficient to inhibit the activity of MEK in the cell. In some embodiments, the present invention provides a method of inhibiting MEK activity in a tissue by contacting the tissue containing the MEK with a compound described herein in an amount sufficient to inhibit the activity of MEK in the tissue. In some embodiments, the present invention provides a method of inhibiting MEK activity in an organism by contacting the organism containing the MEK with an amount of a compound described herein sufficient to inhibit the activity of MEK in the organism. In some embodiments, the invention provides a method of inhibiting MEK activity in an animal by contacting the animal containing MEK with a compound described herein in an amount sufficient to inhibit the activity of MEK in the animal. In some embodiments, the present invention provides a method of inhibiting MEK activity in a mammal by contacting a mammal containing MEK with a compound described herein in an amount sufficient to inhibit activity of MEK in said mammal. In some embodiments, the present invention provides a method of inhibiting MEK activity in a human by contacting a human containing MEK with a compound described herein in an amount sufficient to inhibit the activity of MEK in said human.

A composition comprising a compound of formula I and a compound of formula I and a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof may modulate the activity of the MEK enzyme, ) Is useful for treating such diseases or conditions in which the MEK enzyme activity contributes to the pathology and / or symptoms of the disease or condition.

In some aspects, the invention encompasses administering to a mammal, including a human, an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof, that modulates the MEK cascade , A method of treating a disorder or condition mediated by a MEK cascade in a mammal, including a human. Appropriate dosages for a particular patient may be determined by those skilled in the art according to known methods.

In another aspect, the present invention relates to a method of inhibiting MEK enzyme. In some embodiments, the method comprises contacting the MEK enzyme with an amount sufficient to inhibit the enzyme, including a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof &Lt; / RTI &gt; to inhibit said enzyme. In a further or additional embodiment, the enzyme is inhibited by at least about 1%. In a further or additional embodiment, the enzyme is inhibited by at least about 2%. In a further or additional embodiment, the enzyme is inhibited by at least about 3%. In a further or additional embodiment, the enzyme is inhibited by at least about 4%. In a further or additional embodiment, the enzyme is inhibited by at least about 5%. In a further or additional embodiment, the enzyme is inhibited by at least about 10%. In a further or additional embodiment, the enzyme is inhibited by at least about 20%. In a further or additional embodiment, the enzyme is inhibited by at least about 25%. In a further or additional embodiment, the enzyme is inhibited by at least about 30%. In a further or additional embodiment, the enzyme is inhibited by at least about 40%. In a further or additional embodiment, the enzyme is inhibited by at least about 50%. In a further or additional embodiment, the enzyme is inhibited by at least about 60%. In a further or additional embodiment, the enzyme is inhibited by at least about 70%. In a further or additional embodiment, the enzyme is inhibited by at least about 75%. In a further or additional embodiment, the enzyme is inhibited by at least about 80%. In further or additional embodiments, the enzyme is inhibited by greater than about 90%. In a further or additional embodiment, the enzyme is essentially completely inhibited. In a further or additional embodiment, the MEK enzyme is a MEK kinase. In a further or additional embodiment, the MEK enzyme is MEKl. In a further or additional embodiment, the MEK enzyme is MEK2. In further or additional embodiments, the contacting occurs within the cell. In a further or additional embodiment, the cell is a mammalian cell. In a further or additional embodiment, the mammalian cell is a human cell. In a further or additional embodiment, the MEK enzyme is inhibited by a composition comprising a pharmaceutically acceptable salt of a compound of formula (I).

In a further or additional aspect, the invention provides an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof, Mediated disorder in a subject suffering from a MEK mediated disorder. In some embodiments, a composition comprising a compound of Formula I is administered orally, duodenally, parenterally (e.g., intravenously, subcutaneously, intramuscularly, by intravascular or infusion), topically or rectally. In some embodiments, the pharmaceutical composition is in a form suitable for oral administration. In a further or additional embodiment, the pharmaceutical composition is in the form of tablets, capsules, pills, powders, sustained release formulations, solutions, suspensions, parenteral injections such as sterile solutions, suspensions or emulsions For topical administration such as ointments or creams, or for rectal administration such as suppositories. In a further or additional embodiment, the pharmaceutical composition is in unit dosage form suitable for single administration of precise dosages. In a further or additional embodiment, the pharmaceutical composition further comprises a pharmaceutical carrier, excipient and / or adjuvant.

In further or additional embodiments, the amount of the compound of formula I ranges from about 0.001 to about 1000 mg / kg body weight per day. In further or additional embodiments, the amount of compound of formula I ranges from about 0.5 to about 50 mg / kg / day. In further or additional embodiments, the amount of compound of formula I is from about 0.001 to about 7 g / day. In further or additional embodiments, the amount of the compound of formula I is from about 0.01 to about 7 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.02 to about 5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.05 to about 2.5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.1 to about 1 g / day. In further or additional embodiments, dosage levels below the lower limit of the aforementioned range may be more appropriate. In further or additional embodiments, dosage levels above the upper limit of the above range may be required.

In a further or additional embodiment, the compound of formula I is administered in a single administration once a day. In a further or additional embodiment, the compound of formula I is administered in multiple doses more than once per day. In a further or additional embodiment, the compound of formula I is administered twice a day. In a further or additional embodiment, the compound of formula I is administered three times per day. In a further or additional embodiment, the compound of formula I is administered four times per day. In a further or additional embodiment, the compound of formula I is administered more than 4 times per day. In some embodiments, the subject suffering from a MEK mediated disorder is a mammal. In further or additional embodiments, the subject is a human.

In some embodiments, a composition comprising a compound of formula I is administered in combination with additional therapy. In further or additional embodiments, the additional therapy is radiation therapy, chemotherapy, surgery, or any combination thereof. In a further or additional embodiment, a composition comprising a compound of formula I is administered in combination with one or more therapeutic agents. In a further or additional embodiment, the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenic agents and anti-neoplastic agents. In further or additional embodiments, the anti-neoplastic agent is selected from the group consisting of an alkylating agent, an anti-metabolite, an epipidolipid, an anti-neoplastic enzyme, a topoisomerase inhibitor, a procarbazine, a mitoxantrone, Complexes, biological response modifiers and growth inhibitors, hormone / anti-hormone therapeutics, and hematopoietic growth factors. In a further or additional embodiment, the therapeutic agent is selected from Taxol, Bortezomib, or both.

In some embodiments, the MEK mediated disorder is selected from the group consisting of inflammatory diseases, infections, autoimmune disorders, stroke, ischemia, cardiac disorders, neurological disorders, fibrotic disorders, proliferative disorders, hyperproliferative disorders, non- Atherosclerosis, rheumatoid arthritis, osteoarthritis, heart failure, chronic pain, neuropathic pain, diverticulitis, right-sulcular glaucoma, and wide-angle glaucoma &Lt; / RTI &gt; In a further or additional embodiment, the MEK mediated disorder is an inflammatory disease. In a further or additional embodiment, the MEK mediated disorder is an overt disease. In a further or additional embodiment, the MEK mediated disorder is selected from the group consisting of tumors, leukemias, neoplasms, cancers, carcinomas and malignancies. In a further or additional embodiment, the cancer is gastric cancer, brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, colorectal cancer or leukemia. In a further or additional embodiment, the fibrogenic disorder is skin sclerosis, multiple myositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis. In an additional or additional embodiment, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of Formula I is administered.

The present invention also relates to the use of MEK in combination with an amount of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide with crystalline polymorph Form A to adjust the MEK activity. The modulation may be inhibition or activation of the MEK activity. In some embodiments, the present invention provides a method of inhibiting the activity of MEK in an amount sufficient to inhibit the activity of MEK in the presence of N- (S) - (3,4-difluoro-2- (2-fluoro-4- -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide with crystalline polymorph Form A to inhibit MEK activity. In some embodiments, the present invention relates to a method for the treatment of MEK, comprising contacting a solution containing MEK with an amount of N- (S) - (3,4-difluoro-2- (2- 4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide with crystalline polymorph Form A to inhibit MEK activity in solution &Lt; / RTI &gt; In some embodiments, the present invention provides a method of treating a cell containing MEK in an amount sufficient to inhibit the activity of MEK in said cell by administering an amount of N- (S) - (3,4-difluoro-2- (2- 4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulphonamide in contact with crystalline polymorph Form A to inhibit MEK activity in the cell &Lt; / RTI &gt; In some embodiments, the present invention provides a method of treating a tissue containing MEK in an amount sufficient to inhibit the activity of MEK in said tissue by administering to said tissue an amount of N- (S) - (3,4-difluoro-2- (2- 4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide with crystalline polymorph Form A to inhibit MEK activity in the tissue &Lt; / RTI &gt; In some embodiments, the present invention provides a method of treating an organism containing MEK in an amount sufficient to inhibit the activity of MEK in said organism by administering to said organism an amount of N- (S) - (3,4-difluoro-2- (2- 4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulphonamide with Form A to inhibit MEK activity in the organism &Lt; / RTI &gt; In some embodiments, the invention provides a method of treating an animal that contains MEK in an amount sufficient to inhibit the activity of MEK in said animal by administering an amount of N- (S) - (3,4-difluoro-2- (2- The present invention relates to a method of inhibiting MEK activity in an animal by contacting it with crystalline polymorph Form A of a 4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane- &Lt; / RTI &gt; In some embodiments, the invention provides a method of treating a mammal comprising MEK, comprising administering to the mammal an amount of N- (S) - (3,4-difluoro-2- -Methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide in the presence of MEK Of the present invention. In some embodiments, the invention provides a method of treating a human containing MEK in an amount sufficient to inhibit the activity of MEK in said human by administering to said human an amount of N- (S) - (3,4-difluoro-2- (2- 4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulphonamide in contact with crystalline polymorph Form A to inhibit MEK activity in humans &Lt; / RTI &gt;

cancer

In another aspect, the invention provides a method of treating a cancer in a subject, comprising administering to the subject an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof , &Lt; / RTI &gt; In some embodiments, the compound or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof is administered as a component of a composition that additionally comprises a pharmaceutically acceptable carrier or vehicle. In a further or additional embodiment, the cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, colorectal cancer, gastric cancer or leukemia. In a further or additional embodiment, the fibrogenic disorder is skin sclerosis, multiple myositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis. In a further or additional embodiment, the cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, colorectal cancer, leukemia, melanoma, thyroid cancer or basal cell carcinoma. In a further or additional embodiment, the cancer is brain cancer or adrenocortical carcinoma. In a further or additional embodiment, the cancer is breast cancer. In a further or additional embodiment, the cancer is an ovarian cancer. In a further or additional embodiment, the cancer is pancreatic cancer. In a further or additional embodiment, the cancer is prostate cancer. In a further or additional embodiment, the cancer is kidney cancer. In a further or additional embodiment, the cancer is colorectal cancer. In a further or additional embodiment, the cancer is myelogenous leukemia. In a further or additional embodiment, the cancer is glioblastoma. In a further or additional embodiment, the cancer is follicular lymphoma. In a further or additional embodiment, the cancer is Global-B acute leukemia. In a further or additional embodiment, the cancer is chronic lymphocytic B-leukemia. In a further or additional embodiment, the cancer is mesothelioma. In a further or additional embodiment, the cancer is a small cell lung cancer. In some embodiments, the cancer is gastric cancer.

In some embodiments, a composition comprising a compound of formula I is administered in combination with additional therapy. In further or additional embodiments, the additional therapy is radiation therapy, chemotherapy, surgery, or any combination thereof. In a further or additional embodiment, a composition comprising a compound of formula I is administered in combination with one or more therapeutic agents. In a further or additional embodiment, the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenic agents and anti-neoplastic agents. In further or additional embodiments, the anti-neoplastic agent is selected from the group consisting of an alkylating agent, an anti-metabolite, an epipidolipid, an anti-neoplastic enzyme, a topoisomerase inhibitor, a procarbazine, a mitoxantrone, Complexes, biological response modifiers and growth inhibitors, hormone / anti-hormone therapeutics, and hematopoietic growth factors. In a further or additional embodiment, the therapeutic agent is selected from Taxol, Bortezomib, or both.

In further or additional embodiments, the amount of the compound of formula I ranges from about 0.001 to about 1000 mg / kg body weight per day. In further or additional embodiments, the amount of compound of formula I ranges from about 0.5 to about 50 mg / kg / day. In further or additional embodiments, the amount of compound of formula I is from about 0.001 to about 7 g / day. In further or additional embodiments, the amount of the compound of formula I is from about 0.01 to about 7 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.02 to about 5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.05 to about 2.5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.1 to about 1 g / day. In further or additional embodiments, dosage levels below the lower limit of the aforementioned range may be more appropriate. In further or additional embodiments, dosage levels above the upper limit of the above range may be required.

In some embodiments, the compositions are administered orally, intraduodenally, parenterally (e.g., intravenously, subcutaneously, intramuscularly, by intravascular or infusion), topically or rectally. In a further or additional embodiment, the compound of formula I is administered in a single administration once a day. In a further or additional embodiment, the compound of formula I is administered in multiple doses more than once per day. In a further or additional embodiment, the compound of formula I is administered twice a day. In a further or additional embodiment, the compound of formula I is administered three times per day. In a further or additional embodiment, the compound of formula I is administered four times per day. In a further or additional embodiment, the compound of formula I is administered more than 4 times per day. In some embodiments, the individual suffering from cancer is a mammal. In further or additional embodiments, the subject is a human. In an additional or additional embodiment, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of Formula I is administered.

Abnormal cell growth

Also described herein are compounds, pharmaceutical compositions and methods for inhibiting abnormal cell growth. In some embodiments, the abnormal cell growth occurs in a mammal. A method of inhibiting abnormal cell growth comprises administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate or derivative thereof to inhibit abnormal cell growth . Methods for inhibiting abnormal cell growth in a mammal include administering to the mammal a predetermined amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate or derivative thereof Wherein the amount of said compound or salt is effective in inhibiting abnormal cell growth in a mammal.

In some embodiments, the methods comprise administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate or derivative thereof, in combination with a chemotherapeutic agent Wherein the amount of the compound or a salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate or derivative thereof, and chemotherapeutic agent is effective to inhibit abnormal cell growth together. Currently, many chemotherapeutic agents are known in the art and can be used in combination with the compounds of the present invention. In some embodiments, the chemotherapeutic agent is selected from the group consisting of a mitotic inhibitor, an alkylating agent, an anti-metabolite, an intercalating antibiotic, a growth factor inhibitor, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, a biological response modifier, A hormone agent, an angiogenesis inhibitor and an anti-androgen agent.

Also encompassed by administering a predetermined amount of a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate or derivative thereof in combination with radiation therapy, The amount of the compound or its salts, solvates, polymorphs, esters, amides, tautomers, prodrugs, hydrates or derivatives thereof in combination with radiation therapy is effective in inhibiting abnormal cell growth or treating hyperproliferative disorders in mammals , A method of inhibiting abnormal cell growth in a mammal. Techniques for administering radiotherapy are well known in the art, and such techniques may be used in the combination therapies described herein. Administration of a compound of formula (I) with such combination therapy may be determined as described herein.

The present invention also relates to a method of inhibiting abnormal cell growth in a mammal and to a method of inhibiting abnormal cell growth in a mammal comprising administering a compound of Formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate or derivative thereof, To a pharmaceutical composition for inhibiting abnormal cell growth in a mammal comprising an amount of at least one substance selected from the group consisting of an anti-angiogenic agent, an anti-angiogenic agent, an element-labeled derivative, and an anti-angiogenic agent, a signal transduction inhibitor and an anti-proliferative agent.

An inhibitor of anti-angiogenesis such as MMP-2 (matrix-metalloproteinase 2) inhibitor, MMP-9 (matrix-metalloproteinase 9) inhibitor and COX-11 (cyclooxygenase 11) The compounds of the invention and the pharmaceutical compositions described herein. Examples of useful COX-II inhibitors include CELEBREX (TM) (Alrecoxib), valdecoxib, and ropecox. Examples of useful matrix metalloproteinase inhibitors are disclosed in WO 96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), European Patent Application No. 97304971.1 European Patent Application No. 99308617.2 (filed October 29, 1999), WO 98/07697 (published Feb. 26, 1998), WO 98/03516 (filed January 1998) WO 98/34918 (published August 13, 1998), WO 98/34915 (published August 13, 1998), WO 98/33768 (published August 6, 1998) (Published July 16, 1998), European Patent Publication 606,046 (published July 13, 1994), European Patent Publication 931,788 (published July 28, 1999), WO 90/30566 (Published May 31, 1990), WO 99/52910 (published October 21, 1999), WO 99/52889 (published October 21, 1999), WO 99/29667 Published on March 17), PCT International Application No. PCT / IB98 / 01113 (19 European Patent Application No. 99302232.1 (filed March 25, 1999), United Kingdom Patent Application No. 9912961.1 (filed June 3, 1999), United States Provisional Application No. U.S. Patent 5,863, 949 (granted January 26, 1999), U.S. Patent 5,861, 510 (issued January 19, 1999), U.S. Patent 5,863, 949 European Patent Publication 780,386 (published June 25, 1997), all of which are incorporated herein by reference in their entirety. Some MMP-2 and / or MMP-9 inhibitors have little or no activity to inhibit MMP-1, but some have inhibited MMP-2 and / or MMP-9 with other matrix-metalloproteinases (i.e. MAP- MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12 and MMP-13. Some embodiments of MMP inhibitors useful in the present invention are AG-3340, RO 32-3555 and RS 13-0830.

In another aspect, the present invention provides a method of inhibiting the growth of cancer cells or inhibiting the growth of cancer cells, including the compounds of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof To a method of degrading cancer cells, inhibiting the growth of cancer cells or killing cancer cells, comprising contacting cancer cells with an effective amount of a composition that kills the cancer cells. In some embodiments, the cancer cells include cancer cells of the brain, breast, lung, ovary, pancreas, prostate, kidney or colon rectum.

In a further or additional embodiment, the composition is administered with one or more therapeutic agents. In a further or additional embodiment, the therapeutic agent is Taxol, Bortezomib, or both. In a further or additional embodiment, the therapeutic agent is selected from the group consisting of a cytotoxic agent, an anti-angiogenic agent and an anti-neoplastic agent. In further or additional embodiments, the anti-neoplastic agent is selected from the group consisting of an alkylating agent, an anti-metabolite, an epipidolipid, an anti-neoplastic enzyme, a topoisomerase inhibitor, a procarbazine, a mitoxantrone, Complexes, biological response modifiers and growth inhibitors, hormone / anti-hormone therapeutics, and hematopoietic growth factors.

In some embodiments, cancer cells are degraded. In a further or additional embodiment, 1% of cancer cells are degraded. In a further or additional embodiment, 2% of cancer cells are degraded. In a further or additional embodiment, 3% of cancer cells are degraded. In a further or additional embodiment, 4% of the cancer cells are degraded. In a further or additional embodiment, 5% of the cancer cells are degraded. In a further or additional embodiment, 10% of the cancer cells are degraded. In a further or additional embodiment, 20% of the cancer cells are degraded. In a further or additional embodiment, 25% of the cancer cells are degraded. In a further or additional embodiment, 30% of the cancer cells are degraded. In a further or additional embodiment, 40% of the cancer cells are degraded. In a further or additional embodiment, 50% of the cancer cells are degraded. In a further or additional embodiment, 60% of cancer cells are degraded. In a further or additional embodiment, 70% of the cancer cells are degraded. In a further or additional embodiment, 75% of the cancer cells are degraded. In a further or additional embodiment, 80% of the cancer cells are degraded. In a further or additional embodiment, 90% of the cancer cells are degraded. In a further or additional embodiment, 100% of the cancer cells are degraded. In a further or additional embodiment, essentially all cancer cells are degraded.

In some embodiments, the cancer cells are killed. In a further or additional embodiment, 1% of the cancer cells are killed. In a further or additional embodiment, 2% of cancer cells are killed. In a further or additional embodiment, 3% of the cancer cells are killed. In a further or additional embodiment, 4% of the cancer cells are killed. In a further or additional embodiment, 5% of the cancer cells are killed. In a further or additional embodiment, 10% of the cancer cells are killed. In a further or additional embodiment, 20% of the cancer cells are killed. In a further or additional embodiment, 25% of the cancer cells are killed. In a further or additional embodiment, 30% of the cancer cells are killed. In a further or additional embodiment, 40% of the cancer cells are killed. In a further or additional embodiment, 50% of the cancer cells are killed. In a further or additional embodiment, 60% of the cancer cells are killed. In a further or additional embodiment, 70% of the cancer cells are killed. In a further or additional embodiment, 75% of the cancer cells are killed. In a further or additional embodiment, 80% of the cancer cells are killed. In a further or additional embodiment, 90% of the cancer cells are killed. In a further or additional embodiment, 100% of the cancer cells are killed. In a further or additional embodiment, essentially all cancer cells are killed.

In further or additional embodiments, the growth of cancer cells is inhibited. In further or additional embodiments, the growth of cancer cells is inhibited by about 1%. In further or additional embodiments, the growth of cancer cells is inhibited by about 2%. In further or additional embodiments, the growth of cancer cells is inhibited by about 3%. In further or additional embodiments, the growth of cancer cells is inhibited by about 4%. In a further or additional embodiment, the growth of cancer cells is inhibited by about 5%. In a further or additional embodiment, the growth of cancer cells is inhibited by about 10%. In additional or additional embodiments, the growth of cancer cells is inhibited by about 20%. In a further or additional embodiment, the growth of cancer cells is inhibited by about 25%. In further or additional embodiments, the growth of cancer cells is inhibited by about 30%. In further or additional embodiments, the growth of cancer cells is inhibited by about 40%. In further or additional embodiments, the growth of cancer cells is inhibited by about 50%. In a further or additional embodiment, the growth of cancer cells is inhibited by about 60%. In further or additional embodiments, the growth of cancer cells is inhibited by about 70%. In a further or additional embodiment, the growth of cancer cells is inhibited by about 75%. In further or additional embodiments, the growth of cancer cells is inhibited by about 80%. In a further or additional embodiment, the growth of cancer cells is inhibited by about 90%. In a further or additional embodiment, the growth of cancer cells is inhibited by about 100%. In a further or additional embodiment, a composition comprising a pharmaceutically acceptable salt of a compound of formula I is used.

In addition, the present application describes a method for inhibiting abnormal cell growth. In some embodiments, the abnormal cell growth occurs in a mammal. A method of inhibiting abnormal cell growth comprises administering an effective amount of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide to inhibit abnormal cell growth. Methods for inhibiting abnormal cell growth in a mammal include administering to the mammal an effective amount of N- (S) - (3,4-difluoro-2- (2-fluoro- Iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide.

In some embodiments, the method comprises administering an effective amount of N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide in combination with a chemotherapeutic agent, wherein the N- (S) - (3,4-di Crystalline polymorph form of fluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane- The amount of A and the chemotherapeutic agent is effective to inhibit abnormal cell growth together.

Currently, many chemotherapeutic agents are known in the art and can be used in combination with the compounds and compositions of the present invention. In some embodiments, the chemotherapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti- An angiogenesis inhibitor and an anti-androgen agent.

In some embodiments, the method of inhibiting abnormal cell growth in a mammal comprises administering to the mammal a predetermined amount of N- (S) - (3,4-difluoro-2- (2-fluoro-4- Amino-6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide in combination with radiation therapy, wherein the radiation (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- Hydroxypropyl) cyclopropane-1-sulfonamide is effective in inhibiting abnormal cell growth. Techniques for administering radiotherapy are well known in the art, and such techniques may be used in the combination therapies described herein.

Hyperproliferation  Treatment of Disability

In another aspect, the present invention provides a method of treating a mammal, including a human, comprising administering to a mammal comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, To a method of treating an hyperproliferative disorder in a mammal comprising said mammal.

In another aspect, the present invention provides a method of treating a proliferative disease, disorder or condition in a subject, comprising administering to the subject an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof, Prevention or prevention of &lt; / RTI &gt; In some embodiments, the compound or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof is administered as a component of a composition that additionally comprises a pharmaceutically acceptable carrier or vehicle. In some embodiments, the proliferative disease is cancer, psoriasis, restenosis, autoimmune disease or atherosclerosis. In a further or additional embodiment, the proliferative disorder is an hyperproliferative disorder. In a further or additional embodiment, the proliferative disease is selected from the group consisting of a tumor, leukemia, neoplasm, cancer, carcinoma and malignant disease. In a further or additional embodiment, the cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, gastric cancer, colorectal cancer or leukemia. In a further or additional embodiment, the fibrogenic disorder is skin sclerosis, multiple myositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis. In a further or additional embodiment, the cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, stomach cancer, pancreatic cancer, prostate cancer, kidney cancer, colorectal cancer or leukemia. In a further or additional embodiment, the cancer is brain cancer or adrenocortical carcinoma. In a further or additional embodiment, the cancer is breast cancer. In a further or additional embodiment, the cancer is an ovarian cancer. In a further or additional embodiment, the cancer is pancreatic cancer. In a further or additional embodiment, the cancer is prostate cancer. In a further or additional embodiment, the cancer is kidney cancer. In a further or additional embodiment, the cancer is colorectal cancer. In a further or additional embodiment, the cancer is myelogenous leukemia. In a further or additional embodiment, the cancer is glioblastoma. In a further or additional embodiment, the cancer is follicular lymphoma. In a further or additional embodiment, the cancer is Global-B acute leukemia. In a further or additional embodiment, the cancer is chronic lymphocytic B-leukemia. In a further or additional embodiment, the cancer is mesothelioma. In a further or additional embodiment, the cancer is a small cell lung cancer. In some embodiments, the cancer is gastric cancer.

In some embodiments, a composition comprising a compound of formula I is administered in combination with additional therapy. In further or additional embodiments, the additional therapy is radiation therapy, chemotherapy, surgery, or a combination thereof. In a further or additional embodiment, a composition comprising a compound of formula I is administered in combination with one or more therapeutic agents. In a further or additional embodiment, the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenic agents and anti-neoplastic agents. In further or additional embodiments, the anti-neoplastic agent is selected from the group consisting of an alkylating agent, an anti-metabolite, an epipidolipid, an anti-neoplastic enzyme, a topoisomerase inhibitor, a procarbazine, a mitoxantrone, Complexes, biological response modifiers and growth inhibitors, hormone / anti-hormone therapeutics, and hematopoietic growth factors. In a further or additional embodiment, the therapeutic agent is selected from Taxol, Bortezomib, or both.

In some embodiments, the compositions are administered orally, intraduodenally, parenterally (e.g., intravenously, subcutaneously, intramuscularly, by intravascular or infusion), topically or rectally. In further or additional embodiments, the amount of the compound of formula I ranges from about 0.001 to about 1000 mg / kg body weight per day. In further or additional embodiments, the amount of compound of formula I ranges from about 0.5 to about 50 mg / kg / day. In further or additional embodiments, the amount of compound of formula I is from about 0.001 to about 7 g / day. In further or additional embodiments, the amount of the compound of formula I is from about 0.01 to about 7 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.02 to about 5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.05 to about 2.5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.1 to about 1 g / day. In further or additional embodiments, dosage levels below the lower limit of the aforementioned range may be more appropriate. In further or additional embodiments, dosage levels above the upper limit of the above range may be required.

In a further or additional embodiment, the compound of formula I is administered in a single administration once a day. In a further or additional embodiment, the compound of formula I is administered in multiple doses more than once per day. In a further or additional embodiment, the compound of formula I is administered twice a day. In a further or additional embodiment, the compound of formula I is administered three times per day. In a further or additional embodiment, the compound of formula I is administered four times per day. In a further or additional embodiment, the compound of formula I is administered more than 4 times per day. In some embodiments, the subject suffering from a proliferative disease is a mammal. In further or additional embodiments, the subject is a human. In an additional or additional embodiment, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of Formula I is administered.

Tumor size

In another aspect, the present invention provides a method of treating a subject suffering from a condition selected from the group consisting of: administering to the subject an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof; Or to inhibit tumor growth, to reduce tumor proliferation, or to prevent tumor proliferation. In some embodiments, the compound or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof is administered as a component of a composition that additionally comprises a pharmaceutically acceptable carrier or vehicle. In some embodiments, the size of the tumor is reduced. In a further or additional embodiment, the size of the tumor is reduced by 1% or more. In a further or additional embodiment, the size of the tumor is reduced by 2% or more. In a further or additional embodiment, the size of the tumor is reduced by 3% or more. In a further or additional embodiment, the size of the tumor is reduced by 4% or more. In a further or additional embodiment, the size of the tumor is reduced by 5% or more. In a further or additional embodiment, the size of the tumor is reduced by at least 10%. In additional or additional embodiments, the size of the tumor is reduced by 20% or more. In a further or additional embodiment, the size of the tumor is reduced by at least 25%. In a further or additional embodiment, the size of the tumor is reduced by 30% or more. In a further or additional embodiment, the size of the tumor is reduced by at least 40%. In a further or additional embodiment, the size of the tumor is reduced by 50% or more. In a further or additional embodiment, the size of the tumor is reduced by 60% or more. In a further or additional embodiment, the size of the tumor is reduced by 70% or more. In a further or additional embodiment, the size of the tumor is reduced by at least 75%. In a further or additional embodiment, the size of the tumor is reduced by 80% or more. In a further or additional embodiment, the size of the tumor is reduced by at least 85%. In a further or additional embodiment, the size of the tumor is reduced by 90% or more. In a further or additional embodiment, the size of the tumor is reduced by at least 95%. In a further or additional embodiment, the tumor is eradicated. In some embodiments, the size of the tumor does not increase.

In some embodiments, tumor growth is reduced. In some embodiments, tumor growth is reduced by 1% or more. In some embodiments, tumor growth is reduced by 2% or more. In some embodiments, tumor growth is reduced by 3% or more. In some embodiments, tumor growth is reduced by 4% or more. In some embodiments, tumor growth is reduced by 5% or more. In some embodiments, tumor growth is reduced by 10% or more. In some embodiments, tumor growth is reduced by 20% or more. In some embodiments, tumor growth is reduced by 25% or more. In some embodiments, tumor growth is reduced by 30% or more. In some embodiments, tumor growth is reduced by 40% or more. In some embodiments, tumor growth is reduced by 50% or more. In some embodiments, tumor growth is reduced by 60% or more. In some embodiments, tumor growth is reduced by 70% or more. In some embodiments, tumor growth is reduced by 75% or more. In some embodiments, tumor growth is reduced by 75% or more. In some embodiments, tumor growth is reduced by 80% or more. In some embodiments, tumor growth is reduced by 90% or more. In some embodiments, tumor growth is reduced by 95% or more. In some embodiments, tumor growth is inhibited.

In some embodiments, a composition comprising a compound of formula I is administered in combination with additional therapy. In further or additional embodiments, the additional therapy is radiation therapy, chemotherapy, surgery, or any combination thereof. In a further or additional embodiment, a composition comprising a compound of formula I is administered in combination with one or more therapeutic agents. In a further or additional embodiment, the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenic agents and anti-neoplastic agents. In further or additional embodiments, the anti-neoplastic agent is selected from the group consisting of an alkylating agent, an anti-metabolite, an epipidolipid, an anti-neoplastic enzyme, a topoisomerase inhibitor, a procarbazine, a mitoxantrone, Complexes, biological response modifiers and growth inhibitors, hormone / anti-hormone therapeutics, and hematopoietic growth factors. In a further or additional embodiment, the therapeutic agent is selected from Taxol, Bortezomib, or both.

In some embodiments, the compositions are administered orally, intraduodenally, parenterally (e.g., intravenously, subcutaneously, intramuscularly, by intravascular or infusion), topically or rectally. In further or additional embodiments, the amount of the compound of formula I ranges from about 0.001 to about 1000 mg / kg body weight per day. In further or additional embodiments, the amount of compound of formula I ranges from about 0.5 to about 50 mg / kg / day. In further or additional embodiments, the amount of compound of formula I is from about 0.001 to about 7 g / day. In further or additional embodiments, the amount of the compound of formula I is from about 0.01 to about 7 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.02 to about 5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.05 to about 2.5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.1 to about 1 g / day. In further or additional embodiments, dosage levels below the lower limit of the aforementioned range may be more appropriate. In further or additional embodiments, dosage levels above the upper limit of the above range may be required.

In a further or additional embodiment, the compound of formula I is administered in a single administration once a day. In a further or additional embodiment, the compound of formula I is administered in multiple doses more than once per day. In a further or additional embodiment, the compound of formula I is administered twice a day. In a further or additional embodiment, the compound of formula I is administered three times per day. In a further or additional embodiment, the compound of formula I is administered four times per day. In a further or additional embodiment, the compound of formula I is administered more than 4 times per day. In some embodiments, the individual suffering from cancer is a mammal. In further or additional embodiments, the subject is a human. In an additional or additional embodiment, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of Formula I is administered.

Inflammatory disease

In another aspect, the invention provides a method of treating an inflammatory disease in a subject, comprising administering to the subject an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof, Treating, inhibiting or preventing the disease. In some embodiments, the compound or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug thereof is administered as a component of a composition that additionally comprises a pharmaceutically acceptable carrier or vehicle. In a further or additional embodiment, the inflammatory disease is selected from the group consisting of chronic inflammatory diseases, rheumatoid arthritis, rheumatoid arthritis, spondyloarthropathies, ankylosing spondylitis, gout, tendinitis, bursitis, sciatica, gouty arthritis, osteoarthritis, Inflammatory bowel syndrome, ulcerative colitis, reflux esophagitis, Crohn &apos; s disease, gastritis, asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, acute respiratory distress syndrome, Allergies, respiratory distress syndrome, pancreatitis, chronic obstructive pulmonary disease, pulmonary fibrosis, psoriasis, eczema or scleroderma.

In some embodiments, a composition comprising a compound of formula I is administered in combination with additional therapy. In a further or additional embodiment, a composition comprising a compound of formula I is administered in combination with one or more therapeutic agents. In some embodiments, the compositions are administered orally, intraduodenally, parenterally (e.g., intravenously, subcutaneously, intramuscularly, by intravascular or infusion), topically or rectally. In further or additional embodiments, the amount of the compound of formula I ranges from about 0.001 to about 1000 mg / kg body weight per day. In further or additional embodiments, the amount of compound of formula I ranges from about 0.5 to about 50 mg / kg / day. In further or additional embodiments, the amount of compound of formula I is from about 0.001 to about 7 g / day. In further or additional embodiments, the amount of the compound of formula I is from about 0.01 to about 7 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.02 to about 5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.05 to about 2.5 g / day. In further or additional embodiments, the amount of compound of formula I is from about 0.1 to about 1 g / day. In further or additional embodiments, dosage levels below the lower limit of the aforementioned range may be more appropriate. In further or additional embodiments, dosage levels above the upper limit of the above range may be required.

In a further or additional embodiment, the compound of formula I is administered in a single administration once a day. In a further or additional embodiment, the compound of formula I is administered in multiple doses more than once per day. In a further or additional embodiment, the compound of formula I is administered twice a day. In a further or additional embodiment, the compound of formula I is administered three times per day. In a further or additional embodiment, the compound of formula I is administered four times per day. In a further or additional embodiment, the compound of formula I is administered more than 4 times per day. In some embodiments, the subject suffering from an inflammatory disease is a mammal. In further or additional embodiments, the subject is a human. In an additional or additional embodiment, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of Formula I is administered.

Method of administration

This invention describes a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate or derivative thereof. Also described are pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate or derivative thereof. In accordance with standard pharmaceutical practice, the compounds and compositions described herein may be administered alone or in combination with a pharmaceutically acceptable carrier, excipient or diluent in a pharmaceutical composition.

The present invention also relates to crystalline polymorphs N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) 3-dihydroxypropyl) cyclopropane-1-sulfonamide (Form A). In accordance with standard pharmaceutical practice, the compounds and compositions described herein may be administered alone or in combination with a pharmaceutically acceptable carrier, excipient or diluent in a pharmaceutical composition. Administration can be by any method that allows the compound to be delivered to the site of action. Such methods include, but are not limited to, enteral routes (e. G., Oral, gastric or duodenal feeding tubes, rectal suppositories and rectal enuresis), parenteral (including injection or infusion, e.g. intraarterial, intracardiac, intradermal, Intramuscular, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal And delivery via topical (e.g., epicutaneous, skin, enema, eye drops, ophthalmic, intranasal, vaginal) administration, the most suitable route being, for example, And the disorder. Those skilled in the art will appreciate the dosing techniques in which the compounds and methods of the invention may be employed. By way of example only, the compounds described herein may be formulated for topical application, for example, as a local infusion during surgery, as a cream or ointment, as an injection, as a catheter, or as an implant (e. G., A porous, non-porous or gelatinous material For example, a membrane, such as a sialastic membrane, or an implant made of fiber). Administration may also be by direct injection at the diseased tissue or organ site.

Administration of the compounds and compositions described herein may be by any method that allows the compound to be delivered to the site of action. Such methods include oral routes, intraduodenal routes, parenteral injections (e.g., by intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. For example, the compounds described herein may be administered locally to the area in need of treatment. This may be achieved, for example, by local injection during surgery, topical application such as a cream or ointment, injection, catheter, or implant (e.g., porous, non-porous or gelatinous material such as a membrane, Or an implant made of fiber). Administration may also be by direct injection at the site of the tumor or neoplasm or pre-neoplastic tissue (or former site of such tissue). As discussed in, for example, Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed. Pergamon and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. Are familiar with formulations and administration techniques in which the compounds and methods of the invention may be employed.

The formulations may be administered orally, parenterally (e.g., subcutaneously, intradermally, intramuscularly, intravenously, intraarticularly and intrathecally), intraperitoneally, transmucosally, transdermally, rectally and topically Intravenous) administration, the most suitable route may vary, for example, depending on the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any method known in the pharmaceutical arts. All methods are carried out in the presence of a carrier or excipient, wherein the compound of the invention or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate or derivative thereof &Lt; / RTI &gt; In general, the formulations are prepared by causing the active ingredient to associate uniformly and densely with the liquid carrier or finely divided solid carrier, or both, and then optionally molding the product into the desired formulation.

Formulations suitable for oral administration may be presented as discrete units, each containing a predetermined amount of the active ingredient, for example as a capsule, cachet, or tablet, or as a powder or granules, or as a solution in an aqueous liquid or non- Or may be provided as a suspension or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be provided as a bolus, paper or paste.

Pharmaceutical formulations useful for oral administration include tablets, push-fit capsules made of gelatin, and also soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may optionally be made by compression or molding with one or more accessory ingredients. Compressed tablets may be prepared by compressing the active ingredients in a free-flowing form such as powder or granules, optionally in a suitable machine, mixed with a binder, inert diluent or lubricant, surface-active agent or dispersing agent. Molded tablets may be prepared by molding a mixture of the powdered compound wetted with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored and may be formulated to provide slow release or controlled release of the active ingredient therein. All formulations for oral administration should be suitable doses for such administration. Press-fit capsules or tablets may contain the active ingredient in admixture with a filler such as microcrystalline cellulose, silicified microcrystalline cellulose, pre-gelatinized starch, lactose, dicalcium phosphate, or compressed sugars; Binders such as hiropromol, povidone or starch paste; Disintegrants such as croscarmellose sodium, crospovidone or sodium starch glycolate; A surfactant such as sodium lauryl sulfate and / or a lubricant and a processing aid such as talc, magnesium stearate, stearic acid or colloidal silicon dioxide and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin or liquid polyethylene glycol. A stabilizer may also be added. Cored core is provided with a suitable coating. To this end, concentrated sugar solutions are useful which may optionally comprise gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture have. Dyestuffs or pigments may be added to the tablet or sugar coating to indicate or characterize various combinations of active compound doses.

Pharmaceutical formulations may be formulated for parenteral administration by injection, e. G., Bolus injection or continuous infusion. The injectable preparation may be presented in unit dosage form in which preservative is added, for example as an ampoule or multi-dose container. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. The formulation may be provided in unit-dose or multi-dose containers, such as closed ampoules and vials, and may be provided with a powder only requiring the addition of a sterile liquid carrier, such as a saline or pyrogen-free sterile water, Or in a freeze-dried (lyophilized) state. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind described above.

Parenteral formulations include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; And aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as homoe oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspending agent may also contain suitable stabilizers or agents that increase the solubility of the compound so that a highly concentrated solution can be prepared.

Pharmaceutical formulations may also be formulated into depot formulations. Such sustained-release preparations can be administered by implantation (e. G. Subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compound may be formulated with a suitable polymer or hydrophobic material (e.g., formulated as an emulsion in an acceptable oil) or an ion exchange resin, or may be formulated with an insoluble derivative, &Lt; / RTI &gt;

The compositions for buccal or sublingual administration may be in the form of tablets, lozenges, pastilles or gels formulated in conventional manner. Such compositions may contain the active ingredient in a flavored base such as sucrose and acacia or tragacanth.

Pharmaceutical formulations may also be formulated, for example, in rectal compositions containing conventional suppository bases such as cocoa butter, polyethylene glycols or other glycerides, such as suppositories or retention enemas.

Pharmaceutical formulations may be administered topically, i.e., non-systemically. This includes externally applying the compounds of the present invention to epidermis or nasal passages and injecting them into the ear, eye and nose to prevent them from entering the bloodstream significantly. Conversely, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

Pharmaceutical formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation, such as gels, emulsions, lotions, creams, ointments or pastes, and drips suitable for administration to the eyes, . For topical administration, the active ingredient may comprise from 0.001% to 10% w / w of the formulation, for example from 1 to 2% by weight. However, this may be included as much as 10% w / w of the formulation, or less than 5% w / w or 0.1% to 1% w / w of the formulation.

Pharmaceutical formulations for inhalation administration conveniently are delivered from a delivery device, a nebulizer, a pressurized pack, or other convenient means of delivering an aerosol spray. The pressurized pack may contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve for delivering the metered amount. Alternatively, pharmaceutical formulations for inhaled or aortic administration may be in the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base, such as lactose or starch. The powder composition may be presented in unit dosage form, for example as capsules, cartridges, gelatine or blister packs from which powders may be administered with the aid of an inhaler or insufflator.

In addition to the ingredients specifically mentioned above, it should be understood that the compounds and compositions described herein may include other agents customary in the art for the type of formulation concerned, for example suitable for oral administration include flavoring agents can do.

Formulation

It is to be understood that any of the compositions and compounds described herein may be used in any formulation (which is not intended to be limiting and should not be construed as limiting) as discussed in this section.

The compounds or compositions described herein may be delivered in vesicles, such as liposomes (see, for example, Langer, Science 1990, 249, 1527-1533, Treat et al., Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Bernstein and Fidler, Ed., Liss, NY, pp. 353-365, 1989). The compounds and pharmaceutical compositions described herein may also be delivered to a controlled release system. In one embodiment, a pump can be used (Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14: 201), Buchwald et al. Surgery, 1980 88, 507, Saudek et al. N Engl., J. Med., 1989, 321, (574)). In addition, controlled release systems can be placed in close proximity to therapeutic targets (see Goodson, Medical Applications of Controlled Release, 1984, Vol. 2, pp. 115-138). The pharmaceutical composition described herein may also be in a form suitable for oral use such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups Or as an elixir. Compositions for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, which compositions contain one or more agents selected from the group consisting of sweeteners, flavors, colorants and preservatives, It is possible to provide a pharmaceutical composition having a good shape and a good taste. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for tablet formulation. Such excipients include, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granulating and disintegrating agents; Fillers such as microcrystalline cellulose, silicified microcrystalline cellulose, pre-gelatinized starch, lactose, dicalcium phosphate, or compressed sugars; Binders such as hiropromol, povidone or starch paste; Disintegrants such as croscarmellose sodium, crospovidone or sodium starch glycolate; Surfactants such as sodium lauryl sulfate and / or lubricants and processing aids such as talc, sodium croscarmellose, corn starch, or alginic acid; Binders such as starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricants such as magnesium stearate, stearic acid or colloidal silicon dioxide and optionally talc. The tablets may not be coated or may be coated with known techniques to shield the taste of the drug or delay disintegration and absorption in the gastrointestinal tract to provide a sustained action over a longer period of time. For example, water-soluble taste-shielding materials such as hydroxypropylmethyl-cellulose or hydroxypropylcellulose, or time delay materials such as ethylcellulose or cellulose acetate butyrate may be used if appropriate. Oral formulations may also be in the form of hard gelatine capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or the active ingredient is mixed with a water soluble carrier such as polyethylene glycol or an oil medium, Or as a soft gelatin capsule mixed with paraffin or olive oil. Capsules and tablet dosage forms can be prepared by a variety of processing techniques including dry blending and wet granulation techniques. In the dry blending preparation method, the drug substance may be incorporated into the dosage form by dry blending with an excipient and then by encapsulation into a capsule shell or by compression in the form of a tablet. Dry blending operations may include a screening step that is accessible in a step-wise fashion and facilitates the formation of a uniform blend between blending steps. In the wet granulation preparation process, the drug substance may be added to the dry excipient and mixed and then the binder solution may be added, or the drug substance may be dissolved and added as a solution as part of the granulation. In the wet granulation technique, when a surfactant is used, it may be added to the dry excipient or added to the binder solution to incorporate in solution form. Capsule dosage forms can also be prepared by dissolving the drug substance in a compatible gelatinous capsule shell that can be subsequently sealed with a bandage and in a compatible material. Capsules and tablet dosage forms may also be prepared by dissolving the drug substance in a material such as high molecular weight polyethylene glycol in the molten form and cooling it in the form of a solid and pulverizing and incorporating the material into conventional capsule and tablet manufacturing processes have.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, tragacanth and acacia gum, Particles, such as lecithin or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, such as heptadecaethylene-oxycetanol , Condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sor Gt; monooleate &lt; / RTI &gt; The aqueous suspension may contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents such as sucrose, saccharin or asparagine It may contain tam.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, homoe oil or coconut oil, or a mineral oil such as liquid paraffin. Oily suspensions may contain thickening agents, for example beeswax, hard paraffin or cetyl alcohol. Sweeteners such as those described above, and flavoring agents may be added to provide an oral preparation which is pleasing to the eye. These compositions may be preserved by the addition of anti-oxidants such as butylated hydroxy anisole or alpha-tocopherol.

Dispersible powders and granules suitable for the manufacture of aqueous suspensions by addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant, such as ascorbic acid.

The pharmaceutical composition may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or a mixture thereof. Suitable emulsifiers include condensation products of naturally occurring phosphatides, such as soy lecithin, and partial esters and hexitol anhydrides derived from esters or fatty acids, such as sorbitan monooleate, and the partial esters with ethylene oxide, For example, polyoxyethylene sorbitan monooleate. The emulsifying agent may also contain sweetening agents, flavoring agents, preservatives and anti-oxidants.

Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain dots, preservatives, flavoring and coloring agents and anti-oxidants.

The pharmaceutical composition may be in the form of an injectable sterile aqueous solution. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. Injectable sterile preparations may also be injectable sterile water heavy oil microemulsions in which the active ingredient is dissolved in the oily phase. For example, the active ingredient may first be dissolved in a mixture of soybean oil and lecithin. The oil solution is then introduced into a mixture of water and glycerol and processed to form a microemulsion. The injectable solution or microemulsion may be introduced into the blood stream of the patient via local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way that a constant circulating concentration of the compound of the present invention is maintained. A continuous intravenous delivery device may be used to maintain this constant concentration. An example of such a device is the Deltec CADD-PLUS (TM) Model 5400 intravenous pump. The pharmaceutical composition may be in the form of an injectable, sterile aqueous or sustained suspension for intramuscular and subcutaneous administration. The suspending agent may be formulated as is known in the art using the above-mentioned suitable dispersing or wetting agents and suspending agents. Injectable sterile preparations can also be non-toxic parenterally-acceptable diluents or injectable sterile solution or suspension in a solvent, for example as a solution in 1,3-butanediol. In addition, sterilized essential oils are also commonly used as a solvent or suspending medium. For this purpose, any harmless essential oil can be used including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid are also used in the preparation of injectable preparations.

The pharmaceutical composition may also be administered in the form of suppositories for rectal administration of the drug. Such a composition may be prepared by mixing the inhibitor with a suitable non-stimulant excipient which is solid at normal temperature but liquid at rectal temperature and is melted in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.

For topical use, creams, ointments, jellies, solutions or suspensions containing the compounds or compositions of the present invention are useful for topical administration. As used herein, topical application may include mouthwash and gargle.

The pharmaceutical compositions may be administered intranasally via topical use of suitable intranasal vehicles and delivery devices, or may be administered via the percutaneous route using a form of transdermal patch patch known to those skilled in the art.

The formulations may conveniently be presented in unit dosage form and may be prepared by any method known in the pharmaceutical arts. All methods comprise the step of bringing the compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, or solvate thereof ("active ingredient") into association with a carrier that constitutes one or more accessory ingredients. In general, the formulations are prepared by causing the active ingredient to associate uniformly and densely with the liquid carrier or the finely divided solid carrier, or both, and then optionally molding the product into the desired formulation. Methods of making various pharmaceutical compositions containing a certain amount of active compound are known or will be apparent to those skilled in the art. In the case of administration in the form of transdermal delivery, it is natural that the dosage form should be continuous rather than intermittent throughout the entire dosage period.

Volume

The dosage of the pharmaceutical composition will vary depending on the mammal to be treated first. In the example where the pharmaceutical composition is administered to a human subject, the daily dosage will generally be determined by the prescriber and the dosage will generally vary with the age, sex, diet, weight, general health and response of the individual patient, The severity, the exact indication or condition to be treated, the severity of the indication or condition to be treated, the time of administration, the route of administration, the composition placement, rate of excretion, drug combination, and judgment of the prescription. The route of administration may also depend on the condition and its severity. The pharmaceutical composition may be in unit dosage form. In this form, the agent is subdivided into unit doses containing the active ingredient in an appropriate amount, e.g., an effective amount for achieving the desired purpose. Determination of the proper dosage depending on the particular situation is within the skill of the art. In general, the treatment is initiated with less than the optimal dose of the compound. Thereafter, the dose is increased by a small amount until the optimum effect is achieved in a given situation. For convenience, if desired, the total daily dose may be divided into small doses per day. The dosage and frequency of administration of the compounds described herein and, if applicable, other therapeutic agents and / or therapies, will be adjusted according to the judgment of the attending clinician in view of the factors as described above. Thus, the amount to which a pharmaceutical composition is administered may vary widely. Administration may be in an amount of from about 0.001 mg to about 100 mg per day (administered in single or divided doses) per kilogram of body weight or in an amount of at least about 0.1 mg per kilogram of body weight per day. A particular therapeutic dose may include, for example, from about 0.01 mg to about 7000 mg of the compound, or from about 0.05 mg to about 2500 mg, for example. The amount of active compound in the unit dose of the preparation may be varied or adjusted from about 0.1 mg to 1000 mg, from about 1 mg to 300 mg, or from 10 mg to 200 mg, depending on the particular application. In some instances, dosage levels below the lower limit of the above range may be more appropriate, and in other cases much higher doses may be administered, for example by dividing such larger doses into several smaller doses over the course of a day It can be used without harmful side effects. The dosage will vary depending on the specific IC ₅₀ value of the compound used. When the compound is administered in combination, rather than in a monotherapy, administration of the compound in a smaller amount may still have a therapeutic or prophylactic effect.

Additional capacities are provided herein and in the claims.

Dosage form

The pharmaceutical compositions may be in a form suitable for oral administration, for example, as tablets, capsules, pills, powders, sustained release formulations, solutions, suspensions, or in a form suitable for parenteral injection such as sterile solutions, suspensions or emulsions Or in a form suitable for topical administration such as ointments or creams, or may be in a form suitable for rectal administration such as suppositories. The pharmaceutical composition may be in unit dosage form suitable for single administration of precise dosages. The pharmaceutical compositions comprise conventional pharmaceutical carriers or excipients, and the compounds according to the invention as active ingredients. It may also include other medicinal or pharmaceutical agents, carriers, adjuvants, and the like.

Exemplary parenteral dosage forms include solutions or suspensions of the active compound in a sterile aqueous solution, e. G. Aqueous propylene glycol or dextrose solution. If desired, such dosage forms may be suitably buffered.

Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. If desired, the pharmaceutical composition may contain additional ingredients, such as flavoring agents, binders, excipients, and the like. Thus, in the case of oral administration, tablets containing various excipients such as citric acid may be used with various disintegrants such as starch, alginic acid and certain complex silicates and binders such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed in soft and hard-filled gelatin capsules comprising lactose or lactose and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compounds therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, diluents such as water, ethanol, propylene glycol, glycerin, Can be combined with a combination of these.

Methods of making various pharmaceutical compositions with a certain amount of active compound are known or will be apparent to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Ester, Pa., 18th Edition (1990).

Combination therapy

The compounds described herein or their pharmaceutically acceptable salts, solvates, polymorphs, esters, amides, tautomers, prodrugs, hydrates or derivatives thereof may be administered as monotherapy. The compounds described herein or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate or derivative thereof may also be administered in combination with another therapy (s).

In addition, the present application discloses N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) -1 - (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide (Form A). 2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) Crystalline polymorph Form A of cyclopropane-1-sulfonamide may also be administered in combination with another therapy (s).

By way of example only, when one of the side effects experienced by a patient at the time of administration of one of the compounds described herein is hypertension, it may be appropriate to administer an anti-hypertensive agent in combination with the compound. Alternatively, by way of example only, the therapeutic effect of one of the compounds described herein may be enhanced by administration of the adjuvant (i.e., the adjuvant itself may have only minimal therapeutic benefit, Overall treatment benefit for the patient is enhanced). Or, by way of example only, the benefit experienced by a patient can be increased by administering one of the compounds described herein in combination with another therapeutic agent which also has therapeutic benefit, which includes treatment. By way of example only, in the treatment of diabetes associated with the administration of one of the compounds described herein, an increase in therapeutic benefit may be obtained by providing the patient with another therapeutic agent for diabetes. In any case, the overall benefit experienced by a patient regardless of the disease, disorder or condition being treated may simply be an additional benefit of the two therapeutic agents, or the patient may experience synergistic benefits.

Other therapies include, but are not limited to, administration of other therapeutic agents, radiotherapy, or both. When the compounds described herein are administered in combination with other therapeutic agents, the compounds described herein need not be administered in the same pharmaceutical composition as the other therapeutic agents, since they are different in physical and chemical characteristics and therefore administered by different routes . For example, the compound / composition can be orally administered to produce and maintain its good blood levels, and the other therapeutic agent can be administered intravenously. The mode of administration and the feasibility of administration and the determination of whether administration to the same pharmaceutical composition is possible are within the knowledge of the skilled clinician. Initial dosing can be accomplished according to established protocols known in the art, and subsequently dosages, mode of administration, and time of administration based on the observed effects can be altered by a skilled clinician. The choice of the particular compound (and, where appropriate, other therapeutic agents and / or radiation) will depend on the diagnosis of the attending physician and their judgment regarding the patient's condition and the appropriate treatment protocol. Other therapeutic agents include chemotherapeutic agents such as anti-tumor agents such as mitotic inhibitors such as vinblastine; Alkylating agents such as cis-platin, carboplatin and cyclophosphamide; Metabolites, such as 5-fluorouracil, cytosine arabinic acid and hydroxyurea, or the anti-metabolites described for example in European Patent Application No. 239362, such as N- (5- [N- (3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl) -N-methylamino] -2-te noyl) -1-glutamic acid; Growth factor inhibitors; Cell cycle inhibitors; Intercalating antibiotics such as adriamycin and bleomycin; Enzymes such as interferon; And anti-hormones such as anti-estrogens such as Nolvadex ™ (tamoxifen) or, for example, anti-androgens such as Casodex ™ (4'-cyano-3- -Fluorophenylsulfonyl) -2-hydroxy-2-methyl-3 '- (trifluoromethyl) propionanilide). Such co-treatment may be achieved by administering the individual therapeutic ingredients simultaneously, sequentially or separately.

The compounds and compositions described herein (and, where appropriate, appropriate chemotherapeutic agents and / or radiation) may be administered orally or parenterally, depending on the nature of the disease, the condition of the patient, and the chemotherapy (E. G., Simultaneously, essentially simultaneously or with the same treatment protocol) or sequentially administered according to the actual choice of agent and / or radiation.

In combination application and use, the compound / composition and the chemotherapeutic agent and / or radiation need not be administered simultaneously or essentially simultaneously, and the initial order of administration of the compound / composition and chemotherapeutic agent and / or radiation may not be critical have. Thus, the compounds / compositions of the present invention may be administered first followed by a chemotherapeutic agent and / or radiation, or the compounds / compositions of the present invention may be administered after the first administration of a chemotherapeutic agent and / or radiation . Such alternate dosing can be repeated during a single treatment protocol. The order of administration during the treatment protocol and the number of repetitions of administration of each therapeutic agent are within the knowledge of the skilled artisan after evaluating the condition to be treated and the condition of the patient. For example, a chemotherapeutic agent and / or radiation may be administered first, especially if this is a cytotoxic agent, and thereafter treatment continues with administration of a compound / composition of the present invention, Until a treatment protocol is completed, such as by administering a chemotherapeutic agent and / or radiation. Accordingly, the practicing physician may modify each protocol for the administration of the compound / composition for treatment in accordance with the needs of the individual patient as treatment proceeds based on experience and knowledge. The clinician in charge will be able to determine whether the treatment of the dose used is effective by alleviating the general well-being of the patient and also alleviating the disease-related symptoms, inhibiting tumor growth, inhibiting the actual contraction of the tumor, And the like. The size of the tumor can be measured by standard methods, such as radiation studies, such as CAT or MRI scans, and successive measurements can be used to determine whether tumor growth has been delayed or even reversed. Alleviation of disease-related conditions, such as pain relief, and overall condition, may also be helpful in determining the therapeutic effect.

Non-limiting examples of possible combination therapies include the use of the compounds of the invention in combination with the agents described in the pharmacotherapeutic classifications as indicated below. Such a listing should not be considered closed and should be intended to illustrate a common example in the relevant treatment area of the present invention. In addition, the combination therapy may include various routes of administration and should include topical administration by oral, intravenous, intravaginal, subcutaneous, skin, and inhalation.

In the treatment of tumor diseases, proliferative disorders and cancer, the compounds according to the present invention can be administered in combination with an agent selected from the group comprising: aromatase inhibitors, anti-estrogens, anti-androgens, corticosteroids, Antagonists, antagonists, antagonists, antagonists, antagonists, antagonists, antagonists, antagonists, antagonists, antagonists, antagonists, antagonists, antagonists, antagonists, An angiotensin II antagonist, an angiotensin II receptor antagonist, an angiotensin II receptor antagonist, an angiotensin II antagonist, an angiotensin II antagonist, an anti-angiogenic agent, an angiogenic agent, an anti-angiogenic agent, an Akt inhibitor, an IGF-I inhibitor, an FGF3 modulator, an mTOR inhibitor, An inhibitor of hepcidin, a heparanase inhibitor, a lymphokine inhibitor, a cytokine inhibitor, an IKK inhibitor, a P38MAPK inhibitor, an ARRY-797, an HSP90 inhibitor, a multi-kinase inhibitor Apoptosis pathway agonist, PPAR agonist, RAR agonist, Ras isoform inhibitor, telomerase inhibitor, protease inhibitor, metalloproteinase inhibitor, metalloproteinase inhibitor, bisphosphonate, rapamycin derivative, anti-apoptotic pathway inhibitor, Inhibitors, aminopeptidase inhibitors, SHIP activators-AQX-MN100, Humax-CD20 (oppartum), CD20 antagonists, IL2-diphtheria toxin fusions.

In the treatment of tumor diseases, proliferative disorders and cancer, the compounds according to the present invention may be administered with an agent selected from the group consisting of: dacarbazine (DTIC), actinomycin C ₂ , C ₃ , D And F ₁ , cyclophosphamide, melphalan, estramustine, maytansinol, rifamycin, streptavidin, doxorubicin, daunorubicin, epirubicin, dirubicin, A ₂ and B, camptothecin, Irinotecan ^® , Topotecan ^® , 9-aminocamptothecin, 9-aminocamptothecin, erythropoietin, 2, combretastatin A-4, and the like. [0064] The compound of the present invention may be used alone or in combination of two or more thereof. Neokarcinostatin, epothilone AB, C, and semi-synthetic variants, Herceptin (Hercept in) ^®, Rituxan (Rituxan) ^®, CD40 antibody, asparaginase, interleukins, interferons, leuprolide, and the first page Gaspard, 5-fluorouracil, having a fluorobenzyloxy uridine, program Tora greener, 5 ' Deoxycytidine, bicalutamide, deoxycytidine, deoxycytidine, deoxycytidine, deoxycytidine, deoxycytidine, deoxycytidine, deoxyfluroolidine, deoxifluorosurfurane, UFT, MITC, S-1 capecitabine, diethylstilbestrol, tamoxifen, Diethylstilbestrol, hydroxysterine, diethylstilbestrol, hydroxysterine, meglethesterol acetate, aminoglutethimide, testolactone, testosterone, diethylstilbestrol, hydroxystearin, Roxy progesterone, mitomycin A, B and C, propyromycin, cisplatin, carboplatin, oxaliplatin, tetrapelatin, platinum-DACH, ormaflatin, thalidomide, lenalidomide, CI-973, Statins, CH IR258, Rad 001, SAHA, Tuva new (Tubacin), 17-AAG, seashell penip, JM-216, podophyllotoxin, epi-podophyllotoxin, etoposide, teniposide, Tarceva (Tarceva) ^®, seven days wrap (Iressa) ^® , Imatinib ^® , Miltefosine ^® , Perifosine ^® , aminopterin, methotrexate, metopterin, dichloro-methotrexate, 6-mercaptopurine, thioguanine, 5-azacytosine, gentitavin, 5-azabenzotriazine, 5-azabenzotriazine, 5-azacytidine, - azacytosine - arabinoside, vincristine, vinblastine, vinorelbine, lyrosine, leucydin and vindesine, paclitaxel, taxotere and docetaxel.

In the treatment of inflammatory diseases or pain, the compounds according to the invention and the pharmaceutically acceptable salts of the compounds can be administered together with an agent selected from the group comprising: corticosteroids, non-steroidal anti-inflammatory agents, muscle relaxants And other agents and combinations thereof, anesthetics and other agents and combinations thereof, expectorants and other agents and combinations thereof, anti-depressants, anti-convulsants, and combinations thereof; But are not limited to, anti-hypertensive agents, opioid agents, topical cannabinoids, capsaicin, betamethasone dipropionate (enhanced and non-enhanced), betamethasone valerate, clobetasol propionate, prednisone, methylprednisolone, Dexamethasone, dexocytometer, fluorocinolone acetononide, fluorocinonide, halocinonide, crocortalone pivalate, dexosimethone, fluoranthrenide, But are not limited to, salicylate, ibuprofen, ketoprofen, etodolac, diclofenac, meclofenamate sodium, naproxen, piroxycam, selenocoxib, cyclobenzaprine, baclofen, cyclobenzaprine / lidocaine, / Cyclobenzafurin, Cyclobenzafrine / Lidocaine / Ketoprofen, Lidocaine, Lidocaine / Deoxy-D-Glucose, Prilocaine, EMLA cream (eutectic mixture of topical anesthetic (2.5% of lidocaine and 2.5% of prilocaine), goupfenesin, guaifenesin / ketoprofen / cyclobenzaprine, amitriptyline, doxepin, desipramine, imipramine, But are not limited to, pranine, nortriptyline, protriptyline, duloxetine, mirtazepine, nisecetin, mafrotiline, reboxetine, fluoxetine, fluvoxamine, carbohyphene, felbamate, lamotrigine, topiramate, Gabapentin / carbamazepine, carbamazepine / cyclobenzaprine, anti-hypertensive agents such as clonidine, codeine, lipase, CB1 / CB2 ligand, acetaminophen, infliximab, nitric oxide, nitric oxide, nitric oxide, nitric oxide, Synthetase inhibitors, in particular inducible A mechanism similar to that of PDE4 inhibitor-Ibudilast (AV-411), CDC-801, JNK inhibitor-CC-401, combined TNF / PDE4 inhibitor-CDC-998, inhibitor of nitric oxide synthase, IL-1 antagonist For example, Anakinra-Kineret, AMG 108, (mAb) (targeting IL-1), SHIP activator-AQX-MN100, C5 antagonist, C5a inhibitor, PEXELIZUMAB), a pyrimidine synthesis inhibitor, a lymphokine inhibitor, a cytokine inhibitor, an IKK inhibitor, a P38MAPK inhibitor, an ARRY-797, an HSP90 inhibitor, a multi-kinase inhibitor, a bspospanate, a PPAR agonist, -CD4 therapies, B-cell inhibitors, COX / LOX dual inhibitors, immunosuppressants, iNOS inhibitors, NSAIDs, sPLA2 inhibitors, colchicine, allophurinol, oxipurinol, Gold, Ridaura- Auranofin, Pegasus start, Puricase, PEG-free-radical agent, benzbromarone, sustained beta-2 efficacy (LABA), Salmeterol (Serevent Diskus) and formoterol (Foradil), Leukotriene modifiers such as Montelukast (Singulair) and Jaffe with Lucas (Acolate), inhaled cromolyn (Intal) or nedocromil (Tilade), theophylline, fasting beta-2 agonist, ipratropium ( Ipratropium (Atrovent), immunotherapy - (allergen-desensitization shot), anti-IgE monoclonal antibody-Xolair, conventional DMARDs such as hydroxyquinolone (Plaquenil ), Gold compounds auronopin (Ridaura), sulfasalazine (Azulfidine), minocycline (Dynacin, minocin) and methotrexate (Rheumatrex), (Arava), azathioprine (Imuran), cyclosporine (Neoral), sandy (Sandimmune)) and cyclophosphamide (between toksan (Cytoxan)), Antibiotics, CD80 antagonists, co-stimulating factor antagonists, Humax -CD20 (O Pato mumap); CD20 antagonist, MEK inhibitor, NF kappa B inhibitor, anti-B-cell antibody, denosumab, mAb that specifically targets receptor activator of nuclear factor kappa B ligand (RANKL), IL-17 inactivation antibody, IL -17 receptor antagonist / inhibitor, a CTLA inhibitor, a CD20 inhibitor, a soluble VEGFR-1 receptor, an anti-VEGFR-1 receptor antibody, an anti-VEGF antibody, an integrin receptor antagonist, a Selectin inhibitor, , Inhibitors of phospholipase A2 inhibitors, lipoxygenase inhibitors, RANKL and RANK antagonists / antibodies, osteoprotegerin antagonists, lymphotoxin inhibitors, B-lymphocyte stimulators, MCP-1 inhibitors, MIF inhibitors, A selective inhibitor of chemotaxis, an inhibitor of chemotaxis, an inhibitor of chemotaxis, a CXC receptor and a CXC ligand inhibitor, a chemokine antagonist, a leukocyte chemotaxis inhibitor, an adhesion inhibitor, minute (LFA-1, CD11a) antagonist, Very Late Antigen-4 (VLA-4) antagonist, matrix metalloproteinase inhibitor , Elastase inhibitors, cathepsin inhibitors.

In the treatment of ophthalmic disorders and diseases of the eye, the compounds according to the invention and the pharmaceutically acceptable salts of the compounds can be administered together with an agent selected from the group comprising: beta-blockers, carbonic anhydrase inhibitors, alpha-and-adrenergic antagonists such as a1-adrenergic antagonists, a2 agonists, progestogens, prostaglandin analogues, corticosteroids and immunosuppressants.

In the treatment of ophthalmic disorders and diseases of the eye, the compounds according to the invention and the pharmaceutically acceptable salts of the compounds can be administered together with an agent selected from the group consisting of thymolol, betethosolol, But are not limited to, taxol, carotenol, levobupanol, propranolol, brinzolamide, dorsolamide, nifradilol, iopidine, brimonidine, pilocarpine, epinephrine, latanoprost, traboprost, Unoprostone, dexamethasone, prednisone, methylprednisolone, azathioprine, cyclosporin, and immunoglobulin.

In the treatment of autoimmune disorders, the compounds according to the invention and the pharmaceutically acceptable salts of the compounds can be administered with the agents selected from the group comprising: corticosteroids, immunosuppressants, prostaglandin analogs and anti-metabolites matter.

In the treatment of autoimmune disorders, the compounds according to the present invention may be administered with an agent selected from the group comprising: dexamethasone, prednisone, methylprednisolone, azathioprine, cyclosporine, immunoglobulin, latanoprost , A combination of these with travoprost, bimatofoot, unoprostone, infliximab, rutuximab, methotrexate, non-steroidal anti-inflammatory agents, muscle relaxants and other agents, anesthetics and other agents and combinations thereof , Expectorants and other agents and combinations thereof, anti-depressants, anti-convulsants, and combinations thereof; (Proliferative and non-promoting), betamethasone valerate, clobetasol propionate, prednisone, methylprednisolone, diethanolamine, and the like, as well as other anti-hypertensive agents, anti-hypertensive agents, opioid agents, topical cannabinoids and other agonists such as capsaicin, betamethasone dipropionate Dexamethasone, dexosimethasone, fluorocinolone acetononide, fluorocinonide, halocinonide, crocortalone pivalate, dexosimethasone, fluvastatin, But are not limited to, randolilide, salicylate, ibuprofen, ketoprofen, etodolac, diclofenac, meclofenamate sodium, naproxen, piroxycam, selenecoxib, cyclobenzaprine, Lidocaine / deoxy-D-glucose, frylocaine, EMLA cream (country of origin), lidocaine, baclofen / cyclobenzaprine, cyclobenzaprine / lidocaine / ketoprofen, lidocaine, lidocaine / The use of a eutectic mixture of anesthetics (lidocaine 2.5% and prilocaine 2.5%), guineafenesin, guaifenesin / ketoprofen / cyclobenzaprine, amitriptyline, doxepin, desipramine, imipramine, But are not limited to, cholinesterase inhibitors such as cholinesterase inhibitors, cholinesterase inhibitors, cholinesterase inhibitors, cholinesterase inhibitors, cholinesterase inhibitors, Topiramate, thiabemine, oxcarbazepine, carbamazepine, jonisamid, mexylin, gabapentin / clonidine, gabapentin / carbamazepine, carbamazepine / cyclobenzaprine, anti-hypertensive agents such as clonidine, CB1 / CB2 ligand, acetaminophen, infliximab, ciprofloxacin, ciprofloxacin, ciprofloxacin, ciprofloxacin, cordine, rofemamide, tramadol, morphine, fentanyl, oxycodone, hydrocodone, levorphanol, butorphanol, menthol, methyl salicylate, camphor, eucalyptus, Nitric oxide synthase CDC-801, JNK Inhibitor-CC-401, Combination TNF / PDE4, a mechanism similar to that of other agents such as capsaicin, PDE4 inhibitor-ibudilast (AV-411) Inhibitors - CDC-998, IL-1 antagonists such as anakinra-kineret, AMG 108, (mAb) (targeting IL-1), SHIP activator-AQX-MN100, C5 antagonists, C5a inhibitors, PSPMAPK inhibitor, ARRY-797, HSP90 inhibitor, multi-kinase inhibitor, bspospanate, PPAR agonist, Coxl and cox2 inhibitor, A prodrug, an anti-CD4 regimen, a B-cell inhibitor, a COX / LOX dual inhibitor, an immunosuppressant, an iNOS inhibitor, an NSAID, a sPLA2 inhibitor, colchicine, alopulinol, oxipurinol, gold, lidarra-auranopin, , PEG-free-radical combination preparations, benzbromarone, sustained beta-2 agonists (LABA), (Corticosteroids) and formoterol (forradyl), leukotriene modifiers such as montelukast (singulour) and jaffy lucuste (acacolate), inhaled cromolyne (intrales) or nedocromil (Allergen-desensitization short), anti-IgE monoclonal antibody-ksolayer, common anti-IgE antibody (anti-IgE), theophylline, (Arabinose), methotrexate (muramycin), methotrexate (leukemia rex), leucovorin (arabinoxylan), and the like, as well as DMARDs such as hydroxychloroquine (plenilyl), gold compounds auranophen , Azathioprine (imilane), cyclosporine (neoral, sandwich) and cyclophosphamide (cytoxan), antibiotics, CD80 antagonists, co-stimulatory antagonists, Humax-CD20 (oppartum); CD20 antagonist, MEK inhibitor, NF kappa B inhibitor, anti-B-cell antibody, denosumab, mAb that specifically targets receptor activator of nuclear factor kappa B ligand (RANKL), IL-17 inactivation antibody, IL -17 receptor antagonist / inhibitor, a CTLA inhibitor, a CD20 inhibitor, a soluble VEGFR-1 receptor, an anti-VEGFR-1 receptor antibody, an anti-VEGF antibody, an integrin receptor antagonist, a selectin inhibitor, a P- Lipase A2 inhibitors, lipoxygenase inhibitors, RANKL and RANK antagonists / antibodies, osteoproterenin antagonists, lymphotoxin inhibitors, B-lymphocyte stimulators, MCP-1 inhibitors, MIF inhibitors, inhibitors of the following substances: CD2, CD3, CD4, CD25, CD40 and CD40 ligand CD152 (CTLA4), markrolide immunosuppressive agents, selective inhibitors of nucleotide metabolism, chemotactic inhibitors, CXC receptors and CXC ligand inhibitors, chemokine antagonists, leukocyte chemotaxis inhibitors, Peugu function antigen -1 (LFA-1, CD11a) antagonists, berry rate antigen -4 (VLA-4) antagonists, protease inhibitors, elastase inhibitors, Cathepsin inhibitors to matrix metal.

In the treatment of metabolic disorders, the compounds according to the invention and the pharmaceutically acceptable salts of the compounds can be administered together with an agent selected from the group comprising: insulin, insulin derivatives and mimetics, insulin secretagogues, insulin (PTP-1B) inhibitor, GSK3 (glycogen synthase kinase-3) inhibitor, GLP-1 (glycogen synthase kinase-3) inhibitor, an inhibitor of insulin affinity sulfonylurea receptor ligand, a protein tyrosine phosphatase- (Dipeptidyl peptidase IV) inhibitor, RXR ligand sodium-dependent glucose co-transporter inhibitor, glycogen phosphorylase A inhibitor, AGE breaker, PPAR modulator, LXR And FXR modulators, non-glitazone PPARS agonists, selective glucocorticoid antagonists, metformin, Glipizide, glyburide, Amaryl, SB-216763, NN-57-05441, NN-57-05445, GW-0791, AGN-194204, T-1095, BAY (R) -1- {4- [5-methyl-2 (2-pyrrolidin-1-yl) -1,2,3,4-tetrahydronaphthalene- - (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -benzenesulfonyl} 2,3-dihydro-lH-indole-2-carboxylic acid (carried out in patent application WO 03/043985 Described as Compound 19 of Example 4) and GI-262570.

disease

The present invention is directed to a method of treating a disease comprising administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate or derivative thereof, Describes a method of treating a disease in an individual suffering from a disease.

The present invention also provides a method for treating or preventing a disease or disorder in an individual suffering from the disease or disorder comprising administering to the individual suffering from the disease or disorder an effective amount of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6- Desc / Clms Page number 2 &gt; describes a method of treating a disease or disorder in an individual suffering from a disease or disorder, comprising administering a therapeutically effective amount of a compound of formula &lt; RTI ID = 0.0 & . The present invention relates to the use of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6- Phenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide (Form A).

In some embodiments, the present invention relates to the prophylaxis or treatment of any disease or disorder in which a MEK kinase plays a given role in a human or other mammal, including, but not limited to: tumors, blood systems, Inflammatory, ophthalmic, neurological, immune, cardiovascular and dermatological diseases and also for the treatment of undesired or uncontrolled pro-inflammatory cytokine production such as excessive or unregulated TNF, IL-1, IL-6 and Diseases caused by IL-8 production. The present invention includes such uses and the use of such compounds in the manufacture of medicaments for the treatment of such cytokine-mediated diseases or disorders. Additionally, the invention includes administering an effective amount of a MEK inhibitor to a human to treat any such disease or disorder.

Diseases or disorders in which the MEK kinase plays a predetermined role either directly or via a pre-inflammatory cytokine such as cytokine TNF, IL-1, IL-6 and IL-8 include, but are not limited to: , Glaucoma, autoimmune diseases, inflammatory diseases, destructive-bone disorders, proliferative disorders, neurodegenerative disorders, viral diseases, allergies, infectious diseases, heart attacks, angiogenesis disorders, reperfusion / Conditions associated with vascular hyperplasia, chronic hypoxia, cardiac hypertrophy, thrombin-derived platelet aggregation, and prostaglandin endoperoxidase synthetase-2 (COX-2).

In certain aspects of the invention, the disease includes cancer, hyperplasias, restenosis, inflammation, immune disorders, cardiac hypertrophy, atherosclerosis, pain, migraine, angiogenesis-related conditions or disorders, surgery, angioplasty or other conditions But are not limited to, proliferation induced after, but not limited to, a medical condition.

In a further embodiment, the hyperproliferative condition is selected from the group consisting of blood system and non-blood system cancer. In a further embodiment, the blood group cancer is selected from the group consisting of multiple myeloma, leukemia and lymphoma. In a further embodiment, the leukemia is selected from the group consisting of acute and chronic leukemia. In a further embodiment, the acute leukemia is selected from the group consisting of acute lymphoblastic leukemia (ALL) and acute non-lymphocytic leukemia (ANLL). In a further embodiment, the chronic leukemia is selected from the group consisting of chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML). In a further embodiment, the lymphoma is selected from the group consisting of Hodgkin lymphoma and non-Hodgkin lymphoma. In a further embodiment, the blood-based cancer is multiple myeloma. In another embodiment, the blood-based cancer is low grade, intermediate grade or high grade. In another embodiment, the non-hematological cancer is selected from the group consisting of brain cancer, head and neck cancer, lung cancer, breast cancer, cancer of the reproductive system, cancer of the digestive system, pancreatic cancer, and urinary cancer. In a further embodiment, the cancer of the digestive tract is cancer of the upper digestive tract or colorectal cancer. In a further embodiment, said urinary cancer is bladder cancer or kidney cell carcinoma. In a further embodiment, the cancer of the reproductive system is prostate cancer.

Additional types of cancers that can be treated using the compounds and methods described herein include: cancers of the mouth and pharynx, cancers of the respiratory tract, cancers of the bones and joints, cancers of the soft tissues, skin cancers, Cancer of cancer, eye and orbits, cancer of the nervous system, cancer of the lymphatic system and cancer of the endocrine system. In certain embodiments, these cancers can be selected from the group consisting of: cancer of the tongue, mouth, pharynx or other mouth; Esophageal cancer, stomach cancer or small intestine cancer; Cancer of the colon or rectum, anus or anus rectum; Cancer of the liver, intrahepatic bile duct, gall bladder, pancreas or other biliary or digestive organs; Cancer of the larynx and bronchi, and other cancers of the respiratory organs; Heart cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, other non-epithelial skin cancer; Cancer of the uterus or cervix; Cancer of the uterine body; Cancer of the ovaries, vulva, vagina or other female genitalia; Cancer of the prostate, testicle, penis or other male genitalia; Bladder cancer; Kidney cancer; Renal, pelvic or urethral cancers or other cancers of the genitourinary organs; Cancer of thyroid cancer or other endocrine system; Chronic lymphocytic leukemia; And skin T-cell lymphoma of both granulocytes and mononuclear cells.

Other types of cancer that can be treated using the compounds and methods described herein include: adenocarcinoma, angiosarcoma, astrocytoma, otic neoplasm, undifferentiated astrocytoma, basal cell carcinoma, glioblastoma, chondrosarcoma, choriocarcinoma The present invention relates to a method for the treatment and prophylactic treatment of cancer in a patient suffering from a malignant neoplasm of the stomach, The present invention relates to a method of treating a patient suffering from a disease selected from the group consisting of hepatocellular carcinoma, Kaposi's sarcoma, large cell carcinoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, lymphatic endothelial sarcoma, Papillary adenocarcinoma, papillary adenocarcinoma, parathyroid tumor, chromaffin cell tumor, pineal gland tumor, plasma cell tumor, retinoblastoma, rhabdomyosarcoma, sebaceous carcinoma , Topical adenocarcinoma, skin cancer, melanoma, small cell lung carcinoma, squamous cell carcinoma, gland carcinoma, glia carcinoma, thyroid carcinoma, uveal melanoma, and Wilms tumor.

Also provided is a method of treating a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate or derivative thereof in combination with an anti- &Lt; / RTI &gt; a method of treating hyperproliferative disorders in a mammal. In some embodiments, the anti-tumor agent is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors, biological response modifiers, Anti-angiogenesis agent, SHIP activator-AQX-MN100, Humax-CD20 (oppartum), CD20 antagonist, IL2-diphtheria toxin fusion.

Diseases to be treated using the compounds, compositions and methods described herein may be hematological disorders. In certain embodiments, the hematological disorder is selected from the group consisting of sickle cell anemia, myelodysplastic syndrome (MDS), and myeloproliferative disorders. In a further embodiment, the myeloproliferative disorder is selected from the group consisting of intrinsic erythropoiesis, myelofibrosis and essential thrombocytosis.

The compounds, compositions and methods described herein may be useful as anti-inflammatory agents with the additional benefit of having significantly less harmful side effects. The compounds, compositions and methods described herein are useful for the treatment or prevention of rheumatoid arthritis, spondyloarthropathies, ankylosing spondylitis, gout, gouty arthritis, osteoarthritis, systemic lupus erythematosus, rheumatoid arthritis, acute rheumatoid arthritis, But are not limited to, arthritis, arthritis, and pyogenic arthritis. The compounds, compositions and methods described herein are also useful in the treatment of osteoporosis and other related bone disorders. Such compounds, compositions and methods described herein are also useful in the treatment of gastrointestinal conditions such as reflux esophagitis, diarrhea, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. The compounds, compositions and methods described herein can also be used to treat pulmonary inflammation, such as viral infections and lung inflammation associated with cystic fibrosis. In addition, the compounds, compositions and methods described herein are also useful for organ transplant patients, either alone or in combination with conventional immunomodulators. In addition, the compounds, compositions and methods described herein are useful in the treatment of pruritus and vitiligo. In particular, the compounds, compositions and methods described herein are useful in the treatment of certain inflammatory diseases, such as rheumatoid arthritis.

Additional inflammatory diseases that may be prevented or treated include, but are not limited to, asthma, allergies, respiratory distress syndrome or acute or chronic pancreatitis. In addition, respiratory diseases that may be prevented or treated include, but are not limited to, chronic obstructive pulmonary disease and pulmonary fibrosis. In addition, the MEK kinase inhibitors described herein are also associated with the production of prostaglandin endoperoxidase synthetase-2 (COX-2). The inflammatory mediator of the cyclooxygenase pathway, which is derived from arachidonic acid, such as prostaglandin, is produced by an inducible COX-2 enzyme. Modulation of COX-2 modulates these pro-inflammatory mediators, which affect a variety of cells and are important inflammatory mediators of various disease stages and conditions. In particular, these inflammatory mediators are associated with pain, such as sensitization of pain receptors, and edema. Thus, additional MEK kinase-mediated conditions that can be prevented or treated include edema, painlessness, pain caused by heat and pain, such as neuromuscular pain, headache, toothache, arthritic pain, and cancer.

In addition, the diseases to be treated by the compounds, compositions and methods described herein may be ophthalmic disorders. Other diseases in which the ophthalmic disease that may be treated or prevented and which play a role in the pathogenesis mechanism of angiogenesis are selected from the group consisting of diaphoresis (e.g., Sjogren's syndrome), macular degeneration, right-obscurant and wide angle glaucoma, retinal ganglion degeneration, , Retinitis, retinopathy, uveitis, glare, and inflammation and pain associated with acute injury to the eye tissue. The compounds, compositions and methods described herein are useful for the treatment of glaucoma retinopathy and / or diabetic retinopathy. The compounds, compositions and methods described herein are also useful in the treatment of post-surgical inflammation or pain due to eye surgery, such as cataract surgery and refractive surgery. In a further embodiment, the ophthalmic disorder is selected from the group consisting of diapason, right occlusive glaucoma and wide angle glaucoma.

In addition, the diseases to be treated by the compounds, compositions and methods described herein may be autoimmune diseases. Autoimmune diseases that can be prevented or cured include, but are not limited to, rheumatoid arthritis, inflammatory bowel disease, inflammatory pain, ulcerative colitis, Crohn's disease, periodontal disease, temporomandibular joint disease, multiple sclerosis, diabetes, Autoimmune neutropenia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, atopic dermatitis, graft versus host disease, and psoriasis. Inflammatory diseases that can be prevented or cured include, but are not limited to, asthma, allergies, respiratory distress syndrome or acute or chronic pancreatitis. In particular, the compounds, compositions and methods described herein are useful for the treatment of certain autoimmune diseases, rheumatoid arthritis and multiple sclerosis.

In addition, the diseases to be treated with the compounds, compositions and methods described herein may be dermatological disorders. In certain embodiments, dermatological disorders that can be treated or prevented using the MEK kinase inhibitors of the present invention include melanoma, basal cell carcinoma, squamous cell carcinoma, and other non-epithelial skin cancers and also psoriasis and persistent itching, And other diseases associated with the skin structure.

Metabolic disorders that may be treated or prevented include, but are not limited to, metabolic syndrome, insulin resistance, and type 1 and type 2 diabetes. In addition, the compositions described herein may also be useful in the treatment of other metabolic disorders associated with insulin resistance and typically excessive inflammatory signaling, such as atherosclerosis.

The compounds, compositions and methods described herein are also useful for the treatment of vascular disease, migraine, headache, nodular arteriosclerosis, thyroiditis, aplastic anemia, Hodgkin's disease, encephalopathy, rheumatic fever, type I diabetes, neuromuscular junction disease, Myocardial ischemia, myocardial ischemia, myocardial ischemia, myocardial ischemia, myocardial ischemia, myocardial ischemia, myocardial ischemia, myocardial ischemia, myocardial ischemia, myocardial ischemia, myocardial ischemia, , Cardiovascular ischemia, and secondary ischemia to cardiac arrest, and the like. The compounds, compositions and methods described herein may also be useful in the treatment of allergic rhinitis, respiratory distress syndrome, endotoxic shock syndrome, and atherosclerosis.

In addition, the diseases to be treated by the compounds, compositions and methods described herein may be cardiovascular. In certain embodiments, the cardiovascular condition is induced after a medical condition including, but not limited to, atherosclerosis, cardiac hypertrophy, idiopathic cardiomyopathy, heart failure, angiogenesis-related conditions or disorders, and restenosis due to surgery and angioplasty And proliferation.

In addition, the diseases to be treated with the compounds, compositions and methods described herein may be neurological disorders. In certain embodiments, the neurological disorder is selected from the group consisting of Parkinson's disease, Alzheimer's disease, Alzheimer's dementia, and central nervous system damage due to stroke, ischemia, and trauma. In another embodiment, the neurological disorder is selected from the group consisting of epilepsy, neuropathic pain, depression, and bipolar disorder.

In addition, the diseases to be treated with the compounds, compositions and methods described herein include, but are not limited to, cancers such as acute myelogenous leukemia, thymus, brain, lung, squamous cell, skin, cancer of the eye, retinoblastoma, (CNS), PNS, kidney, kidney, liver, ovary, prostate, rectum, stomach, stomach, stomach, stomach, pancreas, bladder, breast, cervix, AIDS-related (e.g., lymphoma and Kaposi sarcoma) or virus-induced cancer. In some embodiments, the compounds and compositions are used for the treatment of non-cancerous hyperproliferative disorders such as benign hyperplasia of the skin (e.g. psoriasis), restenosis, or benign hyperplasia of the prostate (for example benign prostatic hyperplasia (BPH) . &Lt; / RTI &gt;

In addition, the diseases to be treated with the compounds, compositions and methods described herein in mammals include, but are not limited to, pancreatitis, kidney disease (e.g., proliferative glomerulonephritis and diabetes-induced kidney disease), pain, vasculogenesis, Inflammatory bowel disease, atherosclerosis, skin diseases such as psoriasis, eczema and scleroderma, diabetes, diabetic retinopathy, immature &lt; RTI ID = 0.0 &gt; Retinopathy, aging-related macular degeneration, hemangiomas, tendinitis, bursitis, sciatica, glioma, melanoma, Kaposi sarcoma and ovaries, breast, lung, pancreas, prostate, colon and skin of the epidermis.

In addition, the diseases to be treated with the compounds, compositions and methods described herein may be the prevention of blastocyst implantation in mammals.

Patients who are treated according to the methods of the present invention, or a pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate or derivative thereof, of the compounds described herein, Restenosis; Atherosclerosis; BPH; Breast cancers such as ductal carcinomas, ductal carcinomas, colloid carcinomas, atypical carcinomas and inflammatory breast cancers in ductal tissue of the mammary gland; Ovarian cancer, such as epithelial ovarian tumors, such as adenocarcinoma in the ovary and adenocarcinoma that has migrated from the ovary to the abdominal cavity; Cervical cancer; Adenocarcinoma such as squamous cell carcinoma and adenocarcinoma in the cervical epithelium; Prostate cancer, for example, prostate cancer selected from adenocarcinoma or adenocarcinoma that has migrated to the bone; Pancreatic cancer, such as epithelial carcinoma in the pancreatic duct tissue and adenocarcinoma in the pancreatic duct; Bladder cancer such as transitional cell carcinoma in the bladder, urinary epithelial carcinoma (transitional cell carcinoma), tumor in the urinary epithelium that connects the bladder, squamous cell carcinoma, adenocarcinoma and small cell carcinoma; Leukemia such as acute myelogenous leukemia (AML), acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hair cell leukemia, myelodysplasia and myeloproliferative disorders; Bone cancer; Lung cancer such as non-small cell lung cancer (NSCLC) (squamous cell carcinoma, adenocarcinoma and large cell undifferentiated carcinoma) and small cell lung cancer; Skin cancer such as basal cell carcinoma, melanoma, squamous cell carcinoma and ultraviolet keratosis (sometimes a skin condition developing into squamous cell carcinoma); Retinoblastoma of the eye; Skin or guide (eye) melanoma; Primary liver cancer (liver-initiated cancer); Kidney cancer; Thyroid carcinoma such as papillary, follicular, water and undifferentiated; AIDS-related lymphomas such as diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma and small non-cleaved cell lymphoma; Kaposi's sarcoma; Viral-induced cancers such as hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatocellular carcinoma; Human lymphocytic virus-type 1 (HTLV-1) and adult T-cell leukemia / lymphoma; And human papilloma virus (HPV) and cervical cancer; Cancer of the central nervous system (CNS), such as primary brain tumors such as glioma (astrocytoma, undifferentiated astrocytoma or polymorphic glioblastoma), glioma, ependymoma, meningioma, lymphoma, schwannoma and hematoblastoma; Cancers of the peripheral nervous system (PNS), such as auditory neuronal and malignant peripheral nerve tumors (MPNST), such as neurofibromatosis and schwannomas, malignant fibrous histiocytoma, malignant fibrous histiocytoma, malignant meningioma, malignant mesothelioma and malignant mixed mullerian tumors; Cancers of the oral and oropharynx, such as hypopharyngeal, laryngeal, nasal, and urinary cancers; Gastric cancers such as lymphoma, stomach and gastric tumors and carcinoid tumors; Testicular cancers such as germ cell tumors (GCT) such as normal and non-normal pilates, and gonadal stromal tumors such as Lydia cell tumors and Sertoli cell tumors; Thymoma, such as thymoma, thymic carcinoma, Hodgkin's disease, non-Hodgkin's lymphoma, carcinoid or carcinoid tumor; Rectal cancer; And patients diagnosed with colon cancer.

Kit

The compounds, compositions and methods described herein provide kits for the treatment of disorders, such as the disorders described herein. Such a kit includes the compound (s) or composition described herein in a container and, optionally, instructions that teach how to use the kit in various ways and in accordance with the approach described herein. Such kits may also be used to identify and / or establish the activity and / or benefits of information, such as academic references, package insert materials, clinical trial results, and / And other information useful to the user. This information can be based on the results of various studies, for example, studies using laboratory animals with in vivo models and studies based on human clinical trials. The kits described herein may be provided, sold and / or promoted to health administrators, such as specialists, nurses, pharmacists, prescription handlers, and the like. In some embodiments, the kit may also be sold directly to the consumer.

The compounds described herein can be used as diagnostic and research reagents. For example, the compounds described herein, alone or in combination with other compounds, can be used as a tool in differential and / or combined analysis to reveal expression patterns of genes expressed in cells and tissues. As a non-limiting example, expression patterns in cells or tissues treated with one or more compounds are compared to control cells or tissues not treated with the compound, and the resulting patterns are analyzed for differential gene expression levels , Since this level is related to, for example, the disease relevance, signaling pathway, intracellular location, expression level, size, structure or function of the investigating gene. This assay can be performed on cells that are not stimulated or stimulated in the presence or absence of other compounds that affect the expression pattern.

The compounds and formulations of the invention are useful not only for human treatment but also for veterinary treatments such as companion animals (e.g. dogs, cats), exotic animals and animal animals (e.g. horses) such as mammals, Also useful

The following examples and preparations further illustrate and illustrate the compounds of the present invention and the methods for preparing these compounds. It is to be understood that the scope of the present invention is not limited in any way by the following examples and preparations.

Example

General exemplary procedures for the synthesis of sulfonamides

Procedure A: To a solution of the amine (1 eq.) In anhydrous dichloromethane (3 mL / mmol) was added anhydrous triethylamine (5 eq.). Sulfonyl chloride (1 eq) was added to the solution and the solution was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was purified by flash column chromatography on silica.

Procedure B: To a stirred solution of the amine (1 eq) in anhydrous pyridine (5 mL / mmol) was added sulfonyl chloride (1 to 5 equivalents). The reaction mixture was stirred at 40 &lt; 0 &gt; C for 48 hours. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried (MgSO ₄₎ was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica.

Procedure C: Iodo-substitution of atoms:

Dioxane and water (3: 1) I aryl of 1 equivalent of the de-digested mixture of iodide, 1.5 equivalent of the boronic acid or boronic ester, 0.25 equivalent of PdCl ₂ (dppf) × DCM and 10 eq. Of anhydrous K ₂ The CO ₃ powder-containing suspension was heated in a microwave reactor for 60 minutes at 115 ° C. This was extracted with aqueous NH ₄ Cl / THF and the organic fractions were dried over Na ₂ SO ₄ . It was purified by column chromatography (Si, EtOAc / hexane, or CHCl ₃ / MeOH) - The crude reaction product is purified by flash. Yield: 20% to 40%.

Procedure D: Synthesis of N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) -2- (alkylamino) ethanesulfonamide:

2-chloro-ethanesulfonyl chloride (0.1 mL, 1 mmol) to CH ₂ Cl ₂ -N ¹ with 5,6-di-fluoro (5 mL) - (2-fluoro-4- iodophenyl) benzene- Was added to a solution of 1,2-diamine (0.364 g, 1 mmol) and triethylamine (0.28 mL, 2 mmol) and the reaction mixture was stirred at room temperature for 16 hours. This was then treated with excess amine (10 eq) in solution or as neat liquid. The reaction mixture was further stirred at room temperature for 6 hours. The reaction mixture was diluted with CH ₂ Cl ₂ (10 mL) and water (10 mL). The organic layer was washed sequentially with dilute HCl (2 x 20 mL, 2 N) and saturated NaHCO ₃ (2 x 10 mL) solution. The CH ₂ Cl ₂ layer was then dried (MgSO ₄ ) and evaporated to give the crude product. The impure product was purified under reflux HPLC conditions to yield the pure product in 50-60% yield.

Example  One

N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) methanesulfonamide:

Step A: 2,3-Difluoro-N- (2-fluoro-4-iodophenyl) -6-nitroaniline:

To a solution of 2-fluoro-4-iodoaniline (11.40 g, 47 mmol) in 100 mL of anhydrous THF was added 47 mL of a 1 M LHMDS solution (47 mmol) in THF at 0 ° C. The color of the solution turned dark purple. The solution was transferred via a cannula to a dropping funnel and the solution (containing the amine free base) was added to a solution of 2,3,4-trifluoronitrobenzene (8.321 g, 47.0 mmol) in anhydrous THF (50 mL) 0.0 &gt; 0 C. &lt; / RTI &gt; After the addition was complete, the mixture was stirred at room temperature under argon for 15 hours. After reducing the volume of the solvent, it was extracted with ethyl acetate and brine. The organic layer was dried over sodium sulfate to remove the solvent and the resulting thick oil was purified by flash chromatography (EtOAc / hexane 1: 5, _Rf = 0.58) to give the crude product, which after drying in vacuo gave a brown solid (Yield, 6.23 g, 33.6%): m / z = 393 [M-1] ^- .

Step B: 5,6-Difluoro-N1- (2-fluoro-4-iodophenyl) benzene-

Iron powder (13.74 g, 246 mmol) and ammonium chloride (13.59 g, 254 mmol) were added to a solution of nitro-diarylamine (6.23 g, 15.8 mmol) in 300 mL of ethanol and the mixture was poured into an oil bath 0.0 &gt; C &lt; / RTI &gt; for 14 hours. This was filtered and the residue was washed twice with ethanol. The ethanol was removed in vacuo and the residue was extracted with ethyl acetate / 1 M NaOH solution. During the extraction, more precipitate formed, which was filtered off and discarded. The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was removed and the crude product was recrystallized from CHCl ₃ / hexane (1:50). The product was obtained as a brown needle (2.094 g, 66%). _Rf = 0.44 (EtOAc / Hex 1: 3).

Step C: N- (3,4-Difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) methanesulfonamide:

According to general procedure A, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene-1,2-diamine was reacted with methanesulfonyl chloride to yield the desired product.

Example  2

2N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) cyclopropanesulfonamide:

According to general procedure A, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene-1,2-diamine was reacted with cyclopropanesulfonyl chloride to give the desired product.

Example  3

N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) propane-

According to general procedure A, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene-1,2-diamine was reacted with isopropylsulfonyl chloride to give the desired product. Yield: 39%.

Example  4

N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) butane- 1 -sulfonamide:

According to general procedure A, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene-1,2-diamine was reacted with n-butylsulfonyl chloride to give the desired product . Yield: 55%.

Example  5

N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) -2,2,2- trifluoroethanesulfonamide:

According to the general procedure A, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene- 1,2-diamine was reacted with 1,1,1- trifluoroethylsulfonyl chloride To give the desired product. Yield: 28%. m / z = 509 [M- 1] -.

Example  6

N- (3,4-Difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) butane-

According to the general procedure A, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene-1,2-diamine was reacted with sec-butylsulfonyl chloride to give the desired product . Yield: 22%.

Example  7

N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) -N-methylcyclopropanesulfonamide:

(See Example 2) (283.9 mg, 0.61 mmol) in 3 mL of anhydrous THF was added dropwise a solution of N- (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) phenyl) cyclopropane- ) At -78 &lt; 0 &gt; C was added a 1 M LHMDS solution (0.6 mL, 0.6 mol) and the solution was stirred at this temperature for 10 min. Methyl iodide (0.8 mL, 1.824 g, 12.9 mmol) was then added and the mixture was warmed to room temperature and stirred for 7 hours. The solvent was removed and the residue was extracted with EtOAc and brine. Dry the organic fraction with Na ₂ SO _4, the solvent was removed. The resulting crude product was purified by flash-column chromatography (Si, EtOAc / hexane 1: 2, _Rf = 0.45). Yield, yield: 205 mg, 70%.

Example  8

(3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) methanesulfonamide:

According to general procedure A, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene-1,2-diamine was reacted with chloromethane sulfonyl chloride to give the desired product. m / z = 475 [M- 1] -.

Example  9

N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) -2- methylpropane-

According to general procedure B, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene- 1,2-diamine was reacted with 2-methylpropane-2-sulfonyl chloride To give the desired product.

Example  10

N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) cyclopentane sulfonamide:

According to general procedure B, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene-1,2-diamine was reacted with cyclopentane sulfonyl chloride to give the desired product.

Example  11

N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) cyclohexanesulfonamide:

According to general procedure B, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene-1,2-diamine was reacted with cyclohexanesulfonyl chloride to give the desired product.

Example  12

N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) -1-methylcyclopropane-

Step A: n-Butyl 3-chloro-1-propanesulfonate:

CH ₂ Cl ₂ (50 mL) of triethylamine (28 mL, 200 mmol) to CH ₂ Cl ₂ (250 mL) of 3-chloro-propane-1-sulfonyl chloride (36.6 g, 200 mmol) and 1-butanol (18.4 g, 240 mmol) in an ice-cooled solution and stirring continued for 16 h. The mixture was diluted with CH ₂ Cl ₂ (200 mL), washed (aqueous HCl), dried (MgSO ₄ ) and the solvent evaporated to give the title product 1 (40.85 g, 95%) as a slightly yellow oil Which was used in the next reaction without further purification.

Step B: 1-butylcyclopropanesulfonate:

A solution of 1-butyl 3-chloro-l-propanesulfonate (4.6 g, 21.39 mmol in 25 mL THF) and butyllithium (14.7 mL, 23.53 mmol, 1.6 M, THF) in THF (150 mL) Lt; / RTI &gt; under a nitrogen atmosphere. The solution was allowed to warm to 0 &lt; 0 &gt; C and then quenched with water (2 mL). The volatiles were evaporated under reduced pressure and the residue was extracted with CH ₂ Cl ₂ (150 mL). The extract was washed with water, dried (MgSO ₄₎ and evaporated to afford the desired crude product as a pale yellow oil (3.23 g, 78.22%) as a substantially pure form, it was used without further purification used for the next step.

Step C: Butyl 1-methyl-cyclopropanesulfonate:

To a solution of 1-butylcyclopropanesulfonate (1 g, 5.58 mmol) in THF (15 mL) was slowly added butyl lithium solution (3.84 mL, 6.14 mmol, 1.6 M, THF) at -78 <0> C under a nitrogen atmosphere. After 15 min MeI (0.72 mL, 11.16 mmol) was added and the solution allowed to warm to 0 &lt; 0 &gt; C and quenched with water (1 mL). The volatiles were evaporated under reduced pressure and the residue was extracted with CH ₂ Cl ₂ (100 mL). The extract was washed with water and dried to (MgSO ₄₎ and evaporated. The residue was purified by silica gel chromatography (eluent: hexane / CH ₂ Cl ₂ ) to give the title product (0.59 g, 55.0%) as a colorless oil.

Step D: 1-Potassium 1-methyl-cyclopropanesulfonate:

A mixture of 1-butyl 1-methyl-cyclopropanesulfonate (0.386 g, 2 mmol) and potassium thiocyanate (0.194 g, 2 mmol) in DME (5 mL) and water (5 mL) . The volatiles were evaporated to afford the crude sulfonate (0.348 g, quantitatively) which was dried under vacuum at 50 &lt; 0 &gt; C for 16 h. The crude product was used in the next reaction without further purification.

Step E: 1-Methyl-cyclopropanesulfonyl chloride:

A solution of 1-potassium 1-methyl-cyclopropanesulfonate (0.348 g, 2 mmol), thionyl chloride (5 mL) and DMF (5 drops) was refluxed at 60 ° C for 16 hours. The volatiles were evaporated under reduced pressure and the residue was extracted with CH ₂ Cl ₂ (50 mL). Washing the extract with water, dry (MgSO ₄₎ and evaporated and was yellow and the crude product obtained as free oil, which was used in the next reaction without further purification.

Step F: N- (3,4-Difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) -l-methylcyclopropane-

According to general procedure B, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene- 1,2-diamine is reacted with 1-methyl-cyclopropanesulfonyl chloride to give the desired product &Lt; / RTI &gt;

Example  13

2- (2-fluoro-4-iodophenylamino) phenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide:

Step A: Butyl cyclopropanesulfonate:

Cyclopropanesulfonyl chloride (5 g, 35 mmol, 1 eq.) Was dissolved in excess BuOH (20 mL) and the reaction mixture was cooled at -10 ° C and pyridine (5.8 mL, 70 mmol, 2 eq) . The mixture was slowly warmed to room temperature and stirred overnight. The solvent was removed under reduced pressure, and the resulting white solid was dissolved in CHCl _3. Dried the organic phase was washed with water and brine (MgSO ₄₎ and concentrated to yield an oil (4.8 g, 24.9 mmol, 71 %).

Step B: Butyl 1-allylcyclopropane-1-sulfonate:

Butyl lithium solution (15.6 mL, 24.9 mmol, 1.6 M, THF) and allyl iodide (24.9 mmol) were added to a solution of 1-butylcyclopropanesulfonate (4.8 g, 24.9 mmol) Lt; / RTI &gt; The reaction mixture was stirred at -78 &lt; 0 &gt; C for 2 h and at room temperature for 3 h. The volatiles were evaporated under reduced pressure and the residue was extracted with CH ₂ Cl ₂ (100 mL). The extract was washed with water and dried to (MgSO ₄₎ and evaporated. The residue was purified by silica gel chromatography (eluent: hexane / CH ₂ Cl ₂ ) to give the title product (3.75 g, 69.0%) as a colorless oil.

Step C: Potassium 1-allylcyclopropane-1-sulfonate:

A mixture of 1-butyl 1-methyl-cyclopropanesulfonate (3.75 g, 17.2 mmol) and potassium thiocyanate (1.7 g, 17.2 mmol) in DME (20 mL) and water (20 mL) was refluxed for 16 h . The volatiles were evaporated to give the crude sulfonate (3.44 g, quantitatively) which was dried under vacuum at 50 &lt; 0 &gt; C for 16 h. The crude product was used in the next reaction without further purification.

Step D: 1-Allylcyclopropane-1-sulfonyl chloride:

A solution of potassium 1-allylcyclopropane-1-sulfonate (3.44 g, 17.2 mmol), thionyl chloride (10 mL) and DMF (5 drops) was refluxed at 60 <0> C for 16 h. The volatiles were evaporated under reduced pressure and the residue was extracted with CH ₂ Cl ₂ (50 mL). The extract was washed with water, dried (MgSO ₄₎ and was to afford the crude product as yellow and evaporated free five days, this was washed with hexane and without further purification used for the next reaction (2.7 g, 15 mmol, 87 %).

Step E: 1-Allyl-N- (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) phenyl) cyclopropane-

According to general procedure B, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene-1,2-diamine was reacted with 1-allylcyclopropane- The desired product was obtained. m / z = 507 [M- 1] -.

Step F: Preparation of N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) -1- (2,3-dihydroxypropyl) cyclopropane- amides:

(0.77 g, 1.52 mmol) and 4-methyl (2-fluoro-4- Morpholine N-oxide (0.18 g, 1.52 mmol) was dissolved in THF (50 mL). Osmium tetraoxide (0.152 mmol, 0.965 mL, 4% in H ₂ O) was added at room temperature and the reaction mixture was stirred at room temperature for 16 hours. EtOAc was added, and dried (MgSO ₄₎ the organic phase was washed with water and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: EtOAc / MeOH) to give the title product (0.65 g, 79%).

Example  14

(S) -N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) -1- (2,3-dihydroxypropyl) cyclopropane- Sulfonamide:

The pure S isomer was obtained by chiral HPLC separation of the racemic mixture (Example 13).

Example  15

(2-fluoro-4-iodophenylamino) phenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1- Sulfonamide:

The pure R isomer was obtained by chiral HPLC separation of the racemic mixture (Example 13).

Example  16

2- (2-fluoro-4-iodophenylamino) phenyl) -1- (2-hydroxyethyl) cyclopropane-1-sulfonamide:

Step A: 2-d-Bromocyclopropyl) ethanol:

Trifluoroacetic acid (2.31 mL, 3.4188 g, 30 mmol) was added dropwise very slowly to a solution of pure diethylzinc (3.3 mL, 3.977 g, 30 mmol) in 100 mL of anhydrous DCM at 0 ° C (caution: , Fever!). After the addition of TFA was complete, the suspension was stirred at the same temperature for 20 minutes before diiodomethane (2.45 mL, 8.134 g, 30.4 mmol) was added. This was further stirred at 0 &lt; 0 &gt; C for 20 min before a solution of 3-bromobut-3-en-l-ol (1 mL, 1.523 g, 10.1 mmol) in 10 mL DCM was added at the same temperature. After the addition was complete, the mixture was warmed to room temperature and stirred for 4 hours. The mixture was quenched with 100 mL MeOH and 40 mL brine, which was stirred for an additional 30 minutes. Reducing the solvent, the residue was extracted with CHCl ₃ / aqueous NH ₄ Cl. The organic layer was collected, washed with brine and water, and the solvent was removed to give 2- (1-bromocyclopropyl) -ethanol with sufficient purity (1.6564 g, 100%).

Step B: TBS protected 2- (1-bromocyclopropyl) ethanol:

To a solution of cyclopropyl alcohol (step A) (1.303 g, 7.95 mmol) in 30 mL dry DCM was added anhydrous pyridine (1.2 mL, 1.1736 g, 14.8 mmol) and TBSOTf (2.7 mL, 3.1077 g, 11.76 mol) The solution was stirred at room temperature for 16 hours. This was subjected to extraction with CHCl ₃ / brine, dried the organic fraction with MgSO _4. Reducing the solvent the crude product was purified by flash-was purified by column chromatography (Si, CHCl ₃ / hexane 1:10, R _f = 0.4). Yield, 0.796 g, 36%.

Step C: TBS protected 2- (1-chlorosulfonylcyclopropyl) ethanol:

To a solution of cyclopropyl bromide (1.1227 g, 4.04 mmol) prepared in step B in 15 mL of anhydrous diethyl ether was added 1.7 M t-BuLi solution in pentane (4.8 mL, 8.16 mmol) at -78 <0> C. The solution was stirred at this temperature for 30 minutes and then transferred via a transfer cannula to a solution of freshly distilled sulfuryl chloride (0.65 mL, 1.029 g, 8.1 mmol) in 8 mL of diethyl ether at -78 <0> C. The yellow suspension was allowed to warm to room temperature. The solvent was removed and the residue was dried under vacuum to remove the excess sulforyl chloride. The residue was then extracted twice with hexane, filtered and the solvent was evaporated in vacuo to give the sulfonyl chloride as a colorless oil of sufficient purity. Yield (yield): 870 mg (72%).

Step D: Synthesis of TBS-protected N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) -1- (2-hydroxyethyl) Sulfonamide:

According to general procedure B, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene-1,2-diamine is reacted with the cyclopropylsulfonyl chloride prepared in step C The product was obtained.

Step E: Synthesis of N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) -1- (2-hydroxyethyl) cyclopropane-

To a solution of the TBS-protected sulfonamide (21 mg, 0.033 mmol) prepared in Step D in 1 mL of THF was added 0.1 mL of a 1.2 N aqueous HCl solution at 0 C and the solution was stirred for 2 hours. The solvent was reduced and the residue was extracted with aqueous NaHCO ₃ solution and EtOAc. The organic fractions were dried over MgSO ₄ to remove volatiles. The crude product was purified by flash-column chromatography to give _{(Si, CHCl 3 / MeOH 10} 1, R f = 0.45) to give the pure product. Yield (yield): 16.9 mg (100%).

Example  17

N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) -3- hydroxypropane- 1 -sulfonamide:

8 mL of 1,4-dioxane and H ₂ O ₂ mL of a mixture of 3-chloro -N- (3,4- difluoro-2- (2-fluoro-4-iodo-phenyl) phenyl) - To a solution of propane-1-sulfonamide (69.4 mg, 0.138 mmol) was added KOH powder (0.674 g, 12.0 mmol) and the mixture was heated to reflux for 3 days. This was subjected to extraction with EtOAc / brine, the organic fractions were dried with Na ₂ SO ₄ then the volatiles were removed. The residue was purified by flash-column chromatography (Si, DCM / MeOH 5: 1, _Rf = 0.3). Yield (Yield): 41 mg (62%).

Example  18

2- (2-fluoro-4-iodophenylamino) phenyl) -2-methyl-5- (trifluoromethyl)

According to general procedure B, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene- 1,2-diamine (0.182 mmol) Sulfonyl chloride (0.5 mmol) to give N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) - (trifluoromethyl) furan-3-sulfonamide.

Example  19

Methylthiazol-2-yl) acetamide: &lt; RTI ID = 0.0 &gt; N- (5- (N- (3,4-Difluoro-

According to general procedure B, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene-1,2-diamine (0.182 mmol) (2-fluoro-4-iodophenylamino) phenyl) sulfamoyl chloride (0.5 mmol) to give N- (5- ) -4-methylthiazol-2-yl) acetamide.

Example  20

(3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) Thiophene-2-sulfonamide:

According to general procedure B, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene-1,2-diamine (0.182 mmol) (5-chloro-1,2,4-thiadiazol-3-yl) -N- (4-thiadiazol-3-yl) thiophene- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) thiophene-2-sulfonamide was obtained.

Example  21

N- (3,4-Difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) -3,5-dimethylisoxazole-

According to general procedure B, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene-1,2-diamine (0.182 mmol) was reacted with 3,5-dimethylisoxazole- - sulfonyl chloride (0.5 mmol) to give N- (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) phenyl) -3,5-dimethylisoxazole- - &lt; / RTI &gt; sulfonamide.

Example  22

Fluoro-4-iodophenylamino) phenyl) -1,3-dimethyl-1H-pyrazole-4-sulfonamide: A mixture of 5-chloro-N-

According to general procedure B, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene- 1,2-diamine (0.182 mmol) (2-fluoro-4-iodophenylamino) phenyl) - lH-pyrazole-4-sulfonyl chloride (0.5 mmol) 1,3-dimethyl-1H-pyrazole-4-sulfonamide was obtained.

Example  23

N- (3,4-Difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) -2,5-dimethylfuran-

According to general procedure B, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene- 1,2-diamine (0.182 mmol) (2-fluoro-4-iodophenylamino) phenyl) -2,5-dimethylfuran-3-sulfonamide was prepared by reacting N- (3,4-difluoro- .

Example  24

Phenyl) -1-methyl-3- (trifluoromethyl) -lH-pyrazole-4-sulfone amides:

According to general procedure B, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene-1,2-diamine (0.182 mmol) Methyl-1H-pyrazole-4-sulfonyl chloride (0.5 mmol) to give N- (3,4-difluoro-2- -Methyl-3- (trifluoromethyl) -lH-pyrazole-4-sulfonamide was obtained.

Example  25

N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) -2,4- dimethylthiazole-

According to general procedure B, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene- 1,2-diamine (0.182 mmol) was reacted with 2,4-dimethylthiazol- (4-fluoro-4-iodophenylamino) phenyl) -2,4-dimethylthiazole-5-sulfone Amide. &Lt; / RTI &gt;

Example  26

2- (2-fluoro-4-iodophenylamino) phenyl) -1,2-dimethyl-1H-imidazole-

According to general procedure B, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene- 1,2- diamine was reacted with l, 2-dimethyl- / RTI &gt; chloride to give the title compound.

Example  27

N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) thiophene-

Reaction of 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene-1,2-diamine with thiophene-3-sulfonyl chloride according to general procedure B .

Example  28

N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl)

Reaction of 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene-1,2-diamine with furan-2-sulfonyl chloride according to general procedure B Respectively.

Example  29

N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) -5- methylthiophene-

According to general procedure B, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene-1,2-diamine was reacted with 5-methylthiophene- The title compound was obtained.

Example  30

5- (2-fluoro-4-iodophenylamino) phenyl) thiophene-2-sulfonamide:

According to general procedure B, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene-1,2-diamine was reacted with 5-chlorothiophene- The title compound was obtained.

Example  31

(3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) thiophene-2-sulfonamide:

According to general procedure B, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene-1,2-diamine was reacted with 5-bromothiophene- The title compound was obtained.

Example  32

(3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) thiophene-3-sulfonamide:

According to general procedure B, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene-1,2-diamine was reacted with 4-bromothiophene- The title compound was obtained.

Example  33

(3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) thiophene-2-sulfonamide:

According to general procedure B, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene- 1,2- diamine was reacted with 4-bromo-5-chlorothiophene- / RTI &gt; chloride to give the title compound.

Example  34

(3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) thiophene-2-sulfonamide:

According to general procedure B, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene-1,2-diamine was reacted with 3-bromo-5- / RTI &gt; chloride to give the title compound.

Example  35

2- (2-fluoro-4-iodophenylamino) phenyl) -2,5-dimethylthiophene-3-sulfonamide:

According to general procedure B, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene- 1,2-diamine was reacted with 2,5- dimethylthiophene- To give the title compound.

Example  36

2- (2-fluoro-4-iodophenylamino) phenyl) thiophene-3-sulfonamide:

According to general procedure B, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene- 1,2-diamine was reacted with 2,5- dichlorothiophene- To give the title compound.

Example  37

Methyl 3- (N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) sulfamoyl) thiophene-

According to general procedure B, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene-1,2-diamine was reacted with methyl 3- (chlorosulfonyl) thiophene- Lt; / RTI &gt; to yield the title compound.

Example  38

Methyl 5- (N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) sulfamoyl)

According to the general procedure B, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene- 1,2-diamine was reacted with methyl 5- (chlorosulfonyl) -Pyrrole-2-carboxylate to give the title compound.

Example  39

N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) -5- methylisoxazole-

According to the general procedure A, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene-1,2-diamine was reacted with the corresponding sulfonyl chloride to give the title compound. Yield: 22%. m / z = 508 [M- 1] -.

Example  40

(3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) propane-1-sulfonamide:

According to the general procedure A, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene-1,2-diamine is reacted with 3-chloropropane- The product was obtained.

Example  41

N- (2- (4-chloro-2-fluorophenylamino) -3,4-difluorophenyl) cyclopropanesulfonamide:

See Example 1.

Example  42

N- (3,4-difluoro-2- (4-iodo-2-methylphenylamino) phenyl) cyclopropanesulfonamide:

See Example 1.

Example  43

N- (2- (4-tert-butyl-2-chlorophenylamino) -3,4-difluorophenyl) cyclopropanesulfonamide:

See Example 1.

Example  44

N- (2- (2,4-dichlorophenylamino) -3,4-difluorophenyl) cyclopropanesulfonamide:

See Example 1.

Example  45

4- (trifluoromethyl) phenylamino) phenyl) propane-1-sulfonamide: &lt; EMI ID =

See Example 1.

Example  46

N- (3,4-Difluoro-2- (2-chloro-4-trifluoromethyl) phenylamino) methanesulfonamide:

See Example 1.

Example  47

2- (2-chloro-4-trifluoromethyl) phenylamino) phenyl) propane-1-sulfonamide:

See Example 1.

Example  48

2- (2-bromo-4-trifluoromethyl) phenylamino) phenyl) propane-1-sulfonamide:

See Example 1.

Example  49

(3,4,6-Trifluoro-2- (2-fluoro-4-iodo-phenylamino) -phenyl) -amide:

Step A: (2-Fluoro-4-iodo-phenyl) - (2,3,5-trifluoro-6-nitro- phenyl)

2-Fluoro in dry THF (100 mL) -4- iodo-aniline (3.64 g, 15.37 mmol) cooled to -78 was added ℃ under nitrogen, 1.0 M lithium hexamethyl silah azide (LiN (SiMe ₃ ) ₂ ) A solution of "LHMDS" (15.37 mL, 15.37 mmol) was slowly added. The reaction mixture was stirred at -78 &lt; 0 &gt; C for an additional 1 h before 2,3,4,6-tetrafluoronitrobenzene was added. The reaction mixture was allowed to warm to room temperature and stirring continued for 16 hours. Ethyl acetate (200 mL) was added to the reaction mixture and washed with water. The organic layer was dried over sodium sulfate and further purified by column chromatography to give a yellow solid (3.75 g, yield: 59.24%).

Step B: 3,4,6-Trifluoro-N ² - (2-fluoro-4-iodo-phenyl)

To a stirred solution of (2-fluoro-4-iodo-phenyl) - (2,3,5-trifluoro-6-nitro- phenyl) -amine 3 (5.2 g, 12.62 mmol) in EtOH Was added ammonium chloride (10.12 g, 189.3 mmol) and iron powder (10.57 g, 189.3 mmol). The reaction mixture was continuously refluxed for 16 hours. The reaction mixture was allowed to cool, filtered through celite and concentrated to dryness. The resulting residue was taken up in EtOAc and washed with water. The EtOAc layer was dried over sodium sulfate and further purified by crystallization from EtOH to give an off-white solid (3.2 g, yield: 66.39%).

Step C: 4,6,7-Trifluoro-l- (2-fluoro-4-iodo-phenyl) -1,3-dihydrobenzoimidazol-

Benzene-1,2-diamine 3 (0.285 g, 0.74 mmol) in CH ₂ Cl ₂ (2 mL) was added to a solution of 3,4,6- Was added 1,1'-carbonyldiimidazole (0.125 g, 0.75 mmol). The reaction mixture was continuously stirred at room temperature for 16 hours, at which time the product precipitated. The white solid was filtered and used without further purification (0.2 g, yield: 65.85%): m / z = 407 [M-1] ^- .

Step D / E: Cyclopropanesulfonic acid (3,4,6-Trifluoro-2- (2-fluoro-4-iodo-phenylamino) -phenyl)

To a solution of 4,6,7-trifluoro-l- (2-fluoro-4-iodo-phenyl) -1,3-dihydrobenzimidazol-2-one (0.2 g, 0.41 mmol) was cooled to -78 ° C under nitrogen and a 1.0 M LiHMDS solution (0.41 mL, 0.41 mmol) was slowly added (2 mL), followed by cyclopropanesulfonyl chloride (0.050 mL, 0.49 mmol) Was added. The reaction mixture was stirred continuously at room temperature for 16 h, concentrated to dryness and taken up in EtOAc. The EtOAc was washed with water, dried over sodium sulfate and concentrated to dryness. The obtained residue was purified by silica gel column chromatography to obtain 1-cyclopropanesulfonyl-4,5,7-trifluoro-3- (2- fluoro-4-iodo-phenyl) -1,3-dihydro-benzimidazole- On 5 was taken up in dioxane (2 mL), 1.0 N NaOH (0.5 mL) was added thereto, and stirring was continued for 16 hours in an indoor at 50 ° C. The reaction appeared to be incomplete on TLC and the product was purified by HPLC to give an off-white solid (4.4 mg). M + H & lt ^; + & gt ^; : 484.7, MH & lt ^; + ^& gt ^; : 486.7.

Example  50

N- (3,4-difluoro-2- (4-fluoro-2-iodophenylamino) -6-ethoxyphenyl) cyclopropanesulfonamide:

Step A: (2,3-Difluoro-5-methoxy-6-nitro-phenyl) - (2- fluoro-4- iodo-phenyl)

To a stirred solution of (2-fluoro-4-iodo-phenyl) - (2,3,5-trifluoro-6-nitro- phenyl) -amine (1.23 g, 3 mmol) in anhydrous THF Was cooled to -78 <0> C under nitrogen and a solution of 25% NaOMe (0.68 mL, 0.3 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and stirring continued for 16 hours. The reaction was incomplete at TLC. Ethyl acetate (100 mL) was added to the reaction mixture and washed with water. The organic layer was dried over sodium sulfate and further purified by column chromatography to give a yellow solid (0.6 g, yield: 47.6%). m / z = 424 [M = H] &lt; ^{+ &} gt ;.

Step B: 5,6-Difluoro-N1- (4-fluoro-2-iodophenyl) -3-methoxybenzene-

To a solution of (2,3-difluoro-5-methoxy-6-nitro-phenyl) - (2- fluoro-4- iodo-phenyl) -amine (0.57 g, 1.34 mmol) in EtOH To the stirred solution was added ammonium chloride (1.18 g, 20.16 mmol) and iron powder (1.15 g, 21.44 mmol). The reaction mixture was stirred under reflux for 16 hours. The reaction mixture was allowed to cool, filtered through celite and concentrated to dryness. The resulting residue was taken up in EtOAc and washed with water. The EtOAc layer was dried over sodium sulfate and further purified by crystallization from EtOH to give an off-white solid (0.47 g, yield: 90.3%).

Step C: 6,7-Difluoro-1- (4-fluoro-2- iodophenyl) -4-methoxy-1H- benzo [d] imidazol-

Fluoro-2-iodophenyl) -3-methoxybenzene-l, 2-diamine (0.17 g, 0.43 mmol) in CH ₂ Cl ₂ (2 mL) Was added 1,1'-carbonyldiimidazole (0.085 g, 0.53 mmol). The reaction mixture was continuously stirred at room temperature for 16 hours, at which time the product precipitated. The white solid was filtered off and used without further purification (0.089 g). m / z = 419 [M- 1] -.

Step D / F: N- (3,4-Difluoro-2- (4-fluoro-2-iodophenylamino) -6-methoxyphenyl) cyclopropanesulfonamide:

To a solution of 1- (cyclopropylsulfonyl) -4,5-difluoro-3- (2-fluoro-4-iodophenyl) -7-methoxy-1H- benzo [d] A stirred solution of imidazol-2 (3H) -one (0.89 g, 0.17 mmol) was cooled to -78 C under nitrogen and a 1.0 M LiHMDS solution (0.17 mL, 0.17 mmol) was slowly added (2 mL) Was added cyclopropanesulfonyl chloride (0.021 mL, 0.21 mmol). The reaction mixture was stirred continuously at room temperature for 16 h, concentrated to dryness and taken up in EtOAc. The EtOAc was washed with water, dried over sodium sulfate and concentrated to dryness. The resulting 1- (cyclopropylsulfonyl) -4,5-difluoro-3- (2-fluoro-4-iodophenyl) -7-methoxy-1H- benzo [d] imidazol- 3H) -one was taken up in dioxane (2 mL), to this was added 1.0 N NaOH (0.5 mL) and stirring was continued for 16 h indoors at 50 &lt; 0 &gt; C. The reaction appeared incomplete on TLC and the product was purified by HPLC to give an off-white solid (2.5 mg).

Example  51

(3-Fluoro-4-iodo-phenylamino) -6-methoxy-phenyl) -amide:

To a solution of 5,6-difluoro-N1- (4-fluoro-2-iodophenyl) -3-methoxybenzene-l, 2-diamine (0.150 g, 0.38 mmol) in anhydrous CH ₂ Cl ₂ ) Was slowly added TEA (0.264 mL, 1.9 mmol) and methanesulfonyl chloride. The reaction mixture was continuously stirred at room temperature for 16 hours, and two products were observed with TLC in the starting material, indicating that the reaction was incomplete. The reaction mixture was washed with water, the organic layer was dried over sodium sulfate, concentrated to dryness, and the product was purified by column chromatography. A small amount of product was found to be the expected compound (6.4 mg).

Example  52

2- (4-fluoro-2-iodo-phenylamino) -phenyl] -amide: A solution of 1- (2,3- dihydroxy- propyl) -cyclopropanesulfonic acid [3,4,6-

Step A: 1-Allyl-cyclopropanesulfonic acid [3,4,6-Trifluoro-2- (2- fluoro-4-iodo-phenylamino) phenyl]

According to general procedure B, 1-allyl-cyclopropanesulfonyl chloride was reacted with 3,5,6-trifluoro-N ¹ - (2-fluoro-4-iodophenyl) benzene- To give the title product.

Step B: Synthesis of 1- (2,3-dihydroxypropyl) -N- (3,4,6-trifluoro-2- (2- fluoro-4-iodophenylamino) phenyl) cyclopropane- - sulfonamide:

Phenyl] -amide (110 mg, 0.21 mmol) and 4-methyl (2-fluoro-phenyl) Morpholine N-oxide (24.6 mg, 0.21 mmol) was dissolved in THF (8 mL). Osmium tetroxide (0.021 mmol, 0.153 mL, 4% in H ₂ O) was added at room temperature and the reaction mixture was stirred at room temperature for 16 hours. EtOAc was added, washed with water and the organic phase was concentrated under reduced pressure and dried (MgSO _4). The residue was purified by silica gel chromatography (eluent: EtOAc / MeOH) to give the title product (0.89 g, 75%).

Example  53

(S) -1- (2,3-dihydroxypropyl) -N- (3,4,6-trifluoro-2- (2- fluoro-4-iodophenylamino) phenyl) cyclopropane- 1-sulfonamide:

The pure S isomer was obtained by chiral HPLC separation of the racemic mixture (Example 52).

Example  54

(R) -1- (2,3-dihydroxypropyl) -N- (3,4,6-trifluoro-2- (2- fluoro-4-iodophenylamino) phenyl) cyclopropane- 1-sulfonamide:

The pure R isomer was obtained by chiral HPLC separation of the racemic mixture (Example 52).

Example  55

2- (2-fluoro-4-iodophenylamino) phenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide:

Step A: 1-Allyl-N- 3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6- methoxyphenyl) cyclopropane-

According to general procedure B, 1-allyl-cyclopropanesulfonyl chloride was reacted with 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) -3- methoxybenzene- &Lt; / RTI &gt; to give the title product.

Step B: Preparation of N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) -1- (2,3-dihydroxypropyl) cyclopropane- amides:

Cyclopentane-1-sulfonamide (97 mg, 0.18 mmol) was added to a solution of 1-allyl-N- (3,4-difluoro-2- ) And 4-methylmorpholine N-oxide (21 mg, 0.18 mmol) were dissolved in THF (8 mL). Osmium tetroxide (0.018 mmol, 0.13 mL, 4% in H ₂ O) was added at room temperature and the reaction mixture was stirred at room temperature for 16 hours. EtOAc was added, washed with water and the organic phase was concentrated under reduced pressure and dried (MgSO _4). The residue was purified by silica gel chromatography (eluent: EtOAc / MeOH) to give the title product (0.80 g, 78%).

Example  56

(S) -N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3- Cyclopropane-1-sulfonamide:

The pure S isomer was obtained by chiral HPLC separation of the racemic mixture (Example 55).

Example  57

(2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) Cyclopropane-1-sulfonamide:

The pure R isomer was obtained by chiral HPLC separation of the racemic mixture (Example 55).

Example  58

1- (2-hydroxyethyl) -N- (3,4,6-trifluoro-2- (2-fluoro-4-iodophenylamino) phenyl) cyclopropane-

Step A: Synthesis of TBS-protected 1- (2-hydroxyethyl) -N- (3,4,6-trifluoro-2- (2- fluoro-4-iodophenylamino) phenyl) cyclopropane- 1-sulfonamide:

According to general procedure B, the sulfonyl chloride prepared in step C of Example 16 was reacted with 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) -3-fluorobenzene- 2-diamine to give the title product. Yield: 13%.

Step B: Preparation of l- (2-hydroxyethyl) -N- (3,4,6-trifluoro-2- (2- fluoro-4-iodophenylamino) -phenyl) cyclopropane- amides:

The same procedure as in Step E of Example 16 was followed. Yield: 100%.

Example  59

(2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2-hydroxyethyl) cyclopropane-1-sulfonamide :

Step A: Preparation of TBS-protected N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) Cyclopropane-1-sulfonamide:

According to general procedure B, the sulfonyl chloride prepared in step C of Example 16 was reacted with 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) -3- methoxy- , 2-diamine to give the title product. Yield: 37%.

Step B: Synthesis of N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2-hydroxyethyl) cyclopropane- - sulfonamide:

The same procedure as in Step E of Example 16 was followed. Yield: 100%.

Example  60

2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (3-hydroxy- ) &Lt; / RTI &gt; cyclopropane-1-sulfonamide:

Step A: Dimethyl 2- (2-bromoallyl) malonate:

To a suspension of sodium hydride (5.0 g, 125 mmol) in HMPA (50 mL, distilled from calcium hydride) was added a solution of dimethyl malonate (11.7 mL, 100 mmol) in HMPA (5 mL) . The mixture was heated to 50 &lt; 0 &gt; C and stirred for 1 hour. The solution was then cooled again to 0 C and a solution of 2,3-dibromopropene (12.2 mL, 100 mmol) in HMPA (5 mL) was added to the reaction mixture. The solution was then warmed to 40 &lt; 0 &gt; C and stirred for 1 hour. The reaction mixture was quenched with aqueous HCl (10%, 88 mL) and extracted with ether (3 x 45 mL). The collected organic fractions were dried over MgSO _4, the solvent was removed in vacuo. The crude oil was purified via silica gel chromatography (eluent: chloroform / hexane) to give the title product as a colorless oil (16.3 g, 65%).

Step B: 2- (2-Bromoallyl) propane-1,3-diol:

Lithium aluminum hydride (1.9 g, 7.65 mmol) was slurried in anhydrous diethyl ether (50 mL) and cooled to -78 [deg.] C in a dry ice / acetone bath. A solution of the product from Step A (0.639 g, 16.84 mmol) in anhydrous ether (26 mL) was then added dropwise. After the addition of malonate the solution was allowed to warm to room temperature and stirring continued for 3 hours. The reaction was quenched with brine (50 mL) and extracted with ethyl acetate (3 × 25 mL) and dried over MgSO _4. The solvent was removed in vacuo to give the desired product (1.3 g, 86%) which was used in the next step without further purification.

Step C: Di-tert-butyldimethylsilyl protected 2- (2-bromoallyl) propane-1,3-diol:

The product from Step B (2.8 g, 14.20 mmol) was dissolved in anhydrous THF (140 mL). Anhydrous pyridine (2.5 mL, 31.24 mmol) was added and the solution was cooled to 0 &lt; 0 &gt; C. tert-Butyldimethylsilyl triflate (7.2 mL, 31.24 mmol) was added dropwise, and after completion, the reaction solution was heated to 35 ° C. After stirring for 6 days and then the reaction was quenched with 100 mL brine and extracted with ethyl acetate (3 × 50 mL) and dried over MgSO _4. The combined organic phases were evaporated to give the crude product (5.5 g, 91%) as a yellow oil which was used in the next step without further purification.

Step D: Di-tert-butyldimethylsilyl protected 2 - ((1-bromocyclopropyl) methyl) propane-

Anhydrous CH ₂ Cl ₂ (10 mL) and diethylzinc (1.0 M in hexanes, 4.65 mL, 4.65 mmol) were charged to the reaction flask at 0 ° C. Trifluoroacetic acid (0.358 mL, 4.65 mmol) was added dropwise and the solution was allowed to stir for 20 minutes. Diiodomethane (0.375 mL, 4.65 mmol) was then added and the solution was stirred for an additional 20 minutes. Finally, the product from Step C (0.492 g, 1.16 mmol) was added and the solution was allowed to warm to ambient temperature with stirring for 16 hours. The reaction was quenched with saturated aqueous NH ₄ Cl. The layers were partitioned and the aqueous phase was extracted with chloroform (3 x 5 mL). The combined organic phases were washed with brine (10 mL) and dried in MgSO ₄ and remove the volatiles in vacuo. The resulting crude material was purified via silica gel chromatography (eluent: chloroform / hexane) to give the product as a clear oil (0.280 g, 64%).

Step E: Di-tert-butyldimethylsilyl protected 1- (3-hydroxy-2- (hydroxymethyl) propyl) cyclopropane-1-sulfonyl chloride:

The product from Step D (0.507 g, 1.16 mmol) was dissolved in anhydrous ether (6 mL) and the reaction solution was cooled to -78 &lt; 0 &gt; C. Then, tert-butyllithium (1.7 M in pentane, 1.50 mL, 2.55 mmol) was added dropwise over 5 minutes. After stirring for 0.5 h, the lithiated product was transferred via cannula to a stirred solution of sulfuryl chloride (0.206 mL, 2.55 mmol) in anhydrous ether (6 mL) at -78 &lt; 0 &gt; C. Once the work-up was complete, the solution was allowed to warm to room temperature to evaporate the solvent and the resulting white solid was slurried in anhydrous hexane. The slurry was immediately filtered through celite and all volatiles were removed in vacuo. The resulting crude product (0.376 g, 71%) was isolated as a yellow oil which was used in the next step without further purification.

Step F: Synthesis of di-tert-butyldimethylsilyl protected N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -Hydroxy-2- (hydroxymethyl) propyl) cyclopropane-1-sulfonamide:

2-diamine (8.8 mg, 0.022 mmol) was reacted with anhydrous pyridine (0.5 mL) in an argon atmosphere, to a solution of 5,6- difluoro-N1- (2- fluoro-4-iodophenyl) -3- methoxybenzene- ). The product from step E (20.5 mg, 0.045 mmol) was dissolved in anhydrous pyridine (0.5 mL) and added to the reaction flask and the mixture was heated at 80 &lt; 0 &gt; C for 21 h. The solvent was removed in vacuo and the resulting crude material purified via silica gel chromatography (eluent: ethyl acetate / hexanes) to give the title compound (2.75 mg, 15%). m / z = 813.5 (M-1).

Step G: Synthesis of N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) Methyl) propyl) cyclopropane-1-sulfonamide:

The product from step F (27.9 mg, 0.0342 mmol) was dissolved in THF (1 mL) and treated with aqueous HCl (1.2 N, 0.2 mL) at 0 <0> C. The resulting solution was stirred for 4 hours. The reaction was then quenched with saturated aqueous NaHCO ₃ , extracted with ethyl acetate, dried over MgSO ₄ and the volatiles removed in vacuo. The resulting crude material was purified by silica gel chromatography (eluent: methanol / chloroform) followed by LC-MS purification to give the title compound (11.8 mg, 59%).

Example  61

N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) cyclobutane sulfonamide:

Step A: Cyclobutane sulfonyl chloride:

A solution of cyclobutyl bromide (1.8 mL, 2.5722 g, 19.1 mmol) in 20 mL of diethyl ether was added with vigorous stirring of a suspension of Mg turning (0.790 g, 32.5 mmol) in 20 mL of anhydrous diethyl ether Was added little by little. After the initial exothermic reaction ceased, the mixture was further heated to reflux temperature for 30 minutes. The suspension was cooled to room temperature and the supernatant was added portionwise to an ice cold solution of sulfuryl chloride (4.6 mL, 7.728 g, 57.2 mmol) in 30 mL of anhydrous DCM. After the addition was complete, the suspension was allowed to warm to room temperature and the volatiles were removed in vacuo. The residue was dried under oil-pump vacuum for 15 min before extraction with hexane (150 mL). The hexane suspension was filtered and the hexane was removed in vacuo to give the crude product as a dark purple oil which was used in the next step without further purification. Some unreacted cyclopropyl bromide still existed. Crude yield (Yield): 1.1 g (38%).

Step B: N- (3,4-Difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) cyclobutane Sulfonamide:

According to general procedure B, the cyclobutylsulfonyl chloride prepared in the above step is reacted with 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) -3- methoxy- -Diamine &lt; / RTI &gt; to give the title product. Yield: 75%.

Example  62

1- (2, 3-dihydroxypropyl) cyclopropane-1-sulfone (2-fluoro-4- amides:

Step A: (3,4,5-Trifluorophenyl) methanol:

NaBH ₄ (1.662 g, 43.75 mmol) was added to a cooled (-5 ° C) solution of 3,4,5-trifluorobenzaldehyde (7.0 g, 43.75 mmol) in a mixture of THF and water (50 mL, 9: Lt; / RTI &gt; over a period of 1 minute. The reaction mixture was allowed to reach room temperature over a period of 2 hours and poured carefully into ice cold dilute HCl (200 mL, 1 N). The oil layer was extracted with CH ₂ Cl ₂ (250 mL) and the organic layer was washed with water (200 mL), dried (MgSO ₄ ) and evaporated. The resulting crude product (7.08 g, quant.) Was used without further purification.

Step B: 5- (Bromomethyl) -1,2,3-trifluorobenzene:

To a solution of (3,4,5-trifluorophenyl) methanol (40 mmol) in CH ₂ Cl ₂ (150 mL) was added a solution of thionyl bromide (6.16 mL, 80 mmol) in CH ₂ Cl ₂ Was slowly added. The reaction mixture was stirred at room temperature for 16 hours and poured into ice water (200 mL). The organic layer was separated and washed with saturated NaHCO ₃ (2 × 200 mL) and water (200 mL), dried (MgSO ₄ ) and evaporated to give the corresponding bromo compound as a pale yellow oil in quantitative yield. The crude product was used in the next reaction without further purification.

Step C: 1,2,3-Trifluoro-5-methylbenzene:

The bromo compound (40 mmol) was mixed with triethylsilane (48 mmol) and the reaction mixture was treated with solid PdCl ₂ (4 mmol) little by little. After several minutes, a violent exotherm occurred and the contents of the flask were carefully refluxed using a reflux condenser. The reaction mixture was further stirred at room temperature for 6 hours, allowing the contents to settle over 16 hours. The crude liquid product was then carefully decanted and used for the next reaction without further purification. The reaction was expected to proceed in quantitative yield.

Step D: 1,2,3-Trifluoro-5-methyl-4-nitrobenzene:

1,2,3-Trifluoro-5-methylbenzene (40 mmol) was added to concentrated H ₂ SO ₄ (50 mL) at 0 ° C to 5 ° C. Then, while slowly treated the reaction mixture with concentrated _{HNO 3 (3.39 mL, 48.44 mmol} , 90%) the internal temperature was kept below 20 ℃. The reaction mixture was stirred at room temperature for 16 hours, poured into ice (300 g), and the oil layer was extracted with CH ₂ Cl ₂ (2 x 125 mL). Dried the organic layer was washed with water (2 × 200 mL) and brine (200 mL) (MgSO ₄₎ and evaporated to afford the crude product, obtained product was purified in a flash silica gel chromatography to give the title product (6.5 g, 85%).

Step E: 2,3-Difluoro-N- (2-fluoro-4-iodophenyl) -5-methyl-

Fluoro-4-iodoaniline and 1,2,3-trifluoro-5-methyl-4-nitrobenzene were reacted using the conditions described in Example 1 (step A) to give the title compound Respectively. MH ^{&lt; + &} gt ^; : 407.9

Step F: 5,6-Difluoro-N1- (2-fluoro-4-iodophenyl) -3-methylbenzene-

Reduction of 2,3-difluoro-N- (2-fluoro-4-iodophenyl) -5-methyl-6-nitroaniline using the conditions described in Example 1 (step B) . MH ^{&lt; + &} gt ^; : 377.4

Step G: 1-Allyl-N- (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6- methylphenyl) cyclopropane-

According to general procedure B, 1-allyl-cyclopropanesulfonyl chloride (142 mg, 142 mg) was reacted with 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) -1,2-diamine (150 mg, 0.4 mmol) to give the title product (100 mg, 47%). m / z = 521 [M- 1] -.

Step H: Synthesis of N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methylphenyl) -1- (2,3-dihydroxypropyl) cyclopropane- 1-sulfonamide:

Cyclopropane-1-sulfonamide (150 mg, 0.29 mmol) and (2-fluoro-4-iodophenylamino) 4-Methylmorpholine N-oxide (33 mg, 0.29 mmol) was dissolved in THF (5 mL). Osmium tetroxide (0.029 mmol, 0.18 mL, 4% in H ₂ O) was added at room temperature and the reaction mixture was stirred at room temperature for 16 hours. EtOAc was added, washed with water and the organic phase was concentrated under reduced pressure and dried (MgSO _4). The residue was purified by silica gel chromatography (eluent: EtOAc / MeOH) to give the title product (0.110 g, 68%).

Example  63

1- (2,3-dihydroxypropyl) -N- (6-ethyl-3,4-difluoro-2- (2- Sulfonamide:

Step A: 1- (3,4,5-Trifluorophenyl) ethanol:

An etheric solution of MeMgBr (17.41 mL, 52.24 mmol, 3 M) was added slowly to a solution of 3,4,5-trifluorobenzaldehyde (6.96 g, 43.53 mmol) in THF (125 mL) at -78 < The reaction mixture was stirred at room temperature for 16 hours, cooled (0 C), quenched sequentially using ethyl acetate (10 mL) and water (5 mL). An excess of anhydrous MgSO ₄ (5 g) was added and stirred at room temperature for 30 min. The suspension was filtered through celite and the solid was washed with ethyl acetate (2 x 25 mL). The combined filtrate was evaporated to give the product as a quantitative yield (7.65 g).

Step B: 5- (1-Bromoethyl) -1,2,3-trifluorobenzene:

CH ₂ Cl ₂ (250 mL) of 1-thionyl bromide (18.1 g of (3,4,5-trifluorophenyl) ethanol, CH ₂ Cl ₂ (50 mL) to a solution of (7.65 g, 43.5 mmol), 87 mmol) in THF (5 mL) was slowly added. The reaction mixture was stirred at room temperature for 16 hours and poured into ice water (200 mL). The organic layer was separated and washed with saturated NaHCO ₃ (2 × 200 mL) and water (200 mL), dried (MgSO ₄ ) and evaporated to give the corresponding bromo compound as a pale yellow oil in quantitative yield (10.4 g) Respectively. The crude product was used in the next reaction without further purification.

Step C: 5-Ethyl-1,2,3-trifluorobenzene:

The bromo compound (9.65 g, 40.4 mmol) was mixed with triethylsilane (41 mmol) and the reaction mixture was treated portionwise with solid PdCl ₂ (177 mg, 4 mmol). After several minutes, a violent exotherm occurred and the contents of the flask were carefully refluxed using a reflux condenser. The reaction mixture was further stirred at room temperature for 6 hours, allowing the contents to settle over 16 hours. The crude liquid product was then carefully decanted and used for the next reaction without further purification. The reaction was expected to proceed in quantitative yield.

Step D: 1-Ethyl-3,4,5-trifluoro-2-nitrobenzene:

1,2,3-Trifluoro-5-methylbenzene (6.46 g, 40.4 mmol) was added to concentrated H ₂ SO ₄ (50 mL) at 0 ° C to 5 ° C. Then, while slowly treated the reaction mixture with concentrated _{HNO 3 (3.39 mL, 48.44 mmol} , 90%) the internal temperature was kept below 20 ℃. The reaction mixture was stirred at room temperature for 16 hours, poured into ice (300 g), and the oil layer was extracted with CH ₂ Cl ₂ (2 x 125 mL). Were washed dried (MgSO ₄₎ and evaporated to the organic layer with water (2 × 200 mL) and brine (200 mL) to give the crude product, obtained product was purified in a flash silica gel chromatography to give the title product (6.6 g, 79%).

Step E: 3-Ethyl-5,6-difluoro-N- (2-fluoro-4-iodophenyl) -2-nitroaniline:

2-fluoro-4-iodoaniline (2.05 g, 10 mmol) and 1-ethyl-3,4,5-trifluoro-2- nitrobenzene (2.37 g, 10 mmol) ) To give the title compound (2.47 g, 60%). m / z = 407 [M- 1] -.

Step F: 3-Ethyl-5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene-

1,2,3-Trifluoro-5-methyl-4-nitrobenzene (2.47 g, 5.85 mmol) was reduced using the conditions described in Example 1 (step B) to give the title compound. MH ⁺ : 393

Step G: 1-Allyl-N- (6-ethyl-3, 4-difluoro-2- (2- fluoro-4-iodophenylamino) phenyl) cyclopropane-

According to general procedure B, 1-allyl-cyclopropanesulfonyl chloride (230 mg, 1.27 mmol) was reacted with 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) -1,2-diamine (100 mg, 0.255 mmol) to give the title product (72 mg, 53%). m / z = 535 [M-1].

Step H: 1- (2,3-Dihydroxypropyl) -N- (6-ethyl-3,4-difluoro-2- (2- fluoro- -1-sulfonamide:

(70 mg, 0.13 mmol) and (2-fluoro-4-iodophenylamino) -6-methylphenyl) cyclopropane- 4-Methylmorpholine N-oxide (15 mg, 0.13 mmol) was dissolved in THF (2 mL). Osmium tetroxide (0.013 mmol, 0.075 mL, 4% in H ₂ O) was added at room temperature and the reaction mixture was stirred at room temperature for 16 hours. EtOAc was added, washed with water and the organic phase was concentrated under reduced pressure and dried (MgSO _4). The residue was purified by silica gel chromatography (eluent: EtOAc / MeOH) to give the title product.

Example  64

2- (2-fluoro-4-iodophenylamino) -6- (2-methoxyethoxy) phenyl) -1- (2,3- Propyl) cyclopropane-1-sulfonamide:

Step A: 1,2,3-Trifluoro-5- (2-methoxyethoxy) -4-nitrobenzene:

To a solution of 3,4,5-trifluoro-2-nitrophenol (1.93, 10 mmol), Ph ₃ P (3.93 g, 15 mmol) and 2-methoxy-ethanol (1.18 mL, 15 mmol) in anhydrous THF mmol) in THF (5 mL) was added a solution of diisopropyl azodicarboxylate (2.91 mL, 15 mmol) at 0 ° C and the reaction mixture was stirred at room temperature for 16 hours. The volatiles were evaporated and the residue was dissolved in CH ₂ Cl ₂ (100 mL) and the organic layer was washed with water (100 mL) and brine (100 mL), dried (MgSO ₄ ) and evaporated. The resulting residue was purified by flash silica gel chromatography to give the title product in 68% (1.70 g) yield.

Step B: 2,3-Difluoro-N- (2-fluoro-4-iodophenyl) -5- (2- methoxyethoxy) -6-

4-iodoaniline (1.6 g, 6.8 mmol) and 1,2,3-trifluoro-5- (2-methoxyethoxy) -4-nitrobenzene (1.7 g, 6.8 mmol) Was reacted using the conditions described in Example 1 (step A) to give the title compound (1.02 g, 32%). m / z = 467 [M-1].

Step C: 5,6-Difluoro-N1- (2-fluoro-4-iodophenyl) -3- (2-methoxyethoxy) benzene-

(2-methoxyethoxy) -6-nitroaniline (1.017 g, 2.17 mmol) was reacted with 2,3-difluoro-N- (2- fluoro- Lt; / RTI &gt; using the conditions described in step B) to give the title compound. m / z = 337 [M-1].

Step D: Synthesis of 1-allyl-N- (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6- (2-methoxyethoxy) phenyl) - sulfonamide:

According to general procedure B, 1-allyl-cyclopropanesulfonyl chloride (450 mg, 2.5 mmol) was reacted with 5,6-difluoro-N1- (2- fluoro-4- Benzene-1,2-diamine (219 mg, 2.5 mmol) to give the title product (230 mg, 78%). m / z = 581 [M-I].

Step E: Preparation of N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6- (2-methoxyethoxy) Dihydroxypropyl) cyclopropane-1-sulfonamide:

(2-fluoro-4-iodophenylamino) -6- (2-methoxyethoxy) phenyl) cyclopropane-1-sulfonamide (230 mg, 0.395 mmol) and 4-methylmorpholine N-oxide (46 mg, 0.395 mmol) were dissolved in THF (2 mL). Osmium tetroxide (0.039 mmol, 0.25 mL, 4% in H ₂ O) was added at room temperature and the reaction mixture was stirred at room temperature for 16 hours. EtOAc was added, washed with water and the organic phase was concentrated under reduced pressure and dried (MgSO _4). The residue was purified by silica gel chromatography (eluent: EtOAc / MeOH) to give the title product.

Example  65

(2,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) benzenesulfonamide:

Was synthesized according to Method A using the appropriate sulfonyl chloride. m / z = 571 [M-I].

Example  66

2- (2-fluoro-4-iodophenylamino) phenyl) -4- (trifluoromethyl) benzenesulfonamide:

Was synthesized according to Method A using the appropriate sulfonyl chloride. m / z = 605 [M-1].

Example  67

N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) -2- (trifluoromethoxy) benzenesulfonamide:

Was synthesized according to Method A using the appropriate sulfonyl chloride. m / z = 587 [M-1].

Example  68

4- (N- (3,4-Difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) sulfamoyl) benzoic acid:

Was synthesized according to Method A using the appropriate sulfonyl chloride. m / z = 584 [M-I].

Example  69

N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) benzenesulfonamide:

Was synthesized according to Method A using the appropriate sulfonyl chloride. m / z = 503 [M-1].

Example  70

N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) -2-fluorobenzenesulfonamide:

Was synthesized according to Method A using the appropriate sulfonyl chloride. m / z = 521 [M-I].

General procedure D: Substitution of iodine atoms:

Dioxane and water (3: 1) I aryl of 1 equivalent of the de-digested mixture of iodide, 1.5 equivalent of the boronic acid or boronic ester, 0.25 equivalent of PdCl ₂ (dppf) × DCM and 10 eq. Of anhydrous K ₂ The CO ₃ powder-containing suspension was heated in a microwave reactor for 60 minutes at 115 ° C. This was extracted with aqueous NH ₄ Cl / THF and the organic fractions were dried over Na ₂ SO ₄ . It was purified by column chromatography (Si, EtOAc / hexane, or CHCl ₃ / MeOH) - The crude reaction product is purified by flash. Yield: 20% to 40%.

Example  71

N- (3,4-Difluoro-2- (2-fluoro-4-methylphenylamino) phenyl) cyclopropanesulfonamide:

When the racemic mixture of chiral compounds is divided into individual enantiomers, the phrase "substantially free of" the epimeric "eugenol" means that the enantiomer is at least 90% excess as used herein.

Example  72

4- (1H-pyrazol-4-yl) phenylamino) phenyl) cyclopropanesulfonamide

Step A: 2,3-Difluoro-N- (2-fluoro-4-iodophenyl) -6-nitroaniline:

To a solution of 2-fluoro-4-iodoaniline (11.40 g, 47 mmol) in 100 mL of anhydrous THF was added 47 mL of a 1 M LHMDS solution (47 mmol) in THF at 0 ° C. The color of the solution turned dark purple. The solution was transferred via a cannula to a dropping funnel and the solution (containing the amine free base) was added to a solution of 2,3,4-trifluoronitrobenzene (8.321 g, 47.0 mmol) in anhydrous THF (50 mL) 0.0 &gt; 0 C. &lt; / RTI &gt; After the addition was complete, the mixture was stirred at room temperature under argon for 15 hours. After reducing the volume of the solvent, it was extracted with ethyl acetate and brine. The organic layer was dried over sodium sulfate to remove the solvent and the resulting thick oil was purified by flash chromatography (EtOAc / hexane 1: 5, _Rf = 0.58) to give the crude product, which after drying in vacuo gave a brown solid (Yield, 6.23 g, 33.6%). m / z = 393 [M- 1] -.

Step B: 5,6-Difluoro-N1- (2-fluoro-4-iodophenyl) benzene-

Iron powder (13.74 g, 246 mmol) and ammonium chloride (13.59 g, 254 mmol) were added to a solution of nitro-diarylamine (6.23 g, 15.8 mmol) in 300 mL of ethanol and the mixture was poured into an oil bath 0.0 &gt; C &lt; / RTI &gt; for 14 hours. This was filtered and the residue was washed twice with ethanol. The ethanol was removed in vacuo and the residue was extracted with ethyl acetate / 1 M NaOH solution. During the extraction, more precipitate formed, which was filtered off and discarded. The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was removed and the crude product was recrystallized from CHCl ₃ / hexane (1:50). The product was obtained as a brown needle (2.094 g, 66%). _Rf = 0.44 (EtOAc / Hex 1: 3).

Step C: N- (3,4-Difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) cyclopropanesulfonamide:

According to general procedure A, 5,6-difluoro-N1- (2-fluoro-4-iodophenyl) benzene-1,2-diamine was reacted with cyclopropanesulfonyl chloride to give the desired product.

Step D: N- (3,4-Difluoro-2- (2-fluoro-4- (1H-pyrazol-4-yl) phenylamino) phenyl) cyclopropanesulfonamide:

Example  73

(2-fluoro-4- (1-methyl-1H-pyrazol-4-yl) phenylamino) phenyl) cyclopropanesulfonamide

Example  74

2- (2-fluoro-4- (1H-pyrazol-3-yl) phenylamino) phenyl) cyclopropanesulfonamide

Example  75

N- (3,4-Difluoro-2- (2-fluoro-4- (pyridin-4-yl) phenylamino) phenyl) cyclopropanesulfonamide

Example  76

N- (3,4-difluoro-2- (2-fluoro-4- (pyridin-3- yl) phenylamino) phenyl) cyclopropanesulfonamide

Example  77

N- (2- (4-cyano-2-fluorophenylamino) -3,4-difluorophenyl) cyclopropanesulfonamide

A suspension of aryl iodide (75.5 mg, 0.161 mmol), CuCN (46.6 mg, 0.520 mmol and Pd (OAc) ₂ ) (0.47 mg) in 1 mL of anhydrous DMF was heated in a microwave reactor to 130 &lt; . The mixture was extracted with brine / THF and the organic fractions were dried over Na ₂ SO _4. Subsequent flash-column chromatography gave the product as a deep red semi-solid (R _f = 0.42 (EtOAc / Hexane 1: 1)). Yield: 15%.

m / z = 366 [M- 1] -.

Example  78

N- (3,4-difluoro-2- (3-fluorobiphenyl-4-ylamino) phenyl) cyclopropanesulfonamide

Example  79

N- (2- (3'-acetyl-3-fluorobiphenyl-4-ylamino) -3,4-difluorophenyl) cyclopropanesulfonamide

Example  80

N- (2- (4'-cyano-3-fluorobiphenyl-4-ylamino) -3,4-difluorophenyl) cyclopropanesulfonamide

Example  81

N- (2- (3,4'-difluorobiphenyl-4-ylamino) -3,4-difluorophenyl) cyclopropanesulfonamide

Example  82

Synthesis of N- (3,4-difluoro-2- (3-fluoro-4 '- (methylsulfonamido) biphenyl-4-ylamino) phenyl) cyclopropanesulfonamide

Example  83

N- (3,4-difluoro-2- (2-fluoro-4-methylphenylamino) phenyl) cyclopropanesulfonamide

Example  84

4 '- (6- (cyclopropanesulfonamido) -2,3-difluorophenylamino) -3'-fluorobiphenyl-3-carboxylic acid

Example  85

Synthesis of N- (3,4-difluoro-2- (3-fluoro-3 '- (methylsulfonamido) biphenyl-4-ylamino) phenyl) cyclopropanesulfonamide

Example  86

2- (3-fluoro-2 '- (methylsulfonamido) biphenyl-4-ylamino) phenyl) cyclopropanesulfonamide

Example  87

N- (3,4-difluoro-2- (3-fluoro-4 '- (trifluoromethoxy) biphenyl-4-ylamino) phenyl) cyclopropanesulfonamide

Example  88

2- (2-fluoro-4-iodophenylamino) phenyl) -2- (methylamino) ethanesulfonamide

Example  89

Phenyl) -2- (2- (dimethylamino) ethylamino) ethanesulfonamide &lt; / RTI &gt;

Example  90

2- (ethyl (methyl) amino) ethanesulfonamide &lt; / RTI &gt; was added to a solution of N- (3,4- difluoro-2-

Example  91

Phenyl) -2- (4-methylpiperazin-1-yl) ethanesulfonamide &lt; / RTI &gt;

In vitro  Biological activity

Example  92

IC ₅₀ Of data  produce

Materials and reagents: The human GST-MEK1 and the constitutively active allele GST-MEK1 ^CA (carrying the mutations Ser218Asp and Ser222Asp) were incubated with the yeast expression vector pGEM4Z (Promega, Wisconsin, USA) obtained from the wild type human MEK1 cDNA Madison). GST-MEK1 ^CA was expressed in Escherichia coli and the Glutathione Sepharose 4B affinity resin (Amersham Pharmacia Biotech, Piscataway, NJ) was added &Lt; / RTI &gt; The ERK2 allele was cloned from the MAPK2 / Erk2 cDNA (wild type) of pUSEamp (Upstate Biotechnology, Inc., Walton, Mass.) Into vector pET21a (Novagen, Madison, Wis. ) To generate an N-terminal histidine-tagged murine ERK2 allele. ERK2 was expressed and purified until homogeneous [Zhang, 1993 # 33]. The herbicidal protein (MBP) was purchased from Gibco BRL (Rockville, MD). EasyTides Adenosine 5'-triphosphate (ATP) ([? - ³³ P]) (NEN Perkin Elmer, Wellesley, Mass., USA) . Activated Raf-1 (truncated) and activated MAP kinase 2 / ERK2 were purchased from Upstate, Inc. (Lake Placid, NY). 4% to 20% Criterion Precast gels were purchased from Bio-Rad (Hercules, Calif., USA).

Determination of Enzyme Activity: The compound was diluted with 1 x HMNDE (20 mM HEPES pH 7.2, 1 mM MgCl ₂ , 100 mM NaCl, 1.25 mM DTT, 0.2 mM EDTA) from a stock solution of dimethylsulfoxide (DMSO). A typical 25 [mu] l assay contained 0.002 nanomoles of MEK1 ^CA , 0.02 nanomoles of ERK2, 0.25 nanomoles of MBP, 0.25 nanomoles of unlabeled ATP and 0.1 mu Ci [[gamma] - ³³ P] ATP. The screening assay essentially comprised four additives. 5 [mu] l of the diluted compound was dispensed into a 96 well assay plate. Then, 10 占 퐇 of a 2.5X enzyme cocktail (MEK1 ^CA and ERK2 only) was added to each well and then pre-incubated at ambient temperature for 30 minutes. Subsequently, 10 占 of 2.5x substrate cocktail (labeled ATP and unlabeled ATP + MBP) was added followed by incubation at ambient temperature for 60 minutes. Finally, 100 [mu] l of 10% trichloroacetic acid (TCA) was added and incubated at room temperature for 30 minutes to quench the reaction and precipitate the radiolabeled protein product. The reaction product was harvested on a glass fiber 96 well filter plate previously wetted with water and 1% pyrophosphate. The filter plate was then washed five times with water. Water was replaced with absolute ethanol and the plate allowed to air dry at room temperature for 30 minutes. The back seal was applied by hand and 40 [mu] l of flash cocktail was dispensed into each well. A top seal was applied and the plate was counted for 2 seconds per well in a TopCount.

Some experiments used a truncated version of MEK that requires activation by Raf kinase.

Example  93

EC ₅₀ Of data  produce

The effect of compounds on cells was determined by Western blotting against phosphorylated ERK. MDA-MB-231 breast cancer cells were plated in 48 well plates to 20,000 cells per well and grown in a humidified CO ₂ incubator at 37 ° C. The next day, the growth medium (DMEM + 10% fetal bovine serum) was removed and replaced with starve media (DMEM + 0.1% fetal bovine serum). Cells were incubated in the non-nutrient medium for 16 hours and then treated with a range of compound concentrations for 30 minutes. After incubation with the compound, the cells were stimulated with 100 ng / mL EGF for 5 min. Cells were then lysed and analyzed by Western blotting using monoclonal antibodies generated against phosphorylated ERK. Signals were amplified using a secondary antibody conjugated to near-infrared dye and detected on a Licor Odyssey scanner. The intensity of the signal was quantitated, and the data was used to generate a dose response curve and used for EC ₅₀ calculation.

Indication: A, EC ₅₀ = <2.0 nM; B, EC ₅₀ = 2.0 to 15 nM; C, EC ₅₀ = 15 nM to 100 nM; D, EC ₅₀ > 100 nM, IC ₅₀ <20 μM; F, EC ₅₀ > 100 nM, IC ₅₀ > 20 μM

Indication: A, EC ₅₀ = <2.0 nM; B, EC ₅₀ = 2.0 to 15 nM; C, EC ₅₀ = 15 nM to 100 nM; D, EC ₅₀ = 100 nM to 200 nM; E, EC ₅₀ > 200 nM; ND = not measured

In vivo  Biological activity

Example  94

The compounds and compositions described herein are useful for treating or preventing one or more diseases including but not limited to cancer, inflammatory bowel disease (IBD), psoriasis and rheumatoid arthritis (RA). The compounds and compositions described herein are also useful for once or twice daily oral administration to treat or prevent one or more diseases including but not limited to cancer, IBD, psoriasis, and RA.

An in vivo test of a compound of the following structure (prepared as described herein) is described in this Example:

Human tumors were implanted in nu / nu mice. Compound A was orally administered for 14 days when the tumors were approximately 100 mm ³ in size. The tumor growth inhibition rate (TGI) is defined as the tumor size reduction rate in the treatment group for the vehicle control after 14 days of treatment. The time to endpoint (TTE) was calculated as the time at which the tumor reached the specified endpoint volume or the day of the study, the first of the study days. Treatment results were determined from the tumor growth delay (%) (% TGD), defined as the percentage increase in the central TTE of treated mice for vehicle-treated control mice. The animals were also monitored for retrogressive reactions. Levels of pERK in tumors and brain were determined by Western blotting and correlations with plasma levels of Compound A were determined for pharmacokinetic / pharmacodynamic studies. Many tumor models were evaluated with different doses and dosing regimens. Treatment with once daily (QD) of 25 mg / kg or 50 mg / kg showed statistically significant% TGD in A375 melanoma tumor, Colo205 colon carcinoma tumor and A431 tumoral tumor. Statistically significant TGI was observed not only in these tumor models but also in HT29 colon cancer tumors at oral doses of 25 mg / kg QD. The effects of different dosing regimens were evaluated in A375 xenografts. 100 mg / kg Compound A was administered orally once every two days, a statistically significant% TGD (91%) was observed, but 25 mg / kg QD treatment (143% TGD) or 50 mg / kg QD It was not as effective as treatment (233% TGD). In addition, twice daily (BID) administration was more effective than QD as determined by% TGI. The dose of 12.5 mg / kg BID was 79.5% TGI while the 25 mg / kg QD of Compound A was 51.7%. 25 mg / kg BID administration was 110.1% TGI while 50 mg / kg QD was 69.9% TGI. Pharmacokinetic / pharmacodynamic studies on Colo205 xenografts showed inhibition of pERK formation in tumors but minimal inhibition in the brain suggesting potent anti-tumor activity with CNS penetration limitations.

Compound A is a potent inhibitor of MEKl / 2, inhibiting tumor cell growth in vitro and in vivo. The BRAF status determines susceptibility to inhibition of growth by compounds in fixed-dependent growth, but not in fixed-independent growth or xenografts. Maintaining adequate MEK inhibition during the dosing interval is believed to be more important than higher levels of efficacy with more frequent dosing. Compound A has a favorable pk profile in humans based on xenograft results and has a project treatment dose of 20 to 40 mg / day in humans.

Example  94A

Inhibition of cancer cell growth ( GI ₅₀ )

Fixation-dependent growth inhibition was determined using CellTiterGlo reagent after treating compound A for 48 hours in cells grown on 384 well plates. Fixed-independent growth assays were carried out on media containing 0.15% agarose or cells grown on non-binding plates (A431) for 7 days followed by MTS (methanethiosulfonate) reagents. The growth inhibition value (GI ₅₀ ) is shown in the table below.

Example  94B

Anti-tumor Xenograft  activation

Female nu / nu mice were transplanted with A375 melanoma, Colo205 colon tumor, A431 breast epithelial tumor or HT-29 colon tumor cells, which allowed it to grow to 100-200 mm ³ . Compound A or vehicle was orally administered once a day (25 mg / kg, 50 mg / kg or 100 mg / kg) for 14 days. The mean tumor volume for the vehicle and treatment group is graphed and is shown in FIG.

Example  94C

25 mg / kg QD  Inhibition of tumor growth during use ( TGI )

The inhibition of tumor growth in the group treated with 25 mg / kg Compound A was calculated for the indicated tumor xenografts. Tumor growth inhibition was determined at the end of the once-a-day administration for 14 days and was calculated as follows:

The ranges for A375 and Colo205 are from two separate studies.

^** Degeneracy appeared during the experiment

Example  94D

Colo205 In xenograft ED ₅₀

Colo205 tumor cells were transplanted into male nu / nu mice. After 10 days, the animals were randomized to tumor size (ranging from 126 to 256 mm ³ ) and treated with paclitaxel (IV, QOD x 5), vehicle or Compound A (PO, QD x 14).

Balb / c mice were dosed with 25 mg / kg of Compound A and the pharmacodynamic parameters were determined by extrapolating the values for the lower dose groups and are shown in the following table:

Example  94E

A375 Xenograft  Use of tumor growth inhibition

Compound A was administered to A375 xenograft mice with 50 mg / kg QD, 25 mg / kg BID, 50 mg / kg QD and 12.5 mg / kg BID. The% TGI was calculated and plotted, and it is shown in Fig.

Example  94F

Plasma concentrations in mice

Female nu / nu mice were transplanted with A375 tumor cells, which allowed them to grow to 100-200 mm ³ . Compound A or vehicle was orally administered once daily (QD) or twice daily (BID) (50 mg / kg QD, 25 mg / kg BID, 50 mg / kg QD and 12.5 mg / kg BID). Tumor growth inhibition was determined at the end of the once-a-day administration for 14 days and was calculated as follows:

Example  94G

mouse Xenograft  Tumor and brain MEK  Inhibition of activity

Female nu / nu mice transplanted with Colo205 tumor cells were administered a single dose of vehicle or 2.5, 5, 10 or 25 mg / kg of Compound A. Compound levels were determined in plasma samples and pERK levels were determined in tumor and brain samples collected at 2, 6, 12, and 24 hours post dose. The level of pERK obtained by Western blotting was quantified as LCRO, standardized to the total ERK level, and compared with the vehicle-treated level, the MEK inhibition rate (%) was determined. MEK inhibition in tumor or brain in each mouse was graphed for the corresponding plasma concentration of Compound A in the animal. When using non-linear regression, the EC ₅₀ for MEK inhibition in tumors was 73 nM. The brain EC ₅₀ was > 5000 nM.

A graph of plasma concentration (log nM) versus pERK inhibition rate (%) is shown in FIG.

Preparation of capsules

Example  95A

의 화합물 A (상기 실시예 93에 나타낸 표 참조)의 건조 분말 블렌드 조성물을 함유하는 블루 사이즈(Blue size) 1 경질 젤라틴 캡슐제를 제조하였다. 1 mg and 10 mg amounts of structure

Blue size 1 hard gelatin capsules containing a dry powder blend composition of Compound A (see the table given in Example 93 above) were prepared.

After compound A was prepared as described herein, a fluidic energy mill (pulverizing chamber diameter 50 mm, 50 °. 4 x 0.8 mm nozzle ring, injection nozzle nozzle diameter 0.8 mm and inlet nozzle nozzle length 3 mm spiral jet mill Spiral Jet Mill, electronically pulverized). Compound A and a portion of the microcrystalline cellulose were mixed and screened through a # 20 mesh screen and added to a diffusion-tumble blender (V-blender). The remaining microcrystalline cellulose was screened through a # 20 mesh screen and added to the material in the blender and blended. Croscarmellose sodium and sodium lauryl sulfate were screened through a # 20 mesh screen and added to the material in the blender and blended. The powder blend was passed through a rotating impeller mill (Quadro CoMil), then added to the blender again and blended continuously. Magnesium stearate was screened through a # 20 mesh screen and blended with the milled powder blend. The powder blend was filled into a size 1 capsule. The 10 mg capsule was marked with a band.

The composition of the capsules is shown in the following table:

^{a The} target fill weight is adjusted based on the actual titer of the blend.

A typical batch composition for a batch of 10,000 mg of 1 mg capsule was as follows:

^{a The} target fill weight is adjusted based on the actual titer of the blend.

A typical batch composition for a 10,000-dose batch of 10 mg capsules was as follows:

^{a The} target fill weight is adjusted based on the actual titer of the blend.

Example  95B

의 화합물 B (상기 실시예 93에 나타낸 표 참조)의 건조 분말 블렌드 조성물을 함유하는 블루 사이즈 1 경질 젤라틴 캡슐제를 제조하였다. 1 mg and 10 mg amounts of structure

A blue size 1 hard gelatin capsule containing a dry powder blend composition of Compound B (see the table shown in Example 93 above) was prepared.

Compound B was prepared as described herein, followed by addition of a fluid energy mill (pulverizing chamber diameter 50 mm, 50 °. 4 x 0.8 mm nozzle ring, injection nozzle nozzle diameter 0.8 mm and injection nozzle nozzle length 3 mm, Electronically pulverized). Compound B and a portion of the microcrystalline cellulose were mixed and screened through a # 20 mesh screen and added to a diffusion-tumble blender (V-blender). The remaining microcrystalline cellulose was screened through a # 20 mesh screen and added to the material in the blender and blended. Croscarmellose sodium and sodium lauryl sulfate were screened through a # 20 mesh screen and added to the material in the blender and blended. The powder blend was passed through a rotating impeller mill (quadrocomile) and then added to the blender and continued blending. Magnesium stearate was screened through a # 20 mesh screen and blended with the milled powder blend. The powder blend was filled into a size 1 capsule. The 10 mg capsule was marked with a band.

The composition of the capsules is shown in the following table:

Human In vivo  activation

Example  96

Administration of the capsules described in Example 95A in human cancer patients

Human cancer patients were administered a single dose of the 1 mg or 10 mg capsules composition described above in Example 95A. For the 2 mg dose, 2 mg 1 mg capsules were given to the patient, 4 mg capsules were given to the patient at 4 mg dose, and 6 mg 1 mg capsules to the patient at 6 mg dose , A 10 mg capsule was given to the patient for a dose of 10 mg, and a second capsule of 10 mg to the patient for a dose of 20 mg.

The concentration-time profile was monitored and is shown in Figure 4 and the following table:

Crystalline Polymorph  shape

Example 97 : Synthesis of N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) phenyl) -1- (2,3-dihydroxypropyl) cyclopropane- Preparation of sulfonamide

1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide was reacted with N- (3,4-difluoro-2- (See International Patent Application Publication No. WO 2007/014011) and as summarized below:

Step A: 2-Fluoro-N- (2,3,5-trifluoro-6-nitrophenyl) -4-iodobenzene amine

A solution of 1.0 M lithium hexamethyldisilazide (LiN (SiMe ₃ ) ₂ ) "LHMDS" (15.37 mL, 15.37 mmol) was added to a solution of 2-fluoro-4-iodoaniline (3.64 g, 15.37 mmol) at -78 [deg.] C under nitrogen, and stirring was further continued at -78 [deg.] C for 1 hour. 2,3,4,6-Tetrafluoronitrobenzene was added and the reaction mixture allowed to warm to room temperature and stirring continued for 16 hours. Ethyl acetate (200 mL) was added and the organic phase was washed with water, dried over sodium sulfate and further purified by column chromatography to give the product as a yellow solid (3.75 g, 59.24%).

Step B: 2-Fluoro-N- (2,3-difluoro-5-methoxy-6-nitrophenyl) -4-

To a solution of (2-fluoro-4-iodo-phenyl) - (2,3,5-trifluoro-6-nitro- phenyl) -amine (1.23 g, 3 mmol) in anhydrous THF (25 mL) The stirred solution was cooled to -78 C and a 25% sodium methoxide solution (0.68 mL, 0.3 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and stirring continued for 16 hours. The reaction was incomplete at TLC. Ethyl acetate (100 mL) was added to the reaction mixture and the organic layer was washed with water, dried over sodium sulfate and further purified by column chromatography to give the desired compound (0.6 g, 47.6%) as a yellow solid. m / z = 424 [M + H] &lt; ⁺ &gt;.

Step C: 5,6- difluoro -N ¹ - (2- fluoro-4-iodophenyl) -3-methoxy-benzene-1,2-diamine

(1.18 g, 20.16 mmol) and iron powder (1.15 g, 21.44 mmol) were added to a solution of (2,3-difluoro-5-methoxy- Fluoro-4-iodo-phenyl) -amine (0.57 g, 1.34 mmol). The mixture was stirred at reflux for 16 hours, cooled to room temperature, filtered through celite and the filtrate was concentrated to dryness. The resulting residue was taken up in ethyl acetate, washed with water, dried over sodium sulfate and further purified by crystallization from ethanol to give the product as an off-white solid (0.47 g, 90.3%).

Step D: Synthesis of 1-allyl-N- (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6- methoxyphenyl) cyclopropane-

In anhydrous pyridine (5 mL / mmol) -N ¹ as of 5,6-difluoro- (2-fluoro-4-iodophenyl) -3-methoxy-benzene-1,2-diamine was stirred (1 equivalent) To the solution was added 1-allyl-cyclopropanesulfonyl chloride (1 to 5 equivalents). The reaction mixture was stirred at 40 &lt; 0 &gt; C for 48 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO ₄₎ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica to give the title product.

Step E: Synthesis of N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) Propane-1-sulfonamide

Cyclopentane-1-sulfonamide (97 mg, 0.18 mmol) was added to a solution of 1-allyl-N- (3,4-difluoro-2- ) And 4-methylmorpholine N-oxide (21 mg, 0.18 mmol) were dissolved in THF (8 mL). Osmium tetroxide (0.018 mmol, 0.13 mL, 4% in H ₂ O) was added at room temperature and the reaction mixture was stirred at room temperature for 16 hours. Ethyl acetate was added, washed with water and the organic phase was concentrated under reduced pressure and dried (MgSO _4). The residue was purified by silica gel chromatography (eluent: EtOAc / MeOH) to give the title product (0.80 g, 78%).

Example 98 : Preparation of N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) Hydroxypropyl) cyclopropane-1-sulfonamide

The pure S isomer was obtained by chiral HPLC separation of the racemic mixture.

Example 99 : Preparation of N- (R) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) Hydroxypropyl) cyclopropane-1-sulfonamide

The pure R isomer was obtained by chiral HPLC separation of the racemic mixture.

Example 100 : Synthesis of N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) Hydroxypropyl) cyclopropane-1-sulfonamide Preparation of Crystalline Polymorph Form A

Preparation i) Preparation of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3- (216.10 g) was charged to a 4 L Erlenmeyer flask equipped with a large magnetic stir bar and a magnetic stirrer / hot plate. Ethyl acetate (about 600 mL, purchased from Fisher) was added. Heating and stirring were started to form a brown suspension. The mixture was allowed to slightly reflux and additional ethyl acetate (about 200 mL) was added to complete the dissolution, resulting in a dark brown solution. Heptane (purchased from Acros) was slowly added to the refluxing solution at a rate such that all of the precipitate formed during each addition was rapidly dissolved and reflux was maintained. The solid formed after the addition of 2 L of heptane to the solution was very slowly dissolved under reflux. The heating was stopped and the crystallization mixture was allowed to equilibrate with room temperature while stirring over 16 hours. Over this maturation period, a layer of thick crystalline material was formed around the surface of the glass. The resulting suspension was equilibrated in an ice / water bath with stirring. The suspension was filtered through a 25 cm Buchner funnel equipped with Whatman # 1 filter paper. The collected crystals were washed with heptane (1 L) and allowed to air dry under vacuum. The crystals were further dried over 20 hours at 40 [deg.] C / <1 torr to give the product as a pink crystalline solid (160.99 g, 77.2%).

Preparation ii ) Synthesis of N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6- methoxyphenyl) -1- (2,3- (13.2 g) and ethyl acetate (30 mL) were charged to an Erlenmeyer flask equipped with a large magnetic stir bar and a magnetic stirrer / hot plate. A dark brown solution was obtained by initiating heating to allow stirring and slight reflux to complete the dissolution. Heptane was slowly added to the refluxing solution at such a rate that all the precipitate formed during each addition was rapidly dissolved and reflux was maintained and addition of heptane to the solution caused the solids formed to dissolve very slowly under reflux (About 90 mL heptane). The heating was stopped and the crystallization mixture was allowed to equilibrate with room temperature while stirring over 16 hours. Over this maturation period, a layer of thick crystalline material was formed around the surface of the glass. The resulting suspension was equilibrated in an ice / water bath with stirring. The suspension was filtered through a Buchner funnel equipped with Wattman # 1 filter paper. The collected crystals were washed with heptane and allowed to air dry under vacuum. The crystals were further dried at 40 [deg.] C / < 1 torr for 20 hours to give the product as a pink crystalline solid.

Preparation iii ) Synthesis of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) (44.8 g) and ethyl acetate (750 mL) were charged to an Erlenmeyer flask equipped with a large magnetic stir bar and a magnetic stirrer / hot plate. A dark brown solution was obtained by initiating heating to allow stirring and slight reflux to complete the dissolution. To the refluxing solution was slowly added hexane in small increments, at the rate that all precipitates formed upon each addition were rapidly dissolved and reflux was maintained, and the addition of hexane to the solution gave a solid which was slowly dissolved under reflux (About 2 L of hexane). The heating was stopped and the crystallization mixture was allowed to equilibrate with room temperature while stirring over 16 hours. Over this maturation period, a layer of thick crystalline material was formed around the surface of the glass. The resulting suspension was equilibrated in an ice / water bath with stirring. The suspension was filtered through a Buchner funnel equipped with Wattman # 1 filter paper. The collected crystals were washed and allowed to air dry under vacuum. The crystals were further dried at 40 [deg.] C / < 1 torr for 20 hours to give the product as a pink crystalline solid.

Example 101 : N- (R) - (3,4-Difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) Hydroxypropyl) cyclopropane-1-sulfonamide &lt; / RTI &gt;

2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) Cyclopropane-1-sulfonamide (216.10 g) was charged to a 4 L Erlenmeyer flask equipped with a large magnetic stir bar and a magnetic stirrer / hot plate. Ethyl acetate (about 600 mL) was added. Heating and stirring were started to form a brown suspension. The mixture was allowed to slightly reflux and additional ethyl acetate (about 200 mL) was added to complete the dissolution, resulting in a dark brown solution. Heptane was slowly added to the solution in small increments, at the rate that all precipitates formed upon each addition were rapidly dissolved and reflux was maintained. The solid formed after the addition of 2 L of heptane to the solution was very slowly dissolved under reflux. The heating was stopped and the crystallization mixture was allowed to equilibrate with room temperature while stirring over 16 hours. Over this maturation period, a layer of thick crystalline material was formed around the surface of the glass. The resulting suspension was equilibrated in an ice / water bath with stirring. The suspension was filtered through a 25 cm Buchner funnel equipped with Wattman # 1 filter paper. The collected crystals were washed with heptane (1 L) and allowed to air dry under vacuum. The crystals were further dried at 40 [deg.] C / < 1 torr over 20 hours.

Example 102 : Generation of IC ₅₀ data

Materials and reagents: A yeast expression vector pGEM4Z (Promega, Madison, Wis., USA), obtained from wild-type human MEK1 cDNA, with human GST-MEK1 and the constitutively active allele GST-MEK1 ^CA (possessing mutations Ser218Asp and Ser222Asp) Lt; / RTI &gt; GST-MEK1 ^CA was expressed in Escherichia coli and partially purified using Glutathione Sepharose 4B affinity resin (Amersham Pharmacia Biotech, Piscataway, NJ). The ERK2 allele was subcloned from the MAPK2 / Erk2 cDNA (wild type) of pUSEamp (Upstate Biotechnology, Inc, Walton, MA) to vector pET21a (Novagen, Madison, Wis.) To give N-terminal histidine - tagged murine ERK2 allele. ERK2 was expressed and purified until homogeneous [Zhang, 1993 # 33]. The herbicidal protein (MBP) was purchased from Gibco Bialel (Rockville, MD). ([? - ³³ P]) (Ene En Perkin Elmer, Wellesley, Mass., USA) was a radioligand for all kinase reactions. Activated Raf-1 (truncated form) and activated MAP kinase 2 / ERK2 were purchased from Upstate, Inc. (Lake Placid, NY). 4% to 20% Criterion precast gel was purchased from Bio-Rad (Hercules, CA, USA).

Determination of Enzyme Activity: The compound was diluted with 1 x HMNDE (20 mM HEPES pH 7.2, 1 mM MgCl ₂ , 100 mM NaCl, 1.25 mM DTT, 0.2 mM EDTA) from a stock solution of dimethylsulfoxide (DMSO). A typical 25 [mu] l assay contained 0.002 nanomoles of MEK1 ^CA , 0.02 nanomoles of ERK2, 0.25 nanomoles of MBP, 0.25 nanomoles of unlabeled ATP and 0.1 mu Ci [[gamma] - ³³ P] ATP. The screening assay essentially comprised four additives. 5 [mu] l of the diluted compound was dispensed into a 96 well assay plate. Then, 10 占 퐇 of a 2.5X enzyme cocktail (MEK1 ^CA and ERK2 only) was added to each well and then pre-incubated at ambient temperature for 30 minutes. Subsequently, 10 占 of 2.5x substrate cocktail (labeled ATP and unlabeled ATP + MBP) was added followed by incubation at ambient temperature for 60 minutes. Finally, 100 [mu] l of 10% trichloroacetic acid (TCA) was added and incubated at room temperature for 30 minutes to quench the reaction and precipitate the radiolabeled protein product. The reaction product was harvested on a glass fiber 96 well filter plate previously wetted with water and 1% pyrophosphate. The filter plate was then washed five times with water. Water was replaced with absolute ethanol and the plate allowed to air dry at room temperature for 30 minutes. The backside seal was applied by hand and 40 [mu] l of flash cocktail was dispensed into each well. An upper seal was applied and the plate was counted for two seconds per well in the top count. Some experiments used a truncated version of MEK that requires activation by Raf kinase.

Example 103 : Generation of EC ₅₀ data

The effect of compounds on cells was determined by Western blotting against phosphorylated ERK. MDA-MB-231 breast cancer cells were plated in 48 well plates to 20,000 cells per well and grown in a humidified CO ₂ incubator at 37 ° C. The next day, the growth medium (DMEM + 10% fetal bovine serum) was removed and replaced with non-nutrient medium (DMEM + 0.1% fetal bovine serum). Cells were incubated in the non-nutrient medium for 16 hours and then treated with a range of compound concentrations for 30 minutes. After incubation with the compound, the cells were stimulated with 100 ng / mL EGF for 5 min. Cells were then lysed and analyzed by Western blotting using monoclonal antibodies generated against phosphorylated ERK. Signals were amplified using a secondary antibody conjugated to near-infrared dye and detected on a Lecor Odyssey scanner. The intensity of the signal was quantitated, and the data was used to generate a dose response curve and used for EC ₅₀ calculation.

Example 104 : Activity data of the compound

The compounds described in Examples 1, 2 and 3 were tested by the above test. The results are summarized in the following table (A, EC ₅₀ = <2.0 nM; B, EC ₅₀ = 2.0-15 nM):

Example 105 : XRPD data

XPRD was performed on an Ihnel XRG-3000 diffractometer equipped with a curved position-sensitive detector with a 2 [theta] range of 120 [deg.]. Real time data were collected using Cu Kα radiation at a resolution of 0.03 ° 2θ. The tube voltage and current intensities were set to 40 kV and 30 mA, respectively. The pattern was displayed at 2.5 to 40 degrees 2 &amp;thetas; to facilitate direct pattern comparison. (S) -N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3- Sulfonamides (synthesized as described in Baba, hereinabove) were prepared and packed into thin-walled glass capillaries and analyzed. Each capillary was moved to the goniometer head, which was driven to rotate the capillary during data acquisition. Samples were analyzed for 5 minutes. Instrument calibration was performed daily using silicon reference standards. Figure 5 is a graphical representation of the results of the synthesis of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) Hydroxypropyl) cyclopropane-1-sulfonamide Form A powder X-ray diffraction (PXRD) pattern. Figure 7 is a graphical representation of the reaction of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) Hydroxypropyl) cyclopropane-1-sulfonamide Form A (upper) and amorphous (lower) powder x-ray diffraction (PXRD) patterns.

Example 106 : Differential Scanning Calorimetry (DSC)

Analysis was performed on a TI Instruments differential scanning calorimeter Q1000. The instrument was calibrated using indium as a reference material. The sample was placed in a standard aluminum DSC pan with a non-corrugated lid and the weight recorded accurately. To measure the glass transition temperature (T _g ) of the amorphous material, the sample cell was circulated several times between -40 ° C and 140 ° C. The final temperature was raised to 150 占 폚. T _g is reported from the inflection point of the last periodic transition. Figure 6 is a graphical representation of the results of the synthesis of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) Hydroxypropyl) cyclopropane-1-sulfonamide (Form A). The graph shows the standardized heat flow rates vs. watt / gram (W / g) units. Plot the measured sample temperature (占 폚).

Example 107 : Dynamic Vapor Adsorption / Desorption (DVS)

Moisture absorption / dehumidification data were collected on a VTI SGA-100 vapor adsorption analyzer. Adsorption / desorption data were collected under nitrogen purging at 10% RH over a range of 5% to 95% relative humidity (RH). The sample was not allowed to dry before analysis. The equilibrium criterion used for the analysis was less than the 0.0100% weight change rate for 5 minutes and the maximum equilibration time was set to 3 hours if the above weight criteria were not met. The data were not corrected for the initial moisture content of the sample. Sodium chloride and polyvinylpyrrolidine were used as calibration standards. Figure 8 is a graphical representation of the results of the synthesis of N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) Hydroxypropyl) cyclopropane-1-sulfonamide (Form A). The material was found to be negligible in weight change during the experiment.

Example 108 : Thermogravimetric analysis (TG)

Analysis was carried out on a TI Instrument 2950 Thermogravimetric Analyzer. The calibration standards were nickel and Alumel (TM). Each sample was placed in an aluminum sample pan and inserted into a TG furnace. The sample was equilibrated at 25 캜 and then heated to a final temperature of 350 캜 at a heating rate of 10 캜 / min under a stream of nitrogen. Figure 9 is a graphical representation of the results of the synthesis of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) Hydroxypropyl) cyclopropane-1-sulfonamide (Form A), demonstrating negligible weight loss below 140 &lt; 0 &gt; C and indicating that polymorph Form A was not solvated .

Example 109 : In vitro cancer screening

Human tumor cell lines were grown in RPMI 1640 medium containing 5% fetal bovine serum and 2 mM L-glutamine. Cells were inoculated at 100 [mu] l in 96-well microtiter plates at a plating density ranging from 5,000 to 40,000 cells / well with a doubling time of each cell line. After cell inoculation, the microtiter plates were incubated for 24 hours at 37 ° C, 5% CO ₂ , 95% air and 100% relative humidity before N- (S) - (3,4- 2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide was added.

Twenty-four hours later, two plates of each cell line were clamped in situ with TCA to give N- (S) - (3,4-difluoro-2- (2- fluoro- The cell population was measured at each time point (Tz) at which the methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide was added. 2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) The cyclopropane-1-sulfonamide was solubilized in dimethylsulfoxide at 400 times the final desired maximum test concentration and stored frozen. At the time of addition, the aliquots of the frozen concentrate were thawed and diluted to twice the desired final maximum test concentration using complete medium containing 50 占 퐂 / mL gentamycin. Additional quadruple, 10-fold or 로그 log series dilutions were made to provide a total of five concentration samples and a control. 100 [mu] l aliquots of these various dilutions were added to appropriate micromolar wells pre-loaded with 100 [mu] l of medium to the desired final concentration.

2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) after the addition of cyclopropane-1-sulfonamide, the plate was _{37 ℃, 5% CO 2,} 95% air and 100% more incubated for 48 hours at a relative humidity. For adherent cells, cold TCA was added to terminate the assay. Cells were fixed in the system by gentle addition of 50 [mu] l of cold 50% (w / v) TCA (final concentration, 10% TCA) and incubated at 4 [deg.] C for 60 min. The supernatant was discarded and the plate was washed five times with tap water and air dried. A solution of 0.4% (w / v) Sulforhodamine B (SRB (Sulforhodamine B)) in 1% acetic acid (100 μl) was added to each well and the plate was incubated at room temperature for 10 minutes. After staining, unbound dye was removed by washing 5 times with 1% acetic acid, and the plate was air dried. The bound dye was then solubilized with 10 mM trizamase and the absorbance was read on an automated plate reader at a wavelength of 515 nm. In the case of the suspension cells, the precipitated cells were the same as above, except that 50 μl of 80% TCA (final concentration, 16% TCA) was gently added to the bottom of the wells and the assay was terminated. (S) - (3,4-difluoro-2- (2-fluoro-4-iodo-thiophene) Test growth (Ti) in the presence of 1-phenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide was used to grow The inhibition rate (%) was calculated. Growth inhibition (%) was calculated as follows:

Three dose response parameters were calculated. The 50% growth inhibition (GI ₅₀ ) was calculated as [(Ti-Tz) / (C-Tz)] x 100 = 50, which resulted in a 50% reduction in net protein increase in control cells during drug incubation &Lt; / RTI &gt; SRB staining). (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- 2,3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration was calculated from Ti = Tz. An LC ₅₀ (concentration of drug is determined to be caused a 50% reduction in protein in the medication at the end as compared to when medication started) indicating a net loss of cells after treatment [(Ti-Tz) / Tz ] × 100 = -50 from Respectively. Values were calculated for each of these three parameters when the activity level was reached, but if the effect was not reached or exceeded, the value for the parameter was expressed as above or below the tested maximum or minimum concentration.

A panel corresponding to leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer and breast cancer was examined for the following cell lines and the results are shown below:

Example 110 : In vitro anti-proliferative activity

In this example, a solution of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) (1) activity against growth of several tumor cell lines with different mutations (GI ₅₀ ), (2) different B-Raf mutant cell lines (GI ₅₀ ), (3) effects on fixed-independent cell growth, (4) effects on cell cycle, and (5) toxic effects on liver and kidney cells.

Cell culture / growth inhibition assay

Human melanoma A375 cells and human colon cancer Colo205 cells were obtained from ATCC (Manassas, Va.). A375 cells were maintained in DMEM supplemented with 10% fetal bovine serum, glutamine (2 mM), penicillin (100 U / mL) and streptomycin (100 ug / mL). The cells 37 ℃, was maintained at 5% CO ₂ and 100% humidity. Colo205 cells were maintained in RPMI supplemented with 10% fetal bovine serum, glutamine (2 mM), penicillin (100 U / mL) and streptomycin (100 ug / mL). For growth inhibition experiments, cells were plated on white 384 well microplates at 1000 cells per well / 20 microliters. After 24 hours, 5 占 of the 5x drug stock solution was added. All drugs were initially prepared with 200x stock in DMSO and the final DMSO concentration was 0.5%. Cells were incubated for 48 hours at 37 [deg.] C and ATP levels were determined using a celite gel (Promega, Madison, Wis.). Adenylate kinase (AK) release was determined using Toxilight (Cambrex, Walkersville, Md.). Non-linear curve plotting was performed with GraphPad Prism 4 (GraphPad Software, San Diego, Calif.). Pyrido [2,3-d] pyrimidin-4-yl) pyrido [2,3-d] pyrimidin- Methyl-5- (8H) -one (VRX-14686) is a cytotoxic agent used as a reference compound.

Growth inhibition rate (%) = (RLU-N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6- methoxyphenyl) (RLU of vehicle-1 - (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide) / (RLU of vehicle alone control 1 μM N- (S) - (3,4-difluoro- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide; RLU); 2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) Based on the growth arrest induced by cyclopropane-1-sulfonamide, ATP levels were measured.

Cell viability (%) = (N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) 3-dihydroxypropyl) cyclopropane-1-sulfonamide (RLU of 10 μM VRX-14686) / (RLU of vehicle alone control - 10 μM of RLU of tamoxifen); Based on the cell death induced by VRX-14686, ATP levels were measured.

(%) = (N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- , 3-dihydroxypropyl) cyclopropane-1-sulfonamide) / (RLU of RLU-vehicle alone control of 10 μM tamoxifen); Based on the cell death induced by tamoxifen, the AK release was measured.

RLU = relative light emitting unit

Assessment of cell cycle arrest

A375 cells were plated in 96-well microplates at 10,000 cells / 200 μl / well. After 24 hours, the cells reached approximately 50% full growth and 50 [mu] l of 5x drug stock solution was added. After an additional 24 hours, the cells were trypsinized and fixed in 200 [mu] l of Preference (Anatech, Battle Creek, Mich., USA) and stored at 4 [deg.] C overnight. The cells were then rinsed and permeabilized in PBS to obtain 0.1% Triton X-100, 200 μg / mL DNase-free RNase and 25 μg / mL propidium iodide (Molecular Probes, USA (Guinea, Calif.) And analyzed in Guava PCA-96 (Guava Technologies, Foster City, CA). Data were analyzed using ModFit LT (version 3.0, Verity, Topsham, Maine, USA).

(1) Evaluation of inhibition of fixed-independent cell growth

The wells of a "ultra low binding" plate (Corning, Acton, Mass., USA) were filled with 60 μl of a 0.15% agarose solution in complete RPMI. Subsequently, 60 [mu] l of complete RPMI containing 9000 Colo205 cells in 0.15% agarose was added per well. After 24 hours, 60 [mu] l of 3x drug solution in agarose-free complete RPMI was added. After 7 days, 36 [mu] l of 6x MTS reagent (CellTiter 96 Aqueous, Promega, Madison, Wis.) Was added per well. After 2 hours at 37 ° C, the absorbance at 490 nm was measured on an M5 plate reader (Molecular Devices, Sunnyvale, Calif.). The non-linear curve plotting was performed with the GraphPad Prism 4.

(2) inhibition of growth on MEK-dependent cancer cell growth (GI ₅₀ )

B-Raf mutant cells A375 (human melanoma), A431 (melanoma), Colo205 (colon carcinoma), HT29 (colorectal adenocarcinoma), MDA-MB231 (breast adenocarcinoma) and BxPC3 (pancreatic adenocarcinoma) (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) ) Cyclopropane-1-sulfonamide for 48 hours and analyzed for ATP content. 100% growth was terminated by incubation with 1 μM N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) 3-dihydroxypropyl) cyclopropane-1-sulfonamide.

The following table shows the average GI ₅₀ values from three or more experiments on each cell line and shows that three B-Raf mutant cell lines (A375, Colo205 and HT29) and also one ras / raf / MEK / MAPK (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- 3-dihydroxypropyl) cyclopropane-1-sulfonamide caused growth inhibition (average titer: 79 nM (+/- 9 nM)):

(S) - (3,4-di &lt; / RTI &gt; (dihydroxypyrimidine) (2-fluoro-4- iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide for 48 hours And analyzed for ATP content. The following table shows the GI ₅₀ for each cell line and is shown by the following formula: N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl ) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide caused reverse transverse inhibition close to its EC ₅₀ value for MEK inhibition:

FIGS. 10A and 10B show the synthesis of N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- -Dihydroxypropyl) cyclopropane-1-sulfonamide was used at increasing concentrations to show that the growth of these cells was arrested when exposed to splitting A375 cells at the exponential phase. The cells were analyzed for ATP content. 100% growth was terminated by incubation with 1 μM N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) 3-dihydroxypropyl) cyclopropane-1-sulfonamide.

Adenylate kinase (AK) release was measured and cell supernatants were assayed against cytotoxic lysates. A375 cells in the great-numbered cleavage were treated with N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- , 3-dihydroxypropyl) cyclopropane-1-sulfonamide and PD-325901 for 48 h (100% cell death was determined using 20 μM tamoxifen). The results are shown in Fig. The data indicated that the data were obtained from N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) 1-sulfonamide caused non-toxic growth arrest in several sensitive human cancer cell lines, indicating i) growth arrest crystal (ATP quantitation) and ii) lack of cytotoxic cell lysate (AK release) &Lt; / RTI &gt; The lack of AK release was confirmed for all cell lines tested.

Fixed-Independent Growth Suppression

2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) Fixed-independent growth of Colo205, A375 and MDA-MB231 cells exposed to cyclopropane-1-sulfonamide for 7 days was quantitatively evaluated in 96 well microplate format. Survival rate was determined by MTS test. The GI ₅₀ values were as follows:

Figures 12A-12C illustrate the preparation of N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6- methoxyphenyl) (A) human colon rectal carcinoma Colo205 cells (GI ₅₀ = 11 nM), (B) A375 cells expressing no growth arrest induced by 1- (2,3-dihydroxypropyl) cyclopropane- cells (GI ₅₀ = 22 nM) and (C) N- (S) of MDA-MB231 cells (3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -6 Methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide.

A375 cells in the great-numbered cleavage were treated with N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- , 3-dihydroxypropyl) cyclopropane-1-sulfonamide (1 μM) for 48 hours and the cell supernatants were analyzed for growth inhibition (ATP content) and cytotoxic lysis (AK release). 100% survival (ATP assay) was determined in the vehicle alone control well. The following table summarizes the results of the synthesis of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) Hydroxypropyl) cyclopropane-1-sulfonamide caused non-toxic growth arrest in B-Raf mutant human melanoma A375 cells:

Fixed-Independent Growth Suppression

Fixed-independent growth was quantitatively evaluated in a 96-well microplate format. Figure 13A shows growth inhibition of human colon carcinoma Colo205 cells with GI ₅₀ values of 6 nM and 11 nM, respectively. Figure 13B shows the inhibition of growth of A375 cells with GI ₅₀ values of 5 nM and 22 nM.

N- (S) - (3,4- Difluoro -2- (2- Fluoro -4- Iodophenylamino ) -6- Methoxyphenyl ) -1- (2,3-dihydroxypropyl) Cyclopropane Cell cycle analysis of -1-sulfonamide-induced growth arrest

MEK inhibition was shown to induce G1 / S cell cycle arrest in A375 cells.

A375 cells in the great-numbered cleavage were treated with N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- , 3-dihydroxypropyl) cyclopropane-1-sulfonamide for 24 hours, and the percentage (%) of cells stained with step-dependent amounts of intracellular DNA was determined by flow cytometry.

The following table summarizes the results of the synthesis of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) Hydroxypropyl) cyclopropane-1-sulfonamide and the control (vehicle alone) treated cells (%) in each growth phase:

FIGS. 14A and 14B are graphs showing the results of the synthesis of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -Dihydroxypropyl) cyclopropane-1-sulfonamide on the cell cycle progression and A375 cells were treated with N- (S) - (3,4-difluoro-2- (2- Exposure to 4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide resulted in depletion of cells in both G2 and S phases Lt; RTI ID = 0.0 &gt; G1 &lt; / RTI &gt;

Evaluation of early hepatocyte and kidney cytotoxicity

Cryopreserved rat hepatocytes were obtained from CellzDirect (Austin, Tex., USA) and plated in collagen-coated 96 well plates according to the manufacturer's instructions. The drug was added after 4 hours of plating (final DMSO concentration: 0.5%).

Plated human hepatocytes were obtained from CELSDIRECT and proceeded according to the manufacturer's instructions.

Cryopreserved human kidney proximal tubule epithelial cells (RPTEC) were obtained from Cambrex and proceeded according to the manufacturer's instructions. Cells were proliferated for 4 days and then plated in 96 well plates at 50,000 cells / well and drug exposure was performed.

After 48 hours, supernatant AK levels were determined using toxicolite and cellular ATP levels were determined with a celite gel. Complete kill values were determined using 15 μM VRX-14686.

The results are shown below. Cell lysates were hardly observed. Minimal toxicity (81% survival) was observed in freshly plated invasive human hepatocytes with 30 μM N- (S) - (3,4-difluoro-2- (2- fluoro- Methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide. RPTEC cells showed dose-dependent ATP depletion and apparent cell lysates appeared at 30 μM.

The data show that (1) N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6- methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide inhibits cell growth and division without inducing toxicity in selected human cancer cells, and the GI ₅₀ value in a fixed-dependent proliferation assay Is in the range of 70 to 89 nM, and (2) N- (S) - (3,4-difluoro-2- (2- fluoro- - (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide inhibits cell growth and division in selected human cancer cells and the GI ₅₀ values in the fixation-dependent and fixed-independent proliferation assays are 51 nM And 22 nM, and (3) N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- , 3-dihydroxypropyl) cyclopropane-1-sulfonamide caused G1 arrest in A375 cells and fixed-independent (4) N- (S) - (3,4-difluoro-2- (2-fluoro-4- 6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide is a cytotoxic agent in early normal human hepatocytes, human kidney proximal tubule epithelial cells and rat hepatocytes As shown in Fig.

Example 111 : Synthesis of N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) &Lt; / RTI &gt; hydroxypropyl) cyclopropane-1-sulfonamide &lt; RTI ID = 0.0 &gt;

R _ac : Accumulation index

^* Incorrect estimates due to limited sampling time

2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) (S) - (3,4-difluoro-2- (2-fluoro-4-iodo-phenyl) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide was easily absorbed and the average _Tmax was in the range of 1.33 to 1.50 hours. The mean C _max , C _τ and AUC values increased with dose in a dose - proportional manner. Cumulative indices ranged from 1.49 to 1.76 for C _max and from 1.90 to 2.07 for AUC, indicating a moderate accumulation. The half-life was not precisely measurable due to the limited sampling time after multiple doses, but half-life was expected to be greater than 22 hours after multiple dosing based on cumulative indices. These half-life values were significantly longer than those observed in the mouse efficacy model, which typically ranged from 2 hours to 3 hours. Also, a high-to-low ratio of encouraging was shown at all doses.

Example 112 : Synthesis of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) Hydroxypropyl) cyclopropane-1-sulfonamide in a healthy volunteer after multiple administration of the compound

R _ac : Accumulation index

^* Incorrect estimates due to limited sampling time

2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenyl) cyclopropane-1-sulfonamide Amino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide was readily absorbed and the average T _max ranged from 2.00 to 2.25 hours. Mean C _max , C _τ and AUC values increased with dose. Cumulative indices ranged from 1.14 to 1.23 for C _max and from 1.24 to 1.29 for AUC, indicating that cumulative scores were not significant. The half-lives of the two dose regimens ranged from 13 to 15 hours. These half-life values were shorter than those observed in cancer patients.

Example 113 : In vitro anti-proliferative activity

2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) The effect of cyclopropane-1-sulfonamide on the inhibition of cell proliferation was investigated in cell proliferation assays in cell lines derived from human gastric carcinoma ("gastric cancer").

Cell Culture / Growth Inhibition Assay: Human gastric carcinoma Hs746t cells were obtained from ATCC (Manassas, Virginia, USA). Hs746t cells were maintained in DMEM supplemented with 10% fetal bovine serum, penicillin (100 U / mL) and streptomycin (100 ug / mL). The cells 37 ℃, was maintained at 5% CO ₂ and 100% humidity. For cell proliferation experiments, cells were plated in a white 96-well plate with clear bottoms at 3000 cells / 100 μl per well. After 24 hours, the cell culture medium was removed and various amounts of N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6- methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide. After incubation for 48 hours at 37 ° C, cell lysates (Promega, Madison, Wis.) Were used and luminescent values were determined using a LJL Biosystems Analyst HT Material) to determine the level of ATP. ATP levels for each dose were measured in triplicate in independent wells.

Relative number of cells = (treated) N - (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) Average RLU of 3-dihydroxypropyl) cyclopropane-1-sulfonamide / (mean RLU of vehicle alone control).

Figure 19 shows the number of cells (values for vehicle) vs. 2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-me thiomorpholin- 1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide inhibits the proliferation of human gastric carcinoma Hs746t cells after 48 hours of treatment.

Example 114 : In vitro anti-proliferative activity

2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) The effect of cyclopropane-1-sulfonamide on the inhibition of cell proliferation was examined by cell proliferation assays in cell lines derived from human gastric adenocarcinoma ("gastric cancer").

Cell Culture / Growth Inhibition Assay: Human gastric adenocarcinoma AGS cells were obtained from ATCC (Manassas, Virginia, USA). AGS cells were maintained in DMEM / F12 supplemented with 10% fetal bovine serum, penicillin (100 U / mL) and streptomycin (100 ug / mL). The cells 37 ℃, was maintained at 5% CO ₂ and 100% humidity. For cell proliferation experiments, cells were plated in a white 96-well plate with clear bottoms at 3000 cells / 100 μl per well. After 24 hours, the cell culture medium was removed and various amounts of N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6- methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide. After incubation for 3 days at 37 ° C, a celite gel (Promega, Madison, Wis.) Was used and the luminescence values were read by LJ BioSystems Analysts Inc. (Sunnyvale, CA) . ATP levels for each dose were measured in triplicate in independent wells. In another experiment, cells were plated at 1000 cells / 100 μl per well, treated for 6 days, and assayed as previously described.

Relative number of cells = (treated) N - (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) Average RLU of 3-dihydroxypropyl) cyclopropane-1-sulfonamide / (mean RLU of vehicle alone control).

FIGS. 15A and 15B are cross-sectional views illustrating the synthesis of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) (S) - (3,4-difluoro-2- (2-fluoro-phenyl) -propyl) cyclopropane-1-sulfonamide was exposed to (A) -4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration vs. (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxy Phenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide inhibits proliferation of human gastric adenocarcinoma AGS cell line.

Example 115 : N- (S) - (3,4-Difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- Growth response of orthotopic human Hep3B tumors in nude mice treated with various amounts of cyclopropane-1-sulfonamide

(S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxy ("Compound A") was compared with an optimal dose of 5-fluorouracil (75 mg / kg) BALB / c nu / nu mice.

Animals: In this study, female BALB / c nu / nu mice (University of Adelaide, Wight campus, Sue, AU) between 10 and 14 weeks of age with a body weight range of 19.1 to 29.94 g Were used. The mice were divided into 6 study groups (4 treatment groups and 2 control groups) as follows:

Number of mice per group: Groups 1 to 5 include 10 mice

                   'Take-Rate' control group (Group 6) included 15 animals

Mice were placed under barrier (quiescent) conditions in a controlled environment (target range: temperature 21 +/- 3 DEG C, humidity 30% to 70%, ventilation 10-15 times per hour) with a light / dark cycle of 12 hours . Temperature and relative humidity were monitored continuously. Commercial rodents feed (Rat and Mouse Cubes, Specialty Feeds Pty Ltd, Glen Forest, Western Australia) and tap water were provided unlimited to the animals. Both the feed and water provided were sterilized with an autoclave.

Tumor inoculation: Hep3B human liver carcinoma cells (passage 2 from working stock solution VP-Stock 353) were cultured in RPMI 1640 cell culture medium supplemented with 10% FBS and penicillin-streptomycin (final concentration: 50 IU / mL) Lt; / RTI &gt; The cells were harvested by trypsinization and washed twice in HBSS and counted. The cells were then resuspended in HBSS: Matrigel (1: 1, v / v) and adjusted to contain a final volume of 1 x 10 ⁸ cells / mL. Prior to inoculation, the incision was roughly wiped with an alcohol swab and the abdominal wall was incised to expose the liver. 10 μl of cells (1 × 10 ⁶ cells) were taken out by introducing a needle through the liver surface. Thereby holding the needle in this position for about 30 seconds to Mart to Rigel ^® and the polymerization was not to the tumor cells do not leak into the peritoneal cavity.

Treatment began on day 14 after inoculation. At day 7 of the study (day 21 post-inoculation), all mice in the 'Absorbance' control group were killed and the liver visually assessed for the presence of the tumor.

Materials: The following materials were obtained from each supplier.

Sterile brine solution (0.9% NaCl (aqueous)) was obtained from Baxter Healthcare Australia, Old Tung Gaby, NSW. Cremophor EL was obtained from Sigma-Aldrich Pty Ltd, Castle Hill, NJ, Australia. 5-Fluorouracil, a clear, colorless liquid formulation, was obtained from Mayne Pharma Pty Ltd. RPMI1640 cell culture medium, FBS and HBSS were obtained from Invitrogen Australia Pty Ltd, Wiebold, Australia. Penicillin-streptomycin and Trypan Blue were obtained from Sigma-Aldrich, Castle Hill, NJ, Australia. Hep3B2.1-7 human liver carcinoma cells were provided by the American Type Culture Collection (ATCC), Rockville, Md. Matrigel ^® is Australia yen was obtained from Bio S Video Scientology system (BD Biosciences) W. North Ryde material.

Inoculation suspension of the use of Matrigel ^®, improves the absorption rate of the tumor and reduce the variety of tumor size, growth Hep3B2.1-7 human liver carcinoma is more stable when the inoculation in the presence of this extracellular matrix.

Compound Preparation and Administration: Cremophor EL: Saline (1: 9, v / v; vehicle control), N- (S) - (3,4- difluoro-2- (2- (Compound A) or 5-fluorouracil (compound control) was prepared according to the following schedule: &lt; tb &gt; ______________________________________ &lt; tb &gt; ______________________________________ &lt;&Lt; / RTI &gt;

Vehicle controls were injected once per day for 21 consecutive days (day 0 to day 20) with cremopor EL: saline (1: 9, v / v) at a dose volume of 10 mL / kg. .

2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) Cyclopropane-1-sulfonamide was formulated in cremophor EL: saline (1: 9, v / v). The stock solution was prepared weekly and stored at 4 ° C. The administration solution was prepared on each administration day. 2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) Cyclopropane-1-sulfonamide was administered once a day for 21 days (day 0 to day 20) with a volume of 10 mL / kg . The compounds were administered at doses of 2, 10 and 50 mg / kg.

5-fluorouracil was diluted in sterile saline and dosed at a dose of 10 mL / kg once per week for 3 weeks (Day 0, Day 7 and Day 14) via the tail vein at 75 mg / kg &lt; / RTI &gt; .

The mice in group 6 ('absorptivity' control) were not treated. Mice were killed and exposed to the liver on day 7 (day 21 post-inoculation) to determine the 'uptake rate' and tumor size in the hepatic wall.

Each animal's body weight was measured just prior to administration. The volume to be administered to each mouse was calculated and adjusted based on body weight.

Tumor measurement: The liver and tumor wet weights were measured after post-resection at the end of each study. At the end of the study, the liver was excised and weighed in all mice of each study group. If there is a tumor that can be seen by the naked eye, the number is counted. These tumors were removed from the liver and weighed.

Data Acquisition and Calculation: Each animal's transponder (Bar Code Data Systems Pty Ltd, Botswana, NJ, USA) was read by a bar code reader (Labmax I LabMax I, &lt; / RTI &gt; DataMars, Switzerland). All measurements were obtained using the same miniature caliper (Absolute Digimatic Model CD-6 &quot; CS, Mitutoyo Corporation, Japan). Data transmission software was Pendragon Forms (Forms) 4.0 using (pen Dragon ^® software Corporation (Pendragon ^® software Corporation), Illinois River Thai Bill material) were synchronized to a secure relational database of Non farm (vivoPharm). data reports and data calculations AIDAM v2 .

Statistics and Calculations: All statistical calculations are done with SigmaStat 3.0. (SPSS Australasia Pty Ltd, North Sydney, NSW, Australia). &Lt; / RTI &gt;

A 2-sample t-test was used to determine significance in weight change within the treatment group between day 0 and study termination day. The Mann-Whitney Rank Sum Test was performed only when the data failed in the normality test or the equality variance test.

One-Way Analysis of Variance (ANOVA) (multiple comparison procedures for all pairs and multiple comparisons vs. controls) were performed on liver weight and tumor weight data at the end of the study. Kruskal-Wallis 1-way ANOVA was performed on the rankings if the test did not pass the equi-dispersion test. The same statistical analysis was performed on the data for the tumor-bearing mice of the present study.

A p value of less than 0.05 was considered significant.

The liver weight and tumor weight data for tumor-bearing mice and the average weight of liver and tumor mice per group for tumor-bearing mice

Samples were not collected in mice of group 5 (75 mg / kg of 5-fluorouracil) that died during the study period. The study was terminated at day 18 after initial treatment, as there was a large tumor in some mice, as evidenced by the swollen appearance of the abdomen.

A dose-dependent trend in the reduction of liver and tumor weights was observed for N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6- Phenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide treatment group. Considering only tumor-bearing mice, the average weight of the liver was calculated from the mean weight of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) The group treated with the highest dose of the 1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide (Group 4 at 50 mg / kg) and the group treated with 5-fluorouracil (75 mg / kg < / RTI &gt; group) was significantly different from the vehicle control (Group 1; p &lt; 0.05). In addition, the average weight of the tumors was determined by the method described in Example 1, except that N- (S) - (3,4-difluoro-2- (2-fluoro- 3-dihydroxypropyl) cyclopropane-1-sulfonamide (Group 3 of 10 mg / kg and Group 4 of 50 mg / kg) and 5-fluorouracil treated group (75 mg / kg &lt; / RTI &gt; group 5) was found to be significantly different from the vehicle control group.

These results are presented graphically in Fig. 16 (considering only the mean liver weight-bearing mice) and Fig. 17 (liver tumor weight-bearing mice only).

Example 116 : N- (S) - (3,4-Difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) Growth response of stereotactic human HT-29 colon tumors in nude mice treated with various amounts of cyclopropane-1-sulfonamide

(S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6- methoxyphenyl) - The dose response of 1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide ("Compound A") was compared with 5-fluorouracil (75 mg / kg) to determine BALB / c nu / nu Mice.

Animals: Female BALB / c nu / nu mice (University of Adelaide, Wight campus, Sue, Australia), weighing between 16.58 and 25.39 g (mean 21.52 g), were used. The mice were divided into 6 study groups (4 treatment groups and 2 control groups) as follows:

Number of mice per group: Groups 1 to 5 include 10 mice

                   'Absorption rate' Control group (group 6) included 9 animals

Mice were placed under barrier (quiescent) conditions in a controlled environment (target range: temperature 21 +/- 3 DEG C, humidity 30% to 70%, ventilation 10-15 times per hour) with a light / dark cycle of 12 hours . Temperature and relative humidity were monitored continuously. Commercially available rodent feed (Rat &amp; Mouse Cubes, Specialty Lactose Phytate Wyl Limited, Glen Forest, Western Australia) and tap water were provided unlimited to the animal. Both the feed and water provided were sterilized with an autoclave.

Tumor Inoculation: HT-29 human colon adenocarcinoma cells (passage 4 from working stock VP-Stock 325) were cultured in RPMI 1640 cell culture medium supplemented with 10% FBS and penicillin-streptomycin (final concentration: 50 IU / mL) . The cells were harvested by trypsinization and washed twice in HBSS and counted. The cells were then resuspended in HBSS and adjusted to contain a final volume of 2 x 10 ⁸ cells / mL. Prior to inoculation, the incision was roughly wiped with an alcohol swab and the abdominal wall was incised to expose the caecum wall. 5 μl of cells (1 × 10 ⁶ cells) were taken out by introducing a needle through the surface of the caecum wall.

Materials: The following materials were obtained from each supplier.

Sterile brine solution (0.9% NaCl (aqueous)) was obtained from Baxter Healthcare Australia in Old Tung Gabbih, NSW, Australia. Cremopor EL was obtained from Sigma-Aldrich Pty. Ltd. of Castle Hill, NSW, Australia. 5-Fluorouracil, a clinical formulation of a clear colorless liquid, was obtained from the main Pharmacopeia. RPMI1640 cell culture medium, FBS, and HBSS were obtained from Invitrogen Asteria Pty. Ltd., Vieira-Mount Wembley, Australia. Penicillin-streptomycin and Trippine Blue were obtained from Sigma-Aldrich, Castle Hill, NJ, Australia. HT-29 human colon adenocarcinoma cells were provided by the American Type Culture Collection (ATCC), Rockville, MD.

Compound Preparation and Administration: Cremophor EL: Saline (1: 9, v / v; vehicle control), N- (S) - (3,4- difluoro-2- (2- 6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide or 5-fluorouracil (compound control) was administered according to the following schedule:

Vehicle controls were dosed once daily with cremophor EL: saline (1: 9, v / v) at a dose volume of 10 mL / kg for 21 consecutive days (day 0 to day 20). .

2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) Cyclopropane-1-sulfonamide was formulated in cremophor EL: saline (1: 9, v / v). The stock solution was prepared weekly and stored at 4 ° C. The administration solution was prepared on each administration day. 2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) Cyclopropane-1-sulfonamide was administered once a day for 21 days (day 0 to day 20) at a dose of 2, 10 and 50 mg / kg at a dose of 10 mL / .

5-fluorouracil was diluted in sterile saline and dosed at a dose of 10 mL / kg once per week for 3 weeks (Day 0, Day 7 and Day 14) via the tail vein at 75 mg / kg &lt; / RTI &gt; .

The mice in group 6 ('absorptivity' control) were not treated. At study day 7 (day 21 post-inoculation), mice were killed and colon was exposed to determine the uptake rate and tumor size in the cecal wall.

Each animal's body weight was measured just prior to administration. The volume to be administered to each mouse was calculated and adjusted based on body weight.

Tumor measurement: The cecum and tumor wet weight were measured when each was resected at the end of the study. At the end of the study, the cecum was excised from all mice in each study group and the tumor was kept intact and weighed. Tumors were then excised from the cecum and weighed.

At the end of the study, liver was excised from all mice of each group and fixed in 10% buffered formalin. Five liver samples from the vehicle control were embedded in paraffin and sectioned and stained with hematoxylin and eosin (H &amp; E) for histological evaluation of morphological changes.

Data Acquisition and Calculation: Each animal's transponder (Barcode Data Systems Pty. Ltd., Botswana, NJ, USA) was scanned with a barcode reader (Labmax I, Dataamars, Switzerland) just prior to data acquisition. All measurements were obtained using the same small caliper (Absolute digital Matic Model CD-6 "CS, Mitu Toyo Corporation of Japan Material) as a transfer software data Pen Dragon pomjeu 4.0 (Pen Dragon ^® Software Corporation, Illinois River AIDAM v2.4 was used for data reporting and data calculations. AIDAM v2.4 was used for data reporting and data calculations.

Statistics and Calculations: All statistical calculations are done with SigmaStart 3.0. (SPS AUSTRALIA PATTIWAY LIMITED, NSW, North Sydney).

A 2-sample t-test was used to determine significance in weight change within the treatment group between day 0 and study termination day. Due to the excessive weight loss, it has been found that N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -Dihydroxypropyl) cyclopropane-1-sulfonamide was treated at 2 and 50 mg / kg. In these groups, a 2-sample t-test was used between day 0 and the last day of the study and between the last day of treatment and the end of the study to determine significance in body weight changes within the treatment group. If the data did not pass the normality test or the equilibrium test, the only-witney ranking sum test was performed.

One-way analysis of variance (ANOVA) (multiple comparison procedures for every pair and multiple comparisons vs. controls) was performed on cecal weight and tumor weight data at the end of the study. If the test did not pass the normality test, the value was converted to the natural log value before the procedure.

A p value of less than 0.05 was considered significant.

Observations: Mean weight loss was determined in all study groups, including vehicle controls. Diarrhea and signs of dehydration (loss of skin elasticity) were observed in all study groups, including vehicle control. (S) - (3,4-difluoro-2- (2- (4-fluorophenyl) -2-methyl- 6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide, The treatment was stopped. 2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) All treatments for this group were administered according to a schedule because weight loss in the group receiving cyclopropane-1-sulfonamide at 10 mg / kg was less severe. At the end of the study, the mean weight loss was significant in the group and the 5-fluorouracil treatment group.

Thirty-one days after the inoculation, the rate of absorption of HT-29 tumors in the 'absorptive' group was 100%, but the size of these tumors was much smaller than expected. Thereby, a mixture of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- Hydroxypropyl) cyclopropane-1-sulfonamide treatment group and the vehicle control group. In addition, 5-fluorouracil had no effect on the weight of cecum and HT-29 tumors.

Body weight data were not collected in the 6th group ('Absorbance' control group). The group was killed on day 7 of study (day 21 post-inoculation) and visually assessed whether the tumor was growing adequately for the purpose of the study.

On day 9 of the study, group 2 (2 mg / kg of N- (S) - (3,4-difluoro-2- (2- fluoro- (S) - (3,4-di (tert-butyloxycarbonyl) methyl) (2-fluoro-4- iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide) , Because mice in these groups exhibited excessive weight loss. All the remaining groups performed all treatment schedules during the study period.

The average tumor weight in each group is shown in Fig. The mean weight of tumors for each group included only survivors until the end of the study. The values for the mice that died during the study period were not included in the average value calculation.

A shaded display indicates that the sample was collected from a mouse that died during the study period. These values were excluded in the calculation of mean values for cecum weight and tumor weight. 10 mg / kg N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) Hydroxypropyl) cyclopropane-1-sulfonamide in the HT-29 tumor and cecum weights data.

Example 117 : Tumor growth delay in nude mice bearing human A375 melanoma xenografts

Six groups of tumor-bearing mice (n = 9) were used. The control group received intravenous (IV) injection of 30 mg / kg of paclitaxel as a reference agonist and mouse treated with 10% cremophor EL / saline vehicle for 14 days (qd × 14) once a day by oral gavage (qod x 5) every other day (iv). Four experimental groups were given N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) ("Compound A") was orally administered bid × 14 at 25 mg / kg or 50 mg / kg, qd × 14, or 12.5 or 25 mg / kg. Treatment results were evaluated by TGD, defined as the difference in median time from the treated group to the end tumor volume compared to the control group. Toxicity was assessed by body weight measurements and clinical observations.

Animals: Female athymic nude mice (nu / nu, Harlan) were between 10 and 11 weeks of age on the first day of study and had a body weight (BW) range of 19.3 to 25.5 g. Unlimited to the animals in water (reverse osmosis, 1 ppm Cl), and 18.0% crude protein, 5.0% crude fat, and consisting of 5.0% crude fiber NIH 31 Modified sulfide-and yireyi dieyi suited Lab diet (Modified and Irradiated Lab Diet) ^® Respectively. The mouse 21 ℃ to 22 ℃ (70 ℉ to 72 ℉) and irradiated alpha of under 12 cycles time the light from 40% to 60% humidity, static micro isolator (microisolator) - dry (ALPHA-Dri) ^® bed-o "Jacobs (bed-o'cobs) ^® Laboratories storage animal confined in the bedding (Laboratory Animal bedding). Recommendations for the management and use of laboratory animals have been attached here, with regard to confinement, management, surgical procedures, control of feed and fluid supply, and veterinary care.

Tumor transplantation: Xenotransplantation from A375 human melanoma tumors in athymic nude mice was initiated by series transplantation. A375 tumor fragments (about 1 mm ³ ) were subcutaneously implanted in the right flank of each test mouse and tumor growth was monitored until the average size was between 100 and 150 mm ³ . After 13 days designated as study day 1, the animals were divided into 6 groups each consisting of 9 mice (reduced from 10), wherein the individual tumor volumes ranged from 63 to 221 mm &lt; ³ &gt; The tumor volume was 125.3 to 125.9 mm &lt; ^{3 &} gt ;. Tumor volume was calculated according to the following formula: Tumor volume (mm ³ ) = (w ² × l) / 2, where w = A375 tumor width, l = A375 tumor length (mm).

Materials: N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3- Propyl) cyclopropane-1-sulfonamide was dissolved in 10% crmorphol EL in saline at 5 mg / mL, at which time sonication, shaking and heating at 35 DEG C helped dissolve. The 5 mg / mL solution was used as a 50 mg / kg treatment solution and the 25 mg / kg and 12.5 mg / kg treatment solutions were prepared by serial dilution. The dosing solution was stored for up to one week at room temperature with blocking of light.

The solution of paclitaxel (NPI) was prepared by diluting 3 mg / mL in 5% ethanol, 5% cremophor EL (5% dextrose in water (D5W)) from 30 mg / mL stock on each use day. Paclitaxel administration was performed at 30 mg / kg.

Action: The following table shows the treatment method:

Group 1 mice received a vehicle consisting of 10% cremophor EL in saline daily administered 14 times (qd x 14) via oral gavage (po), which was used as a control for tumor progression. Group 2 animals received paclitaxel as a reference agonist at 30 mg / kg five times (qod x 5) intravenously (iv) once every other day. The mice of Groups 3 to 6 were treated with N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6- (2, 3-dihydroxypropyl) cyclopropane-1-sulfonamide was orally administered: 50 mg / kg, qd x 14; 25 mg / kg twice daily for 14 days. One dose on the first and last day (bid × 14); 25 mg / kg, qd × 14; And 12.5 mg / kg, bid × 14. All doses were administered in a volume of 0.2 mL per 20 g body weight and the dose was calculated according to the weight of the animal.

Endpoints: Tumors of all groups were calibrated twice weekly. Each animal was euthanized on the first day of the day when the tumor reached its end point size of 2000 mm &lt; ³ &gt; or the last day of the study (day 60). The time to endpoint (TTE) for each mouse was calculated according to the following equation: TTE (days) = [log ₁₀ (endpoint volume, mm ³ ) - b] / m where b is the log- The slice of the straight line obtained by linear regression of the data set, and m is the slope thereof).

The data set consisted of the first observation exceeding the endpoint volume of the study and three consecutive observations immediately before reaching the endpoint volume. Animals that did not reach the end point were assigned the same TTE value as the last day of the study. Animals classified as NTR (Non-Treatment-Related) deaths by accident (NTRa) or by unknown cause (NTRu) were excluded from the TTE calculation (and all further analyzes). Animals assigned to TR (treatment-related) death or NTRm (non-treatment-related due to metastasis) were assigned the same TTE as death.

Treatment results were determined from tumor growth delay (TGD), and TGD was defined as the increase in the central TTE (time to end point) [TGD = T - C (expressed in days)] in the treated group compared to the control group, (%) TTE = (T - C) / C 占 100 where T = the central TTE of the treated group and C = the central TTE of the control group (the first group).

Treatment may cause partial regression (PR) or complete regression (CR) of the tumor in the animal. In the PR response, three consecutive tumor volumes during the study period were less than 50% of the tumor volume on day 1, and at least one of these three measurements was greater than 13.5 mm ³ . In the CR response, three consecutive tumor volume measurements during the study period were less than 13.5 mm ³ . At the end of the study, the animals that showed CR response were further classified as Tumor-Free Survivor (TFS). Tumor regression was monitored and recorded.

Side effects: The animals were weighed daily for the first 5 days of the study, and then weighed twice weekly. Mice were frequently observed for signs of symptoms of any adverse treatment-related adverse events, and clinical signs were noted when such events were observed. Acceptable tolerability is defined as the group with an average weight loss of less than 20% during the test and no more than one treatment-related death in the animal group. Any dosage regimen that does not meet these criteria is considered to exceed the maximum tolerated dose (MTD). Death is classified as TR if it is apparent that it is due to a clinical side effect and / or autopsy by treatment side effects, or may be classified as TR even if it is due to unknown causes during the administration period or within 10 days after the last dose. If there is no evidence that death is related to the side effect of the treatment, classify such death as NTR.

Statistical Analysis and Graph Analysis: The log rank test was used to analyze the significance of differences between the TTE values of the treated and control groups. Both statistical analyzes were performed with significance level P = 0.05.

The central tumor growth curve shows the median tumor volume of the corresponding group as a function of time. If animals were excluded from the study due to tumor size or TR death, the final tumor volume recorded for that animal was included in the data used to calculate the median tumor volume of the corresponding group at a later time. After excluding 50% of the animals in the group due to tumor progression, both ends of the curve were removed. Kaplan-Meier plots were constructed to show the percentage of animals remaining in the study as a function of time, and the same data set was used for the log rank test. A prism for Windows 3.03 (graph pads) was used for all graphical and statistical analyzes.

Growth of A375 tumors in control mice (Group 1): Group 1 animals received 10% cremophor EL / saline vehicle po, qd x 14. Tumors in control mice were spontaneously grown to a volume of 2000 mm ³ point, with a median TTE of 22.8 days and establishing the maximum possible TC or 163% TGD at study day 37.1.

Effect of paclitaxel treatment (Group 2): Group 2 animals received paclitaxel as a reference agonist at 30 mg / kg, iv, qod x 5. All nine animals reached the tumor volume endpoint. Tumor growth was similar and slightly shifted to the right compared to the control group. The median TTE value was 28.8 days, which corresponds to 26% TGD and was found to be significant by logarithmic analysis (Table 2, P = 0.0088 G1 vs. G2). There was no tumor regression associated with paclitaxel treatment.

N- (S) - (3,4- difluoro-2- (2-fluoro-4-iodo-phenylamino) -6-methoxy-phenyl) - 1 - (2,3-dihydroxypropyl) (S) - (3,4-difluoro-2- (2-fluoro-3-fluoro-phenyl) -4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide was orally administered as monotherapy. Group 3 animals received 50 mg / kg qd × 14 schedule. Nine tumors of the group reached the volume endpoint. The study period was increased because there was little net change in the central tumor volume of the group for the first 10 days. One animal showed tumor PR. The median TTE value was 27.5 days or 21% TGD, which was significant (P = 0.0054 G1 vs. G).

Animals in Group 4 received 25 mg / kg of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide was administered on a bid × 14 schedule. Four of the nine animals in the group remained on TFS all day 60. Two additional of the nine animals reached the end of the tumor volume one day before the end of the study. The groups were 4/9 PR, 5/9 CR and 4/9 TFS. During the first few days of the study, the central tumor volume began to decrease and lasted for about 30 days. Tumor regrowth occurred in 5 out of 9 animals, and central tumor growth was recovered from day 32 and continued until the end of the study. The median TTE of the group was 59.9 days and the maximum possible TGD was 163% (P <0.0001, Table A1).

In addition, the mice of the fifth group were also treated with 25 mg / kg of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) 1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide, but proceeded with a less intense qd × 14 schedule. All nine animals in group 5 reached the tumor volume end point and there was no tumor degeneration. Tumor growth was similar to that of the control group. The median TTE was 25.6 days, which was not significant but was 12% TGD (P = 0.0662 G1 vs. G5).

The animals of group 6 received 12.5 mg / kg of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide was administered on a bid × 14 schedule. All tumors in this group reached the end of volume. Similar to Group 4, in Group 6, the central tumor volume was reduced early in the study, but this reduction lasted only about 9 days and was associated with a single PR response. Tumor volume increased from day 10 to end of study. The median TTE of the group was 27.5 days, corresponding to a significant 21% TGD (P = 0.0424 G1 vs. G6).

Briefly, a mixture of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) Hydroxypropyl) cyclopropane-1-sulfonamide exhibited dose-related anti-tumor activity in both the once-a-day and twice-a-day oral doses for human A375 melanoma xenografts. Twice daily dosing was superior to once-daily dosing in the size of the TGD produced and the number of desired responses. Thus, the synthesis of N- (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) Propyl) cyclopropane-1-sulfonamide anti-tumor activity is dose-dependent and schedule-dependent.

Example 118 : Subcutaneous Colo205 activity for human colon carcinoma xenografts

Animals: Female athymic nude mice (nu / nu, Haaran) were between 12 and 13 weeks of age on the first day of study and had a body weight (BW) range of 18.3 to 27.3 g. And it provided to the animals in water (reverse osmosis, 1 ppm Cl), and 18.0% crude protein, 5.0% crude fat, and consisting of 5.0% crude fiber NIH 31 Modified and-sulfide yireyi dieyi suited Lab Diet ^® unlimited. The mouse 21 ℃ to 22 ℃ (70 ℉ to 72 ℉) and alpha under a 12 cycle time light from 40% to 60% humidity irradiated in static micro isolator-Dry ^® bed-o 'Jacobs ^® Laboratories storage animal bedding . Here, recommendations on guidelines for the management and use of laboratory animals in relation to confinement, management, surgical procedures, control of feed and fluid supply, and veterinary care have been added.

Tumor transplantation: Xenotransplantation from Colo205 human colon carcinoma cells was initiated. Tumor cells were treated with 10% heat-inactivated fetal bovine serum, 100 units / mL penicillin G sodium, 100 g / mL streptomycin sulfate, 0.25 g / mL amphotericin B and 25 g / mL gentamicin, 2 mM glutamine , 1 mM sodium pyruvate, 10 mM HEPES and 0.075% sodium bicarbonate. The cell cultures were maintained in a tissue culture flask in a humidified incubator at 37 ° C under an atmosphere of 5% CO ₂ and 95% air. At the day of tumor cell transplantation, Colo205 cells were harvested during macrophage growth and resuspended at a concentration of 5x10 ⁶ cells / mL in a 50% Matrigel matrix (Vidi Biocysis) in PBS. 1 implanted subcutaneously gae × 10 ⁶ Colo205 cells in the right flank of each test mouse, and tumor growth was monitored until the average size of them in the range of 80 to 120 mm ^3. After 14 days designated as Study Day 1, the animals were divided into 8 groups (N = 9), wherein the individual tumor volumes ranged from 63 to 196 mm ³ and the mean tumor volume of the group ranged from 118 to 119 mm ³ . Tumor volume was calculated according to the following formula: Tumor volume (mm ³ ) = (w ² × l) / 2, where w = Colo 205 tumor width, l = Colo 205 tumor length (mm). Tumor weight can be estimated on the assumption that 1 mg is equivalent to a tumor volume of 1 mm ³ .

Materials: The administration solution of Compound A was prepared fresh daily by dissolving the required amount of the compound in 100% of the cremophor EL and diluting it 10 times with ordinary saline. The concentration of the final administration solution was 2.5, 5, 10, or 20 mg / mL, thereby providing each dose of 25, 50, 100, or 200 mg / kg in a 10 mL / kg administration volume. Paclitaxel (Natural Pharmaceuticals, Inc.) was freshly prepared on each day of administration on a vehicle (5% EC vehicle) consisting of 5% ethanol and 5% cremophor EL in 90% D5W .

Action: The following table shows the treatment method:

Group 1 received vehicle formulation (10% cremophor EL in saline) and was used as a tumor growth control. For group 2, the reference drug, paclitaxel, was administered according to its optimal schedule in nude mice (30 mg / kg i.v. qod x 5). Compound A was administered to groups 3 to 6 at a dose of 25, 50, 100, and 200 mg / kg, respectively, and the dose of p.o. And group 6 (200 mg / kg) stopped due to toxicity after 6 days. All doses were calculated according to animal weight (0.2 mL per 20 g body weight).

End point: The tumor was measured twice weekly with a caliper. Each animal was euthanized on the first day of the day when the tumor reached its intended end point size of 2000 mm &lt; ³ &gt; or the last day of the study (day 74). However, control tumors did not exhibit features of large-stem growth after reaching a size of approximately 800 mm ³ . Thus, an end tumor size of 800 mm ³ was used for tumor growth delay (TGD) analysis. The time to endpoint (TTE) for each mouse was calculated according to the following formula: TTE (days) = [log ₁₀ (endpoint volume, mm ³ ) - b] / m, where b is log- The slice of the straight line obtained by linear regression of the data set, and m is the slope thereof). The data set consisted of the first observation exceeding the endpoint volume of the study and three consecutive observations immediately before reaching the endpoint volume. Animals that did not reach the end point were assigned the same TTE value as the last day of the study. Animals classified as NTR (NTRa) or NTR (non-treatment related) deaths due to unknown causes (NTRu) were excluded from the TTE calculation (and any further analysis). Animals assigned to TR (treatment-related) death or NTRm (metastasis-free, non-treatment-related) were assigned the same TTE as death.

Treatment results were determined from tumor growth delay (TGD), and TGD was defined as the increase in the central TTE (time to end point) [TGD = T - C (expressed in days)] in the treated group compared to the control group, (% TGD = (T - C) / C 占 100 where T = central TTE of the treated group, C = centralized TTE of the control group).

The control group was a mouse of the first group.

Treatment may cause partial regression (PR) or complete regression (CR) of the tumor in the animal. In the PR response, three consecutive tumor volumes during the study period were less than 50% of the tumor volume on day 1, and at least one of these three measurements was greater than 13.5 mm ³ . In the CR response, three consecutive tumor volume measurements during the study period were less than 13.5 mm ³ . The regression response was monitored and recorded.

Side effects: The animals were weighed daily for the first 5 days of the study, and then weighed twice weekly. Mice were frequently observed for signs of symptoms of any adverse treatment-related adverse events and recorded when clinical signs of toxicity were observed. Acceptable toxicity is defined as a group of less than one treatment-related (TR) death among 10 treated animals with an average weight loss of less than 20% during the study, and any of the more toxic dosing methods, Is considered to exceed. Death is classified as TR if it is apparent that it is due to a clinical side effect and / or autopsy by treatment side effects, or may be classified as TR even if it is due to unknown causes during the administration period or within 10 days after the last dose. If there is no evidence that death is related to the side effect of the treatment, classify such death as NTR. Animals were monitored frequently and BW measurements were performed to monitor adverse events. BW changes were not noteworthy, and all procedures except for group 6 were tolerably tolerated. In the case of 200 mg / kg Compound A administered po 6 times once a day, 1 was evaluated as TR death on the 7th day, and 2 additional TR deaths occurred on the 8th day. All mice in group 6 exhibited clinical signs of toxicity including backbone, decreased activity and loose stools.

Statistical Analysis and Graph Analysis: The log rank test was used to analyze the significance of differences between the TTE values of the treated and control groups. Both statistical analyzes were performed with significance level P = 0.05.

The central tumor growth curve is plotted by plotting the median tumor volume of the corresponding group as a function of time on a log scale. If animals were excluded from the study due to tumor size or TR death, the final tumor volume recorded for that animal was included in the data used to calculate the median tumor volume of the corresponding group at a later time. 50% of the animals in the group were excluded from the study due to tumor progression, or both ends of the curve were removed after the second TR death in the group occurred. Kaplan-Meier plots were constructed to represent the percentage of animals remaining in the study as a function of time and the same data set was used for the log rank test. A prism for Windows 3.03 (graph pads) was used for all graphical and statistical analyzes.

In control mice COLO205  Tumor growth (Group 1)

Group 1 tumors showed slow and uneven growth. Vehicle-treated group 1 tumors in 7 out of 9 control mice reached a tumor volume endpoint of 800 mm ³ , and 2 mice remained at the end of the study. The median TTE of group 1 was 41.0 days, and the maximum TGD possible in this 74 day study was 33.0 days (80%).

Paclitaxel  Effect of treatment (Group 2)

Eight of the second group mice (N = 9) treated with paclitaxel remained in the study on day 74, and MTV was 143 mm ³ . This corresponds to the maximum possible TGD (33.0 days or 80%) and statistically significant activity (P = 0.002). Five PR reactions were recorded. The central tumor growth curve showed no change until day 47 after MTV decline by day 19, but tumor growth resumed from that time.

Treatment effect of Compound A (Group 3 to 6)

In the third, fourth and fifth groups, the central TTE was 47.9, 59.1 and 74.0, respectively. The logarithms of the third and fourth groups were not significant, and the fifth group reached the significant borderline (P = 0.058) in the logarithmic test. The number of regressions in these treatments was dose-dependent, but the type of regression response (PR vs. CR) and the number of surviving animals per 74 days per group were not correlated with dose. The central tumor growth curves exhibited similar activity at the three dose levels early in the study (up to day 29), followed by dose - dependent delay in tumor regrowth. Three TR deaths occurred in group 6 and discontinued after day 6. Thus, 200 mg / kg treatment was considered to exceed MTD and TGD could not be assessed.

Compound A showed dose-dependent activity against Colo205 colon carcinoma xenografts. When administered at 25 mg / kg, Compound A showed a TGD of 3%. At 50 mg / kg, compound A showed a TGD of 46%. 100 mg / kg treatment was tolerated tolerably and the number of regression responses similar to the maximum possible TGD in the experiment was similar to that of paclitaxel treatment. At 200 mg / kg treatment, 3/9 TR mortality occurred and exceeded MTD. A more pronounced initial decrease in tumor load was observed by Compound A compared to paclitaxel, but the duration of effect was shorter. Tumor regrowth in the 25 and 50 mg / kg groups initially progressed more rapidly than the control group, and at the end of the study MTV was close to that of the control group. 100 mg / kg treatment did not exhibit this rapid regrowth but showed more rapid tumor growth than in the case of paclitaxel.

Example 119 : Human clinical trial

In patients with advanced or metastatic pancreatic cancer without chemotherapy, Placebo will be used to perform randomized, double-blind, open, historical control, single-group assignment, safety / efficacy phase I human trials.

The first objective of this study was to evaluate the safety and tolerability of Compound A. The second outcome will evaluate the rate of response, clinical benefit, and tumor shrinkage after Compound A treatment. In addition, the study will be designed to assess the time to disease progression and the overall survival rate of patients with pancreatic cancer. In addition, pharmacokinetic changes in tumor vascular parameters will be assessed with DCE-MRI (eg, blood flow, blood volume, peak ROC (Time to Receiver Operator Characteristics curve)).

In addition, biological markers such as MEK1 and MEK2 gene polymorphisms and serum proteomics will be used to correlate the results. This will also allow the evaluation of tumor resection rates after treatment and also the MTD for Compound A to be assessed.

During the study, Compound A was administered at a dose of about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5 mg, About 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, or about 15 mg.

The criteria included in the study will be based on the following factors:

● Histologically / pathologically confirmed as locally advanced or unresectable pancreatic cancer, with no evidence of metastatic disease.

● Diagnosed as locally advanced, unresectable pancreatic cancer based on evaluation by dual-phase CT scan and / or endoscopic ultrasound (EUS) (EUS is described in Appendix F).

● It is measurable by RECIST within 14 days before protocol therapy and confirmed by double-phase CT scan.

● Dual-phase computed tomography scans have tumors greater than 2 cm in size.

As is apparent from the following, within 14 days of administration, adequate organ function was identified: absolute neutrophil count> 1500 / mm ³ , platelet count 100,000 / mm ³ , hemoglobin 9 g / dL (AST and / or ALT) ≤ 2.5 x ULN, PT (or INR) ≤ 1.5 x ULN, and aPTT (warfarin or not) within normal limits Patients receiving anti-coagulant therapy as agents such as heparin are allowed to participate. In the case of patients treated with warfarin, the INR may be stable based on pre-dose measurements, as defined by local standards , Followed by at least weekly close-up monitoring), creatinine clearance calculated by Cockcroft-Gault equation> 60 mL / min.

Exclusion criteria would include: if there is clinical evidence of duodenal mucosal infiltration (identified by endoscopy or endoscopic ultrasonography) with tumor prior to Compound A within 6 months prior to administration, within 14 days of the study If there is a major surgical procedure, significant traumatic injury, or severe non-healing wounds, ulcers or fractures within 14 days of the study in the case of small surgical procedures (eg microneedle or needle biopsy) Any of the following symptoms within 6 months: severe / unstable angina (resting angina), newly developed angina (started within the last 3 months) or myocardial infarction, congestive heart failure, antiarrhythmic therapy Cardiac ventricular arrhythmia, a history of a thrombotic or angiogenic event, such as a cerebrovascular accident or a temporary ischemic attack within the past 6 months, If you have a history of a history of arthropathy or arteriovenous malformation, you are known to have a human immunodeficiency virus (HIV) infection or a chronic hepatitis B or C infection, and you have a clinically serious active infection with a CTCAE level of> 2, If there is uncontrolled hypertension (regardless of optimal medical management) defined as having any study agent administered, defined as a systolic blood pressure greater than 150 mmHg or a diastolic blood pressure greater than 90 mmHg, CTCAE rating within 4 weeks of study If there is evidence of a hemorrhagic or clotting disorder or if there is a history of hemorrhage / bleeding in excess of 2, any other bleeding event in excess of CTCAE grade 3 within 4 weeks of the study, if aspirin or other When chronic non-steroidal anti-inflammatory drugs are routinely treated daily, St. John's Wort, If the patient is known or suspected to be allergic to Compound A when using ketoconazole, itaconazole, ritonavir or grapefruit juice, then the patient may be given any condition that is problematic in his ability to swallow the whole pill, There is an experimental abnormality that can increase the risk associated with absorption disorder problems, other severe, acute or chronic medical or psychiatric conditions, or involvement in research or study medication, or interfere with the interpretation of the study results, If the investigator deems the patient to be inadequate to participate in the study, if there is a history of collagen vascular disease, or if there is any contraindication to magnetic resonance imaging.

Example 120 : Human clinical trial

Double-blind, open-label, control with past history, single-group assignment, safety / efficacy Phase I clinical trial using Compound A in patients with advanced or metastatic gastric cancer without chemotherapy Example 117 Is performed in the same manner as described above except that patients diagnosed with lymphoma, gastric stromal tumors, or carcinoid tumors of the stomach are excluded.

Example 121 : Carrageenan-induced foot edema (CPE) in rats [

Oral administration of Compound A (6, 20 and 60 mg / kg) or indomethacin (3 mg / kg) to male Sprague-Dawley rats (N = 6 per treatment group) A 1% suspension of Kenan was injected on the bottom of the right hindpaw. After 3 hours, paw volume was assessed by pelvic examination and paw edema was measured. More than 30% reduction of hind paw swelling shows significant acute inflammatory activity. Indomethacin (Indo) was used as a positive control drug. Figure 22 shows the foot volume increase for each treatment group and demonstrates that oral administration of Compound A produces significant anti-inflammatory activity in all dose groups of the rat carrageenan foot edema model.

Example 122 : Rat adjuvant arthritis inflammation assay

In the rat adjuvant-induced arthritis model, a complete Freund's Adjuvant (CFA) was injected into the right hind paw of the rats to induce a pathology similar to rheumatoid arthritis in humans. Compound A was orally administered at 2, 6 and 20 mg / kg for 5 consecutive days. In addition, dexamethasone was orally administered at 5 mg / kg for 5 days. Enbrel was administered subcutaneously on days 1 and 4 at 10 mg / kg. CFA was injected into the right hind paw 1 hour after the first dose of the first day. The percent inhibition of the right hind paw swell was determined as the acute phase for the vehicle-treated controls on days 1 and 5 and the inhibition rate (%) of the left hind paw swollen to the vehicle-treated controls on the 14th and 18th day, ) Was determined to be a retarder. Multiple arthritis was scored as having swelling in the forepaw, tail, nose or ear.

Figures 23A and 23B show percent inhibition of swelling relative to control for different treatment groups. 20 mg / kg of Compound A showed a significant reduction in swelling in both the acute phase and the delayed phase. In the case of multiple arthritis scoring, all six animals in the vehicle-treated group had swelling in the forelimb and tail. In 20 mg / kg Compound A treatment group, 2 out of 6 mice had no forehead swelling and 4 out of 6 had no swelling in the tail. In the Enbrel group, no animals were protected from the frontal swelling, and three of the six animals had no swelling in the tail.

Example 123 : Inhibition of collagen-antibody induced arthritis (CAIA) in mice

Male Balb / c mice (N = 8 per treatment group) were injected intravenously (tail vein) with 2 mg of collagen antibody cocktail (Chondrex) on day 0. RDEA119 (1, 3 and 10 mg / kg QD) or dexamethasone (1 mg / kg QD) was orally administered on day 0 to day 4 and Enbrel was subcutaneously injected on day 1 and day 3. Peritoneal injection of LPS (50 [mu] g) was performed on day 3 to all mice except untreated animals. The arthritis score was determined in all limbs and is shown in Fig. 24 (maximum score 16). There was significant anti-inflammatory activity in all test and reference drugs. Enbrel and dexamethasone were used as positive controls.

Example 124 : In vivo cell proliferation assay

Methods for determining the number of cell proliferation in cancerous cells treated with MEK protein kinase inhibitors are well known in the art and are described in Kenny, L.M. et al., Positron Emission Tomography (PET) Imaging of Cell Proliferation in Oncology, Clinical Oncology, 16: 176-185 (2004), which is incorporated herein by reference in its entirety. MEK protein kinase inhibitors (e.g., Compound A) were investigated in vivo to determine the effect on proliferation of cancerous cells. Fifty patients voluntarily participated in the study, all of whom had pancreatic cancer at a similar stage of cancer. Twenty-five patients received a combination of Compound A. The remaining 25 patients received placebo. Each patient was dosed with a daily dose of radiolabeled tracer, e.g., labeled fluoro-2-deoxy-DF-glucose (FDG) for 14 days.

Fourteen days after treatment, a skilled practitioner detected tumor cell proliferation using a non-invasive positron emission tomography (PET) imaging apparatus. In addition, a skilled practitioner determined cell proliferation numbers in both tumor and normal cell tissue of Compound A and placebo-treated patients. This result showed a reduction in cell proliferation between the MEK protein kinase inhibitor (e.g., Compound A) and the placebo. Such assays for determining cell proliferation using labeled tracers and PET imaging are referred to herein as "in vivo cell proliferation methods. &Quot; Other methods of in vivo cell proliferation are known in the art.

A similar analysis can be used to determine the reduction in tumor size.

Example 125 : In vivo cell apoptosis assay

MEK inhibitors, such as Compound A, were investigated in vivo to determine the effect of cancer cells on apoptosis. Forty patients were voluntarily involved in the study, all of whom had pancreatic cancer at a similar stage of cancer development. Twenty patients received Compound A and 20 patients received placebo. Each patient was given a daily dose of 14 days.

After 14 days, each patient was conjugated with a detectable lipid polysaccharide binding protein (LBP) reagent coupled to a label. According to WO 2006/054068 (which is hereby incorporated by reference), each patient is then placed in the area of the scanning device and the scanning device detects the used reagent bound to the dead cell. The number of dead cells may be correlated with the level of apoptosis in each patient. The levels of apoptosis in patients treated with the combination and those treated with a single agent were compared to each other and compared to the placebo-treated cohort group. This assay for detecting apoptosis levels using a polysaccharide binding protein and a scanning device is referred to herein as "in vivo apoptosis ".

Example 126 : Dissolution study

A capsule containing Compound A was prepared as described in the above examples. The following dissolution data were obtained by the USP < 711 > method for dissolution:

Claims (80)

To a solution of amorphous N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) cyclopropane- ) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide. 2. The process of claim 1, wherein the mixture of ethyl acetate and heptane is a ratio of about 1 to 4 parts of ethyl acetate to about 2 to 10 parts of heptane. 2. The process of claim 1, wherein the mixture of ethyl acetate and heptane is a ratio of about 2 parts ethyl acetate to about 5 parts heptane. 2. A process according to claim 1, which comprises reacting ethyl acetate and amorphous N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide are combined together to form a brown solution, followed by adding heptane while maintaining the reflux, followed by stopping the heating, and stirring the resulting crystallization mixture Thereby creating a crystalline material around the surface of the glass, then the resulting suspension is equilibrated in an ice / water bath with stirring, the suspension is filtered, the collected crystals are washed with heptane, And air-drying under vacuum. 2. The method of claim 1 wherein the amorphous N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) (3-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1-cyclopentan-1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide. 6. The compound of claim 5, which is selected from the group consisting of amorphous racemic N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) Dihydroxypropyl) cyclopropane-1-sulfonamide is obtained by a process represented by the following reaction formula.

2. The method of claim 1 wherein the amorphous N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) (R) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) - cyclopropane- 1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide. 8. The method of claim 7 wherein the amorphous N- (R) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) 3-dihydroxypropyl) cyclopropane-1-sulfonamide is reacted with amorphous racemic N- (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl ) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide by chiral HPLC separation. 2. The method of claim 1 wherein the amorphous N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) - cyclopropane- 1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide. 10. The method of claim 9, wherein the amorphous N- (S) - (3,4-difluoro-2- (2- fluoro- 3-dihydroxypropyl) cyclopropane-1-sulfonamide is reacted with amorphous racemic N- (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl ) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide by chiral HPLC separation. 10. The method of claim 9, wherein the polymorph is selected from the group consisting of N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl ) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide:
(a) a powder x-ray diffraction pattern substantially identical to the powder x-ray diffraction pattern shown in Fig. 5 for the crystalline polymorph,
(b) a differential scanning calorimetric pattern substantially identical to the differential scanning calorimetric pattern shown in Fig. 6 for the crystalline polymorph, or
(c) a melting point of about 143 캜 measured by differential scanning calorimetry for the crystalline polymorph.
5,

6,

12. The method of claim 11, wherein the crystalline polymorph has at least two of the following characteristics:
(a) a powder x-ray diffraction pattern substantially identical to the powder x-ray diffraction pattern shown in Fig. 5 for the crystalline polymorph,
(b) a differential scanning calorimetric pattern substantially identical to the differential scanning calorimetric pattern shown in Fig. 6 for the crystalline polymorph and / or
(c) a melting point of about 143 캜 measured by differential scanning calorimetry for the crystalline polymorph. 12. The method of claim 11, wherein the crystalline polymorph has all three of the following characteristics:
(a) a powder x-ray diffraction pattern substantially identical to the powder x-ray diffraction pattern shown in Fig. 5 for the crystalline polymorph,
(b) a differential scanning calorimetric pattern substantially identical to the differential scanning calorimetric pattern shown in Fig. 6 for the crystalline polymorph, and
(c) a melting point of about 143 캜 measured by differential scanning calorimetry for the crystalline polymorph. 12. The process of claim 11 wherein the mixture of ethyl acetate and heptane is a ratio of from about 1 to 4 parts of ethyl acetate to about 2 to 10 parts of heptane. 13. The process of claim 12, wherein the mixture of ethyl acetate and heptane is a ratio of about 2 parts ethyl acetate to about 5 parts heptane. 14. The process according to claim 13, which comprises reacting ethyl acetate and amorphous N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide are combined together to form a brown solution, followed by adding heptane while maintaining the reflux, followed by stopping the heating, and stirring the resulting crystallization mixture Thereby creating a crystalline material around the surface of the glass, then the resulting suspension is equilibrated in an ice / water bath with stirring, the suspension is filtered, the collected crystals are washed with heptane, And air-drying under vacuum. 14. The method of claim 13, wherein the amorphous N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) (3-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1-cyclopentan-1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide. 14. The method of claim 13, wherein the amorphous N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) (R) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) - cyclopropane- 1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide. 14. The method of claim 13, wherein the amorphous N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) - cyclopropane- 1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide. 2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) Cyclopropane-1-sulfonamide, and a compound selected from the group consisting of a lipid or protein kinase targeting agent, an apoptosis pathway agonist, a multi-kinase inhibitor, and sorapenib. 21. The compound according to claim 20, which is N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- -Dihydroxypropyl) cyclopropane-1-sulfonamide, and a compound selected from the group consisting of a lipid or protein kinase targeting agent, an apoptosis pathway agonist, a multi-kinase inhibitor, and sorapenib. 21. The compound according to claim 20, which is N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- -Dihydroxypropyl) cyclopropane-1-sulfonamide, and a kit comprising a separate pack of a compound selected from the group consisting of a lipid or protein kinase targeting agent, an apoptotic pathway agonist, a multi-kinase inhibitor and sorafenib Combination. 21. The pharmaceutical combination of claim 20 comprising a lipid or protein kinase targeting agent. 21. The pharmaceutical combination of claim 20 comprising a lipid or protein kinase targeting agent that is periospin. 21. The pharmaceutical combination according to claim 20 comprising an apoptosis pathway agonist. 21. The pharmaceutical combination according to claim 20 comprising an apoptosis pathway agonist which is gemcitabine, cladribine or fludarabine. 21. The pharmaceutical combination according to claim 20, comprising a multi-kinase inhibitor. 21. The pharmaceutical combination according to claim 20 comprising sorapenib. 21. The compound according to claim 20, which is N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- - dihydroxypropyl) cyclopropane-1-sulfonamide is a crystalline form having at least one of the following properties:
(a) a powder x-ray diffraction pattern substantially identical to the powder x-ray diffraction pattern shown in FIG. 5,
(b) a differential scanning calorimetric pattern substantially the same as the differential scanning calorimetric pattern shown in Fig. 6, or
(c) a melting point of about 143 캜 measured by differential scanning calorimetry.
5,

6,

21. The compound according to claim 20, which is N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) Propyl) cyclopropane-1-sulfonamide was prepared from the mixture of ethyl acetate and heptane by reaction with amorphous N- (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6- ) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide. 21. A pharmaceutical combination according to claim 20, which is used to treat, but not to prevent, MEK mediated disorders. 32. The pharmaceutical combination of claim 31, wherein the MEK mediated disorder is a cytokine mediated disorder. 32. The pharmaceutical combination according to claim 31, wherein the MEK mediated disorder is selected from the group consisting of immune disorders, inflammatory disorders, infectious disorders and proliferative disorders. 32. The pharmaceutical combination of claim 31, wherein the MEK mediated disorder is cancer. 32. The pharmaceutical combination of claim 31, wherein the MEK mediated disorder is a fibrogenic disorder. 32. The pharmaceutical combination of claim 31, co-administered with a second active agent. 32. The combination of claim 31, co-administered with a cytotoxic agent, an anti-angiogenic agent, an anti-neoplastic agent, or a combination thereof. 32. The combination of claim 31, wherein the pharmaceutical combination is used in conjunction with surgery and / or radiation therapy. 35. The pharmaceutical combination of claim 34, wherein the cancer is multiple myeloma, leukemia or lymphoma. A pharmaceutically acceptable carrier and /

or

&Lt; / RTI &gt; 41. The compound of claim 40, wherein compound

or

RTI ID = 0.0 &gt; of S &lt; / RTI &gt; isomers. 41. The compound of claim 40, wherein compound

or

RTI ID = 0.0 &gt; R &lt; / RTI &gt; isomer. 41. The compound of claim 40, wherein compound

or

Lt; RTI ID = 0.0 &gt; 10%. &Lt; / RTI &gt; 41. The compound of claim 40, wherein compound

or

RTI ID = 0.0 &gt; R-isomer. &Lt; / RTI &gt; 41. The method of claim 40,

Lt; RTI ID = 0.0 &gt; 1 &lt; / RTI &gt; to 100 mg. 41. The method of claim 40,

RTI ID = 0.0 &gt; 1 &lt; / RTI &gt; to 50 mg of a compound having the structure of formula &lt; RTI ID = 0.0 &gt; 41. The pharmaceutical composition of claim 40, further comprising microcrystalline cellulose. 41. The method of claim 40,
rescue

About 1 mg,
About 222.2 mg of microcrystalline cellulose,
About 12.0 mg of croscarmellose sodium,
About 2.4 mg of sodium lauryl sulfate, and
Magnesium stearate Approximately 2.4 mg
&Lt; / RTI &gt; 41. The method of claim 40,
rescue

About 10 mg,
About 213.2 mg of microcrystalline cellulose,
About 12.0 mg of croscarmellose sodium,
About 2.4 mg of sodium lauryl sulfate, and
Magnesium stearate Approximately 2.4 mg
&Lt; / RTI &gt; 41. The method of claim 40,
rescue

About 20 mg of a compound of formula &lt;
About 203.2 mg of microcrystalline cellulose,
About 12.0 mg of croscarmellose sodium,
About 2.4 mg of sodium lauryl sulfate, and
Magnesium stearate Approximately 2.4 mg
&Lt; / RTI &gt; 41. The method of claim 40,
rescue

&Lt; / RTI &gt; about 40 mg,
About 183.2 mg of microcrystalline cellulose,
About 12.0 mg of croscarmellose sodium,
About 2.4 mg of sodium lauryl sulfate, and
Magnesium stearate Approximately 2.4 mg
&Lt; / RTI &gt; 41. The pharmaceutical composition of claim 40, used to inhibit the MEK enzyme by at least 25%. 41. The pharmaceutical composition of claim 40, used to treat a MEK mediated disorder in an individual. 41. The pharmaceutical composition of claim 40, used to treat, but not to prevent, a proliferative disorder in an individual. 41. The pharmaceutical composition of claim 40, used for treating, but not for preventing, inflammatory disease in an individual. 41. The pharmaceutical composition according to claim 40, which is used for decomposing cancer cells, inhibiting the growth of cancer cells or killing cancer cells. 41. The method of claim 40,

or

To a C _max of about 0.01 [mu] g / mL to about 1.0 [mu] g / mL on the first day. 41. The method of claim 40,

or

Wherein the AUC has an AUC from about 0 占 퐂 占 hr hr / mL to about 5.0 占 퐂 占 hr r / mL from 0:00 to 12:00. 41. The method of claim 40,

or

_Has a _{Tmax of} from 0.5 hours to 5.0 hours. 40. The method of claim 40, wherein the subject is a pharmaceutical composition used to treat, but not prevent, gastric cancer, brain cancer, breast cancer, non-small cell lung cancer, ovarian cancer, pancreatic cancer, liver cancer, prostate cancer, kidney cancer, colon cancer or leukemia. . 41. The pharmaceutical composition of claim 40, used to treat, but not to prevent, rheumatoid arthritis or multiple sclerosis. 41. The method of claim 40, wherein upon administration to a human subject,

or

To a C _max of about 0.01 [mu] g / mL to about 1.0 [mu] g / mL on the first day. 41. The method of claim 40, wherein upon administration to a human subject,

or

Wherein the AUC has an AUC from about 0 占 퐂 占 hr hr / mL to about 5.0 占 퐂 占 hr r / mL from 0:00 to 12:00. 41. The method of claim 40, wherein upon administration to a human subject,

or

_Has a _{Tmax of} from 0.5 hours to 5.0 hours. (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) A composition for the treatment of a MEK mediated disorder, which comprises a crystalline polymorph of 1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide,
(a) a powder x-ray diffraction pattern substantially identical to the powder x-ray diffraction pattern shown in Fig. 5 for the crystalline polymorph,
(b) a differential scanning calorimetric pattern substantially identical to the differential scanning calorimetric pattern shown in Fig. 6 for the crystalline polymorph, or
(c) a melting point of about 143 캜 measured by differential scanning calorimetry for the crystalline polymorph.
5,

6,

To a solution of amorphous N- (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide, which comprises the step of crystallizing a therapeutically effective amount of N- (3,4-difluoro-2- (MEK-mediated disorder), including the crystalline polymorph of the crystalline polymorph of MEK-4-iodophenylamino) -6-methoxyphenyl) -1- (2,3-dihydroxypropyl) cyclopropane- Wherein the composition is for treatment of mediated disorders. 67. The composition of claim 66, wherein the mixture of ethyl acetate and heptane is about 1 to about 4 parts ethyl acetate to about 2 to about 10 parts heptane. 67. The composition of claim 66, wherein the mixture of ethyl acetate and heptane is a ratio of about 2 parts ethyl acetate to about 5 parts heptane. (S) - (3,4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) A composition for the treatment of a MEK mediated disorder, which comprises a crystalline polymorph of 1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide,
(a) a powder x-ray diffraction pattern corresponding to the powder x-ray diffraction pattern shown in Fig. 5 for the crystalline polymorph,
(b) a differential scanning calorimetric pattern corresponding to the differential scanning calorimetric pattern shown in Fig. 6 for the crystalline polymorph, or
(c) a melting point of about 143 캜 measured by differential scanning calorimetry for the crystalline polymorph.
5,

6,

70. The compound according to claim 69, wherein the compound is N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) - dihydroxypropyl) cyclopropane-1-sulfonamide having at least two of the following characteristics:
(a) a powder x-ray diffraction pattern corresponding to the powder x-ray diffraction pattern shown in Fig. 5 with respect to the crystalline polymorph,
(b) a differential scanning calorimetric pattern corresponding to the differential scanning calorimetric pattern shown in Fig. 6 for the crystalline polymorph, or
(c) a melting point of about 143 캜 measured by differential scanning calorimetry for the crystalline polymorph. 70. The compound according to claim 69, wherein the compound is N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) - dihydroxypropyl) cyclopropane-1-sulfonamide having the following characteristics:
(a) a powder x-ray diffraction pattern corresponding to the powder x-ray diffraction pattern shown in Fig. 5 with respect to the crystalline polymorph,
(b) a differential scanning calorimetric pattern corresponding to the differential scanning calorimetric pattern shown in Fig. 6 for the crystalline polymorph, and
(c) a melting point of about 143 캜 measured by differential scanning calorimetry for the crystalline polymorph. 70. The compound according to claim 69, wherein the compound is N- (S) - (3,4-difluoro-2- (2- fluoro-4-iodophenylamino) -6-methoxyphenyl) -Dihydroxypropyl) cyclopropane-1-sulfonamide has a powder x-ray diffraction pattern corresponding to the powder x-ray diffraction pattern shown in Fig. 5 for the crystalline polymorph. 65. The composition of claim 65, co-administered with a second active agent. 65. The composition of claim 65, co-administered with a cytotoxic agent, an anti-angiogenic agent, an anti-neoplastic agent, or a combination thereof. 66. The composition of claim 65, for use in conjunction with surgery and / or radiation therapy. 66. The composition of claim 65 or 66 wherein the MEK mediated disorder is a cytokine mediated disorder. 66. The composition of claim 65 or 66, wherein the MEK mediated disorder is selected from the group consisting of immune disorders, inflammatory disorders, infectious disorders, proliferative disorders, and combinations thereof. 66. The composition of claim 65 or 66 wherein the MEK mediated disorder is cancer. 66. The composition of claim 65 or 66, wherein the MEK mediated disorder is a fibrogenic disorder. 66. The composition of claim 66, coadministered with a cytotoxic agent, an anti-angiogenic agent, an anti-neoplastic agent, or a combination thereof, and / or used in conjunction with surgery and / or radiation therapy.

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