KR20120028882A - Heterocyclic compounds as mek inhibitors - Google Patents

Abstract

The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts. These compounds can act as potential MEK inhibitors in the treatment of hyperproliferative diseases such as cancer and inflammation. The present invention also discloses their preparation method.
<Formula I>

Description

Heterocyclic compound as MEB inhibitor {HETEROCYCLIC COMPOUNDS AS MEK INHIBITORS}

The present invention relates to compounds that are specific inhibitors of kinase activity of MEK. The invention also relates to the use of said compound, prodrug thereof, or a pharmaceutically acceptable composition comprising said compound or prodrug thereof in the management of hyperproliferative diseases such as cancer and inflammation.

Hyperproliferative diseases such as cancer and inflammation have attracted the attention of the scientific community to provide therapeutic benefits. In this regard, efforts have been made to identify and target specific mechanisms that play a role in propagating the disease.

Overactivation of the mitogen-activated protein (MAP) kinase cascade is known to play an important role in cell proliferation and differentiation. This pathway can be activated when a growth factor binds to its receptor tyrosine kinase. This interaction promotes the binding of RAS to RAF and initiates a phosphorylation cascade leading from MEK (MAP kinase kinase) to ERK. Inhibition of this pathway is known to be beneficial in hyperproliferative diseases. MEK is an attractive therapeutic target because the only substrates known for MEK phosphorylation are the MAP kinases ERK1 and ERK2. Constitutive activation of MEK / ERK has been found in pancreatic, colon, lung, kidney and ovarian primary tumor samples.

Phosphorylation of MEK appears to increase its affinity for ERK and its catalytic activity, as well as its affinity for ATP. The present invention describes compounds that inhibit MEK activity by the modulation of ATP binding and inhibit the binding of MEK with ERK by competitive and / or allosteric and / or noncompetitive mechanisms.

Activation of MEK has been demonstrated in a number of disease models, whereby inhibition of MEK has been shown to affect various diseases, such as

? Pain: Evidence of Efficacy in Pain Models (J. Neurosci. 22: 478, 2002; Acta Pharmacol Sin. 26: 789 2005; Expert Opin Ther Targets. 9: 699, 2005; Mol. Pain. 2: 2, 2006])

? Stroke: Evidence of Efficacy in Stroke Models (Significant Neuroprotection Against Ischemic Brain Injury by Inhibition of MEK) (J. Pharmacol. Exp. Ther. 304: 172, 2003); Brain Res. 996: 55, 2004])

? Diabetes: Evidence from Diabetic Complications (Am. J. Physiol. Renal. 286, F120 2004)

? Inflammation: Evidence of Efficacy in Inflammation Models (Biochem Biophy. Res. Com. 268: 647, 2000)

? Arthritis: Evidence of Efficacy in Experimental Osteoarthritis (Arthritis & (J. Clin. Invest. 116: 163. 2006))

Suggests that it may have potential therapeutic benefits.

Inhibition of MEK has been shown to have potential therapeutic benefits in several studies.

Thus, as a first embodiment, the present invention provides a compound of formula (I) and a pharmaceutically acceptable salt thereof.

<Formula I>

Where

X is C _{1 -3} - ^{alkylene, -N (R 6) -,} -O- or -S (O) _p - represents;

R ¹ represents aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein the ring is optionally substituted by one or more groups independently selected from List 1;

R ² represents H, cyano or the group -YR ⁷ ;

R ³ and R ⁴ are independently H, C _{1 -6} - alkyl, C _{1 -6} - haloalkyl, C _{1 -6} - hydroxyalkyl, hydroxyl, C _{1 -6} - alkoxy, amino, C _{1 -6} - alkylamino, di -C _{1 -6} - represents an alkyl or amino, or R ³ denotes a monocyclic cycloalkyl or monocyclic heterocycloalkyl further, where the ring is independently selected from the list 11 Optionally substituted by the above groups;

R ⁵ is H, halogen, C _{1 -3} - alkyl, C _{1 - 3} alkoxy, -SC _{1 - 3} alkyl or C _{1 -3} - represents a haloalkyl;

Y represents a group selected from -D-, -E-, -D-E- or -E-D-;

D is -N (R ⁸ )-, -CO-, -CO _2- , -SO-, -SO _2- , CON (R ⁹ ) O-, -CON (R ¹⁰ )-, -N (R ¹¹ ) SO _2- , -N (R ²⁴ ) SO ₂ NR ^25- , -SO ₂ N (R ¹² )-, -N (R ¹³ ) CO-, -N (R ¹⁴ ) CON (R ¹⁵ )-, -N (R ¹⁶ ) represents a group selected from CO— or —C (═NH) N (R ¹⁷ ) —;

E represents monocyclic arylene, heteroarylene, cycloalkylene or heterocycloalkylene, wherein said ring is optionally substituted by one or more groups independently selected from List 1;

If alkynyl, cycloalkyl, aryl, heterocycloalkyl or a heteroaryl group represents a alkyl, wherein R ⁷ is other than H - R ⁷ is H, C _{1 -6} - alkyl, C _{2 -6} - alkenyl, C _{2 -6} halogen, cyano, hydroxyl, C _{1 -6} - alkoxy, C ₂ -C ₆ - alkenyloxy, C ₂ -C ₆ - alkynyloxy, C _{1 -6} - thioalkyl, C _{1 - 6} haloalkyl , amino, C _{1 - 6} alkylamino, di -C _{1 - 6} alkylamino, C _{1 - 6} acylamino, C _{1 - 6} acyl C _{1 - 6} alkyl, monocyclic cycloalkyl or monocyclic heterocycloalkyl by from one to selected independently from 1 to 3 groups is optionally substituted, where the ring is halogen, cyano, hydroxyl, C _{1 -6} - alkoxy, C ₂ -C ₆ - alkenyloxy, C ₂ -C ₆ - alkynyl aryloxy carbonyl, C _{1 -6} - thioalkyl, C _{1 -6} - haloalkyl, amino, C _{1 -6} - alkylamino, di -C _{1 -6} - alkylamino, C _{1 -6} - acylamino and C _{1 - 6} - acyl C _{1 -6-1} also independently selected from alkylamino Optionally two groups may be optionally substituted;

Z is O or N (R ¹⁸ );

List 1 is hydroxyl, cyano, nitro, C _{1 -6} - alkyl, C _{2 -6} - alkenyl, C _{2 -6} - alkynyl, C _{1 -6} - alkoxy, C _{2 -6} - alkenyloxy, C _{2 -6} - alkynyloxy, halogen, C _{1 -6} - alkyl-carbonyl, carboxy, C _{1 -6} - alkoxycarbonyl, amino, C _{1 -6} - alkylamino, di -C _{1 -6} - alkylamino , C _{1 -6} - alkyl-aminocarbonyl, di -C _{1 -6} - alkyl-aminocarbonyl, C _{1 -6} - alkylcarbonylamino, C _{1 -6} - alkyl-carbonyl (C _1-6 - alkyl) amino , C _{1 -6} - alkylsulfonylamino, C _{1 -6} - alkylsulfonyl (C _1-6 - alkyl) amino, C _{1 -6} - thioalkyl, C _{1 -6} - alkylsulfinyl, C _{1 -6} -alkyl-sulfanyl, C _{1-6-alkylsulfonyl,} aminosulfonyl, C _{1 -6-alkyl-aminosulfonyl} and di -C _{1 -6-alkyl} is selected from aminosulfonyl, wherein each of the above-mentioned hydrocarbon group one or more halogen, hydroxyl, C _{1 -6} - alkoxy, amino, C _{1 -6} - alkylamino, di -C _{1 -6} - alkylamino or by cyano, optionally Can be substituted;

R ²⁶ is H, C _{1 -6} - alkyl, C _{1 -6} - haloalkyl, C _{1 -6} - hydroxyalkyl, hydroxyl, C _{1 -6} - alkoxy, amino, C _{1 -6} - alkylamino or di -C _{1 -6} - represents an alkyl amino;

^{R 6, R 8, R 9} , R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17 R 18, R 24 and R ²⁵ are independently H or C _{1 -6} - Alkyl;

m and n are independently 0, 1, 2 or 3; m + n = 2 or 3;

p is 0, 1 or 2; here

Alkyl or alkylene means a straight chain, branched and / or cyclic hydrocarbon having 1 to 20 carbon atoms, wherein the alkyl moiety having 1 to 5 carbons is referred to as "lower alkyl", for example methyl, Ethyl, propyl, isopropyl, n-butyl, t-butyl and isobutyl;

Cycloalkyl or cycloalkylene represents a 3 to 14 membered monocyclic or bicyclic carbocyclic ring, wherein the monocyclic ring, or one of the bicyclic rings, is saturated or partially unsaturated, optionally -C (O) - may further comprise a ring member, other ring may be aromatic, saturated or partially unsaturated, -C (= O), -N (R 20) q -, -O- and S (O) _r ( wherein, r ²⁰ is H or C _{1 -6} - alkyl, q is from 0 to 1, r may comprise 0 to 2 1 to 3 ring members selected from Im);

Aryl or arylene represents a 6 to 14 membered monocyclic or bicyclic carbocyclic ring, wherein one of the monocyclic ring or bicyclic rings is aromatic and the other ring can be aromatic, saturated or partially unsaturated And -C (O), -N (R ¹⁹ ) _q- , -O- and S (O) _r , wherein R ¹⁹ is H or C _1-6 -alkyl, q is 0 to 1, r May comprise 0 to 2 ring members selected from 0 to 2;

Heteroaryl or heteroarylene represents a 5 to 14 membered monocyclic or bicyclic ring, wherein one of the monocyclic ring, or bicyclic rings is (a) 1 to 4 nitrogen atoms, (b) one Oxygen or one sulfur atom, or (c) an aromatic group comprising one oxygen atom or one sulfur atom and one or two nitrogen atoms, the other ring may be aromatic, saturated or partially unsaturated, and -C ( ^{O), -N (r 21)} q -, -O- and S (O) _r (wherein, r ²¹ is H or C _{1 -6} - alkyl, q is 0 to 1, r is from 0 to 2; May comprise 1 to 3 ring members selected from:

Heterocycloalkyl or heterocycloalkylene represents a 3 to 14 membered monocyclic or bicyclic ring, wherein one of the monocyclic ring, or bicyclic rings, is -N (R ²² )-, -O- and- A saturated or partially unsaturated group comprising one or two ring members selected from S (O) _r −, optionally further comprising a -C (O)-ring member, the other ring being aromatic, saturated or partially unsaturated And may include from 1 to 3 ring members selected from -C (= 0), -N (R ²³ ) _q- , -O- and S (O) _r (where R ²² or R ²³ is H or C _{1 -6} - alkyl, q is 0 to 1, r is from 0 to 2;).

The following specific embodiments of the invention according to formula (I) can be incorporated into the definition of formula (I) and can be combined in any number of suitable ways.

In one embodiment, X represents -N (H)-.

In another embodiment, R ¹ represents optionally substituted phenyl.

In another embodiment, any substitution on the R ¹ is a fluoroalkyl containing a halogen, such as bromo or iodo, C _{1 -6} - alkyl, for example ethyl, C _{2 -6} - alkynyl, e.g. ethynyl, C _{1 -6} - haloalkyl, such as trifluoromethyl, and C _{1 -6} - thioalkyl, for example, is represented by one selected from 1 to 3 groups independently from thiomethyl.

In another embodiment, R ¹ is represented by phenyl substituted in the 2-, 4- and optionally 6-positions, suitably in the 2- and 4-positions. In a further embodiment, R ¹ is 2-fluoro and 4-bromo, or 2-iodo-2-fluorophenyl, or 2- and iodo, trifluoromethyl, thiomethyl, ethynyl or ethyl; Represented by any combination of 4- substitutions.

In another embodiment, -D- is -C (O)-, -CO _2- , C (O) N (H) O-, -C (O) N (Ci_ ₆ -alkyl) O-, A group selected from -C (O) N (H)-and -C (O) N (C _1-6 -alkyl)-.

In another embodiment, -E- represents 5-membered heteroarylene or 5-membered heterocycloalkylene. In further embodiments, E is

로부터 선택된 고리를 나타낸다.

Ring selected from.

In another embodiment, when Y represents -DE-, -D- may represent -C (O) N (H)-and -E- is optionally substituted cycloalkyl, for example cyclopentyl Or optionally substituted heteroaryl such as thiazole.

In another embodiment, when Y represents -ED-, -E- may represent an optionally substituted heteroaryl, for example oxadiazole, and -D- is -C (O) N (H) Can represent-.

In another embodiment, Y represents a group -D- or -E-.

In another embodiment, R ⁷ is H, C _{1 -6-alkyl,} such as methyl or ethyl, substituted C _{1 -6-alkyl} (e. G., Di-hydroxyl and other hydroxyl, C _{1 - 6-alkoxy,} such as methoxy, C ₂ -C ₆ - alkenyloxy, for example, ethenyl oxy, di -C _{1 -6-alkylamino,} such as dimethylamino, C _{1 -6-acylamino} , For example acetylamino, and optionally substituted monocyclic cycloalkyl, for example one to three groups selected from cyclopropyl, in another embodiment substituted by one to two groups).

In another embodiment, R ⁷ is H, methyl, ethyl, cyclopropylmethyl, 2-hydroxyethyl, 2-ethenyloxyethyl, 3-hydroxypropyl, 2-methoxyethyl, acetylaminomethyl, 2- Dimethylaminoethyl or 2,3-dihydroxypropyl.

In another embodiment, R ² is —CO ₂ H, COH, —CO ₂ Et, C (O) N (H or CH ₃ ) OR ^7a , wherein R ^7a is methyl, ethyl, cyclopropylmethyl, 2- Ethenyloxyethyl, 2-hydroxyethyl and 2,3-dihydroxypropyl), -C (O) N (H or CH ₃ ) R ^7b , where R ^7b is H, methyl, ethyl, cyclo Propylmethyl, 2-methoxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, acetylaminomethyl, 2-dimethylaminoethyl, cyclopentyl or 2-thiazolyl), or R ² is oxa Diazolylamino.

In another embodiment, the present invention encompasses compounds of Formula I wherein R ² represents CONHOR ^7a , wherein R ^7a represents cyclopropylmethyl or 2-hydroxyethyl.

In another embodiment, m and n are both 1 or one of m and n is 1 and the other is 2.

In another embodiment, R ³ and R ⁴ represent H.

In another embodiment, R ⁵ is H, halogen, for example fluoro or chloro, C _{1 - 3} alkoxy, for example methoxy or ethoxy, -SC _{1 - 3} alkyl, e.g., SCH _3, or C _{1 - 3} represents an alkyl, for example methyl or ethyl. In further embodiments, R ⁵ is fluoro. In further embodiments, R ⁵ is methyl.

In another embodiment, Z represents O.

In another embodiment, aryl or arylene each represent optionally substituted phenyl or phenylene.

In another embodiment, cycloalkyl or cycloalkylene represents an optionally substituted 3-7 membered saturated monocyclic carbocyclic ring, for example cyclopropyl or cyclopentyl.

In another embodiment, heteroaryl or heteroarylene is (a) 1 to 4 nitrogen atoms, (b) 1 oxygen or 1 sulfur atom, or (c) 1 oxygen atom or 1 sulfur atom and 1 Or an optionally substituted 5-6 membered monocyclic aromatic group comprising two nitrogen atoms, for example tetrazolyl, thiazolyl or oxadizolyl.

In another embodiment, heterocycloalkyl or heterocycloalkylene is optionally substituted 5 to 5, including one or two ring members selected from -N (R ²² )-, -O-, and -S (O) _r-. 6-membered saturated monocyclic ring.

In another embodiment of the invention, the compound forms a pharmaceutically acceptable salt selected from the group comprising acid addition salts and base addition salts.

In another embodiment, the present invention includes a pharmaceutical composition comprising a compound of Formula I or Id and a pharmaceutically acceptable carrier or excipient. In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or (Id) in combination with a second active agent, and a pharmaceutically acceptable carrier or excipient.

In another embodiment, the present invention encompasses compounds of Formula Id and salts thereof.

<Formula Id>

Where

Rd ¹ represents H, halogen, C _{1 -3} - alkyl or C _{1 -3} - represents a haloalkyl;

Rd ² represents H, cyano or the group -Y-Rd ⁵ ;

Rd ³ and Rd ⁴ is independently hydroxyl, cyano, nitro, C _{1 -6} - alkenyl, C _{2 -6} - - alkyl, C _{2 -6-alkynyl,} C _{1 -6} - alkoxy, C _{2 -6} - alkenyloxy, C _{2 -6-alkynyloxy,} halogen, C _{1 -6-alkyl-carbonyl,} carboxy, C _{1 -6-alkoxy-carbonyl,} amino, C _{1 -6-alkylamino,} di -C _{1 6} - alkylamino, C _{1 -6-alkyl-aminocarbonyl,} di -C _{1 -6-alkyl-aminocarbonyl,} C _{1 -6-alkyl-carbonylamino,} C _{1 -6-alkyl-carbonyl} (C _{1- 6-alkyl)} amino, C _{1 -6-alkyl-sulfonyl-amino,} C _{1 -6-alkyl-sulfonyl} (C _1-6 -alkyl) amino, C _{1 -6-alkyl} thio, C _{1 -6-alkylsulfinyl} , C _{1 -6} - alkyl sulfanyl, C _{1 -6} - alkylsulfonyl, aminosulfonyl, C _{1 -6} - alkyl aminosulfonyl, and di -C _{1 -6} - alkyl represents an amino-sulfonyl, wherein each for alkylamino or cyano-the above-mentioned hydrocarbon group is one or more halogen, hydroxyl, C _{1 -6-alkoxy,} amino, C _{1 -6-alkylamino,} di -C _{1 -6} Optionally substituted by;

Y represents a group selected from -D-, -E-, -D-E- or -E-D-;

D is -N (Rd ⁸ )-, -CO-, -CO _2- , -SO-, -SO _2- , CON (Rd ⁹ ) O-, -CON (Rd ¹⁰ )-, -N (Rd ¹¹ ) SO _2- , -N (Rd ¹² ) SO ₂ NRd ^13- , -SO ₂ N (Rd ¹⁴ )-, -N (Rd ¹⁵ ) CO-, -N (Rd ¹⁶ ) CON (Rd ¹⁷ )-, -N A group selected from (Rd ¹⁸ ) CO- or -C (= NH) N (Rd ¹⁹ )-;

E represents monocyclic arylene, heteroarylene, cycloalkylene or heterocycloalkylene, wherein said ring is optionally substituted by one or more groups independently selected from list 1 as defined herein;

Rd ⁵ is H, C _{1 -6} - For non-alkynyl, cycloalkyl, aryl, heterocycloalkyl or a heteroaryl group represents a alkyl, where Rd is ⁵ H - alkyl, C _{2 -6} - alkenyl, C _{2 -6} halogen, cyano, hydroxyl, C _{1 -6} - alkoxy, C ₂ -C ₆ - alkenyloxy, C ₂ -C ₆ - alkynyloxy, C _{1 -6} - thioalkyl, C _{1 - 6} haloalkyl , amino, C _{1 - 6} alkylamino, di -C _{1 - 6} alkylamino, C _{1 - 6} acylamino, C _{1 - 6} acyl C _{1 - 6} alkyl, monocyclic cycloalkyl or monocyclic heterocycloalkyl by from one to selected independently from 1 to 3 groups is optionally substituted, where the ring is halogen, cyano, hydroxyl, C _{1 -6} - alkoxy, C ₂ -C ₆ - alkenyloxy, C ₂ -C ₆ - alkynyl aryloxy carbonyl, C _{1 -6} - thioalkyl, C _{1 -6} - haloalkyl, amino, C _{1 -6} - alkylamino, di -C _{1 -6} - alkylamino, C _{1 -6} - acylamino and C _{1 - 6} - acyl C _{1 -6-1} also independently selected from alkylamino May be optionally substituted by two groups;

Rd Rd ⁶ and ⁷ is independently a hydroxyl, cyano, nitro, C _{1 -6} - alkyl, C _{2 -6} - alkenyl, C _{2 -6} - alkynyl, C _{1 -6} - alkoxy, C _{2 -6} - alkenyloxy, C _{2 -6-alkynyloxy,} halogen, C _{1 -6-alkyl-carbonyl,} carboxy, C _{1 -6-alkoxy-carbonyl,} amino, C _{1 -6-alkylamino,} di -C _{1 6} - alkylamino, C _{1 -6-alkyl-aminocarbonyl,} di -C _{1 -6-alkyl-aminocarbonyl,} C _{1 -6-alkyl-carbonylamino,} C _{1 -6-alkyl-carbonyl} (C _{1- 6-alkyl)} amino, C _{1 -6-alkyl-sulfonyl-amino,} C _{1 -6-alkyl-sulfonyl} (C _1-6 -alkyl) amino, C _{1 -6-alkyl} thio, C _{1 -6-alkylsulfinyl} , C _{1 -6} - alkyl sulfanyl, C _{1 -6} - alkylsulfonyl, aminosulfonyl, C _{1 -6} - alkyl aminosulfonyl, and di -C _{1 -6} - alkyl represents an amino-sulfonyl, wherein each for alkylamino or cyano-the above-mentioned hydrocarbon group is one or more halogen, hydroxyl, C _{1 -6-alkoxy,} amino, C _{1 -6-alkylamino,} di -C _{1 -6} Optionally substituted by;

j and g independently represent 0, 1, 2 or 3;

^{Rd 8, Rd 9, Rd 10} , Rd 11, Rd 12, Rd 13, Rd 14, Rd 15, Rd 16, Rd 17, Rd 18 ¹⁹ and Rd are independently H or C _{1 -6} - alkyl.

In one embodiment j and g are independently 0, 1, 2 or 3 and j + g = 2, 3 or 4. In another embodiment, j is 0, 1 or 2 and g is 1, 2 or 3. In further embodiments, j is 0 and g is 0, 1 or 2.

With respect to formulas (I) and (Id), alkyl, alkenyl, alkynyl and alkoxy groups containing the required number of carbon atoms may be unbranched or branched. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy.

"Halogen" or "halo" may be fluorine, chlorine, bromine or iodine.

"C _{1 -6} - haloalkyl" refers to alkyl groups substituted by a fluoroalkyl group containing a halogen, for example, of less than 7. For example, when the substituent is fluoro, typical haloalkyl groups are trifluoroalkyl, 2,2,2-trifluoroethyl or 2,2,2,1,1-pentafluoroethyl groups.

The term "alkenyl" refers to a monovalent group derived from a hydrocarbon having at least one carbon-carbon double bond. The term "C ₂ -C ₆ -alkenyl" refers to a monovalent group derived from a hydrocarbon having 2 to 6 carbon atoms and comprising at least one carbon-carbon double bond.

The term "alkynyl" refers to a monovalent group derived from a hydrocarbon having at least one carbon-carbon triple bond. The term "C ₂ -C ₆ -alkynyl" refers to a monovalent group derived from a hydrocarbon having 2 to 6 carbon atoms and comprising at least one carbon-carbon triple bond.

The term "alkoxy" refers to a group to which an alkyl group is attached to oxygen, where alkyl is as previously defined.

It is to be understood that the term C (O), whether ketone, aldehyde or acid or acid derivative, refers to the group —C═O. Similarly, S (O) refers to the group —S═O.

Examples of cycloalkyl groups as defined in Formula I include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

Examples of aryl groups as defined in formula (I) include phenyl, naphthyl, anthracyl and phenanthryl.

Examples of heterocycloalkyl groups as defined in formula (I) include [1,3] dioxolane, [1,4] dioxane, oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, Pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholino, thiomorpholinyl, piperazinyl, azefinyl, oxapinyl, oxazinyl and diazepinyl.

Examples of monocyclic heteroaryl groups as defined in formula (I) are pyridyl, thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tria Zolyl, oxadiazolyl, thiadiazolyl and tetrazolyl. Examples of bicyclic heteroaryl groups include indolyl, benzofuranyl, quinolyl, isoquinolyl, indazolyl, indolinyl, isoindoleyl, indolinyl, benzamidazolyl and quinolinyl.

Throughout this specification and in the claims that follow, unless the context requires otherwise, the word “comprises” or ending change, such as “comprising” or “comprises”, refers to an integer or step mentioned, or It is to be understood that it is meant to include integers or a group of steps, but not to exclude any other integer or step or a group of integers or steps.

In another embodiment of the invention, the compound is a stereoisomer or tautomer.

Suitable individual compounds of the invention

7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester;

7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid;

7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropyl-methoxy-amide;

7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid dimethyl amide;

7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methoxyl amide;

7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid amide;

7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethoxy amide;

7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-hydroxy ethyl) amide;

7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methyl amide;

7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methoxy-ethyl-amide;

7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carbaldehyde;

6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropyl methoxy- amides;

6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid amide;

7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid;

7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropyl methoxy- amides;

7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid amide;

7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid;

7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropyl methoxy-amide ;

7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-vinyloxy- Ethoxy) -amide;

7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid amide;

7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methoxy-amide;

7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethoxy-amide;

2- (4-bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-1-carboxylic acid ethyl ester;

2- (4-Bromo-2-fluoro-phenyl-amino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-1-carboxylic acid;

2- (4-Bromo-2-fluoro-phenyl-amino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-1-carboxylic acid-cyclopropyl-methoxy amides;

2- (4-bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-1-carboxylic acid amide;

2- (4-Bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-1-carboxylic acid- (2-vinyloxy- Ethoxy) -amide;

2- (4-bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-1-carboxylic acid methoxy amide;

2- (4-bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-1-carboxylic acid ethoxy amide;

7- (4-Bromo-2-fluorophenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-hydroxyethoxy )amides;

7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (3-hydroxy-propyl) -amide ;

7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-methoxy-ethyl) -amide ;

7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-acetylamino-ethyl) -amide ;

7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-dimethylamino-ethyl) -amide ;

6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-hydroxy -Ethoxy) -amide;

7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopentylamide;

7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethylamide;

7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (3-methoxy- Propyl) -amide;

7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid;

7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid amide;

7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy-amide;

7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester;

7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-hydroxy-ethoxy)- amides;

7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methoxy-amide;

7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethoxy-amide;

7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2,3-dihydroxy-pro Foxy) -amide;

7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid;

7- (4-Bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy-amide ;

7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methoxy-amide;

7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid amide;

7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethoxy-amide;

7- (4-Bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2,3-di Hydroxy-propoxy) -amide;

6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid;

6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy-amide ;

6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methoxy-amide;

6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid amide;

6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethoxy-amide;

6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2,3-di Hydroxy-propoxy) -amide;

7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizin-8-carboxylic acid thiazol-2-yl amides;

7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (3-hydroxy- Propyl) -amide;

7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid dimethylamide;

7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-methoxy- Ethyl) -amide;

7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-acetylamino- Ethyl) -amide;

7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (pyridin-2-yl Methyl) -amide;

6-fluoro-7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid;

6-Fluoro-7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylme Oxy-amide;

6-Fluoro-7- (2-fluoro-4-methylsulfanyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy -amides;

7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-8- [5- (2-hydroxy-ethylamino)-[1,3,4] oxadiazole-2- Sun] -2,3-dihydro-1H-indolizin-5-one;

7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methoxy-amide;

7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethoxy-amide;

7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-hydroxy -Ethoxy) -amide;

7- (4-Bromo-2-methyl-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid;

7- (4-Bromo-2-methyl-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy-amide ;

7- (4-bromo-2-methyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid;

7- (4-bromo-2-methyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy-amide;

6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -8- (3-hydroxy-3-piperidin-2-yl-azetidine-1-carbonyl) -2 , 3-dihydro-1H-indolizin-5-one hydrochloride;

7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-8- (3-hydroxy-3-piperidin-2-yl-azetidine-1-carbonyl) -2 , 3-dihydro-1H-indolizin-5-one;

6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -8- (3-hydroxy-3-piperidin-2-yl-azetidine-1-carbonyl) -2 , 3-dihydro-1H-indolizin-5-one;

Cyclopropanesulfonic acid [7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide ;

N- [7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -N, N-dimethyl-amino-sulfonamide;

2,3-dihydroxy-propane-amino-sulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro -Indolizin-8-yl] -amide;

1- [7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-ylsulfamoyl]- Pyrrolidine-2-carboxylic acid;

2-hydroxymethyl-pyrrolidine-1-sulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro -Indolizin-8-yl] -amide;

7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-8- (1-hydroxy-but-3-enyl) -2,3-dihydro-1H-indolizin-5 -On;

7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-8- (1-hydroxy-allyl) -2,3-dihydro-1H-indolizin-5-one;

7- (4-Bromo-2-fluoro-phenylamino) -8- (2,3-dihydroxy-propionyl) -6-fluoro-2,3-dihydro-1H-indolizin-5 -On;

7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-8- (2-hydroxy-acetyl) -2,3-dihydro-1H-indolizin-5-one;

7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester;

7- (2-Fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid;

7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy-amide;

7- (2-Fluoro-4-methoxy-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy-amide;

7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carbaldehyde oxime;

7- (4-Bromo-2-fluoro-phenylamino) -8- (3-hydroxy-3-pyridin-2-yl-azetidine-1-carbonyl) -2,3-dihydro-1H Indolizin-5-one;

7- (4-bromo-2-fluoro-phenylamino) -8- (3-hydroxy-azetidin-1-carbonyl) -2,3-dihydro-1H-indolizin-5-one;

3- (4-bromo-2-fluoro-phenyl) -1-methanesulfonyl-1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2 , 5-dione;

Cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide;

N- [7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -4-fluoro-benzenesulphone amides;

[7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -carbamic acid tert-butyl ester;

Cyclohexanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide;

N- [7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -4-trifluoromethyl- Benzenesulfonamide;

N- [7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -N, N-dimethylaminosulfone amides;

5- (4-Bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclo Penta [a] indene-4-carboxylic acid;

7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester ;

7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropyl Methoxy-amide;

7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2 -Hydroxy-ethoxy) -amide;

7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclobutyl Methoxy-amide;

7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (3 -Hydroxy-2-methyl-propoxy) -amide;

1- (2,3-Dihydroxy-propyl) -cyclopropanesulfonic acid [6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3, 5-tetrahydro-indolizin-8-yl] -amide;

1- (2,3-Dihydroxy-propyl) -cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5 -Tetrahydro-indolizin-8-yl] -amide;

1- (2,3-Dihydroxy-propyl) -cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3, 5-tetrahydro-indolizin-8-yl] -amide;

6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2,3- Dihydroxy-propoxy) -amide;

7- (2-fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropyl methoxy amide;

7- (2-Fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-hydroxy- Ethoxy) -amide;

7- (2-Fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclobutylmethoxy-amide ;

1- (2,3-Dihydroxy-propyl) -cyclopropanesulfonic acid [7- (2-fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5 -Tetrahydro-indolizin-8-yl] -amide; And

Cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide,

Or pharmaceutically acceptable salts thereof.

Numerous compounds represented by formulas I and Id can form acid addition salts, particularly pharmaceutically acceptable acid addition salts. Pharmaceutically acceptable acid addition salts of compounds of formula (I) include, but are not limited to, inorganic acids such as hydrochloride acids, such as hydrochloric acid, hydrobromic acid or salts of iodide, nitric acid, sulfuric acid, phosphoric acid; And organic acids such as aliphatic monocarboxylic acids such as formic acid, acetic acid, propionic acid and butyric acid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids such as maleic acid or succinic acid, aromatic carboxyl Acids such as benzoic acid, p-chlorobenzoic acid, diphenylacetic acid or triphenylacetic acid, aromatic hydroxy acids such as o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxynaphthalene-2-carboxylic acid or 3- Hydroxynaphthalene-2-carboxylic acid, and salts of sulfonic acids such as methanesulfonic acid or benzenesulfonic acid. These salts can be prepared from compounds of formulas I and Id by known salt-forming procedures.

Compounds of formulas (I) and (Id) containing acidic groups (eg, carboxyl groups) may also form salts with bases, especially pharmaceutically acceptable bases such as those known in the art; Suitable such salts are metal salts, in particular alkali or alkaline earth metal salts, such as sodium, potassium, magnesium or calcium salts, or with ammonia or pharmaceutically acceptable organic amines or heterocyclic bases such as ethanolamine, benzylamine or pyridine. Salts. These salts can be prepared from compounds of formulas I and Id by known salt-forming procedures.

In these compounds with asymmetric carbon atoms, the compounds exist in the form of individual optically active isomers or mixtures thereof, for example racemic or diastereomeric mixtures. The present invention includes both individual optically active R and S isomers, as well as mixtures thereof, such as racemic or diastereomeric mixtures.

The present invention relates to all pharmaceutically acceptable isotopically-labelled formulas (I) wherein one or more atoms have the same atomic number but are replaced by atoms having an atomic mass or mass number that is different from the atomic mass or mass number generally found in nature; It includes a compound of Id.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen such as ² H and ³ H, isotopes of carbon such as ¹¹ C, ¹³ C and ¹⁴ C, isotopes of chlorine such as ³⁶ Cl, Isotopes of fluorine such as ¹⁸ F, isotopes of iodine such as ¹²³ I and ¹²⁵ I, isotopes of nitrogen such as ¹³ N and ¹⁵ N, isotopes of oxygen such as ¹⁵ O, ¹⁷ O and ¹⁸ O, isotopes of phosphorus Elements such as ³² P, and isotopes of sulfur such as ³⁵ S.

Substitution with heavier isotopes, such as deuterium, i.e. ² H, may provide certain therapeutic benefits due to better metabolic stability, for example, an increase in half-life in vivo or a decrease in dosage requirements, and therefore may be desirable in some situations. can do.

Isotopically-labeled compounds of Formulas (I) and (Id) are generally unlabeled reagents previously used by conventional techniques known to those skilled in the art, or by methods similar to those described in the appended Examples and Preparations sections. Instead, it can be prepared using appropriate isotopically-labeled reagents.

The present invention, in another aspect, provides a process for the preparation of compounds of formula (I) and (Id). The schemes described in detail below show general schemes for synthesizing compounds of Formulas (I) and (Id). It is recognized that the compounds corresponding to the Roman numerals in the scheme do not correspond to the Roman numerals of the claimed compounds.

<Scheme 1>

Compounds of formula (II) are described in J. Chem. Org. Chem., 1995, 60, 2912, and Tetrahedron, 2002, 58, 2821.

Compounds of formula (II) can be converted to compounds of formula (III) by reacting with halogenating agents such as phosphorus oxybromide (pure or in a suitable solvent such as toluene) at temperatures ranging from room temperature to 140 ° C.

Alternatively, the compound of formula (II) is nonafluorobutane sulfonyl fluoride in a solvent such as dichloromethane in the presence of a base such as diisopropyl ethylamine and a catalyst such as N, N-dimethyl-4-aminopyridine at room temperature Or N-phenyltrifluoromethanesulfonimide in a suitable solvent such as 1,2-dimethoxyethane in the presence of a base such as diisopropylethyl amine at a temperature ranging from room temperature to the reflux temperature of the solvent. Can be reacted with. In addition, the compounds of formula II can be treated with trifluoromethanesulfonic anhydride in a solvent such as dichloromethane in the presence of a base such as pyridine at temperatures ranging from -20 ° C to ambient temperature.

Compounds of formula IV can be obtained from compounds of formula III by reaction with the appropriate aniline or phenol or thiophenol using Buchwald-Hartwig C-N / S / O coupling conditions. The Buchwald-Hartwig reaction is a catalyst such as tris (dibenzylideneacetone) dipalladium (0) or palladium acetate at temperatures ranging from room temperature to the reflux temperature of the solvent, or at temperatures ranging from 70 ° C. to 150 ° C. under microwave irradiation. Bases such as potassium phosphate, sodium tert-butoxide, 1.8-diazobicyclo [5.4.1] undes-7-ene or cesium carbonate, ligands such as 9,9'-dimethyl-4,5-bis Phenylphosphino) -xanthene, 2,2'-bis (diphenylphosphino) -1-1'-binafyl, 2-dicyclohexylphosphino-2 '-(N, N-dimethylamino) ratio Suitable solvents in the presence of phenyl, 2-dicyclohexylphosphino-2 ', 6'-(dimethoxy) biphenyl or tributylphosphine, such as toluene, 1,2-dimethoxyethane, tetrahydrofuran or dioxane It can be carried out in the.

Compounds of formula (V) can be obtained from compounds of formula (IV) by reacting with a base such as sodium hydroxide in a protic solvent such as ethanol or methanol at a temperature ranging from room temperature to the reflux temperature of the solvent.

Compounds of formula (V) are subjected to an aprotic solvent such as tetrahydrofuran, N, in the presence of N-hydroxybenzotriazole with a suitable base such as diisopropylethylamine or triethylamine at temperatures ranging from 0 ° C. to room temperature. In N-dimethylformamide or dichloromethane functionalized hydroxylamines or amines, and suitable coupling agents such as O- (7-azabenzo-triazol-1-yl) -N, N, N ', N' Tetra-methyluronium hexafluorophosphate, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride or N, N-dicyclohexylcarbodiimide treated the compound of Formula VI Can be obtained. Alternatively, compounds of formula VI can be reacted directly with compounds of formula VI by reacting with amines or hydroxylamines in a solvent such as dichloromethane in the presence of a Lewis acid such as trimethyl aluminum at a temperature ranging from room temperature to the reflux temperature of the solvent. Can be obtained.

<Scheme 2>

Compounds of formula III may be prepared by reacting reagents such as [1- (chloromethyl) -4-fluoro-1,4-diazoniabicyclo [2.2.2] octane in suitable solvents such as acetonitrile at temperatures ranging from room temperature to 70 ° C. -Bis (tetrafluoroborate)] can be converted to the compound of formula VII by electrophilic halogenation.

Compounds of formula (VII) can be converted to compounds of formula (VIII) using conditions as described for the preparation of compounds of formula (IV) (Scheme 1).

Compounds of formula (VIII) can be converted to compounds of formula (IX) using the conditions as described for the preparation of compounds of formula (V) (Scheme 1).

Compounds of formula (IX) can be converted to compounds of formula (X) using conditions as described for the preparation of compounds of formula (VI) (Scheme 1).

Alternatively, the compound of formula X can be obtained directly by reacting with a amine or hydroxylamine from the compound of formula VIII using the conditions as described for the preparation of the compound of formula VI (Scheme 1).

<Scheme 3>

Compounds of formula (XI) may be prepared from compounds of formula (II) with bases such as NaH and alkylating agents such as methyl iodide or halogenating agents such as desorption in a suitable solvent such as THF or DMF at a temperature ranging from room temperature It can be prepared by reacting with oxyfluorine, NCS, NBS, NIS.

Compounds of formula (XI) can be converted to compounds of formula (VII) using the same conditions as described for the preparation of compounds of formula (II) (Scheme 1).

<Scheme 4>

Compounds of formula (XII) can be obtained from compounds of formula (VII) by reacting with a base such as sodium hydroxide or lithium hydroxide in a protic solvent such as ethanol or methanol at a temperature ranging from room temperature to the reflux temperature of the solvent.

The compound of formula XII may then be converted to the compound of formula IX using an S _N AR reaction. The S _N AR reaction is typically carried out in a suitable solvent such as THF using an amide base such as LDA, LiHMDS, NaHMDS or KHMDS at appropriate temperatures ranging from -78 ° C to room temperature.

Compounds of formula (IX) can be converted to compounds of formula (X) using the same conditions as described for the preparation of compounds of formula (VI) (Scheme 1).

Scheme 5

Compounds of formula (IX) can be converted to compounds of formula (XIII) using hydrazine by standard coupling procedures using reagents such as EDCI or PyBOP in a suitable organic solvent such as DMF, THF or dichloromethane in the presence of HOBt.

The compound of formula (XIII) can then be converted to the compound of formula (XIV) using a carbonyldiimidazole, phosgene or phosgene equivalent in a suitable organic solvent such as DMF, toluene or dichloromethane.

Compounds of formula (XV) are accessible from compounds of formula (XIV) by adding appropriate amines and then re-ringing the intermediate acyl hydrazides with triphenylphosphine, triethylamine and CCl ₄ in dichloromethane.

<Scheme 6>

Aldehydes and ketones of formula XVI can be prepared from acids of formula IX using standard methods, such as by converting the acid to the corresponding Weinreb amide and then treating with an appropriate organo-metal reagent.

Oxadiazoles of formula (XVII) can be prepared by acylating each amidoxime and then dehydrating cyclization.

Acyl azide of formula (XVIII) can be prepared from compounds of formula (IX) via acid halides such as acid chlorides using standard conditions. The compound of formula XVIII may then be modified via Curtius rearrangement to provide a compound of formula XIX.

According to standard methodology, the acid of formula (IX) is converted to the corresponding amide, which is then dehydrated to give the corresponding nitrile of formula (XX). Compounds of formula (XX) can be treated with trimethylsilyl azide or NaN ₃ in a suitable aprotic solvent such as N, N-dimethylformamide at temperatures ranging from room temperature to 100 ° C. to afford compounds of formula (XI).

Inhibitory properties of compounds of Formulas (I) and (Id) can be demonstrated using the following test procedures:

The BRAF-MEK-ERK cascade assay is used to assess the effect of these compounds as inhibitors of the MAP kinase pathway. Enzymatic cascade assays include recombinant human activated BRAF (V599E) kinase (catalog number 14-557), human full length inactive MEK1 kinase (catalog number 14-706) and human full length inactive MAP kinase 2 / ERK2 obtained from Upstate. (Catalog No. 14-536) Set up using enzyme. TR-FRET (Time Resolved Fluorescence Resonance Energy Transfer) detection technology is used for reading. The assay buffer solution was 50 mM Tris pH 7.5, 10 mM MgCl ₂ , 1 mM DTT, 0.01% Tween 20, 0.1 nM activated BRAF, 2 nM inactive MEK1, 10 nM inactive ERK2, 100 μM ATP and It contains 500 nM long chain biotin-peptide substrate (LCB-FFKNIVTPRTPPP). Kinase reaction was stopped after 90 minutes using 10 mM EDTA and Lance detection mix (2 nM Eu-labeled phospho-serine / threonine antibody (catalog number AD0176-Perkin Elmer), 20 nM SA-APC (Catalog No. CR130-100-Perkin Elmer) is added. TR-FRET signal (excitation at 340 nm, emission at 615 nm and 665 nm) is read with a 50 μs delay time on a Victor3 V fluorometer. Data is calculated using the ratio of readings at 665 nm to readings at 615 nm. The final concentration of DMSO in the assay is 2.5%. Enzymes are pre-incubated for 45 minutes in the presence of test compounds to screen compounds at 10 μM concentration.

Each individual IC50 uses a 10 point dose response curve generated by GraphPad Prism software version 4 (San Diego, CA, USA) using a nonlinear regression curve fit for sigmoidal dose response (variable slope). Decide by

In vitro MAP kinase assays are set up using activated MAP kinase 2 / ERK2 (catalog numbers 14-550) obtained from Upstate. TR-FRET detection technique is used for reading.

Assay buffer solution was treated with 50 mM Tris pH 7.5, 10 mM MgCl ₂ , 1 mM DTT, 0.01% Tween 20, 1 nM activated ERK2, 100 μM ATP and 500 nM long chain biotin-peptide substrate (LCB-FFKNIVTPRTPPP) in 384 well format. It contains. The kinase reaction was stopped after 90 minutes with 10 mM EDTA and the lance detection mix (2 nM Eu-labeled phospho-serine / threonine antibody (catalog number AD0176-Perkin Elmer), 20 nM SA-APC (catalog number CR130 -100-Perkin Elmer)). TR-FRET signal (excitation at 340 nm, emission at 615 nm and 665 nm) is read with a 50 μs delay time on a Victor 3 V fluorometer. Data is calculated using the ratio of readings at 665 nm to readings at 615 nm. The final concentration of DMSO in the assay is 2.5%. Enzymes are pre-incubated for 45 minutes in the presence of test compounds to screen compounds at 10 μM concentration.

Radioactive filter binding assays are standardized using recombinant human activated BRAF (V599E) kinase (catalog no. 14-557) and kinase deactivation (ME97) (K97R) (catalog no. 14-737) obtained from Upstate. Incorporation of ³² P into MEK1 (K97R) by BRAF (V599E) was carried out at 50 mM Tris pH 7.5, 10 mM MgCl ₂ , 1 mM DTT, 100 mM sucrose, 100 μM sodium orthovanadate, 5 μM ATP and 2 Final assay buffer of μCi [γ ³² P] ATP and measurement using 500 mg of MEK1 kinase deactivation substrate. The enzymatic reaction is stopped after 120 minutes with 8N HCl (hydrochloric acid) and 1 mM ATP. The solution is spotted on P81 filter paper, washed four times with 0.75% orthophosphoric acid, and finally with acetone. The dried P81 filter paper is read on a micro-beta Trilux scintillation counter. The final concentration of DMSO in the assay is 1%. Enzymes are pre-incubated for 45 minutes in the presence of test compounds to screen compounds at 10 μM concentration.

These assays described above are described in Han, Shulin, et al., Bioorganic & Medicinal Chemistry Letters (2005) 15, 5467-5473 and Yeh, et al., Clin Cancer Res (2007) 13 (5), 1576-. 1583, all in detail.

Cell viability assays of A375 cells are set up in 96-well plate format using XTT.

XTT is a yellow tetrazolium salt that is cleaved with an orange formazan dye by mitochondria of metabolically active cells. The procedure allows for quick judgment on the microtiter plate, providing a reproducible and sensitive result.

A375 cells are grown in DMEM medium containing 10% FBS and 1 mM sodium pyruvate. Cells are trypsinized and seeded at 1000 cells / well. After the cells attach overnight, compounds are added to the wells at the following final concentrations: 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.001 and 0.0001 μΜ. Assays are set up in triplicates for each concentration. DMSO concentration is maintained at 0.5% / well. Three days after compound addition, an XTT assay is performed. The wells are washed once with PBS. 100 μL of DMEM medium without phenol red or FBS is added to each well. A working solution of XTT containing 1 mg / mL XTT and 100 μL of PMS (stock concentration 0.383 mg / mL) per 5 mL is prepared. 50 μL of working solution of XTT is added to each well. Absorbance of the plate is read at 465 nm using Spectramax 190 (Molecular Devices). Absorbance from wells containing medium and XTT alone but no cells is considered a blank and subtracted from readings from all wells.

Survival percentages are calculated by considering blank subtraction values from wells treated with DMSO alone as 100% survival. GI50 values are calculated using GraphPad Prism, using non-linear regression curve fit for sigmoidal dose response (variable slope).

Cell viability assays are described in Scudiero, et al., Cancer Research (1988) 48, 4827-4833; Weislow, et al., J. Natl. Cancer Institute, (1989) 81, 577-586; And Roehm, et al., J. Immunol. Methods [1991] 142: 257-265.

The compounds of the present invention are useful as both prophylactic and curative treatments for diseases or conditions related to the overactivity of MEK, as well as diseases or conditions regulated by the Raf / Ras / Mek pathway.

Thus, as a further aspect, the invention relates to a disease or condition related to overactivity of MEK, or to a disease or condition controlled by the MEK cascade, comprising administration of a therapeutically effective amount of a compound of Formula (I) or (Id) or a pharmaceutically acceptable salt thereof It is about how to treat it.

As a further aspect, the present invention relates to a method of treating a proliferative disease, such as cancer, comprising administration of an effective amount of a compound of formula (I) or (Id) or a pharmaceutically acceptable salt thereof.

Examples of cancer include, but are not limited to: hemangiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyosarcoma, fibrosarcoma, lipoma, teratoma; Tracheal carcinoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, alveolar (bronchiole) carcinoma, bronchial adenocarcinoma, lymphoma, cartilaginous hyperplasia, mesothelioma, esophageal squamous cell carcinoma, leiomyosarcoma, leiomyosarcoma, ductal carcinoma, insulinoma , Glucagon, gastrin, VIP, gastric and small intestinal carcinoid tumor, adenocarcinoma, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroid, coronary adenocarcinoma, chorionic adenoma, hyperoma, Wilm tumor [myoblastoma, leukemia , Bladder and urethral squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, normal carcinoma, teratoma, embryonic carcinoma, teratoma, choriocarcinoma, stromal cell carcinoma, fibroadenoma, adenocarcinoma, hepatocellular carcinoma (hepatocarcinoma), cholangiocarcinoma, Hepatoblastoma, Hepatocellular Adenoma, Hemangioma, Osteosarcoma (Osteosarcoma), Malignant Fibrous Histiocytoma, Cartilage Sarcoma, Ewing's Sarcoma, Malignant Lymphoma (Reticulosarcoma), Multiple Myeloma, Malignant Cell tumors, chondromas, osteochondromas (osteochondrosis), benign chondromas, chondroblastomas, chondromyeloma, osteomyomas and giant cell tumors, osteomas, granulomas, yellowomas, degenerative osteomyelitis, meningiomas, meningiosarcoma, glioma, Astrocytoma, medulloblastoma, glioma, glioblastoma, germoma [pineal carcinoma], glioblastoma multiforme, oligodendroma, schwannomas, retinoblastoma, congenital tumors, spinal cord neurofibromas, meningiomas, glioma, endometrial carcinoma, cervical carcinoma , Pre-tumor cervical dysplasia, ovarian carcinoma, serous cystic carcinoma, mucinous cystic carcinoma, granulosa-follicular cell tumor, Sertoli-Lidihi cell tumor, undifferentiated germ cell tumor, malignant teratoma, intraepithelial carcinoma, adenocarcinoma, Melanoma], vaginal clear cell carcinoma, staphylosarcoma (embryonic rhabdomyosarcoma), fallopian tube carcinoma, acute and chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative vagina , Multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma, malignant lymphoma, malignant melanoma, basal cell carcinoma, nevi, dysplastic nevi, hemangioma, skin fibrosis, keloids, psoriasis and neuroblastoma.

The compounds of the present invention may also be useful for the treatment of other diseases or conditions related to the overactivity of MEK. Thus, as a further aspect, the present invention relates to a method of treating a disorder selected from: xenografts (cell, skin, limb, organ or bone marrow transplant) rejection; Osteoarthritis; Rheumatoid arthritis; Cystic fibrosis; Diabetic complications (including diabetic retinopathy and diabetic nephropathy); Hepatomegaly; Cardiac hypertrophy; Stroke (eg, acute focal ischemic stroke and forebrain ischemia); Heart failure; Septic shock; asthma; Chronic obstructive pulmonary disorder; Alzheimer's disease; And chronic or neuropathic pain.

The term "chronic pain" for the purposes of the present invention includes, but is not limited to, idiopathic pain and pain associated with chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism. Chronic pain is associated with a number of conditions, including but not limited to inflammation, and postoperative pain.

As used herein, the term "neuropathic pain" refers to inflammation, postoperative pain, ring pain, burn pain, gout, trigeminal neuralgia, acute herpes and postherpetic pain, burning pain, diabetic neuropathy, plexus extraction, neuroma, vasculitis, virus It is associated with a number of conditions, including but not limited to infections, crush damage, compression damage, tissue damage, limb amputation and nerve damage between the peripheral and central nervous system.

The compounds of the invention are also useful as antiviral agents for the treatment of viral infections such as HIV, hepatitis (B) virus (HBV), human papilloma virus (HPV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections. can do.

The compounds of the present invention may also be useful for the treatment of restenosis, psoriasis, allergic contact dermatitis, autoimmune diseases, atherosclerosis and inflammatory bowel diseases such as Crohn's disease and ulcerative colitis.

The MEK inhibitors of the present invention may be usefully combined with another pharmacologically active compound or with two or more other pharmacologically active compounds, especially in the treatment of cancer. For example, a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above may be a chemotherapeutic agent, for example, a mitosis inhibitor such as taxanes, vinca alkaloids, paclitaxel, docetaxel, vincristine, vinblastine, vino Selected from levin or vinfluin, and other anticancer agents such as cisplatin, 5-fluorouracil or 5-fluoro-2-4 (1H, 3H) -pyrimidinedione (5FU), flutamide or gemcitabine It may be administered in combination with one or more agents simultaneously, sequentially or separately.

Such a combination can provide important benefits including synergistic activity in therapy.

Compounds of formula (I) or formula (Id) may also be advantageously used in combination with other antiproliferative compounds. Such antiproliferative compounds include aromatase inhibitors; Antiestrogens; Topoisomerase I inhibitors; Topoisomerase II inhibitors; Microtubule active compounds; Alkylated compounds; Histone deacetylase inhibitors such as LBH589; Compounds that induce cell differentiation processes; Cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors such as RAD001; Anti-neoplastic anti metabolites; Platinum compounds; Compounds that target / reduce protein or lipid kinase activity and additional antiangiogenic compounds; Compounds that target, decrease or inhibit the activity of a protein or lipid phosphatase; Gonadorelin agonists; Anti-androgens; Methionine aminopeptidase inhibitors; Bisphosphonates; Biological response modifiers; Antiproliferative antibodies; Heparanase inhibitors; Inhibitors of Ras oncogene isotypes; Telomerase inhibitors; Proteasome inhibitors; Compounds used to treat hematologic malignancies; Compounds which target, decrease or inhibit the activity of Flt-3, such as PKC412; Hsp90 inhibitors, such as 17-AAG (17-allylamino-geldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), conforma terraphytics ( IPI-504, CNF1010, CNF2024, CNF1010, and AUY922 from Conforma Therapeutics); Temozolomide (temodal); Kinesin spindle protein inhibitors such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine / chlorpromazine from CombinatoRx; PI3K inhibitors such as BEZ235; RAF inhibitors such as RAF265; EDG binding agents, anti-leukemic compounds, ribonucleotide reductase inhibitors, S-adenosylmethionine decarboxylase inhibitors, antiproliferative antibodies or other chemotherapeutic compounds. Alternatively or additionally, they may also be used in combination with other tumor treatment approaches, including surgery, ionizing radiation, photodynamic therapy, transplantation, for example corticosteroids, hormones, or they may be used as radiosensitizers. . Also included in anti-inflammatory and / or anti-proliferative treatments are combinations with anti-inflammatory drugs. Combinations with antihistamine drug substances, bronchodilator drugs, NSAIDs, or antagonists of chemokine receptors are also possible.

The term "aromatase inhibitor" as used herein relates to a compound which inhibits estrogen production, ie, a compound which inhibits the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term is used for steroids, in particular atamestane, exemestane and formestan, and in particular non-steroidal, in particular aminoglutetimide, rogletimide, pyridoglutetimide, trilostane, testosterone, ketoconazole, borosol , But not limited to, padrosol, anastrozole, and letrozole. Exemestane can be administered, eg, in the form as it is marketed, eg under the trademark AROMASIN. Formestan can be administered, eg, in the form as it is marketed, eg under the trademark LENTARON. Fadrozole can be administered, eg, in the form as it is marketed, eg under the trademark AFEMA. Anastrozole can be administered, eg, in the form as it is marketed, eg under the trademark ARIMIDEX. Letrozole can be administered, eg, in the form as it is marketed, eg under the trademark FEMARA or FEMAR. Aminoglutetimide can be administered, eg, in the form as it is marketed, eg under the trademark ORIMETEN. The combination of the present invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors such as breast tumors.

As used herein, the term “antiestrogen” relates to a compound that antagonizes the effect of estrogen at the estrogen receptor level. The term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen can be administered, eg, in the form as it is marketed, eg under the trademark NOLVADEX. Raloxifene hydrochloride can be administered, eg, in the form as it is marketed, eg under the trademark EVISTA. Fulvestrant can be formulated as disclosed in US Pat. No. 4,659,516 or can be administered, eg, in the form as it is marketed, eg under the trademark Faslodex (FASLODEX). Combinations of the present invention comprising a chemotherapeutic agent that is an antiestrogenic are particularly useful for the treatment of estrogen receptor positive tumors such as breast tumors.

The term “antiandrogen” as used herein relates to any substance capable of inhibiting the biological effects of androgen hormones, and bicalutamide (CASODEX), which may be formulated as disclosed, for example, in US Pat. No. 4,636,505. Including, but not limited to.

The term “gonadorelin agonist” as used herein includes, but is not limited to, abarelix, goserelin and goserelin acetate. Goserelin is disclosed in US 4,100,274 and can be administered, eg, in the form as it is marketed, eg under the trademark ZOLADEX. Abarelix can be formulated, for example, as disclosed in US 5,843,901.

The term “topoisomerase I inhibitor” as used herein refers to topotecan, gimatecan, irinotecan, camptothecin and analogs thereof 9-nitrocamptothecin and macromolecule camptothecin conjugate PNU-166148 (WO99 / 17804). Compounds A1) in include, but are not limited to. Irinotecan can be administered, eg, in the form as it is marketed, eg under the trademark CAMPTOSAR. Topotecan can be administered, eg, in the form as it is marketed, eg under the trademark HYCAMTIN.

As used herein, the term “topoisomerase II inhibitor” refers to anthracyclines such as doxorubicin (including liposome preparations such as CAELYX), daunorubicin, epirubicin, idarubicin and nemorubicin. , Anthraquinone mitoxantrone and roxanthrone, and podophyllotoxin etoposide and teniposide. Etoposide can be administered, eg, in the form as it is marketed, eg under the trademark ETOPOPHOS. Teniposide can be administered, eg, in the form as it is marketed, eg under the trademark VM 26-BRISTOL. Doxorubicin can be administered, eg, in the form as it is marketed, eg under the trademark ADRIBLASTIN or ADRIAMYCIN. Epirubicin can be administered, eg, in the form as it is marketed, eg under the trademark FARMORUBICIN. Idarubicin can be administered, eg, in the form as it is marketed, eg under the trademark ZAVEDOS. Mitoxantrone can be administered, eg, in the form as it is marketed, eg under the trademark NOVANTRON.

The term “microtubule active compound” refers to taxanes such as paclitaxel and docetaxel, vinca alkaloids such as vinblastine, in particular vinblastine sulphate, vincristine, especially vincristine sulphate, and vinorelbine, discordermol Microtubule stabilization, microtubule destabilizing compounds and microtubule polymerization inhibitors, including but not limited to lead, coquisin, and epothilones and derivatives thereof, such as epothilone B or D or derivatives thereof. Paclitaxel can be administered, eg, in the form as it is marketed, eg, in the form of TAXOL. Docetaxel can be administered, eg, in the form as it is marketed, eg under the trademark TAXOTERE. Vinblastine sulphate can be administered, eg, in the form as it is marketed, eg under the trademark VINBLASTIN R.P .. Vincristine sulfate can be administered, eg, in the form as it is marketed, eg under the trademark FARMISTIN. Discordolide can be obtained, for example, as disclosed in US Pat. No. 5,010,099. Also included are the epothilone derivatives disclosed in WO 98/10121, US Pat. No. 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO 00/31247. Epothilones A and / or B are particularly preferred.

The term "alkylated compound" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or gliadel). Cyclophosphamide can be administered, eg, in the form as it is marketed, eg under the trademark CYCLOSTIN. Ifosfamide can be administered, eg, in the form as it is marketed, eg under the trademark HOLOXAN.

The term "histone deacetylase inhibitor" or "HDAC inhibitor" relates to a compound that inhibits histone deacetylase and retains antiproliferative activity. It is a compound such as sodium butyrate, LDH589 disclosed in WO 02/22577, in particular N-hydroxy-3- [4-[[(2-hydroxyethyl) [2- (1H-indol-3-yl) ethyl]- Amino] methyl] phenyl] -2E-2-propenamide, N-hydroxy-3- [4-[[[2- (2-methyl-1H-indol-3-yl) -ethyl] -amino] methyl ] Phenyl] -2E-2-propenamide and pharmaceutically acceptable salts thereof, especially lactate salts. It is also particularly known as subveroylanilide hydroxamic acid (SAHA), MS275, FK228 (formerly FR901228), trichostatin A, and compounds disclosed in US Pat. No. 6,552,065, in particular N-hydroxy-3- [4-[[[2- (2-methyl-1H-indol-3-yl) -ethyl] -amino] methyl] phenyl] -2E-2-propenamide, or a pharmaceutically acceptable salt thereof.

The term "anti-neoplastic anti-metabolic" refers to 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylated compounds such as 5-azacytidine and decitabine, methotrexate and edrexate, and folic acid Antagonists such as but not limited to pemetrexed. Capecitabine can be administered, eg, in the form as it is marketed, eg under the trademark XELODA. Gemcitabine can be administered, eg, in the form as it is marketed, eg under the trademark GEMZAR.

As used herein, the term “platinum compound” includes but is not limited to carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatin can be administered, eg, in the form as it is marketed, eg under the trademark CARBOPLAT. Oxaliplatin can be administered, eg, in the form as it is marketed, eg under the trademark ELOXATIN.

As used herein, the term “compound that targets / decreases protein or lipid kinase activity”; Or "protein or lipid phosphatase activity"; Or “additional antiangiogenic compounds” are protein tyrosine kinases and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, eg

a) compounds that target, decrease or inhibit the activity of platelet-derived growth factor-receptors (PDGFR), such as compounds that target, decrease or inhibit the activity of PDGFR, in particular those that inhibit the PDGF receptor Compounds such as N-phenyl-2-pyrimidin-amine derivatives such as imatinib, SU101, SU6668 and GFB-111;

b) compounds targeting, decreasing or inhibiting the activity of fibroblast growth factor-receptors (FGFR);

c) compounds targeting, decreasing or inhibiting the activity of insulin-like growth factor receptor I (IGF-IR), such as compounds targeting, decreasing or inhibiting the activity of IGF-IR, in particular IGF Compounds that inhibit kinase activity of the -I receptor, such as those disclosed in WO 02/092599, or antibodies targeting the extracellular domain of the IGF-I receptor or its growth factors;

d) compounds targeting, decreasing or inhibiting the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors;

e) compounds targeting, decreasing or inhibiting the activity of the Axl receptor tyrosine kinase family;

f) compounds targeting, decreasing or inhibiting the activity of Ret receptor tyrosine kinase;

g) targets the activity of a Kit / SCFR receptor tyrosine kinase, i.e., a C-Kit receptor tyrosine kinase-(part of PDGFR class), a compound such as the c-Kit receptor tyrosine kinase class Compounds that inhibit, decrease or inhibit, in particular compounds that inhibit the c-Kit receptor, such as imatinib;

h) members of the c-Abl family, their gene-fusion products (eg BCR-Abl kinase) and compounds targeting, decreasing or inhibiting the activity of the mutants, such as members of the c-Abl family and Compounds which target, decrease or inhibit the activity of their gene-fusion products, such as N-phenyl-2-pyrimidine-amine derivatives such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC680410; PD173955 from ParkeDavis; Or dasatinib (BMS-354825);

i) members of the Raf class of protein kinase C (PKC) and serine / threonine kinases, members of MEK, SRC, JAK, FAK, PDK1, PKB / Akt, and Ras / MAPK class members, and / or cyclin-dependent kinases Compounds which target, decrease or inhibit the activity of members of the class (CDK), and especially those staurosporin derivatives disclosed in US Pat. No. 5,093,330, for example midostauline (examples of additional compounds are for example UCN -01, safingol, BAY 43-9006, bryostatin 1, perifosine; imofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531 / LY379196; isokinolin compounds such as those disclosed in WO 00/09495 FTI, including BEZ235 (P13K inhibitor) or AT7519 (CDK inhibitor);

j) Targeting or decreasing the activity of a protein-tyrosine kinase inhibitor, including compounds that target, decrease or inhibit the activity of a protein-tyrosine kinase inhibitor, such as imatinib mesylate (glyvec) or tyrphostin. Or inhibiting compounds (tyrphostine is preferably a low molecular weight (mw <1500) compound or a pharmaceutically acceptable salt thereof, in particular a compound selected from the class of benzylidenemalonitrile or the S-arylbenzenemalonyl or double substrate quinoline class Compounds of, more particularly Tyrfostine A23 / RG-50810; AG 99; Tyrfostine AG 213; Tyrfostine AG 1748; Tyrfostine AG 490; Tyrfostine B44; Tyrfostine B44 (+) enantiomer; Tyrfostine AG 555; AG 494; Tyrfostine AG 556, AG 957 and adapostin (4-{[(2,5-dihydroxyphenyl) methyl] amino} -benzoic acid adamantyl ester; NSC 680410, Adapo Being any of the compounds selected from the group consisting of tin));

k) compounds targeting, decreasing or inhibiting the activity of epidermal growth factor family of receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and mutants thereof such as epidermal growth Compounds that target, decrease or inhibit the activity of the factor receptor class, in particular members of the EGF receptor tyrosine kinase class, eg, bind to EGF receptors, ErbB2, ErbB3 and ErbB4, or bind to EGF or EGF related ligands Compounds, proteins or antibodies, and in particular WO 97/02266 (eg, compounds of Example 39) or EP 0 564 409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0 787 722, EP 0 837 063, US 5,747,498, WO 98/10767, WO 97/30034, WO 97/49688, WO 97/38983 and especially WO 96/30347 (eg compounds known as CP 358774), WO 96/33980 (eg For example, compound ZD 1839) and WO 95/03283 (eg, compound Z) M 105180) in general and specifically disclosed compounds, proteins or monoclonal antibodies such as trastuzumab (herceptin), cetuximab (erbitux), iresa, tarceva, OSI-774, CI- 1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo- [2 , 3-d] pyrimidine derivatives (disclosed in WO 03/013541); And

l) compounds that target, decrease or inhibit the activity of the c-Met receptor, such as compounds that target, decrease or inhibit the activity of the c-Met, in particular inhibit the kinase activity of the c-Met receptor A compound or antibody that targets the extracellular domain of c-Met or binds to HGF

Including, but not limited to.

Additional anti-angiogenic compounds include other mechanisms for their activity, such as compounds having mechanisms independent of protein or lipid kinase inhibition, for example thalidomide (talimide) and TNP-470.

Compounds that target, decrease or inhibit the activity of a protein or lipid phosphatase include, for example, inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or derivatives thereof.

Compounds that induce cell differentiation processes are, for example, retinoic acid, or tocopherol or tocotrienol.

As used herein, the term cyclooxygenase inhibitors include, for example, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives such as celecoxib (celecrex), rofecoxib (biox), Etoricoxib, valdecoxib or 5-alkyl-2-arylaminophenylacetic acid, for example 5-methyl-2- (2'-chloro-6'-fluoroanilino) phenyl acetic acid, lumiracoxib Including but not limited to.

As used herein, the term “bisphosphonate” includes, but is not limited to, edridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. "Etridonic acid" can be administered, eg, in the form as it is marketed, eg under the trademark DIDRONEL. "Clononic acid" can be administered, eg, in the form as it is marketed, eg under the trademark BONEFOS. "Tiludronic acid" can be administered, eg, in the form as it is marketed, eg under the trademark SKELID. "Palmidonic acid" can be administered, eg, in the form as it is marketed, eg under the trademark AREDIA. "Alendronic acid" can be administered, eg, in the form as it is marketed, eg under the trademark FOSAMAX. "Ibandronic acid" can be administered, eg, in the form as it is marketed, eg under the trademark BONDRANAT. "Reddronic acid" can be administered, eg, in the form as it is marketed, eg under the trademark ACTONEL. "Zoledronic acid" can be administered, eg, in the form as it is marketed, eg under the trademark ZOMETA.

The term “mTOR inhibitor” relates to compounds that inhibit the stunt animal target (mTOR) of rapamycin and possess antiproliferative activity, such as sirolimus (rapamycin), everolimus (sertican), CCI-779 and ABT578 will be.

As used herein, the term “heparanase inhibitor” refers to a compound that targets, reduces or inhibits heparin sulphate degradation. The term includes, but is not limited to, PI-88.

As used herein, the term “biological response modulator” refers to lymphokines or interferons such as interferon.

As used herein, the term “inhibitor of Ras oncogenic isotype”, eg, H-Ras, K-Ras, or N-Ras, is a compound that targets, decreases or inhibits oncogenic activity of Ras, eg Eg, "farnesyl transferase inhibitor", for example L-744832, DK8G557 or R115777 (Zarnestra).

The term "telomerase inhibitor" as used herein refers to a compound that targets, decreases or inhibits the activity of telomerase. Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, for example telomestatin.

As used herein, the term "methionine aminopeptidase inhibitor" refers to a compound that targets, decreases or inhibits the activity of methionine aminopeptidase. Compounds that target, decrease or inhibit the activity of methionine aminopeptidase include, for example, bengamide or derivatives thereof.

The term “proteasome inhibitor” as used herein refers to a compound that targets, decreases or inhibits the activity of the proteasome. Compounds that target, decrease or inhibit the activity of proteasomes are, for example, bortezomide (Velcarde) and MLN341.

The term "matrix metalloproteinase inhibitor" or ("MMP" inhibitor), as used herein, refers to collagen peptidomimetics and non-peptide mimetic inhibitors, tetracycline derivatives such as hydroxyxamate peptide mimetic inhibitors batti. Mastad and its orally bioavailable analogs Marimastat (BB-2516), Prinostat (AG3340), Metastat (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996 However, the present invention is not limited thereto.

As used herein, the term “compounds used in the treatment of blood malignancies” targets, decreases or inhibits the activity of FMS-like tyrosine kinase inhibitors, eg, FMS-like tyrosine kinase receptors (Flt-3R). Compound; Interferon, 1-b-D-arabinofuransylcytosine (ara-c) and bisulfan; And compounds that target, decrease or inhibit ALK inhibitors, such as anaplastic lymphoma kinases.

Compounds that target, decrease or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R) include, in particular, compounds, proteins or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, TKI258, midostaurine, staurosporin derivatives, SU11248 and MLN518.

As used herein, the term “HSP90 inhibitor” refers to compounds which target, decrease or inhibit the intrinsic ATPase activity of HSP90; Compounds that degrade, target, reduce or inhibit HSP90 client proteins via the ubiquitin proteasome pathway include, but are not limited to. Compounds that target, decrease or inhibit the intrinsic ATPase activity of HSP90 include, in particular, compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG ), Geldanamycin derivatives; Other geldanamycin related compounds; And radicicol.

The term "antiproliferative antibody" as used herein refers to trastuzumab (herceptin), trastuzumab-DM1, erbitux, bevacizumab (avastin), rituximab (rituxan), PRO64553 (anti-CD40) And 2C4 antibodies. Antibodies refer to, for example, intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from two or more intact antibodies, and antibody fragments, within the limits of the intended biological activity.

For the treatment of acute myeloid leukemia (AML), the compounds of formula (I) can be used in combination with standard leukemia therapies, in particular in combination with the therapies used for the treatment of AML. In particular, the compounds of formula (I) are for example useful in farnesyl transferase inhibitors and / or other drugs useful for the treatment of AML such as daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone And idarubicin, carboplatinum and PKC412.

The term “anti-leukemia compound” includes the pyrimidine analog Ara-C, which is, for example, a 2-alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included are the purine analogs of hypoxanthine 6-mercaptopurine (6-MP) and fludarabine phosphate.

As used herein, somatostatin receptor antagonists refer to compounds that target, treat, or inhibit the somatostatin receptor, such as octreotide and SOM230 (pasirotited).

Tumor cell damaging approaches refer to approaches such as ionizing radiation. The term "ionizing radiation" mentioned above and below means ionizing radiation which occurs as electromagnetic radiation (eg X-rays and gamma rays) or particles (eg alpha and beta particles). Ionizing radiation is provided in (but not limited to) radiation therapy and is known in the art. Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4th Edition, Vol. 1, pp. 248-275 (1993).

The term "EDG binding agent" as used herein refers to a class of immunosuppressive agents that regulate lymphocyte recycling, such as FTY720.

The term “ribonucleotide reductase inhibitor” refers to fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (in particular ALL) And in combination with ara-C) and / or pentostatin, to pyrimidine or purine nucleoside analogues. Ribonucleotide reductase inhibitors include, in particular, hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives such as PL-1, PL-2, PL-3, PL-4, PL-5, PL-6, PL-7 or PL-8 (referenced in Nandy et al., Acta Oncologica, Vol. 33, No. 8, pp. 953-961 (1994)).

The term "S-adenosylmethionine decarboxylase inhibitor" as used herein includes, but is not limited to, the compounds disclosed in US Pat. No. 5,461,076.

Furthermore, in particular the monoclonal antibodies of the compounds, proteins or VEGFs disclosed in WO 98/35958, for example 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine or pharmaceutically acceptable thereof Salts, for example succinate, or those disclosed in WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO 00/27819 and EP 0 769 947; Prewett et al., Cancer Res, Vol. 59, pp. 5209-5218 (1999); Yuan et al., Proc Natl Acad Sci U S A, Vol. 93, pp. 14765-14770 (1996); Zhu et al., Cancer Res, Vol. 58, pp. 3209-3214 (1998); And Mordenti et al., Toxicol Pathol, Vol. 27, No. 1, pp. 14-21 (1999); Those described by WO 00/37502 and WO 94/10202; Angiostatin (described by O'Reilly et al., Cell, Vol. 79, pp. 315-328 (1994)); Entostatin (described in O'Reilly et al., Cell, Vol. 88, pp. 277-285 (1997)); Anthranilic acid amide; ZD4190; ZD6474; SU5416; SU6668; Bevacizumab; Or anti-VEGF antibodies or anti-VEGF receptor antibodies such as rhuMAb and RHUFab, VEGF aptamers such as makugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgG1 antibodies, angiozyme (RPI 4610) and bevacizumab (avastin).

Photodynamic therapy as used herein refers to a therapy that uses certain chemicals known as photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include treatment with compounds such as, for example, bisudine and porphymer sodium.

As used herein, angiogenesis steroids are compounds that block or inhibit angiogenesis such as, for example, anecortave, triamcinolone, hydrocortisone, 11-epihydrocortisol, cortexsolone, 17-hydroxyprogesterone, corticosterone , Desoxycorticosterone, testosterone, estrone and dexamethasone.

Corticosteroid containing implants refer to compounds such as, for example, fluorocinolone, dexamethasone.

"Other chemotherapy compounds" include plant alkaloids, hormonal compounds and antagonists; Biological response modifiers, preferably lymphokines or interferons; Antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; Or other various compounds, or compounds having different or unknown mechanisms of action.

The structure of the active compound identified by code number, common name or trade name can be found in the standard list "The Merck Index" current edition or database, for example, Patents International (eg, IMS World Pub). From IMS World Publications.

The citation of a reference within the present disclosure should not be understood as an admission that the cited reference is a prior art which negatively affects the patentability of the present invention.

The compounds of the present invention may also be administered simultaneously, separately or sequentially in combination with one or more other suitable active agents selected from the following classes of agents: anti IL-1 agonists such as Anakinra; Anticytokine and anticytokine receptor agonists such as anti IL-6 R Ab, anti IL-15 Ab, anti IL-17 Ab, anti IL-12 Ab; B-cell and T-cell regulatory drugs such as anti CD20 Ab; CTL4-Ig, disease-improving anti-rheumatic agents (DMARDs) such as methotrexate, lefluamide, sulfasalazine; Gold salts, penicillamine, hydroxychloroquine and chloroquine, azathioprine, glucocorticoids and non-steroidal anti-inflammatory agents (NSAIDs) such as cyclooxygenase inhibitors, selective COX-2 inhibitors, regulating the migration of immune cells Agents such as chemokine receptor antagonists, adhesion molecule modulators such as LFA-1, VLA-4 inhibitors.

The invention also relates to a pharmaceutical composition comprising a compound of formula (I) or (Id) or a prodrug thereof and a pharmaceutically acceptable excipient.

In another embodiment of the invention, the prodrug is selected from the group comprising esters and hydrates.

The term prodrug is also intended to include any covalently bonded carrier which releases the active compound of the invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of the invention can be prepared by modifying the functional groups present in the compounds of the invention, either in routine manipulation or in a manner that the cleavage of the parent compound of the invention is in vivo.

In another embodiment of the invention, the excipient is from the group consisting of binders, antiadhesives, disintegrants, fillers, diluents, flavors, colorants, glidants, lubricants, preservatives, adsorbents and sweeteners or combination (s) thereof. Is selected.

In another embodiment of the invention, the composition is a tablet, troche, lozenge, aqueous or oily suspension, ointment, patch, gel, lotion, toothpaste, capsule, emulsion, cream, spray, drop, dispersible powder or granule , Hard or soft gel capsules in various dosage forms selected from the group comprising emulsions, syrups and elixirs.

Of course, the dosage of the agents of the invention used in the practice of the invention will depend, for example, on the particular condition to be treated, the effect desired and the mode of administration. In general, suitable daily dosages for oral administration are on the order of 0.1 to 10 mg / kg.

The invention is also illustrated by the following non-limiting examples, where the following abbreviations are used:

TEA: triethylamine

DPPA: diphenylphosphoryl azide

LDA: Lithium Diisopropylamide

EDCI: 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide

DMAP: 4-dimethylaminopyridine

HOBt: 1-hydroxybenzotriazole

Selectfluor: 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octane bis (tetrafluoroborate)

Dess-martin Feriodinan: 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one

DCM: dichloromethane

THF: tetrahydrofuran

DMF: Dimethylformamide

DIBAL-H: diisobutylaluminum hydride

EtOH: ethanol

EtOAc: ethyl acetate

Triflic acid anhydride: trifluoromethanesulfonic anhydride;

DCM: dichloromethane;

Pd (OAc) ₂ : palladium acetate;

Cs ₂ CO ₃ : cesium carbonate;

BINAP: 2,2'-bis (diphenylphosphino) -1,1'-binafyl;

LiOH: lithium hydroxide;

EDCI: 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide;

RT: room temperature;

TLC: thin layer chromatography,

NCS: N-chlorosuccinimide,

NBS: N-bromosuccinamide,

NIS: N-iodosuccinimide,

LiHMDS: lithium bis (trimethylsilyl) amide,

LDA: lithium diisopropylamide,

NaHMDS: sodium bis (trimethylsilyl) amide,

KHMDS: Potassium Bis (trimethylsilyl) amide,

ByBOP: Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate,

TMS: trimethylsilyl,

MgCl ₂ : magnesium chloride,

TBTU: O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate,

NMR: nuclear magnetic resonance,

DMSO-d6: deuterated dimethyl sulfoxide,

CDCl ₃ : deuterated chloroform,

LC-MS: liquid chromatography-mass spectrometry,

HPLC: high pressure liquid chromatography or high performance liquid chromatography.

The examples provided herein are for illustrative purposes only and therefore should not be construed as limiting the scope of the invention.

Example 1.

Step 1.

The compounds of steps I and II are described in J. Org. Chem., 1995, 60, 2912, and Tetrahedron, 2002, 58, 2821.

Synthesis of 5-methoxy-3,4-dihydro-2H-pyrrole

Pyrrolidin-2-one (85 g, 1 mol) was added dropwise to a stirred solution of dimethyl sulfate (126 g, 1 mol) over a period of 2 hours under a nitrogen atmosphere. The reaction mixture was stirred at 60 ° C. for 16 h. The reaction mixture was poured into ice and saturated potassium carbonate solution, extracted with diethyl ether (2x500 mL), washed with brine and dried (anhydrous sodium sulfate). The organic extract was removed at 20 ° C. under reduced pressure to give 73 g of crude 5-methoxy-3,4-dihydro-2H-pyrrole as a pale yellow liquid. The compound was used for next step without further purification. The NMR spectrum of the title compound is consistent with the theory.

Step 2.

Synthesis of 7-hydroxy-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester

Triethylamine was added to a mixture of 5-methoxy-3,4-dihydro-2H-pyrrole (73 g, 0.73 mmol) and 3-oxopentanedionate diethyl ester (200 g, 0.99 mmol) at room temperature. . After stirring the resulting solution for 5 days, the reaction mixture was filtered to obtain 39 g of 7-hydroxy-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester (24 % Yield) was obtained as a white solid. The NMR spectrum of the title compound is consistent with the theory.

Step 3.

Synthesis of 5-oxo-7-trifluoromethanesulfonyloxy-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester.

7-hydroxy-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester (60 mg, 0.2 mmol) and triethylamine (30 mg, in 5 mL dichloromethane 0.4 mmol) of the stirred solution was cooled to -78 ° C. Triflic anhydride (91 mg, 0.32 mmol) was then added dropwise over 20 minutes and the resulting reaction mixture was stirred at ambient temperature for 12 hours with TLC monitoring (100% EtOAc). The reaction mixture was washed with aqueous sodium bicarbonate solution (4 mL) and water (4 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ , concentrated and the resulting product was purified by column chromatography on silica gel (60-120 mesh) using 15% ethyl acetate in hexane as eluent to give 40 mg of the title compound. (48% yield) was obtained.

Step 4.

Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester

5-oxo-7-trifluoromethanesulfonyloxy-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester (2.3 g, 6.4 mmol) in toluene (100 mL), 2 Of -fluoro-4-bromo-aniline (1.25 g, 6.5 mmol), cesium carbonate (3.17 g, 9.7 mmol), BINAP (0.6 g, 0.97 mmol) and Pd (OAc) ₂ (0.15 g, 0.64 mmol) The stirred suspension was heated at 80 ° C. for 16 h. The reaction was monitored by TLC (9: 1 CHCl ₃ -MeOH v / v). The reaction mixture was diluted with ethyl acetate (60 mL) and filtered. The filtrate was washed with water (100 mL) and the aqueous layer was reextracted with ethyl acetate (30 mL). The combined organic extracts were dried (anhydrous Na ₂ SO ₄ ), concentrated and the crude product was purified by column chromatography on silica gel (60-120 mesh) using 0.1-0.5% MeOH in chloroform to give 336 mg ( 13% yield).

Example 2.

Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid

7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin in THF: MeOH (4: 1, v / v, 6 mL) To a solution of -8-carboxylic acid ethyl ester (280 mg, 0.71 mmol) was added 1N aqueous LiOH solution (2 mL). The resulting mixture was stirred for 3 h at room temperature with TLC monitoring (CHCl ₃ -MeOH, 8: 2). The pH of the reaction mixture was adjusted to 1 using 10% aqueous HCl solution, the resulting precipitate was filtered and washed with water (20 mL) and ethyl acetate (10 mL) to give 240 mg (92% yield) of the title compound. It was.

Example 3.

Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropyl-methoxy-amide

7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid in 10 mL dry DMF (140 mg, 0.38 To a stirred solution of mmol) were added EDCI (220 mg, 1.14 mmol) and HOBt (160 mg, 1.14 mmol). The reaction mixture was stirred for 30 minutes and then treated with O-cyclopropylmethylhydroxylamine (141 mg, 1.14 mmol) and TEA (232 mg, 1.14 mmol). The resulting reaction mixture was stirred for 16 h with TLC monitoring (MeOH-CHCl ₃ 2: 8, v / v). The reaction mixture was diluted with ethyl acetate (20 mL) and washed with saturated aqueous NH ₄ Cl solution (25 mL), saturated aqueous NaHCO ₃ solution (25 mL) and brine (25 mL). The combined organic extracts were dried (anhydrous Na ₂ SO ₄ ) and concentrated. The residue was purified by column chromatography on silica gel (1% MeOH in CHCl ₃ ) to afford the title compound in 36% yield.

Example 4.

Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methoxyl amide.

7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8- using the same reaction conditions as in Example 3 Carboxylic acid (0.2 g, 0.544 mmol) was reacted with methoxylamine hydrochloride (136 mg, 1.63 mmol) to give the crude product. The product was purified by column chromatography on silica gel (4% methanol in CHCl ₃ ) followed by preparative HPLC to afford the title compound in 16% yield.

Example 5.

Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid amide.

7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8- using the same reaction conditions as in Example 3 Carboxylic acid (0.2 g, 0.544 mmol) was converted to the title compound using ammonium chloride and triethyl amine. The test compound was purified by column chromatography on silica gel (5% methanol in CHCl ₃ ) to give 30% yield as a white solid.

Example 6.

Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethoxy amide.

7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8- using the same reaction conditions as in Example 3 Carboxylic acid (0.2 g, 0.54 mmol) was converted to the title compound using ethoxylamine hydrochloride. The product was purified by column chromatography on silica gel (5% methanol in CHCl ₃ ) followed by preparative HPLC to give the test compound as a white solid in 28% yield.

Example 7.

Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carbaldehyde

7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methoxymethyl in 5 mL of dry THF under nitrogen To a solution of amide (0.1 g, 0.25 mmol) 0.76 mL (0.76 mmol) of DIBAH-H (1.0 M solution in diethyl ether) was added dropwise at −78 ° C. over a period of 5 minutes. The reaction mixture was stirred at −78 ° C. for 4 hours and quenched with saturated aqueous ammonium chloride solution (10 mL). The reaction mixture was extracted with ethyl acetate and the combined organic extracts were washed with water and brine, then dried (anhydrous sodium sulfate) and concentrated. The title compound was purified by column chromatography on silica gel (2% methanol in CH ₂ Cl ₂ ) to give 41% yield.

Example 8.

Step 1.

Synthesis of 7-chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester

To a suspension of 7-hydroxy-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester (500 mg, 2.2 mmol) in POCl ₃ (2 g, 13.4 mmol) TEA (0.226 g, 2.2 mmol) was added and the reaction mixture was stirred for 14 h. The reaction was poured into ice water and the pH of the mixture was adjusted to 7 using aqueous K ₂ CO ₃ solution. The reaction mixture was extracted with EtOAc and the combined organic extracts were dried (anhydrous Na ₂ SO ₄ ) and concentrated. The title compound was purified by column chromatography on silica gel (1: 1 EtOAc-hexane, v / v) to give 74% yield.

Step 2.

Synthesis of 7-chloro-6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester

7-Chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester (14.5 g, 0.06 mol) and 1- (chloromethyl)-in 700 mL CH ₃ CN A mixture of 4-fluoro-1,4-diazoniabicyclo [2.2.2] octane-bis (tetrafluoroborate) (44.7 g, 0.13 mol) was heated at 80 ° C. with stirring for 5-10 minutes ; The heat source was removed. The volatile components were removed under reduced pressure and the residue was dissolved in water and extracted with EtOAc. The combined organic extracts were dried (anhydrous Na ₂ SO ₄ ) and concentrated to give 14 g of crude product. The title compound was obtained in 33% yield after column chromatography on silica gel (40% EtOAc in hexanes) and used in the next step without further purification.

Step 3.

Synthesis of 7-chloro-6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid

A solution of THF: MeOH containing 5.2 g (0.02 mol) of 7-chloro-6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester (4 : 1, v / v) 30 mL of 1N LiOH aqueous solution was added to 120 mL, and the whole was stirred at ambient temperature for 3 hours. The pH of the reaction mixture was adjusted to 1, which was extracted with EtOAc. The combined organic extracts were dried (anhydrous Na ₂ SO ₄ ) and concentrated to give crude product. Trituration with EtOAc gave the title compound in 78% yield as a gray solid.

Step 4.

Synthesis of 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid.

A stirred solution of 2-fluoro-4-iodo-phenylamine (6.4 g, 0.027 mol) in 60 mL THF was treated with LDA (4 g, 0.037 mol) at -78 ° C under nitrogen. After 20 minutes, a solution of THF containing 7-chloro-6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2.5 g, 0.011 mol) ( 330 mL) was added. The reaction mixture was further stirred at −78 ° C. for 30 minutes and then allowed to warm to ambient temperature. The reaction mixture was stirred for 3 days and the volatile components were removed under reduced pressure. The residue was partitioned between 50 mL of 3N HCl solution and 50 mL of diethyl ether. After stirring for 15 minutes, the resulting solid was collected to yield the title compound in 72% yield as a light brown solid.

Example 9.

6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy- Synthesis of Amide

Using the same reaction conditions as in Example 3, 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3, in 6 mL of dry DMF A mixture of 5-tetrahydro-indoligin-8-carboxylic acid (100 mg, 0.23 mmol), EDCI (133 mg, 0.69 mmol) and HOBt (93 mg, 0.69 mmol) was stirred for 30 minutes and O-cyclo Combined with propylmethyl-hydroxylamine (86 mg, 0.69 mmol) and TEA (70 mg, 0.69 mmol) after column chromatography on silica gel (0-2% MeOH in CHCl ₃ ) the title compound was obtained as a gray solid in 34% yield. Obtained.

Example 10.

Synthesis of 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid amide

6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetra using the same reaction conditions and reagents as described in Example 5 Hydro-indoligin-8-carboxylic acid (300 mg, 0.69 mmol) was converted to 200 mg of the crude title compound. Trituration with EtOAc and diethyl ether gave the test compound as a light yellow solid in 40% yield.

Example 11.

Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid

Using the same reaction conditions and reagents as in Example 8, step 4, 4-bromo-2-fluoro-phenylamine (925 mg, 4.8 mmol) was added with 7-chloro-6-fluoro-5-oxo- Combined with 1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (450 mg, 1.94 mol) to afford the title compound in 60% yield as a light brown solid.

Example 12.

7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy- Synthesis of Amide

7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro using the same reaction conditions and reagents as in Example 9 Indolizine-8-carboxylic acid (100 mg, 0.25 mmol) was converted to 32% yield by the title compound as a white solid by silica gel chromatography (0-2% MeOH in CHCl ₃ ).

Example 13.

Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid amide

Using the same reaction conditions and reagents as described in Example 5, 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetra Hydro-indoligin-8-carboxylic acid (250 mg, 0.64 mmol) was converted to 140 mg of the crude title compound. Trituration with EtOAc and diethyl ether gave the test compound as a pale yellow solid in 25% yield.

Example 14.

Step 1.

Synthesis of 7-hydroxy-6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester:

A solution of 7-hydroxy-5-oxo-1,2,3,5-tetrahydro-indolizin-8-carboxylic acid ethyl ester (7.5 g, 33.6 mmol) in THF was added to a stirred suspension of sodium hydride in THF. Dropwise at 0 ° C. under inert atmosphere. The reaction mixture was allowed to warm to ambient temperature and then treated with iodomethane. The resulting reaction mixture was stirred for 2 days (TLC monitoring, 100% EtOAc) and then quenched with ice. The volatiles were removed under reduced pressure and the remaining aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine and concentrated. The crude product was column chromatography on silica gel (70% ethyl acetate in hexanes) to give 38% of the title compound.

Step-2

Synthesis of 6-methyl-5-oxo-7-trifluoromethanesulfonyloxy-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester

Using the same reaction conditions as those of Example 1, Step 3, 7-hydroxy-6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester ( 0.75 g, 3.16 mmol) was stirred at ambient temperature for 12 hours and then converted to the title compound using triflic anhydride (1.06 g, 3.79 mmol). Test compounds were obtained in 40% yield after silica gel column chromatography (25% ethyl acetate in hexane).

Step 3.

Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester.

6-Methyl 5-oxo-7-trifluoromethanesulfonyloxy-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester (0.47 g, 1.26 mmol), 2-fluoro 4-bromo-aniline (0.287 g, 1.26 mmol), cesium carbonate (0.617 g, 1.89 mmol), BINAP (0.6 g, 0.19 mmol) and Pd (OAc) ₂ (0.028 g, 0.126 mmol) A stirred solution of toluene (100 mL) was heated at 90 ° C. for 4 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was taken up in ethyl acetate and washed twice with brine, then dried (anhydrous Na ₂ SO ₄ ) and concentrated. The crude product was column chromatography on silica gel (75% ethyl acetate in hexanes) to give the title compound in 19% yield.

Example 15.

Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid.

NaOH aqueous solution (1 mL, 1N) was added 7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo- in a solvent mixture of THF: MeOH (3: 1, v / v). To 1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester (40 mg, 0.10 mmol). The resulting reaction mixture was stirred at rt for 3 h. The pH of the reaction mixture was adjusted to 1.5 using 1N HCl aqueous solution and the resulting precipitate was filtered and washed with water (20 mL) and ethyl acetate (10 mL) to give the title compound in 53% yield.

Example 16.

7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy-amide Synthesis.

7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro using the same reaction conditions and reagents as in Example 9 -Indolizine-8-carboxylic acid (300 mg, 0.787 mmol) was purified by silica gel chromatography (1% MeOH in CHCl ₃ ) to give the title compound in 8% yield using O-cyclopropylmethyl hydroxylamine. Switched to

Example 17.

Step 1

7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-vinyloxy- Synthesis of Ethoxy) -amide.

7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8 in 6 mL dry DMF and 2 mL dichloromethane To a stirred solution of carboxylic acid (300 mg, 0.787 mmol) was added EDCI (165 mg, 0.865 mmol) and HOBt (116 mg, 0.865 mmol) at 0 ° C. The resulting reaction mixture was stirred at 0 ° C. for 2 hours and then treated successively with O- (2-vinyloxy-ethyl) -hydroxylamine (71 mg, 0.787 mmol) and TEA (158 mg, 1.57 mmol). . After 12 hours, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous NaHCO ₃ solution. The organic phase was dried (anhydrous Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was chromatographed on silica gel (1% MeOH in CHCl ₃ ) to afford 180 mg of the title compound in low purity.

Step 2

7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,3,5-tetrahydro-indoligin-8-carboxylic acid (2-hydroxy-ethoxy Synthesis of) -amide.

Crude 7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-vinyl Oxy-ethoxy) -amide (180 mg, 0.386 mmol) was dissolved in ethanol containing 1 mL of 1N HCl and stirred at room temperature for 16 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The organic phase was washed with brine, concentrated and the residue was column chromatography on silica gel (2% MeOH in CHCl ₃ ) to give the title compound in 30% yield.

Example 18.

Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid amide.

7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid in 6 mL THF (200 To a solution of mg, 0.524 mmol) was added a THF solution containing TBTU (292 mg, 0.787 mmol) and TEA (79 mg, 0.787 mmol) at 0 ° C. The reaction mixture was allowed to warm slowly to room temperature and then stirred for 1 hour. Ammonium chloride was added and the reaction mixture was further stirred at ambient temperature for 12 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The organic phase was washed with aqueous NaHCO ₃ solution and concentrated. The title compound is obtained in 25% yield after column chromatography on neutral alumina (2% MeOH in CHCl ₃ ).

Example 19.

Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methoxy-amide .

7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro using the same reaction conditions and reagents as in Example 4 Indolizine-8-carboxylic acid (200 mg, 0.525 mmol) was converted to the title compound using methoxylamine hydrochloride (45 mg, 0.55 mmol). Column chromatography on silica (1% MeOH in CHCl ₃ ) gave the test compound in 19% yield.

Example 20.

Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethoxy-amide .

7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indole using the same reaction conditions as in Example 3 Lysine-8-carboxylic acid (200 mg, 0.523 mmol) was reacted with ethoxylamine hydrochloride (53 mg, 0.55 mmol) to afford the title compound. Test samples were obtained in 23% yield by column chromatography on silica gel (1% MeOH in CHCl ₃ ).

Example 21.

2- (4-Bromo-2-fluoro-phenyl-amino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-1-carboxylic acid-cyclopropyl-methoxy Synthesis of Amides.

2- (4-Bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-1-carrier according to the procedure specified in Example 3 150 mg of acid (0.39 mmol) was converted to the title compound using O-cyclopropylmethylhydroxylamine. The title compound was obtained in 29% yield after column chromatography on silica gel (3% methanol in CHCl ₃ ).

Example 22.

Step 1

2- (4-Bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-1-carboxylic acid- (2-vinyloxy- Synthesis of Ethoxy) -amide.

Example 17, 2- (4-bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro in 5 mL DMF, using the same reaction conditions as in step 1 -4H-quinolizine-1-carboxylic acid (200 mg, 0.52 mmol) was converted to the title compound using O- (2-vinyloxy-ethyl) -hydroxylamine (64 mg, 0.62 mmol). The purified product was obtained by column chromatography on silica gel (methanol: chloroform) in 62% yield.

Step 2

2- (4-Bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-1-carboxylic acid- (2-hydroxy- Synthesis of Ethoxy) -amide.

Example 17, using the same reaction conditions as in step 2, 2- (4-bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-qui Norizine-1-carboxylic acid- (2-vinyloxy-ethoxy) -amide (150 mg, 0.032 mmol) was converted to the title compound, which was obtained in 12% yield by preparative HPLC.

Example 23.

Synthesis of 2- (4-bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-1-carboxylic acid methoxy-amide.

Using the same reaction conditions and reagents as in Example 5, 2- (4-bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-qui Norizine-1-carboxylic acid (200 mg, 0.52 mmol) was converted to the title compound using methoxylamine hydrochloride (131 mg, 1.52 mmol). The product was purified by column chromatography on silica gel (3.5% MeOH in CHCl ₃ ) followed by preparative HPLC to give 25 mg of test compound.

Example 24.

Synthesis of 2- (4-bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-1-carboxylic acid ethoxy-amide.

Using the same reaction conditions and reagents as in Example 3, 2- (4-bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-qui Norizine-1-carboxylic acid (200 mg, 0.52 mmol) was reacted with ethoxylamine hydrochloride (153 mg, 1.5 mmol) to give 55 mg (25% yield) of the title compound after preparative HPLC.

Example: 25

Steps 1 to 4 were performed in a similar manner to that described for Example 1, and step 5 was performed in a similar manner to that described for Example 2.

Steps: 6

7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (3-hydroxy-propyl) -amide Synthesis.

EDCI (390 mg, 0.002 mol) and HOBt (162 mg, 0.002 mol) were added to 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3 in DMF (6 mL). To a stirred solution of, 5-tetrahydro-indoligin-8-carboxylic acid (250 mg, 0.001 mol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 h. To this was added 3-amino-propanol (0.156 mL, 0.002 mol) followed by TEA (1 mL, 0.012 mol). The reaction mixture was stirred at rt overnight. The reaction mixture was partitioned between ethyl acetate and cold water (20 mL). The organic layer was washed with NaHCO ₃ solution and concentrated. Purification by preparative HPLC gave 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (3-hydride 41 mg (14.13% yield) of oxy-propyl) -amide were obtained.

Example: 26

Steps 1 to 4 were carried out in a similar manner as described for Example 8.

Step: 5

6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-vinyloxy Synthesis of -ethoxy) -amide.

EDCI (530 mg, 0.003 mol) and HOBt (364 mg, 0.003 mol) were added to 6-fluoro-7- (2-fluoro-4-iodo-phenylamino in DMF (20 mL) and DCM (10 mL). To a stirred solution of) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (200 mg, 0.46 mmol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C for 2 h. O- (2-vinyloxy-ethyl) -hydroxylamine (280 mg, 0.003 mol) followed by TEA (272 mg, 0.003 mol) was added to the reaction flask and stirring was continued for 20 hours at room temperature. The reaction mixture was partitioned between water and ethyl acetate (20 mL). Saturated organic layer with NaHCO ₃ (20 mL), Washed with NH ₄ Cl (20 mL) and brine solution (20 mL), dried over Na ₂ SO ₄ , and concentrated. Residual crude product (450 mg) was used in the next step without further purification.

Steps: 6

6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-hydroxy Synthesis of -ethoxy) -amide.

IN HCl (3 mL) was added 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2, in a 1: 1 mixture of THF and EtOH (12 mL). To a stirred solution of 3,5-tetrahydro-indoligin-8-carboxylic acid (2-vinyloxy-ethoxy) -amide (450 mg, 0.22 mmol) was added. The reaction mixture was stirred for 90 minutes. The solvent was distilled off from the reaction mixture, the reaction mixture was dissolved in water (3 mL), the pH was adjusted to 6 using 2N NaOH solution and partitioned using EtOAc. The organic layer was dried over Na ₂ S0 ₄ and concentrated. Purification by preparative HPLC to give 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxyl 61 mg (26% yield) of acid (2-hydroxy-ethoxy) -amide were obtained as a white solid.

<Reaction Scheme 7>

Example: 27

Tier: 1

Synthesis of 7-chloro-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester.

TEA (58.27 mmol, 8.4 mL) was distilled from POCl ₃ To a stirred solution of 7-hydroxy-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester (13 g, 58.27 mmol) in (32 mL, 349 mmol) It was. The reaction mixture was stirred for 16 h at room temperature under a nitrogen atmosphere. POCl ₃ was distilled from the reaction mixture and the residue was poured into ice cold water and basified with saturated K ₂ CO ₃ solution (pH = 8.5). The reaction mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na ₂ SO ₄ , concentrated and the concentrate was purified by column chromatography (silica gel, and 75% ethyl acetate in hexane as eluent) to give 7-chloro-1,2,3, 7.5 mg (53.5% yield) of 5-tetrahydro-indoligin-8-carboxylic acid ethyl ester were obtained as a yellow solid.

Tier: 2

Synthesis of 7-chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid.

1N LiOH (40 mL) was converted to 7-hydroxy-5-oxo-1,2,3,5-tetrahydro-indolin-8-carboxylic acid ethyl ester in (4: 1) THF: MeOH (75 mL). (7.5 g, 31.1 mmol) was added to the stirred solution. The reaction mixture was stirred at rt for 15 h. The reaction mixture was concentrated, acidified with 1N HCl and the precipitate formed to collect 5.2 g (78.7% yield) of 7-chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid. ) Was obtained as a white solid.

Steps: 3

Synthesis of 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid.

Lithium diisopropylamide (16.5 mL, 32.8 mmol) was added to a stirred solution of 2-fluoro-4-iodoaniline (5.6 g, 23.47 mmol) in dry THF (40 mL) at -78 ° C under nitrogen atmosphere. . This is followed by addition of 7-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2 g, 9.38 mmol) in dry THF (150 mL) and resulting The resulting mixture was first stirred at −78 ° C. for 30 minutes and then at room temperature for the next 5 days. The reaction mixture was concentrated and acidified with 1N HCl until pH was about 2. The precipitate formed was collected and washed with diethyl ether to give 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carr 2.5 g (65.7% yield) of acid was obtained as a white solid.

Example: 28

Steps 1 to 3 were carried out in a similar manner as described for Example 27.

Steps: 4

Synthesis of 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid amide.

EDCI (0.415 mg, 2.17 mmol) and HOBt (0.293 mg, 1.7 mmol) were added to 7- (2-fluoro-4-iodo-phenylamino) -5-oxo in DMF (5 mL) and TEA (0.05 mL). To a stirred solution of -1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (0.300 mg, 0.72 mmol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 30 minutes under a nitrogen atmosphere. This was followed by NH ₄ Cl (0.115 mg, 2.17 mmol) followed by TEA (0.3 mL, 2.17 mmol) and the reaction mixture was stirred at rt for 6 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine solution. The precipitate formed was collected and 0.040 mg (13 of 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid amide (13 % Yield) was obtained as a white solid.

Example: 29

Steps 1 to 3 were carried out in a similar manner as described for Example 27.

Steps: 4

Synthesis of 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy-amide.

EDCI (0.101 mg, 0.53 mmol) and HOBt (0.072 mg, 0.53 mmol) were added with 7- (2-fluoro-4-iodo-phenylamino)-in DMF (4 mL) and TEA (0.1 mL, 1.44 mmol). To a stirred solution of 5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (0.200 mg, 0.48 mmol) was added at room temperature. The reaction mixture was stirred for 30 minutes at room temperature under a nitrogen atmosphere. This was followed by addition of O-cyclopropylmethyl-hydroxylamine hydrochloride (0.072 mg, 0.57 mol), TEA (0.4 mL, 1.44 mmol) and the reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, NaHCO ₃ and brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was recrystallized from DCM (5 mL) and methanol (1 mL) to give 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro- 0.059 mg (25% yield) of indolizin-8-carboxylic acid cyclopropylmethoxy-amide were obtained as a brown solid.

Example: 30

Steps 1 to 3 were carried out in a similar manner as described for Example 27.

Steps: 4

Synthesis of 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester.

Dark H ₂ SO ₄ (0.6 mL) 7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (0.300) dissolved in EtOH (5 mL) mg, 0.72 mol) was added to the stirred solution and the reaction mixture was stirred for 3 days at 85 ° C. under a nitrogen atmosphere. The reaction mixture was concentrated and partitioned between EtOAc and water. The organic layer was washed with NaHCO ₃ , brine solution, concentrated and washed with diethyl ether. Purified by column chromatography (silica gel, and 1.5% methanol in chloroform as eluent) to 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5- 0.095 mg (29.6% yield) of tetrahydro-indoligin-8-carboxylic acid ethyl ester were obtained as a white solid.

Example: 31

Steps 1 to 3 were carried out in a similar manner as described for Example 27.

Steps: 4

7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-vinyloxy-ethoxy)- Synthesis of Amide

EDCI (0.138 mg, 0.72 mmol) and HOBt (0.097 mg, 0.72 mmol) were added with 7- (2-fluoro-4-iodo-phenylamino)-in DMF (5 mL) and TEA (0.13 mL, 0.96 mmol). To a stirred solution of 5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (0.200 mg, 0.48 mmol) was added at room temperature. This was followed by addition of O- (2-vinyloxy-ethyl) -hydroxylamine (0.99 mg, 0.96 mmol), TEA (0.13 mL, 0.96 mmol), and the reaction flask stirred at room temperature under nitrogen atmosphere for 5 hours. It was. The reaction mixture was diluted with water and partitioned using EtOAc. The organic layer was washed with NH ₄ Cl, NaHCO ₃ , brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated. Purification by preparative HPLC gave 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-vinyl 135 mg (56% yield) of oxy-ethoxy) -amide were obtained as a brown gummy solid.

Step: 5

7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-hydroxy-ethoxy)- Synthesis of Amides.

IN HCl (1.5 mL) and EtOH (3 mL) were added 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8- To a stirred solution of carboxylic acid- (2-vinyloxy-ethoxy) -amide (0.135 mg, 0.27 mmol) was added and the reaction mixture was stirred at rt for 3 h. The pH was adjusted to 5-7 with 2N NaOH solution. The reaction mixture was extracted with EtOAc. The organic layer was washed with water, brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated. Purification by preparative HPLC gave 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-hydride 12 mg (10% yield) of oxy-ethoxy) -amide were obtained as a white solid.

Example: 32

Steps 1 to 3 were carried out in a similar manner as described for Example 27.

Steps: 4

7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methoxy-amide.

EDCI (0.280 mg, 0.001 mol) and HOBt (0.197 mg, 0.001 mmol) were added to 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3 in DMF (5 mL). To a stirred solution of, 5-tetrahydro-indoligin-8-carboxylic acid (0.200 mg, 0.0005 mol), TEA (0.005 mL) and chloroform (2 mL) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1.30 h under a nitrogen atmosphere. This was followed by O-methoxy-hydroxylamine hydrochloride (0.121 mg, 0.001 mol) followed by TEA (0.2 mL, 0.001 mol) and the reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, NaHCO ₃ and brine solution. The reaction mixture was dried over anhydrous Na ₂ SO ₄ and concentrated. The concentrate was purified by preparative HPLC to give 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid 6 mg (2.8% yield) of oxy-amide were obtained as a white solid.

Example: 33

Steps 1 to 3 were carried out in a similar manner as described for Example 27.

Steps: 4

Synthesis of 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethoxy-amide.

EDCI (0.277 mg, 0.001 mol) and HOBt (0.200 mg, 0.001 mmol) were added to 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3 in DMF (5 mL). To a stirred solution of, 5-tetrahydro-indoligin-8-carboxylic acid (0.200 mg, 0.0005 mol), TEA (0.1 mL) and DCM (2 mL) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1.30 h under a nitrogen atmosphere. This was followed by O-ethoxy-hydroxylamine hydrochloride (0.141 mg, 0.001 mol) followed by TEA (0.2 mL, 0.001 mol) and the reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, NaHCO ₃ and brine solution. The reaction mixture was dried over anhydrous Na ₂ SO ₄ and concentrated. Purification by preparative HPLC gave 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethoxy-amide 13 mg (6% yield) were obtained as a white solid.

Example: 34

Steps 1 to 4 were performed in a similar manner to that described for Example 1, and step 5 was performed in a similar manner to that described for Example 2.

Steps: 6

7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2,2-dimethyl- [1, 3] Synthesis of Dioxolane-4-ylmethoxy) -amide.

EDCI (155 mg, 0.816 mmol) and HOBt (110 mg, 0.816 mmol) were added to 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3 in DMF (6 mL). To a stirred solution of, 5-tetrahydro-indoligin-8-carboxylic acid (0.2 g, 0.544 mmol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 h. This was followed by O- (4,4-dimethyl- [1,3] dioxolan-2-ylmethyl) -hydroxylamine (180 mg, 0.653 mmol), TEA (0.45 mL, 3.264 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was partitioned between ethyl acetate (50 mL) and cold water (50 mL). The organic layer was washed with saturated NaHCO ₃ solution, dried over Na ₂ SO ₄ and concentrated. Purified by column chromatography (silica gel, 5% methanol in chloroform as eluent) to 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetra 50 mg (19.13% yield) of hydro-indoligin-8-carboxylic acid (2,2-dimethyl- [1,3] dioxolan-4-ylmethoxy) -amide were obtained as the desired product.

Steps: 7

7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2,3-dihydroxy-pro Synthesis of Foxy) -amides.

7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin- dissolved 1N HCl (1 mL) in ethanol (2 mL) To a stirred solution of 8-carboxylic acid (2,2-dimethyl- [1,3] dioxolan-4-ylmethoxy) -amide (50 mg, 0.010 mmol) was added. The reaction mixture was stirred at rt for 3 h. Ethanol was distilled off and the reaction mixture was partitioned between water and ethyl acetate (20 mL). The organic layer was dried over Na ₂ SO ₄ , concentrated and the concentrate was purified by recrystallization with DCM to give 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2 25 mg (17.35% yield) of 3,5-tetrahydro-indoligin-8-carboxylic acid (2,3-dihydroxy-propoxy) -amide were obtained as the desired product.

<Reaction Scheme 8>

Example: 35

Tier: 1

Synthesis of 7-chloro-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester.

TEA (58.27 mmol, 8.4 mL) was distilled from POCl ₃ To a stirred solution of 7-hydroxy-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester (13 g, 58.27 mmol) in (32 mL, 349 mmol) The reaction mixture was stirred for 16 h at room temperature under a nitrogen atmosphere. POCl ₃ was distilled off, and the reaction mixture was poured into ice-cold water and basified to pH about 8.5 with saturated K ₂ CO ₃ solution. The reaction mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na ₂ S0 ₄ and concentrated. The concentrate was purified by column chromatography (silica gel, using 75% ethyl acetate in hexanes as eluent) to 7-chloro-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester 7.5 mg (53.5% yield) were obtained as a yellow solid.

Tier: 2

Synthesis of 6,7-dichloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester.

NCS (304 mg, 0.002282 mol) is added to a solution of 7-chloro-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester (500 mg, 0.00201 mol) dissolved in DMF. The reaction mixture was stirred for 18 hours at room temperature under a nitrogen atmosphere. The reaction mixture was extracted with ethyl acetate and washed with water and brine solution. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to 400 mg (70% of 6,7-dichloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester Yield) was obtained as the desired product.

Steps: 3

Synthesis of 6,7-dichloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid.

1N LiOH (10 mL) was converted to 6,7-dichloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid in (4: 1) THF: MeOH (10 mL). To a stirred solution of ester (400 mg, 0.001 mol) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and acidified to pH about 2 with 1N HCl. The precipitate was collected under reduced pressure to give 375 mg (100% yield) of 6,7-dichloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid as the desired product.

Steps: 4

Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid.

n-butyl lithium (2 mL, 0.003 mol) was added dropwise to a stirred solution of diisopropyl amine (0.65 mL, 0.005 mol) in dry THF (40 mL) at −78 ° C. over a period of 5 minutes and the reaction mixture was Stir for 30 minutes, then add 4-bromo-2-fluoro-phenylamine (462 mg, 0.002 mol) dissolved in dry THF (5 mL) at -78 ° C. The reaction mixture was stirred for an additional 30 minutes and then dissolved in dry THF (10 mL) with stirring at −78 ° C., 6,7-dichloro-5-oxo-1,2,3,5-tetrahydro-indoligin -8-carboxylic acid (200 mg, 0.001 mol) was added over a period of 30 minutes. Stirring was continued for an additional 16 hours at room temperature. THF was distilled off and the residue was acidified by addition of 1N HCl with stirring for 10 minutes followed by ether. The precipitate formed is collected, washed with ether and dried to 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indole 232 mg (72% yield) of lysine-8-carboxylic acid were obtained as the desired product.

Example: 36

Step: 5

7- (4-Bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy-amide Synthesis.

step:

EDCI (143 mg, 0.001 mol) and HOBt (102 mg, 0.001 mol) were added to 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1 in DMF (3 mL). To a stirred solution of 2,3,5-tetrahydro-indoligin-8-carboxylic acid (100 mg, 0.0002 mol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1.5 h. This was followed by addition of O-cyclopropylmethyl-hydroxylamine hydrochloride (92 mg, 0.001 mol), TEA (0.1 mL, 0.001 mol) at 0 ° C. The reaction mixture was stirred at rt for 18 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated NH ₄ Cl solution, NaHCO ₃ solution and brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated. Purification by preparative HPLC, 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid 42 mg (36% yield) of cyclopropylmethoxy-amide were obtained as the desired product.

Example: 37

Steps 1 to 4 were carried out in a similar manner as described for Example 1.

Step: 5

Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methoxy-amide .

EDCI (286 mg, 0.001 mol) and HOBt (202 mg, 0.001 mol) were dried in 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo- in dry DMF (5 mL). To a stirred solution of 1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (200 mg, 0.0005 mol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1.30 h. This was followed by the addition of O-methoxy-hydroxylamine hydrochloride (125 mg, 0.001 mol), TEA (0.21 mL, 0.001 mol) at 0 ° C. The reaction mixture was stirred for 16 h at room temperature under a nitrogen atmosphere. The reaction mixture was partitioned between EtOAc and water. Water organic layer, saturated NaHCO ₃ Solution and brine solution, dried over anhydrous Na ₂ SO ₄ , concentrated, and the crude product was washed with methanol 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5- 0.020 g (9.3% yield) of oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methoxy-amide were obtained as a white solid.

Example: 38

Steps 1 to 4 were carried out in a similar manner to that described for Example 1.

Step: 5

Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid amide.

EDCI (286 mg, 0.001 mol) and HOBt (202 mg, 0.0.001 mol) were dried in 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5- in dry DMF (5 mL). To a stirred solution of oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (200 mg, 0.005 mol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1.30 h. This was followed by NH ₄ Cl (80 mg, 0.001 mol) followed by TEA (0.2 mL, 0.001 mol) at 0 ° C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was partitioned between EtOAc and water. Water organic layer, saturated NaHCO ₃ Solution and brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated to 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3, 0.020 g (9.3% yield) of 5-tetrahydro-indoligin-8-carboxylic acid amide was obtained as the desired product.

Example: 39

Steps 1 to 4 were carried out in a similar manner as described for Example 1.

Step: 5

Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethoxy-amide .

EDCI (286 mg, 0.001 mol) and HOBt (202 mg, 0.001 mol) were dried in 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo- in dry DMF (5 mL). To a stirred solution of 1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (200 mg, 0.0005 mol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1.30 h. This was followed by O-ethoxy-hydroxylamine hydrochloride (145 mg, 0.001 mol) followed by TEA (0.2 mL, 0.001 mol) at 0 ° C. The reaction mixture was stirred for 18 hours at room temperature under a nitrogen atmosphere. The reaction mixture was partitioned between EtOAc and water. Water organic layer, saturated NaHCO ₃ Washed with solution and brine solution, dried over anhydrous Na ₂ SO ₄ , concentrated and the crude product was recrystallized with methanol to give 7- (4-bromo-2-fluoro-phenylamino) -6-chloro 52 g (23.6% yield) of -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethoxy-amide were obtained as the desired product.

Example: 40

Steps 1 to 4 were carried out in a similar manner as described for Example 1.

Step: 5

7- (4-Bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2,2-dimethyl Synthesis of-[1,3] dioxolan-4-ylmethoxy) -amide.

EDCI (572 mg, 0.003 mol) and HOBt (191.7 mg, 0.003 mol) were dried in 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo- in dry DMF (10 mL). To a stirred solution of 1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (400 mg, 0.0016 mol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1.30 h. This was followed by O- (2,2-dimethyl- [1,3] dioxolan-4-ylmethyl) -hydroxylamine (440 mg, 0.003 mol), TEA (0.4 mL, 0.003 mol) at 0 ° C. Addition and stirring was continued for 16 h at room temperature. The reaction mixture was partitioned between EtOAc and water. Water organic layer, saturated NaHCO ₃ Solution and brine solution, dried over anhydrous Na ₂ SO ₄ , Concentrated. Purified by column chromatography (silica gel, using 2% methanol and chloroform as eluent) to 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3 0.3 g (56.8% yield) of, 5-tetrahydro-indoligin-8-carboxylic acid (2,2-dimethyl- [1,3] dioxolan-4-ylmethoxy) -amide were obtained as the desired product.

Steps: 6

7- (4-Bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2,3-di Synthesis of hydroxy-propoxy) -amides.

7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro dissolved 1N HCl (0.6 mL) in EtOH (12 mL) -To a stirring solution of indolizin-8-carboxylic acid (2,2-dimethyl- [1,3] dioxolan-4-ylmethoxy) -amide (300 mg, 0.001 mol). The reaction mixture was stirred at room temperature for 2 hours. Ethanol was distilled off and the residue was extracted with EtOAc. The organic layer was washed with water, saturated NaHCO ₃ solution, brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated. Recrystallization from methanol gives 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ( 50 mg (18.5% yield) of 2,3-dihydroxy-propoxy) -amide were obtained as a white solid.

Example: 41

Steps 1 to 3 were carried out in a similar manner to that described for Example 1.

Steps: 4

Synthesis of 6-Chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid.

n-butyl lithium (20 mL, 0.032 mol) was added dropwise to a stirred solution of diisopropyl amine (4.5 mL, 0.032 mol) in dry THF (5 mL) at -78 ° C. for 5 minutes and the reaction mixture was stirred for 30 minutes. Stirred. This was followed by addition of 2-fluoro-4-iodo-phenylamine (5.75 g, 0.002 mol) dissolved in dry THF (10 mL) at -78 ° C. The reaction mixture was stirred for an additional 30 minutes, followed by 6,7-dichloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8- dissolved in dry THF (130 mL). Carboxylic acid (2 g, 0.008 mol) was added over a period of 30 minutes with stirring at -78 ° C. Stirring was continued for an additional 2 days at room temperature under a nitrogen atmosphere. THF was distilled off and the remaining reaction mixture was acidified by addition of 1N HCl. Diethyl ether was added and stirred for 10 minutes to give a precipitate which was collected, washed with diethyl ether and dried to give 6-chloro-7- (2-fluoro-4-iodo-phenylamino) 2.3 g (63.8% yield) of -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid were obtained as the desired product.

Example: 42

Step: 5

6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy-amide Synthesis.

EDCI (256 mg, 0.001 mol) and HOBt (181 mg, 0.001 mol) were dried with 6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo- in dry DMF (5 mL). To a stirred solution of 1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (200 mg, 0.0004 mol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1.30 h. This was followed by addition of O-cyclopropylmethyl-hydroxylamine hydrochloride (165 mg, 0.001 mol), TEA (0.2 mL, 0.001 mol) at 0 ° C. The reaction mixture was stirred for 16 h at room temperature under a nitrogen atmosphere. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with water, saturated NH ₄ Cl, saturated NaHCO ₃ Solution and brine solution, dried over anhydrous Na ₂ SO ₄ , concentrated and the concentrate was washed with methanol to give 6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5- 55 mg (24% yield) of oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy-amide were obtained as the desired product.

Example: 43

Steps 1 to 3 were performed in a similar manner to that described for Example 1, and step 4 was performed in a similar manner to that described for Example 6.

Step: 5

Synthesis of 6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methoxy-amide .

EDCI (256 mg, 0.001 mol) and HOBt (181 mg, 0.001 mol) were dried with 6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo- in dry DMF (10 mL). To a stirred solution of 1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (200 mg, 0.0004 mol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1.30 h. This was followed by O-methyl-hydroxylamine hydrochloride (111 mg, 0.001 mol) followed by TEA (0.2 mL, 0.001 mol) at 0 ° C. The reaction mixture was stirred for 16 h at room temperature under a nitrogen atmosphere. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with water, saturated NaHCO ₃ solution and brine solution, dried over anhydrous Na ₂ SO ₄ , concentrated and the concentrate was washed with methanol to give 6-chloro-7- (2-fluoro-4-io 105 mg (48% yield) of do-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methoxy-amide were obtained as the desired product.

Example: 44

Steps 1 to 3 were performed in a similar manner to that described for Example 1, and step 4 was performed in a similar manner to that described for Example 6.

Step: 5

Synthesis of 6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid amide.

EDCI (256 mg, 0.001 mol) and HOBt (181 mg, 0.001 mol) were dried with 6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo- in dry DMF (5 mL). To a stirred solution of 1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (200 mg, 0.0004 mol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1.30 h under a nitrogen atmosphere. This was followed by NH ₄ Cl (0.071 g, 0.001 mol) followed by TEA (0.2 mL, 0.001 mol) at 0 ° C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was partitioned between EtOAc and water. Water organic layer, saturated NaHCO ₃ Solution and brine solution, dried over anhydrous Na ₂ SO ₄ , concentrated and the concentrate was washed with methanol to give 6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5- 60 mg (30% yield) of oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid amide were obtained as the desired product.

Example: 45

Steps 1 to 3 were performed in a similar manner to that described for Example 1, and step 4 was performed in a similar manner to that described for Example 6.

Step: 5

Synthesis of 6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethoxy-amide .

EDCI (256 mg, 0.001 mol) and HOBt (181 mg, 0.001 mol) were dried with 6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo- in dry DMF (5 mL). To a stirred solution of 1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (200 mg, 0.000446 mol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1.30 h under a nitrogen atmosphere. Following this, O-ethyl-hydroxylamine hydrochloride (130 mg, 0.001 mol), TEA (0.2 mL, 0.001 mol) were added at 0 ° C. The reaction mixture was stirred at rt for 18 h. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with water, saturated NaHCO ₃ solution and brine solution, dried over anhydrous Na ₂ SO ₄ , concentrated and the concentrate was washed with methanol to give 6-chloro-7- (2-fluoro-4-io 105 mg (48% yield) of do-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethoxy-amide were obtained as the desired product.

Example: 46

Steps 1 to 3 were performed in a similar manner to that described for Example 1, and step 4 was performed in a similar manner to that described for Example 6.

Step: 5

6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2,2-dimethyl Synthesis of-[1,3] dioxolan-4-ylmethoxy) -amide.

EDCI (256 mg, 0.001 mol) and HOBt (180 mg, 0.001 mol) were dried with 6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo- in dry DMF (5 mL). To a stirred solution of 1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (200 mg, 0.0004 mol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1.30 h under a nitrogen atmosphere. This was followed by O- (2,2-dimethyl- [1,3] dioxolan-4-ylmethyl) -hydroxylamine (196 mg, 0.001 mol), TEA (0.2 mL, 0.001 mol) at 0 ° C. Added. The reaction mixture was stirred at rt for 18 h. The reaction mixture was partitioned between EtOAc and water. Water organic layer, saturated NaHCO ₃ Solution and brine solution, dried over anhydrous Na ₂ SO ₄ , and concentrated to give 6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3, 170 mg (66% yield) of 5-tetrahydro-indoligin-8-carboxylic acid (2,2-dimethyl- [1,3] dioxolan-4-ylmethoxy) -amide were obtained as the desired product.

Steps: 6

6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2,3-di Synthesis of hydroxy-propoxy) -amides.

6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro dissolved 1N HCl (0.6 mL) in EtOH (6 mL) Add to a stirred solution of indolizin-8-carboxylic acid (2,2-dimethyl- [1,3] dioxolan-4-ylmethoxy) -amide (170 mg, 0.0003 mol). The reaction mixture was stirred at rt for 2 h. Ethanol was distilled off, and the crude product was purified by recrystallization with methanol to give 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5- 25 mg (17.35% yield) of tetrahydro-indoligin-8-carboxylic acid (2,3-dihydroxy-propoxy) -amide were obtained as a white solid.

Example: 47

Steps 1 to 3 were carried out in a similar manner as described for Example 8.

Steps: 4

Synthesis of 6-Fluoro-7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid.

LDA (416 mg, 0.004 mol) was added to a solution of 2-fluoro-4-trifluoromethyl-phenylamine (484 mg, 0.003 mol) in THF (10 mL) at -78 ° C, and the resulting mixture was added. Stir at -78 ° C for 1 h. This was followed by 7-chloro-6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (250 mg, 0.001 mol) in THF (30 mL). Add at −78 ° C. and continue stirring for an additional 18 hours at room temperature. THF was distilled from the reaction mixture, followed by 1N HCl (5 mL) and ether (10 mL). The reaction mixture was stirred for 15 minutes, and the precipitate was collected by collecting 6-fluoro-7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetra 150 mg (37% yield) of hydro-indoligin-8-carboxylic acid were obtained as the desired product.

Example: 48

Steps 1 to 3 were performed in a manner similar to that described for Example 8, and step 4 was performed in a similar manner to that described for Example 47.

Step: 5

6-Fluoro-7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylme Synthesis of oxy-amide.

EDCI (138 mg, 0.001 mol) and HOBt (98 mg, 0.001 mol) were added to 6-fluoro-7- (2-fluoro-4-trifluoromethyl-phenylamino) -5- in DMF (6 mL). To a stirred solution of oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (90 mg, 0.0002 mol) was added and the reaction mixture was stirred at room temperature for 30 minutes. This was followed by addition of O-cyclopropylmethyl-hydroxylamine hydrochloride (90 mg, 0.001 mol) and TEA (73 mg, 0.001 mol). The reaction mixture was stirred at rt for 20 h. The reaction mixture was partitioned between water and ethyl acetate (20 mL). Saturated organic layer with NaHCO ₃ (20 mL), Washed with NH ₄ Cl (20 mL) and brine solution (20 mL), dried over Na ₂ SO ₄ , concentrated, and the concentrate was dissolved in methanol (0.5 mL) and diethyl ether (10 mL). The precipitate formed was collected to give 6-fluoro-7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carr 35 mg (33% yield) of the acid cyclopropylmethoxy-amide were obtained as the desired product.

Example: 49

Steps 1 to 3 were carried out in a similar manner as described for Example 8.

Step: 3a

Synthesis of 2-fluoro-4-thiocyanato-phenylamine.

2-Fluoro-phenylamine (2 g, 0.018 mol) is added to a solution of Select Fluoride Reagent (5.9 g, 0.017 mol) and KSCN (1.81 g, 0.019 mol) in acetonitrile and the resulting reaction is 70 at room temperature. Stir for hours. The solvent was distilled off, the reaction was dissolved in water (300 mL), extracted twice with DCM (75 mL), and the organic layer was washed with water (100 mL) and brine solution (100 mL). The reaction mixture is dried over Na ₂ SO ₄ , concentrated, and the concentrate is purified by column chromatography (silica gel, using 5-10% ethyl acetate in hexane as eluent) to 2-fluoro-4-thiocyt. 740 mg (25% yield) of anato-phenylamine were obtained as a pale yellow liquid.

Step: 3b

Synthesis of 2-fluoro-4-methylsulfanyl-phenylamine.

Na ₂ S (1.04 g, 0.011 mol) in water (2.2 mL) is added to a solution of 2-fluoro-4-thiocyanato-phenylamine (730 mg, 0.004 mol) in ethanol (12 mL), The reaction mixture was stirred at 50 ° C. for 2 hours. This was followed by the addition of CH ₃ I (683 mg, 0.0047 mol) in ethanol (2 mL) and stirring continued for an additional 3 hours. The reaction was diluted with ethyl acetate, followed by water (50 mL) and extracted with ethyl acetate. The organic layer was washed with water (20 mL), brine solution (20 mL) and concentrated to give 610 mg (89% yield) of 2-fluoro-4-methylsulfanyl-phenylamine as the desired product.

Steps: 4

Synthesis of 6-fluoro-7- (2-fluoro-4-methylsulfanyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid.

LDA (316 mg, 0.00296 mol) was added to a solution of 2-fluoro-4-methylsulfanyl-phenylamine (322 mg, 0.002 mol) in THF (10 mL) at -78 ° C, and the resulting mixture was- Stir at 78 ° C. for 1.30 h. This was followed by 7-chloro-6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (190 mg, 0.001 mol) in THF (30 mL). Add at -78 ° C and stirring continued for an additional 24 hours at room temperature. THF was distilled from the reaction mixture, followed by 1N HCl (12 mL) and ether (10 mL). The reaction mixture was stirred for 15 minutes, and the precipitate was collected to collect 6-fluoro-7- (2-fluoro-4-methylsulfanyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro 128 mg of -indolizin-8-carboxylic acid were obtained with starting material which was used in the next step without further purification.

Step: 5

6-Fluoro-7- (2-fluoro-4-methylsulfanyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy -Synthesis of amides.

EDCI (227 mg, 0.001 mol) and HOBt (160 mg, 0.001 mol) were added to 6-fluoro-7- (2-fluoro-4-methylsulfanyl-phenylamino) -5-oxo in DMF (5 mL). To a stirred solution of -1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (120 mg, 0.0003 mol) was added and the reaction mixture was stirred at room temperature for 1 hour. This was followed by addition of O-cyclopropylmethyl-hydroxylamine hydrochloride (147 mg, 0.001 mol) and TEA (120 mg, 0.001 mol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated NaHCO ₃ , NH ₄ Cl, brine solution, dried over Na ₂ SO ₄ and concentrated. The concentrate was dissolved in methanol (0.5 mL) and diethyl ether (10 mL). The precipitate was collected to give 6-fluoro-7- (2-fluoro-4-methylsulfanyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid 7 mg (9.8% yield) of cyclopropylmethoxy-amide were obtained as the desired product.

Example: 50

Steps 1 to 3 were performed in a similar manner as described for Example 8, and step 4 was performed in a similar manner to that described for Example 11.

<Reaction Scheme 9>

Step: 5

7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid pentafluorophenyl ester Synthesis.

2,3,4,5,6-pentafluoro-benzoic acid trifluoromethyl ester (136 mg, 0.0005 mol) and pyridine (38 mg, 0.0005 mol) were added to 7- (4-bromo in DMF (3 mL). To a solution of 2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (170 mg, 0.0004 mol) and The reaction mixture was stirred at rt for 4 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with NaHCO ₃ , 1M HCl solution (twice) and brine solution. The organic layer was dried over Na ₂ SO ₄ and concentrated to 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro- 256 mg of indolizin-8-carboxylic acid pentafluorophenyl ester was obtained as a crude product which was used in the next step without further purification.

Steps: 6

Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid hydrazide.

TEA (98 mg, 0.001 mol) was added to a stirred solution of hydrazine hydrochloride (35 mg, 0.001 mol) in DCM (5 mL) and the reaction mixture was stirred for 1 hour. This is followed by 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid penta Fluorophenyl ester (251 mg, 0.0005 mol) was added and stirring continued for an additional 8 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water (twice), saturated NaHCO ₃ and brine solution (twice). The organic layer was dried over Na ₂ SO ₄ and concentrated to 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro- 138 mg (55% yield) of indolizin-8-carboxylic acid hydrazide were obtained as the desired product.

Step: 6a

Synthesis of 2- (tert-butyl-dimethyl-silanyloxy) -ethylamine.

Imidazole (23.4 g, 0.344 mol) was added to a solution of 2-amino-ethanol (20 g, 0.327 mol) in DMF (400 mL) and the reaction mixture was cooled to 0 ° C. This was followed by addition of tert-butyl-chloro-dimethyl-silane (51.8 g, 0.344 mol) and the reaction mixture was stirred at rt for 3 h. The residue was diluted with water (1 L) and extracted twice with ethyl acetate (300 mL). The ethyl acetate layer was washed with water, 0.1N HCl (100 mL) and brine solution (100 mL). The organic layer was dried over Na ₂ SO ₄ , concentrated and the crude product was purified by column chromatography (silica gel, using 30-40% ethyl acetate in hexane as eluent) to 2- (tert-butyl-dimethyl- 18.1 g (31% yield) of silanyloxy) -ethylamine were obtained as the desired product.

Step: 6b

Synthesis of imidazole-1-carboxylic acid [2- (tert-butyl-dimethyl-silanyloxy) -ethyl] -amide.

2- (tert-butyl-dimethyl-silanyloxy) -ethylamine (7.3 g, 0.042 mol) in DCM (150 mL) was added to a solution of CDI (10.11 g, 0.062 mol) in THF (60 mL) at room temperature. The reaction mixture was stirred at 50 ° C. for 8 hours. The solvent was distilled off from the reaction mixture, and the residual crude product was purified by column chromatography (silica gel, using 20-40% ethyl acetate in hexane as eluent) to imidazole-1-carboxylic acid [2- (tert- 2.1 g (19% yield) of butyl-dimethyl-silanyloxy) -ethyl] -amide were obtained as the desired product.

Steps: 7

7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid N'-2- Synthesis of (tert-Butyl-dimethyl-silanyloxy) -ethyl-amino-carbonyl-hydrazide.

Acetic acid (63 mg, 0.0003 mol) and 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8 -Carboxylic acid hydrazide (135 mg, 0.0003 mol) was imidazole-1-carboxylic acid [2- (tert-butyl-dimethyl-silanyloxy) -ethyl] -amide (91 mg in THF (10 mL) , 0.0003 mol), and the reaction mixture was stirred at rt for 14 h. The solvent was distilled off from the reaction mixture to give 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carr 213 mg of the acid N'-2- (tert-butyl-dimethyl-silanyloxy) -ethyl-amino-carbonyl-hydrazide were obtained as crude product which was used in the next step without further purification.

Steps: 8

7- (4-Bromo-2-fluoro-phenylamino) -8- {5- [2- (tert-butyl-dimethyl-silanyloxy) -ethylamino]-[1,3,4] oxadia Synthesis of zol-2-yl} -6-fluoro-2,3-dihydro-1H-indolizin-5-one.

Tosyl chloride (63 mg, 0.0003 mol) and TEA (84 mg, 0.0008 mol) were added to 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo in DCM (8 mL). -1,2,3,5-tetrahydro-indoligin-8-carboxylic acid N'-2- (tert-butyl-dimethyl-silanyloxy) -ethyl-amino-carbonyl-hydrazide (200 mg, 0.0003 mol) was added to the stirred solution and the reaction mixture was stirred at rt for 12 h. DCM was distilled from the reaction mixture, the remaining mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over Na ₂ SO ₄ and concentrated to 7- (4-bromo-2-fluoro-phenylamino) -8- {5- [2- (tert-butyl-dimethyl-silanyloxy)- Ethylamino]-[1,3,4] oxadiazol-2-yl} -6-fluoro-2,3-dihydro-1H-indolizin-5-one 18.1 g (31% yield) as crude product Obtained as and used in the next step without further purification.

Steps: 9

7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-8- [5- (2-hydroxy-ethylamino)-[1,3,4] oxadiazole-2- Synthesis of Il] -2,3-dihydro-1H-indolizin-5-one.

Acetic acid (25 mg, 0.0004 mol) and tetra butyl ammonium fluoride (168 mg, 0.0006 mol) were added to 7- (4-bromo-2-fluoro-phenylamino) -8- {5- in THF (6 mL). [2- (tert-Butyl-dimethyl-silanyloxy) -ethylamino]-[1,3,4] oxadiazol-2-yl} -6-fluoro-2,3-dihydro-1H-indole To a solution of lysine-5-one (250 mg, 0.0004 mol) was added at 0 ° C. and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with NaHCO ₃ solution, 1M HCl and brine solution, dried over Na ₂ SO ₄ and concentrated. The crude product is dissolved in DCM (2 mL), followed by addition of diethyl ether, the precipitate formed is collected and dried to 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro Rho-8- [5- (2-hydroxy-ethylamino)-[1,3,4] oxadiazol-2-yl] -2,3-dihydro-1H-indolizin-5-one 27.5 mg (14% yield) was obtained as the desired product.

Example: 51

Steps 1 to 4 were carried out in a similar manner as described for Example 8.

Step: 5

Of 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methoxy-amide synthesis.

EDCI (296 mg, 0.0015 mol) and HOBt (209 mg, 0.0015 mol) were added to 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo- in DMF (5 mL). To a stirred solution of 1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (200 mg, 0.0005 mol) was added and the reaction mixture was stirred at room temperature for 1 hour. This was followed by addition of O-methyl-hydroxylamine (130 mg, 0.002 mol) and TEA (156 mg, 0.002 mol). The reaction mixture was stirred at rt for 19 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated NaHCO ₃ , saturated NH ₄ Cl, and brine solution, dried over Na ₂ SO ₄ and concentrated. The concentrate was dissolved in IPA (2 mL), followed by diethyl ether (15 mL). The precipitate formed was collected and 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid 57 mg (27% yield) of methoxy-amide were obtained as the desired product.

Example: 52

Steps 1 to 4 were carried out in a similar manner as described for Example 8.

Step: 5

Of 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethoxy-amide synthesis.

EDCI (296 mg, 0.002 mol) and HOBt (209 mg, 0.002 mol) were added to 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo- in DMF (5 mL). To a stirred solution of 1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (200 mg, 0.0005 mol) was added and the reaction mixture was stirred at room temperature for 1 hour. This was followed by O-ethyl-hydroxylamine (152 mg, 0.002 mol) and TEA (156 mg, 0.002 mol). The reaction mixture was stirred at rt for 18 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated NaHCO ₃ , saturated NH ₄ Cl and brine solution, dried over Na ₂ SO ₄ and concentrated. The concentrate was dissolved in methanol (1 mL), ether (10 mL) was added thereto, and the precipitate formed was collected by 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5 97 mg (44% yield) of -oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethoxy-amide were obtained as the desired product.

Example: 53

Steps 1 to 4 were carried out in a similar manner as described for Example 8.

Step: 5

7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-vinyloxy Synthesis of -ethoxy) -amide.

EDCI (148 mg, 0.001 mol) and HOBt (104 mg, 0.001 mol) were added to 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo- in DMF (3 mL). To a stirred solution of 1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (100 mg, 0.0003 mol) was added and the reaction mixture was stirred at rt for 1.30 h. This was followed by addition of O- (2-vinyloxy-ethyl) -hydroxylamine (80 mg, 0.001 mol) and TEA (78 mg, 0.001 mol). The reaction mixture was stirred at rt for 19 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated NaHCO ₃ , saturated NH ₄ Cl and brine solution, dried over Na ₂ SO ₄ and concentrated to give 110 mg of crude product which was used in the next step without further purification.

Steps: 6

7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-hydroxy Synthesis of -ethoxy) -amide.

IN HCl (1.6 mL) was added 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2, in a 1: 1 mixture of THF and EtOH (2 mL). To a stirred solution of 3,5-tetrahydro-indoligin-8-carboxylic acid (2-vinyloxy-ethoxy) -amide (110 mg, 0.0002 mol) was added. The reaction mixture was stirred for 1 hour. The reaction mixture is diluted with ethyl acetate; The pH was adjusted to 5 with 2N NaOH and extracted with EtOAc.

The organic layer was dried over Na ₂ S0 ₄ and concentrated. The concentrate was dissolved in 2 mL of IPA, 10 mL of ether was added thereto, and the precipitate formed was collected by 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1 8 mg (7% yield) of 2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-hydroxy-ethoxy) -amide were obtained as the desired product.

Example: 54

Steps 1 to 3 were carried out in a similar manner as described for Example 8.

Steps: 4

Synthesis of 7- (4-bromo-2-methyl-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid.

LDA (2.33 g, 0.011 mol) is added to a solution of 4-bromo-2-methyl-phenylamine (1.4 mg, 0.008 mol) in THF (10 mL) at -78 ° C, and the resulting mixture is -78 ° C. Stirred for 1 h. This was followed by 7-chloro-6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (700 mg, 0.003 mol) in THF (50 mL). Add at -78 ° C and stirring continued for an additional 20 hours at room temperature. THF was distilled off, followed by 1N HCl (20 mL), water (25 mL) and ether (10 mL). The precipitate formed was collected and 7- (4-bromo-2-methyl-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid 281 mg (24% yield) was obtained.

Example: 55

Steps 1 to 3 were performed in a similar manner to that described for Example 8, and step 4 was performed in a similar manner to that described for Example 54.

Step: 5

7- (4-Bromo-2-methyl-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy-amide Synthesis.

EDCI (346 mg, 0.002 mol) and HOBt (244 mg, 0.002 mol) were added to 7- (4-bromo-2-methyl-phenylamino) -6-fluoro-5-oxo-1 in DMF (3 mL). To a stirred solution of 2,3,5-tetrahydro-indoligin-8-carboxylic acid (230 mg, 0.001 mol) was added and the reaction mixture was stirred at rt for 1 h. This was followed by addition of O-cyclopropylmethyl-hydroxylamine (224 mg, 0.002 mol) and TEA (183 mg, 0.002 mol). The reaction mixture was stirred at rt for 24 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated NaHCO ₃ , saturated NH ₄ Cl and brine solution, dried over Na ₂ SO ₄ and concentrated. The concentrate was dissolved in 5 mL of methanol, 25 mL of diethyl ether was added thereto, and the precipitate formed was collected by 7- (4-bromo-2-methyl-phenylamino) -6-fluoro-5-oxo- 40 mg (14.7% yield) of 1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy-amide were obtained as the desired product.

Example: 56

Steps 1 to 3 were carried out in a similar manner as described for Example 8.

Steps: 4

Synthesis of 7- (4-bromo-2-methyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid.

LDA (2.7 g, 0.0253 mol) was added to a solution of 4-bromo-2-methyl-phenylamine (3.28 mg, 0.018 mol) in THF (30 mL) at -78 ° C, and the resulting mixture was -78 ° C. Stirred for 45 min. This was followed by addition of 7-chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (1.5 g, 0.01 mol) in THF (90 mL) at -78 ° C. And stirring was continued for an additional 21 hours at room temperature. THF was distilled off, followed by 60 mL of 1N HCl (pH = 1), water (115 mL) and diethylether (115 mL). The precipitate formed was collected to give 610 mg (36% yield) of 7- (4-bromo-2-methyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid. ) Was obtained.

Example: 57

Steps 1 to 3 were performed in a similar manner to that described for Example 8, and step 4 was performed in a similar manner to that described for Example 56.

Step: 5

Synthesis of 7- (4-bromo-2-methyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy-amide.

EDCI (473 mg, 0.002 mol) and HOBt (334 mg, 0.002 mol) were added to 7- (4-bromo-2-methyl-phenylamino) -5-oxo-1,2,3, in DMF (3 mL). To a stirred solution of 5-tetrahydro-indoligin-8-carboxylic acid (300 mg, 0.001 mol) was added and the reaction mixture was stirred at room temperature for 1 hour. This was followed by addition of O-cyclopropylmethyl-hydroxylamine (306 mg, 0.002 mol) and TEA (250 mg, 0.002 mol). The reaction mixture was stirred at rt for 26 h. The reaction mixture was partitioned between EtOAc and water. The organic layer was saturated with NH ₄ Cl, saturated NaHCO ₃ Washed with solution and brine solution, dried over Na ₂ S0 ₄ and concentrated. The concentrate was dissolved in 2.5 mL of methanol, 10 mL of diethyl ether was added thereto, and the precipitate formed was collected by 7- (4-bromo-2-methyl-phenylamino) -5-oxo-1,2,3 47 mg (13% yield) of, 5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy-amide were obtained as the desired product.

Example: 58

Steps 1 to 4 were carried out in a similar manner as described for Example 8.

Step: 5

2- {1- [6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carbonyl ] -3-hydroxy-azetidin-3-yl} -piperidine-1-carboxylic acid tert-butyl ester.

EDCI (154 mg, 0.001 mol) and HOBt (100 mg, 0.001 mol) were added to 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo- in DMF (4 mL). To a stirred solution of 1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (140 mg, 0.0003 mol) was added and the reaction mixture was stirred at rt for 1 h. This is followed by 2- (3-hydroxy-azetidin-3-yl) -piperidine-1-carboxylic acid tert-butyl ester (S-isomer) (166 mg, 0.001 mol) and TEA (98 mg , 0.001 mol) was added. The reaction mixture was stirred at rt for 16 h. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with saturated NH ₄ Cl, saturated NaHCO ₃ solution and brine solution, dried over Na ₂ SO ₄ and concentrated. The concentrate was purified by column chromatography (silica gel, 2-3% methanol in DCM as eluent) to afford 2- {1- [6-fluoro-7- (2-fluoro-4-iodo-phenyl Amino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carbonyl] -3-hydroxy-azetidin-3-yl} -piperidine-1-carboxylic acid tert 180 mg (82.9% yield) of -butyl ester (S-isomer) were obtained as the desired product.

Steps: 6

6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -8- (3-hydroxy-3-piperidin-2-yl-azetidine-1-carbonyl) -2 Synthesis of, 3-dihydro-1H-indolizin-5-one hydrochloride.

4N dioxane (2.5 mL) in HCl was dissolved in 2- {1- [6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1, in methanol (2 mL). 2,3,5-tetrahydro-indoligin-8-carbonyl] -3-hydroxy-azetidin-3-yl} -piperidine-1-carboxylic acid tert-butyl ester (S-isomer) ( 50 mg, 0.0001 mol) was added to the solution and the resulting mixture was stirred at room temperature for 1 hour. The solvent is distilled from the reaction mixture and the residue is triturated with ether to give 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -8- (3-hydroxy-3-piperi 34 mg (75% yield) of din-2-yl-azetidine-1-carbonyl) -2,3-dihydro-1H-indolizin-5-one hydrochloride (S-isomer) were obtained as the desired product. .

Example: 59

Steps 1 to 3 were performed in a similar manner as described for Example 8, and step 4 was performed in a similar manner to that described for Example 11.

Step: 5

2- {1- [7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carbonyl ] -3-hydroxy-azetidin-3-yl} -piperidine-1-carboxylic acid tert-butyl ester.

EDCI (185 mg, 0.001 mol) and HOBt (131 mg, 0.001 mol) were added to 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo- in DMF (5 mL). To a stirred solution of 1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (250 mg, 0.001 mol) was added and the reaction mixture was stirred at rt for 1 h. This is followed by 2- (3-hydroxy-azetidin-3-yl) -piperidine-1-carboxylic acid tert-butyl ester (racemic mixture) (199 mg, 0.001 mol) and TEA (196 mg , 0.002 mol) was added. The reaction mixture was stirred at rt for 16 h. The reaction mixture was partitioned between EtOAc and water. The organic layer was saturated NH ₄ Cl (10 mL), saturated NaHCO ₃ Washed with solution (10 mL) and brine solution (10 mL), dried over Na ₂ SO ₄ , and concentrated. The concentrate was dissolved in 3 mL of ethyl acetate to give a precipitate, which was collected by 2- {1- [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo- 1,2,3,5-tetrahydro-indoligin-8-carbonyl] -3-hydroxy-azetidin-3-yl} -piperidine-1-carboxylic acid tert-butyl ester (racemic mixture ) 200 mg (49.6% yield) were obtained as the desired product.

Steps: 6

7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-8- (3-hydroxy-3-piperidin-2-yl-azetidine-1-carbonyl) -2 Synthesis of, 3-dihydro-1H-indolizin-5-one.

4N dioxane (4 mL) in HCl was dissolved in 2- {1- [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1, in methanol (1 mL), 2,3,5-tetrahydro-indoligin-8-carbonyl] -3-hydroxy-azetidin-3-yl} -piperidine-1-carboxylic acid tert-butyl ester (racemic mixture) ( 75 mg, 0.0001 mol) was added and the resulting mixture was stirred at room temperature for 1 hour. The solvent was distilled off from the reaction mixture. Trituration with 5 mL of diethyl ether gave a precipitate, which was collected by 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-8- (3-hydroxy-3-pi 48 mg (71.6% yield) of ferridin-2-yl-azetidin-1-carbonyl) -2,3-dihydro-1H-indolizin-5-one (racemic mixture) were obtained as the desired product.

Example: 60

Steps 1 to 4 were carried out in a similar manner as described for Example 8.

Step: 5

2- {1- [6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carbonyl ] -3-hydroxy-azetidin-3-yl} -piperidine-1-carboxylic acid tert-butyl ester.

EDCI (165 mg, 0.001 mol) and HOBt (178 mg, 0.001 mol) were added to 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo- in DMF (5 mL). To a stirred solution of 1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (250 mg, 0.001 mol) was added and the reaction mixture was stirred at rt for 1 h. This is followed by 2- (3-hydroxy-azetidin-3-yl) -piperidine-1-carboxylic acid tert-butyl ester (racemic mixture) (180 mg, 0.001 mol) and TEA (175 mg , 0.002 mol) was added. The reaction mixture was stirred at rt for 16 h. The reaction mixture was partitioned between EtOAc and water. The organic layer was saturated NH ₄ Cl (10 mL), saturated NaHCO ₃ Washed with solution (10 mL) and brine solution (10 mL), dried over Na ₂ SO ₄ , and concentrated. Concentrate (100 mg) was used for next step without further purification.

Steps: 6

6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -8- (3-hydroxy-3-piperidin-2-yl-azetidine-1-carbonyl) -2 Synthesis of, 3-dihydro-1H-indolizin-5-one.

4N dioxane (5 mL) in HCl was diluted with 2- {1- [6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1, in methanol (1 mL), 2,3,5-tetrahydro-indoligin-8-carbonyl] -3-hydroxy-azetidin-3-yl} -piperidine-1-carboxylic acid tert-butyl ester (racemic mixture) ( 100 mg, 0.0001 mol) was added to the solution and the resulting mixture was stirred at room temperature for 1 hour. The solvent was distilled off from the reaction mixture to give a precipitate which was purified by preparative HPLC to give 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -8- (3-hydroxy-3 15 mg (16.6% yield) of -piperidin-2-yl-azetidine-1-carbonyl) -2,3-dihydro-1H-indolizin-5-one (racemic mixture) as the desired product It was.

Example: 61

<Reaction Scheme 10> ^*

^{* In} Step 8, B must be 2.

Steps 1 to 3 were performed in a similar manner as described for Example 8, and step 4 was performed in a similar manner to that described for Example 11.

Step: 5

3- (4-bromo-2-fluoro-phenyl) -4-fluoro-1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2, Synthesis of 5-dione.

TEA (0.12 mL, 0.001 mol) and DPPA (0.18 mL, 0.001 mol) were added to 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo- in DMF (5 mL). To a solution of 1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (300 mg, 0.001 mol) was added and the reaction mixture was stirred for 4 hours at room temperature under a nitrogen atmosphere. Following this, toluene (5 mL) was added and the reaction mixture was heated to 90 ° C. for 2 hours. The reaction mixture is concentrated under reduced pressure, water is added to give a precipitate which is collected and dried to give 3- (4-bromo-2-fluoro-phenyl) -4-fluoro-1,6,7, 250 mg (84% yield) of 8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2,5-dione were obtained as the desired product.

Steps: 6

3- (4-Bromo-2-fluoro-phenyl) -1-cyclopropanesulfonyl-4-fluoro-1,6,7,8-tetrahydro-3H-1,3,5a-triaza- Synthesis of as-indacene-2,5-dione.

60% NaH (30 mg, 0.001 mol) was added to 3- (4-bromo-2-fluoro-phenyl) -4-fluoro-1,6,7,8-tetrahydro- in dry DMF (4 mL). To a stirred solution of 3H-1,3,5a-triaza-as-indacene-2,5-dione (0.2 g, 0.001 mol) was added at 0-5 ° C. under a nitrogen atmosphere, and the resulting mixture was stirred at 1 room temperature. Stir for hours. This was followed by the dropwise addition of cyclopropanesulfonyl chloride (110 mg, 0.001 mol) in dry THF over a period of 10 minutes at 0 ° C. and stirring continued at room temperature for the next 16 hours. The crude product was used for next step without further purification.

Steps: 7

Cyclopropanesulfonic acid [7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide Synthesis.

1N aqueous NaOH (6 mL) 3- (4-bromo-2-fluoro-phenyl) -1-cyclopropanesulfonyl-4-fluoro-1,6,7,8-tetrahydro-3H-1 To 3,5a-triaza-as-indacene-2,5-dione, the resulting mixture was heated to 65 ° C. for 4 hours. Ice-cold water was added to the reaction mixture, neutralized to pH 4 with 5% ice-cold HCl, and the reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na ₂ SO ₄ , concentrated under reduced pressure, and the concentrate was purified by column chromatography (silica gel, using 2% methanol in DCM as eluent) to cyclopropanesulfonic acid [7- (4-bromo 21 mg (8.5% yield) of -2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide as the desired product Obtained.

Example: 62

Steps 1 to 4 were performed in a similar manner to that described for Example 8, and step 5 was performed in a similar manner to that described for Example 61.

Steps: 6

3- (4-bromo-2-fluoro-phenyl) -4-fluoro-2,5-dioxo-2,3,5,6,7,8-hexahydro-1,3,5a-tri Synthesis of Aza-as-indacene-1-carboxylic acid tert-butyl ester.

60% NaH (0.4 g, 0.01 mol) was added 3- (4-bromo-2-fluoro-phenyl) -4-fluoro-1,6,7,8-tetrahydro- in dry DMF (20 mL). To a stirred solution of 3H-1,3,5a-triaza-as-indacene-2,5-dione (2.5 g, 0.007 mol) was added under nitrogen atmosphere at room temperature. The resulting mixture was stirred for 30 minutes. This was followed by the dropwise addition of BOC anhydride (1.9 g, 0.009 mol) in dry THF over a period of 5 minutes at 0 ° C. and the reaction mixture was stirred at room temperature for 4 hours. The crude product was used for next step without further purification.

Steps: 7

[7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -carbamic acid tert- Synthesis of Butyl Ester.

1N aqueous NaOH (15 mL) was added 3- (4-bromo-2-fluoro-phenyl) -4-fluoro-2,5-dioxo-2,3,5,6,7,8-hexahydro To -1,3,5a-triaza-as-indacene-1-carboxylic acid tert-butyl ester was added at 0 ° C. and the resulting mixture was stirred at room temperature for 6 hours. The reaction was extracted with ethyl acetate. The organic layer was washed with water, dried over Na ₂ SO ₄ and concentrated under reduced pressure to [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2, 1.15 g (28% yield) of 3,5-tetrahydro-indolizin-8-yl] -carbamic acid tert-butyl ester were obtained as the desired product.

Steps: 8

Synthesis of 8-amino-7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-2,3-dihydro-1H-indolizin-5-one.

1N concentrated HCl (4 mL) was added [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetra in THF (10 mL). To a stirred solution of hydro-indolizin-8-yl] -carbamic acid tert-butyl ester (0.9 g, 0.002 mol) was added and the reaction mixture was stirred at rt for 4 h. The reaction mixture was concentrated under reduced pressure, saturated NaHCO ₃ solution was added and extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to afford 8-amino-7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-2,3-dihydro-1H 360 mg (72% yield) of -indolizin-5-one were obtained as the desired product.

Steps: 9

N- [7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -N, Synthesis of N-dimethyl-amino-sulfonamide.

Pyridine (2 mL) was added to 8-amino-7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-2,3-dihydro-1H-indolizin-5-one (200 mg , 0.001 mol), and the reaction mixture was stirred for 5 minutes under a nitrogen atmosphere. Following this, DMAP (5 mg, 0.0004 mol) is added, the reaction is cooled to 0 ° C., N, N-dimethyl-sulfonyl chloride (85 mg, 0.001 mol) is added and at room temperature for the next 16 hours. Stirring was continued. The reaction was monitored by TLC (100% ethyl acetate) indicating the presence of starting material. The reaction mixture was heated to 50 ° C. for 2 hours. The reaction mixture was partitioned between ethyl acetate (3x50 mL) and water. The organic layer was washed with saturated NH ₄ Cl solution, dried over Na ₂ SO ₄ , concentrated under reduced pressure, and the concentrate was purified by column chromatography (neutral alumina, using ethyl acetate as eluent) to give N- [7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -N, N-dimethyl-amino 22 mg (8% yield) of sulfonamide were obtained as the desired product.

Example: 63

Steps 1-4 were performed in a similar manner to that described for Example 8, step 5 was performed in a similar manner to that described for Example 61, and steps 6-8 were similar to those described for Example 62. It was done in a manner.

Steps: 8a

Synthesis of N- (2,2-dimethyl- [1,3] dioxolan-4-ylmethyl) -chloro-sulfonamide.

C- (2,2-dimethyl- [1,3] dioxolan-4-yl) -methylamine (300 mg, 0.00229 mol) and DMAP (295 mg, 0.0024 mol) in dry DCM were added to sulfuryl chloride in DCM ( 320 mg, 0.0023 mol) was added to the stirred solution at -78 ° C and the resulting mixture was stirred at -78 ° C for 1 hour, at -50 ° C for 2 hours, and at room temperature for 2 hours. The product formed was used for the next step.

Steps: 9

N- [7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -C- Synthesis of (2,2-dimethyl- [1,3] dioxolan-4-yl) -methylamine-sulfonamide.

N- (2,2-dimethyl- [1,3] dioxolan-4-ylmethyl) -chloro-sulfonamide (0.001 mol) was dried with 8-amino-7- (4-bromo in pyridine (3 mL). To a stirred solution of -2-fluoro-phenylamino) -6-fluoro-2,3-dihydro-1H-indolizin-5-one (200 mg, 0.001 mol) and DMAP (50 mg, 0.0004 mol) Dropwise at 0 ° C. over a period of 10 minutes, and the reaction mixture was heated to 40 ° C. for 16 hours. The reaction mixture was concentrated under reduced pressure and the concentrate was partitioned between ethyl acetate and water. The organic layer was concentrated and the concentrate was purified by column chromatography (neutral alumina, using DCM as eluent) to give N- [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro- 5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -C- (2,2-dimethyl- [1,3] dioxolan-4-yl) -methylamine-sulfonamide 26 mg (5% yield) were obtained as the desired product.

Steps: 10

2,3-dihydroxy-propane-amino-sulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro Synthesis of Indolizin-8-yl] -amide.

Concentrated HCl (1 mL) was added N- [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5- in ethanol (4 mL). To a stirred solution of tetrahydro-indolizin-8-yl] -C- (2,2-dimethyl- [1,3] dioxolan-4-yl) -methylamine-sulfonamide (26 mg, 0.00005 mol) 20 It was added at C and the reaction mixture was stirred at rt for 4 h. The reaction mixture is concentrated under reduced pressure, diethyl ether is added, decanted and dried under reduced pressure to give 2,3-dihydroxy-propane-amino-sulfonic acid [7- (4-bromo-2-fluoro-) 16 mg (70% yield) of phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide were obtained as the desired product.

Example: 64

Steps 1-4 were performed in a similar manner to that described for Example 8, step 5 was performed in a similar manner to that described for Example 61, and steps 6-8 were similar to those described for Example 62. It was done in a manner.

<Reaction Scheme 11>

Steps: 8a

Synthesis of Pyrrolidine-2-carboxylic Acid Benzyl Ester Hydrochloride

Thionyl chloride (8 mL) and pyrrolidine-2-carboxylic acid (3 g, 0.026 mol) are added to benzyl alcohol (20 mL) at −10 ° C. under a nitrogen atmosphere, and the reaction mixture is stirred at room temperature for 16 hours. Stirred. The reaction was diluted with dry diethyl ether and stirred at room temperature for 2 hours to give a precipitate, which was washed with excess diethyl ether, decanted and dried under reduced pressure to give pyrrolidine-2-carboxylic acid benzyl 4 g (66% yield) of ester hydrochloride were obtained as the desired product.

Step: 8b

Synthesis of 1-chlorosulfonyl-pyrrolidine-2-carboxylic acid benzyl ester

DMAP (0.5 g, 0.004 mol) and TEA (1.6 mg, 0.016 mol) were added to a stirred solution of pyrrolidine-2-carboxylic acid benzyl ester hydrochloride (3 g, 0.015 mol) in dry toluene (40 mL) at room temperature. Was added and the resulting mixture was stirred for 20 minutes. The reaction mixture was cooled to −10 ° C., and sulfuryl chloride (2 g, 0.015 mol) was then added dropwise over a period of 15 minutes and stirring was continued at room temperature for 3 hours. Quench the reaction with saturated NH ₄ Cl solution, extract with DCM, and dry the organic layer over Na ₂ SO ₄ and concentrate to give 1.2 g of 1-chlorosulfonyl-pyrrolidine-2-carboxylic acid benzyl ester Obtained as product.

Steps: 9

1- [7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-ylsulfamoyl]- Synthesis of Pyrrolidine-2-carboxylic Acid Benzyl Ester.

Pyridine (3 mL) and DMAP (20 mg, 0.0002 mol) were added to 8-amino-7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-2,3-dihydro-1H- To indolizin-5-one (110 mg, 0.0003 mol) was added under a nitrogen atmosphere and the reaction mixture was cooled to 0 ° C. This is followed by the dropwise addition of 1-chlorosulfonyl-pyrrolidine-2-carboxylic acid benzyl ester (300 mg, 0.001 mol) in DCM over a period of 15 minutes, stirring at room temperature for 1 hour, and at 60 ° C. Heated for 16 h. The reaction was concentrated under reduced pressure and the concentrate was partitioned between ethyl acetate and water. The organic layer was dried over Na ₂ SO ₄ and purified by column chromatography (silica gel, using 100% ethyl acetate as eluent) to give 1- [7- (4-bromo-2-fluoro-phenylamino)-. 65 mg (33% yield) of 6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-ylsulfamoyl] -pyrrolidine-2-carboxylic acid benzyl ester Obtained as product.

Steps: 10

1- [7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-ylsulfamoyl]- Synthesis of Pyrrolidine-2-carboxylic Acid.

LiOH solution (20 mg, 0.0004 mol) was dissolved in methanol: THF (2: 3) 1- [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1, To a stirred solution of 2,3,5-tetrahydro-indoligin-8-ylsulfamoyl] -pyrrolidine-2-carboxylic acid benzyl ester (65 mg, 0.0001 mol), the resulting mixture was added at room temperature Stir for 3 hours. The reaction was concentrated under reduced pressure, diluted with water, neutralized to pH about 2 with 10% HCl, and the formed precipitate was collected and dried to give 1- [7- (4-bromo-2-fluoro-phenylamino 20 mg (36% yield) of 6-Fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-ylsulfamoyl] -pyrrolidine-2-carboxylic acid Obtained as product.

Example: 65

Steps 1-4 were performed in a similar manner to that described for Example 8, step 5 was performed in a similar manner to that described for Example 61, and steps 6-8 were similar to those described for Example 62. It was done in a manner.

Steps: 8

Synthesis of 1-chlorosulfonyl-pyrrolidine-2-carboxylic acid methyl ester

DMAP (0.5 g, 0.00409 mol) and TEA (2.54 g, 0.0251 mol) were added to a stirred solution of pyrrolidine-2-carboxylic acid methyl ester hydrochloride (4 g, 0.024 mol) in dry toluene (50 mL) at room temperature. Was added and the resulting mixture was stirred for 10 minutes. The reaction mixture is cooled to −20 ° C. and then sulfuryl chloride (3.3 g, 0.024 mol) is added dropwise over a period of 30 minutes and stirring is continued for 1 hour at −10 ° C. and for another 2 hours at room temperature. It was. The reaction was diluted with DCM and washed with aqueous NH ₄ Cl solution. The organic layer was dried over Na ₂ SO ₄ and concentrated to give 1.2 g (24% yield) of 1-chlorosulfonyl-pyrrolidine-2-carboxylic acid methyl ester as the desired product.

Steps: 9

1- [7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-ylsulfamoyl]- Synthesis of Pyrrolidine-2-carboxylic Acid Methyl Ester.

DMAP (50 mg, 0.0004 mol) was added to 8-amino-7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-2,3-dihydro-1H in dry pyridine (5 mL). -Added to a stirred solution of indolizin-5-one (300 mg, 0.001 mol) and cooled the reaction mixture to 0 ° C. under a nitrogen atmosphere. This was followed by the dropwise addition of 11-chlorosulfonyl-pyrrolidine-2-carboxylic acid methyl ester (1 g, 0.004 mol) in DCM over a period of 10 minutes and the resulting mixture stirred at room temperature for 4 hours. It was. The reaction mixture was heated to 65 ° C. for 16 h. The reaction was concentrated under reduced pressure and the concentrate was partitioned between ethyl acetate and water. The organic layer was washed with brine solution, concentrated under reduced pressure, and the concentrate was purified by column chromatography (silica gel, using 70% ethyl acetate in hexane as eluent) to give 1- [7- (4-bromo-2). -Fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-ylsulfamoyl] -pyrrolidine-2-carboxylic acid methyl ester 110 mg (24% yield) were obtained as the desired product.

Steps: 10

2-hydroxymethyl-pyrrolidine-1-sulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro Synthesis of Indolizin-8-yl] -amide.

NaBH ₄ (25 mg, 0.00065 mol) 1- [7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin- in dry THF (3 mL) To a stirred solution of 8-ylsulfamoyl] -pyrrolidine-2-carboxylic acid methyl ester (110 mg, 0.0002 mol) was added under a nitrogen atmosphere and the resulting mixture was heated at 60 ° C. This was followed by dropwise addition of methanol (2 mL) over a period of 5 minutes while maintaining the temperature at 60 ° C. for 1 hour. The reaction was concentrated under reduced pressure, ice-cold water was added, neutralized with 5% dilute HCl, extracted with ethyl acetate, and the organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product was dissolved in 1: 9 methanol: DCM, ether was added, and the precipitate formed was collected by 2-hydroxymethyl-pyrrolidine-1-sulfonic acid [7- (4-bromo-2-fluoro-) 75 g (70% yield) of phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide were obtained as the desired product.

Example: 66

<Reaction Scheme 12>

Add to:

Steps 1 to 3 were performed in a similar manner as described for Example 8, and step 4 was performed in a similar manner to that described for Example 11.

Step: 5

7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methoxy-methyl- Synthesis of Amides.

EDCI (0.99 g, 0.005 mol) and HOBt (0.702 g, 0.005 mol) were added to 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo- in DMF (50 mL). To a stirred solution of 1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (1 g, 0.003 mol) was added and the reaction mixture was stirred at rt for 1.30 h. This was followed by addition of O, N-dimethyl-hydroxylamine hydrochloride (0.506 g, 0.005 mol) and TEA (2.16 mL, 0.016 mol) under a nitrogen atmosphere. The reaction mixture was stirred at rt for 16 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated NH ₄ Cl, brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated to 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo 0.800 mg (72.7% yield) of -1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methoxy-methyl-amide were obtained as the desired product.

Steps: 6

Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carbaldehyde.

DIBAL-H (1.0 M solution in toluene) (5.7 mL, 5.7 mmol) was dried with 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo in dry THF (20 mL). To a solution of -1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methoxy-methyl-amide (0.7 g, 1.635 mmol) was added at -78 ° C, and the reaction mixture at -78 ° C. Stir for 2 hours. The reaction was quenched with saturated NH ₄ Cl and extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with water, brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated. The concentrate was purified by column chromatography (silica gel, using 2% methanol in DCM as eluent) to 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1 0.2 g (33.16% yield) of 2,3,5-tetrahydro-indoligin-8-carbaldehyde were obtained as the desired product.

Steps: 7

7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-8- (1-hydroxy-but-3-enyl) -2,3-dihydro-1H-indolizin-5 Synthesis of -one.

Allyl magnesium bromide (11.65 mL, 0.011653 mol) was dried with 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3, in dry THF (10 mL). To a solution of 5-tetrahydro-indoligin-8-carbaldehyde (0.430 g, 0.001 mol) was added at -78 ° C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated NH ₄ Cl solution and extracted with ethyl acetate. The organic layer was washed with water, brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated. The concentrate was purified by column chromatography (silica gel, using 1-1.5% methanol in DCM as eluent) to give 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-8- ( 0.250 mg (52.4% yield) of 1-hydroxy-but-3-enyl) -2,3-dihydro-1H-indolizin-5-one were obtained as the desired product.

Example: 67

Steps 1 to 3 were performed in a similar manner to that described for Example 8, step 4 was performed in a similar manner to that described for Example 111, and steps 5 to 6 were similar to those described for Example 66. It was done in a manner.

Steps: 7

Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-8- (1-hydroxy-allyl) -2,3-dihydro-1H-indolizin-5-one .

Vinyl magnesium bromide (1M solution in THF) (1.62 mL, 0.002 mol) was dried with 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo- in dry THF (10 mL). To a solution of 1,2,3,5-tetrahydro-indoligin-8-carbaldehyde (0.1 g, 0.0003 mol) was added at -78 ° C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated NH ₄ Cl solution at −78 ° C. and extracted with ethyl acetate at room temperature. The organic layer was washed with water, brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated. The concentrate was purified by preparative HPLC to give 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-8- (1-hydroxy-allyl) -2,3-dihydro-1H 10 mg (9% yield) of -indolizin-5-one were obtained as the desired product.

Example: 68

Steps 1 to 3 were performed in a similar manner to that described for Example 8, step 4 was performed in a similar manner to that described for Example 11, and steps 5 to 6 were similar to those described for Example 66. Was carried out in a similar manner to that described for Example 67.

Steps: 8

Synthesis of 8-acryloyl-7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-2,3-dihydro-1H-indolizin-5-one.

Dess-Martin periodinan (0.582 g, 0.001 mol) was added to 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-8- (1-hydroxy- in DCM (10 mL). To a stirred solution of allyl) -2,3-dihydro-1H-indolizin-5-one (0.440 g, 0.001 mol) was added and the reaction mixture was stirred at rt for 12 h. Then, 0.8 g of NaHCO ₃ dissolved in 10 mL of water and 2.48 g of sodium thiosulfate-5H ₂ O dissolved in 10 mL of water were added, and stirring was continued for the next 5 minutes. The reaction mixture is extracted with DCM and the organic layer is washed with saturated NaHCO ₃ solution, brine, dried over anhydrous Na ₂ SO ₄ and concentrated to 8-acryloyl-7- (4-bromo-2-fluoro 0.400 g of -phenylamino) -6-fluoro-2,3-dihydro-1H-indolizin-5-one as a crude product were obtained, which were used in the next step without further purification.

Steps: 9

7- (4-Bromo-2-fluoro-phenylamino) -8- (2,3-dihydroxy-propionyl) -6-fluoro-2,3-dihydro-1H-indolizin-5 Synthesis of -one.

4-Methyl-morpholine-N-oxide (0.118 g, 0.001012 mol) and osmium tetraoxide (0.025 g, 0.0001 mol) were added to 8-acryloyl-7- (4-bromo in THF (10 mL). To a stirred solution of 2-fluoro-phenylamino) -6-fluoro-2,3-dihydro-1H-indolizin-5-one (0.4 g, 0.001 mol) was added under a nitrogen atmosphere and the resulting mixture was Was stirred at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous Na ₂ SO ₄ , concentrated and the concentrate was purified by column chromatography (silica gel, using 1.5% methanol in DCM as eluent) to give a yellow solid, which was further purified by preparative HPLC. Purified with 7- (4-bromo-2-fluoro-phenylamino) -8- (2,3-dihydroxy-propionyl) -6-fluoro-2,3-dihydro-1H-indole 10 mg (2.3% yield) of lysine-5-one were obtained as the desired product.

Example: 69

Steps 1 to 3 were performed in a similar manner to that described for Example 8, step 4 was performed in a similar manner to that described for Example 11, and steps 5 to 6 were similar to those described for Example 66. It was done in a manner.

Steps: 7

7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-8- (1-hydroxy-2-methoxymethoxy-ethyl) -2,3-dihydro-1H-indole Synthesis of Lysine-5-one.

n-butyl lithium (2.5M solution in hexane) (6.6 mL, 6.775 mmol) was added to a stirred solution of tributyl-methoxymethoxymethyl-stannan (3.72 g, 10.17 mmol) in dry THF for 5 minutes at -78 ° C. Was added dropwise over a period of time and the resulting mixture was stirred for 5 minutes. This is followed by 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carb in THF Aldehyde (250 mg, 0.678 mmol) was added at -78 ° C and stirring was continued for an additional 40 minutes at -78 ° C. The reaction mixture was quenched with saturated NH ₄ Cl solution at −78 ° C., warmed to room temperature and diluted with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated. The concentrate was used for next step without further purification.

Steps: 8

7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-8- (2-methoxymethoxy-acetyl) -2,3-dihydro-1H-indolizin-5-one Synthesis.

Dess-Martin periodinan (0.180 g, 0.0004 mol) was added to 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-8- (1-hydroxy- in DCM (10 mL). To a stirred solution of 2-methoxymethoxy-ethyl) -2,3-dihydro-1H-indolizin-5-one (0.160 g, 0.0004 mol) was added and the reaction mixture was stirred at rt for 1.30 h. This was followed by the addition of 10 mL of saturated NaHCO ₃ containing 300 mg of sodium thiosulfate-5H ₂ O and stirring continued for the next 10 minutes. The remaining mixture was extracted with ethyl acetate and the organic layer was washed with saturated NaHCO ₃ solution, brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The concentrate was purified by column chromatography (silica gel, using 60-65% ethyl acetate in hexane as eluent) to give 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-8- 100 mg (62.8% yield) of (2-methoxymethoxy-acetyl) -2,3-dihydro-1H-indolizin-5-one were obtained as the desired product.

Steps: 9

Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-8- (2-hydroxy-acetyl) -2,3-dihydro-1H-indolizin-5-one .

10% aqueous HCl (4 mL) and water (3 mL) were added with 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-8- (2-methoxy in methanol (3 mL). To a stirred solution of methoxy-acetyl) -2,3-dihydro-1H-indolizin-5-one (100 mg, 0.0002 mol) was added and the resulting mixture was stirred at rt for 18 h. The reaction mixture was neutralized with saturated NaHCO ₃ solution, diluted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The concentrate was purified by preparative HPLC to give 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-8- (2-hydroxy-acetyl) -2,3-dihydro-1H 14 mg (15.7% yield) of -indolizin-5-one were obtained as the desired product.

<Reaction Scheme 13>

Example: 70

Tier: 1

Synthesis of 5-oxo-7-trifluoromethanesulfonyloxy-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester.

7-hydroxy-6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid in which TEA (5.082 g, 0.0502242 mol) was dissolved in DCM (70 mL) To a solution of ethyl ester (7.0 g, 0.031 mol) was added and the reaction mixture was cooled to -78 ° C. Triflic anhydride (11.51 g, 0.041 mol) was added to the reaction mixture and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was washed with sodium bicarbonate solution (20 mL) and the organic layer was dried and concentrated. The concentrate was purified by column chromatography (silica gel, using 5% MeOH in CHCl ₃ as eluent) to give 5-oxo-7-trifluoromethanesulfonyloxy-1,2,3,5-tetrahydro-indole 7.78 g (73.0% yield) of lysine-8-carboxylic acid ethyl ester were obtained as the desired product.

Tier: 2

Synthesis of 7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester.

Palladium acetate (0.063 g, 0.003 mol), BINAP (0.263 g, 0.0003 mol), cesium carbonate (1.37 g, 0.004 mol) were dissolved in toluene and the resulting mixture was aerated with nitrogen for 30 minutes. This is followed by 5-oxo-7-trifluoromethanesulfonyloxy-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester (1 g, 0.003 mol) and 2-fluoro Rho-4-trifluoromethyl aniline (0.549 g, 0.003 mol) was added and the reaction flask was again aerated for another 15 minutes. The reaction mixture was heated at 110 ° C. for 1.30 h. The reaction mixture was filtered through celite and the filtrate was concentrated. The concentrate was purified by column chromatography (silica gel of mesh size 60-120, using 70% MeOH in CHCl ₃ as eluent) to give 7- (2-fluoro-4-trifluoromethyl-phenylamino)- 0.4 g (37% yield) of 5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester was obtained as the desired product.

Example: 71

Steps 1 and 2 were performed in a manner similar to that described for Example 70.

Steps: 3

Synthesis of 7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid.

7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5- dissolved LiOH (0.07 g, 0.002 mol) in MeOH: THF (6 mL) To a stirred solution of tetrahydro-indoligin-8-carboxylic acid ethyl ester (0.30 g, 0.0008 mol) was added and the reaction mixture was stirred at rt for 4 h. The reaction mixture is concentrated and the concentrate is acidified with 10% HCl to give a precipitate which is collected and dried to 7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo 0.270 g (95.74% yield) of -1,2,3,5-tetrahydro-indoligin-8-carboxylic acid was obtained as the desired product.

Example: 72

Steps 1 and 2 were performed in a similar manner to that described for Example 70, and step 3 was performed in a similar manner to that described for Example 71.

Steps: 4

Synthesis of 7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy amide.

EDCI (0.322 g, 0.002 mol), HOBt (0.23 g, 0.002 mol) and 7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetra Hydro-indoligin-8-carboxylic acid (0.2 g, 0.001 mol) was dissolved in DMF in an inert atmosphere and the reaction mixture was stirred at room temperature for 30 minutes. This was followed by addition of cyclopropylmethyl hydroxylamine hydrochloride (0.21 g, 0.002 mol) and TEA (0.17 g, 0.002 mol) and the reaction mixture was stirred at rt for 16 h. Water was added to the reaction mixture, the reaction mixture was quenched with saturated NH ₄ Cl and extracted with ethyl acetate. The organic layer was washed with saturated bicarbonate solution, brine solution and dried over Na ₂ SO ₄ to give a precipitate which was triturated with ether to give 7- (2-fluoro-4-trifluoromethyl-phenyl 0.1 g (41.8% yield) of amino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy amide were obtained as pure product.

Scheme 14

Example: 73

Step 1 was carried out in a similar manner as described for Example 70.

Tier: 2

Synthesis of 7- (2-fluoro-4-methoxy-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester.

Palladium acetate (0.06 g, 0.003 mol), BINAP (0.26 g, 0.0002 mol), cesium carbonate (1.37 g, 0.004 mol) were dissolved in toluene and the resulting mixture was aerated with nitrogen for 30 minutes. This is followed by 5-oxo-7-trifluoromethanesulfonyloxy-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester (1 g, 0.003 mol) and 2-fluoro Ro-4-methoxy aniline (0.54 g, 0.003 mol) was added and the reaction flask was again aerated for another 15 minutes. The reaction mixture was heated at 110 ° C. for 1.30 h. The reaction mixture was filtered through celite and the filtrate was concentrated. The concentrate was purified by column chromatography (silica gel, using 70% MeOH in CHCl ₃ as eluent) to 7- (2-fluoro-4-methoxy-phenylamino) -5-oxo-1,2,3 0.230 g (23.6% yield) of, 5-tetrahydro-indoligin-8-carboxylic acid ethyl ester was obtained as the desired product.

Steps: 3

Synthesis of 7- (2-fluoro-4-methoxy-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid.

7- (2-fluoro-4-methoxy-phenylamino) -5-oxo-1,2,3,5-tetrahydro dissolved LiOH (0.05 g, 0.001 mol) in MeOH: THF (6 mL) To a stirred solution of -indolizin-8-carboxylic acid ethyl ester (0.19 g, 0.001 mol) was added and the resulting mixture was stirred at rt for 4 h. The solvent was distilled off and the crude product was acidified with 10% HCl to give a precipitate which was collected and dried to give 7- (2-fluoro-4-methoxy-phenylamino) -5-oxo-1, 0.130 g (76.023% yield) of 2,3,5-tetrahydro-indoligin-8-carboxylic acid was obtained.

Steps: 4

Synthesis of 7- (2-fluoro-4-methoxy-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy amide.

EDCI (0.22 g, 0.001 mol), HOBt (0.15 g, 0.001 mol) and 7- (2-fluoro-4-methoxy-phenylamino) -5-oxo-1,2,3,5-tetrahydro- Indolizin-8-carboxylic acid (0.12 g, 0.0004 mol) was dissolved in DMF in an inert atmosphere and the reaction mixture was stirred at room temperature for 30 minutes. This was followed by addition of cyclopropylmethyl hydroxylamine hydrochloride (0.140 g, 0.001 mol) and TEA (0.114 g, 0.001 mol) and the reaction mixture was stirred at rt overnight. Water was added to the reaction mixture, followed by saturated NH ₄ Cl and extracted with ethyl acetate. The organic layer was washed with saturated bicarbonate solution, brine solution, dried over Na ₂ SO ₄ to give a precipitate, which was triturated with ether to give 7- (2-fluoro-4-methoxy-phenylamino). 0.09 g (61.6% yield) of -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy amide was obtained as the desired product.

Example: 74

Scheme 15

Steps 1 and 2 were carried out in a similar manner as described for Example 27.

Steps: 3

Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid.

LDA (50 mL) was added to a solution of 2-fluoro-4-bromo-phenylamine (7 g, 0.037 mol) in THF (550 mL) at -78 ° C, and the resulting mixture was stirred for 1 hour. . This was followed by 7-chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (5.5 g, 0.025 mol) in dry THF (200 mL) at -78 ° C. Was added and the reaction was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure and neutralized with dilute HCl. Diethyl ether was added and stirred for 1 hour to give a precipitate, which was collected by 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetra 5.2 g (56% yield) of hydro-indoligin-8-carboxylic acid were obtained as the desired product.

Steps: 4

Synthesis of 3- (4-bromo-2-fluoro-phenyl) -1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2,5-dione .

TEA (1.52 mg, 0.015 mol) was dried under nitrogen atmosphere in 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro in DMF (8 mL). -Added to a solution of indolizin-8-carboxylic acid (5 g, 0.014 mol) and the reaction mixture was stirred for 30 minutes. This was followed by the dropwise addition of DPPA (4.14 g, 0.015 mol) with stirring at 10 ° C. over a period of 15 minutes. Stirring was continued for an additional 5 hours at room temperature. This was followed by addition of toluene (80 mL) and the reaction heated to 90 ° C. for 4 hours. The reaction was concentrated under reduced pressure, then cooling water was added. The precipitate formed was collected and dried to 3- (4-bromo-2-fluoro-phenyl) -1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as-indacene 3.4 g (70% yield) of -2,5-dione were obtained as the desired product.

Step: 5

3- (4-bromo-2-fluoro-phenyl) -1-methanesulfonyl-1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2 , 5-dione synthesis.

60% NaH (70 mg, 0.003 mol) was added 3- (4-bromo-2-fluoro-phenyl) -1,6,7,8-tetrahydro-3H-1,3 in dry DMF (10 mL). To a stirred solution of 5a-triaza-as-indacene-2,5-dione (300 mg, 0.001 mol) was added at 0-5 ° C. under a nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 1 hour. This was followed by the dropwise addition of methanesulfonyl chloride (150 mg, 0.001 mol) in dry THF at 0 ° C. over a period of 5 minutes and stirring at room temperature for the next 16 hours. Ice cold water was added to the reaction flask for 5 minutes with stirring and the pH was adjusted to 5. Extract with ethyl acetate, then dry over Na ₂ SO ₄ and concentrate under reduced pressure to afford 3- (4-bromo-2-fluoro-phenyl) -1-methanesulfonyl-1,6,7,8-tetrahydro 160 mg (47% yield) of -3H-1,3,5a-triaza-as-indacene-2,5-dione were obtained as the desired product.

Example: 75

Steps 1 to 2 were performed in a similar manner to that described for Example 27, and steps 3 to 4 were performed in a similar manner to that described for Example 74.

Step: 5

3- (4-Bromo-2-fluoro-phenyl) -1-cyclopropanesulfonyl-1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as-indacene- Synthesis of 2,5-dione.

60% NaH (20 mg) was added 3- (4-bromo-2-fluoro-phenyl) -1,6,7,8-tetrahydro-3H-1,3,5a- in dry DMF (5 mL). To a stirred solution of triaza-as-indacene-2,5-dione (200 mg, 0.001 mol) was added at 0-5 ° C. under a nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 1 hour. This was followed by dropwise addition of cyclopropanesulfonyl chloride (150 mg, 0.002 mol) in dry THF over a period of 10 minutes at 0 ° C., and stirring continued at room temperature for the next 16 hours. NaH (20 mg) was added to the reaction mixture at 0 ° C. and stirred for 15 minutes, followed by addition of cyclopropanesulfonyl chloride (150 mg, 0.002 mol) in dry DMF and stirring at room temperature for an additional 5 hours. Continued. The crude product was used for next step without further purification.

Steps: 6

Synthesis of cyclopropanesulfonic acid [7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide.

IN aqueous aq. NaOH (7 mL) 3- (4-bromo-2-fluoro-phenyl) -1-cyclopropanesulfonyl-1,6,7,8-tetrahydro-3H-1,3,5a- To triaza-as-indacene-2,5-dione, the resulting mixture was heated to 75 ° C. for 4 hours. Ice cold water was added to the reaction mixture, neutralized to pH about 3 with 5% ice cold HCl, and then partitioned between ethyl acetate and water. The organic layer was dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (silica gel, using 3% methanol in DCM as eluent) to cyclopropanesulfonic acid [7- (4-bromo-2-fluoro) 17 mg (7% yield) of -phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide were obtained as the desired product.

Example: 76

Steps 1 to 2 were performed in a similar manner to that described for Example 27, and steps 3 to 4 were performed in a similar manner to that described for Example 74.

Step: 5

3- (4-Bromo-2-fluoro-phenyl) -1- (4-fluoro-benzenesulfonyl) -1,6,7,8-tetrahydro-3H-1,3,5a-triaza Synthesis of -as-indacene-2,5-dione.

60% NaH (50 mg, 0.001 mol) was dried in 3- (4-bromo-2-fluoro-phenyl) -1,6,7,8-tetrahydro-3H-1,3 in dry DMF (6 mL). To a stirred solution of 5a-triaza-as-indacene-2,5-dione (300 mg, 0.001 mol) was added at 0-5 ° C. under a nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 1 hour. This was followed by the dropwise addition of 4-fluoro-benzenesulfonyl chloride (200 mg, 0.001 mol) in dry THF over a period of 10 minutes and stirring continued at room temperature for the next 16 hours. The crude product was used for next step without further purification.

Steps: 6

N- [7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -4-fluoro-benzenesulphone Synthesis of Amides.

1N NaOH solution (6 mL) was added 3- (4-bromo-2-fluoro-phenyl) -1- (4-fluoro-benzenesulfonyl) -1,6,7,8-tetrahydro-3H- To 1,3,5a-triaza-as-indacene-2,5-dione, the resulting mixture was heated to 60 ° C. for 1 hour. Ice-cold water was added to the reaction mixture, neutralized to pH about 4 with 5% HCl, and then partitioned between ethyl acetate and water. The organic layer was washed with NaHCO ₃ , dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (silica gel, using 2% methanol in DCM as eluent) to N- [7- (4-bromo -2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -4-fluoro-benzenesulfonamide 20 mg (6% yield) Obtained as product.

Example: 77

Steps 1 to 2 were performed in a similar manner to that described for Example 27, and steps 3 to 4 were performed in a similar manner to that described for Example 74.

Step: 5

3- (4-Bromo-2-fluoro-phenyl) -2,5-dioxo-2,3,5,6,7,8-hexahydro-1,3,5a-triaza-as-inda Synthesis of sen-1-carboxylic acid tert-butyl ester.

60% NaH (67 mg, 0.003 mol) was dried in 3- (4-bromo-2-fluoro-phenyl) -4-fluoro-1,6,7,8-tetrahydro- in dry DMF (10 mL). To a stirred solution of 3H-1,3,5a-triaza-as-indacene-2,5-dione (2.5 mg, 0.001 mol) was added at 0 ° C. under a nitrogen atmosphere. This was followed by dropwise addition of BOC anhydride (260 mg, 0.001 mol) in dry THF over a period of 5 minutes at 0 ° C. and the resulting mixture stirred at room temperature for 4 hours. The crude product was used for next step without further purification.

Steps: 6

Synthesis of [7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -carbamic acid tert-butyl ester.

1N aqueous NaOH (6 mL) was added 3- (4-bromo-2-fluoro-phenyl) -2,5-dioxo-2,3,5,6,7,8-hexahydro-1,3, 5a-triaza-as-indacene-1-carboxylic acid tert-butyl ester was added and the resulting mixture was heated to 65 ° C. for 3 hours. Ice-cold water was added to the reaction mixture, neutralized to pH about 7 with 5% HCl, and the reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na ₂ SO ₄ , concentrated under reduced pressure, and the concentrate was purified by column chromatography (neutral alumina, using 3% methanol in DCM as eluent) to [7- (4-bromo-2- 165 mg (43.8% yield) of fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -carbamic acid tert-butyl ester were obtained as the desired product.

Example: 78

Steps 1 to 2 were performed in a similar manner to that described for Example 27, steps 3 to 4 were performed in a similar manner to that described for Example 74, and steps 5 to 6 were described for Example 77. It was performed in a similar manner to that.

Steps: 7

Synthesis of 8-amino-7- (4-bromo-2-fluoro-phenylamino) -2,3-dihydro-1H-indolizin-5-one.

TFA (1 mL) was dried [7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8 in DCM (5 mL). To a stirred solution of -yl] -carbamic acid tert-butyl ester (200 mg, 0.0005 mol) was added dropwise over a period of 5 minutes at -10 ° C, and the resulting mixture was stirred at room temperature for 4 hours. The reaction was concentrated under reduced pressure. Water was added, neutralized with NaHCO ₃ solution, extracted with ethyl acetate, dried over Na ₂ SO _4, 8-amino-7- (4-bromo-2-fluoro-phenylamino) -2, 120 mg (79% yield) of 3-dihydro-1H-indolizin-5-one were obtained as the desired product.

Steps: 8

Synthesis of cyclohexanesulfonic acid [7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide.

Pyridine (4 mL) in DCM was diluted with 8-amino-7- (4-bromo-2-fluoro-phenylamino) -2,3-dihydro-1H-indolizin-5-one (110 mg, 0.0003 mol). ) And the reaction mixture was stirred under nitrogen atmosphere for 10 minutes. Following this, DMAP (5 mg, 0.0004 mol) is added, the reaction is cooled to 0-5 ° C. and cyclohexyl sulfonyl chloride (80 mg, 0.0004 mol) in DCM is added dropwise over a period of 10 minutes, Stirring was continued for the next 16 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and water and the organic layer was washed with water and 1N dilute HCl. The organic layer was dried over Na ₂ S0 ₄ , concentrated and the concentrate was purified by column chromatography (silica gel, using 2% methanol in DCM as eluent) to cyclohexanesulfonic acid [7- (4-bromo-2) 10 mg (8.5% yield) of -fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide were obtained as the desired product.

Example: 79

Steps 1 to 2 were performed in a similar manner to that described for Example 27, and steps 3 to 4 were performed in a similar manner to that described for Example 74.

Step: 5

3- (4-bromo-2-fluoro-phenyl) -1- (4-trifluoromethyl-benzenesulfonyl) -1,6,7,8-tetrahydro-3H-1,3,5a- Synthesis of Triaza-as-indacene-2,5-dione.

60% NaH (31 mg, 0.001 mol) was added to 3- (4-bromo-2-fluoro-phenyl) -1,6,7,8-tetrahydro-3H-1,3 in dry DMF (4 mL). To a stirred solution of, 5a-triaza-as-indacene-2,5-dione (200 mg, 0.001 mol) was added at 0 ° C. and the resulting mixture was stirred at rt for 1 h. This was followed by the dropwise addition of 4-trifluoromethyl-benzenesulfonyl chloride (180 mg, 0.001 mol) in dry THF at 0 ° C. over a period of 10 minutes. Stirring was continued at room temperature for the next two days to afford the crude product, which was used in the next step without further purification.

Steps: 6

N- [7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -4-trifluoromethyl- Synthesis of Benzenesulfonamide.

1N aqueous NaOH (15 mL) was added 3- (4-bromo-2-fluoro-phenyl) -1- (4-trifluoromethyl-benzenesulfonyl) -1,6,7,8-tetrahydro- To 3H-1,3,5a-triaza-as-indacene-2,5-dione, the resulting mixture was heated to 65 ° C. for 2 hours. Diluted HCl (pH = 4) was added to the reaction at room temperature, then the pH was adjusted to 7 with aqueous Na ₂ CO ₃ and the reaction was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO ₄ , concentrated under reduced pressure, and the concentrate was purified by column chromatography (silica gel, using 1.5% methanol in DCM) to give 102 mg (33% yield). Obtained as the desired product.

Example: 80

Steps 1 to 2 were performed in a similar manner to that described for Example 27, steps 3 to 4 were performed in a similar manner to that described for Example 74, and steps 5 to 6 were described for Example 77. Was carried out in a similar manner to, and step 7 was carried out in a similar manner to that described for Example 78.

Steps: 8

N- [7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -N, N-dimethylaminosulfone Synthesis of Amides.

N, N-dimethyl sulfonyl chloride (40 mg, 0.0003 mol) was dried with 8-amino-7- (4-bromo-2-fluoro-phenylamino) -2,3-dihydro-1H-indole in dry THF. To a solution of lysine-5-one (80 mg, 0.0002 mol) and DMAP (30 mg, 0.0002 mol) was added at -35 ° C and the reaction mixture was stirred at room temperature for 2 hours. Following this, dry pyridine (1.5 mL) was added and the reaction mixture was heated to 40 ° C for 4 h. The reaction was concentrated under reduced pressure and the concentrate was purified by preparative HPLC to give N- [7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro 6 mg (9% yield) of Indolizin-8-yl] -N, N-dimethylaminosulfonamide were obtained as the desired product.

Scheme 16

Example: 81

Tier: 1

5-hydroxy-2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylic acid ethyl Synthesis of esters.

Malonyl chloride (8.10 g, 0.057 mol) was added (2,2-dimethyl-tetrahydro- [1,3] dioxolo [4,5-c] pyrrole-4-ylidene) -acetic acid in DCM (300 mL). To a solution of ethyl ester (J. Chem. Soc., Perkins Transactions 1: Organic and Bio-organic Chemistry, pgs 2371-2376, (1987)) (10.2 g, 0.048 mol) dropwise over a period of 30 minutes. The reaction mixture was stirred at rt for 3 h. The reaction was quenched with 5 mL of TEA and the solvent was concentrated. The concentrate was purified by column chromatography (silica gel, using 30-45% ethyl acetate in hexane as eluent) to give 5-hydroxy-2,2-dimethyl-7-oxo-3a, 7,8,8a-tetra. 9.25 g (69% yield) of hydro-1,3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylic acid ethyl ester were obtained as the desired product.

Tier: 2

2,2-dimethyl-7-oxo-5-trifluoromethanesulfonyloxy-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a] indene-4 Synthesis of Carboxylic Acid Ethyl Ester.

TEA (4.9 g, 0.049 mol) was added 5-hydroxy-2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a- in DCM (200 mL). To a solution of aza-cyclopenta [a] indene-4-carboxylic acid ethyl ester (9.25 g, 0.033 mol) was added at -70 ° C. This was followed by dropwise addition of triflic acid anhydride (12.06 g, 0.0427 mol) in DCM (500 mL) and the reaction mixture was stirred at rt for 1 h. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine solution and concentrated. The concentrate was purified by column chromatography (using silica gel, as eluent) to give 2,2-dimethyl-7-oxo-5-trifluoromethanesulfonyloxy-3a, 7,8,8a-tetrahydro-1, 9 g (64.3% yield) of 3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylic acid ethyl ester were obtained as the desired product.

Steps: 3

5- (4-Bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclo Synthesis of penta [a] indene-4-carboxylic acid ethyl ester.

Palladium acetate (0.47 g, 0.002 mol), BINAP (1.96 g, 0.003 mol), cesium carbonate (10.26 g, 0.032 mol) were dissolved in toluene (200 mL) and the resulting mixture was bubbled with nitrogen for 30 minutes. This is followed by 2,2-dimethyl-7-oxo-5-trifluoromethanesulfonyloxy-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza- with continued aeration. Cyclopenta [a] indene-4-carboxylic acid ethyl ester (9 g, 0.021 mol) and 2-fluoro-4-bromo aniline (4.4 g, 0.023 mol) were added for an additional 15 minutes. The reaction mixture was heated to 90 ° C. for 1.30 h. The reaction mixture was cooled, diluted with 200 mL of ethyl acetate, washed with water, brine solution, dried over Na ₂ SO ₄ and concentrated. The concentrate was purified by column chromatography (silica gel, using 10-70% ethyl acetate in hexane as eluent) to give 5- (4-bromo-2-fluoro-phenylamino) -2,2-dimethyl-7 5 g (51.5% yield) of oxo-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylic acid ethyl ester as the desired product Obtained.

Steps: 4

5- (4-Bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclo Synthesis of penta [a] indene-4-carboxylic acid.

5- (4-Bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo- in which LiOH (0.22 g, 0.005 mol) in water was dissolved in MeOH: THF (1: 4) To a stirred solution of 3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylic acid ethyl ester (1 g, 0.002 mol), The resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated, the residue was partitioned between ethyl acetate and water and the aqueous layer was acidified with 10% citric acid solution (pH 2.5). The precipitate formed was collected and dried under reduced pressure to give the crude product which was purified by preparative HPLC to give 5- (4-bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo- 50 mg (58.5% yield) of 3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylic acid were obtained as the desired product.

Example: 82

Steps 1 to 12 were performed in a similar manner as described for Example 81.

Step: 5

5- (4-Bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclo Synthesis of penta [a] indene-4-carboxylic acid cyclopropylmethoxy-amide.

EDCI (262.4 mg, 1.369 mmol), HOBt (184.61 mg, 1.369 mmol) and DIPEA (387 mg, 2.736 mmol) were added 5- (4-bromo-2-fluoro in DMF (5 mL) and DCM (5 mL). R-phenylamino) -2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylic acid (200 mg, 0.456 mmol) was added to the stirred solution. This was followed by addition of O-cyclopropylmethyl-hydroxylamine (168.38 mg, 1.369 mmol) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated NaHCO ₃ , brine solution, dried over Na ₂ SO ₄ and concentrated to 5- (4-bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo- 120 mg (51.7% yield) of 3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylic acid cyclopropylmethoxy-amide Obtained as.

Steps: 6

7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropyl Synthesis of Methoxy-amide.

Concentrated HCl (3 mL) dissolved in methanol (3 mL) 5- (4-bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo-3a, 7,8,8a To a solution of -tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylic acid cyclopropylmethoxy-amide (120 mg), the resulting mixture was added at room temperature 3 Stir for hours. The reaction mixture was concentrated and the concentrate was triturated twice with ethyl acetate (2 x 0.5 mL). The residue was dried to give 7- (4-bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indoligin-8- 20 mg (18.2% yield) of carboxylic acid cyclopropylmethoxy-amide were obtained as the desired product.

Example: 83

Steps 1 to 12 were performed in a similar manner as described for Example 81.

Step: 5

5- (4-Bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclo Synthesis of penta [a] indene-4-carboxylic acid (2-hydroxy-ethoxy) -amide.

EDCI (262.4 mg, 1.369 mmol), HOBt (186.6 mg, 1.369 mmol), TEA (279 mg, 2.736 mmol) and O- (2-tert-butoxy-ethyl) -hydroxylamine (182 mg, 1.369 mmol) Was prepared in 5- (4-bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydro in DMF (5 mL) and DCM (5 mL). To a stirred solution of -1,3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylic acid (200 mg, 0.456 mmol) was added. The reaction mixture was stirred at rt for 16 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated NaHCO ₃ , brine solution, dried over Na ₂ SO ₄ and concentrated. The concentrate was purified by column chromatography (silica gel, 2% methanol in DCM as eluent) to afford 5- (4-bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo- 100 mg (39.5%) of 3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylic acid (2-hydroxy-ethoxy) -amide Yield) was obtained as the desired product.

Steps: 6

7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2 Synthesis of -hydroxy-ethoxy) -amide.

Concentrated HCl (3 mL) was added 5- (4-bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydro in methanol (3 mL). To a solution of -1,3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylic acid (2-hydroxy-ethoxy) -amide (100 mg, 0.18 mmol) and the reaction mixture Was stirred at rt for 3 h. The reaction mixture was concentrated and the concentrate was triturated with ethyl acetate. The collected precipitate was purified by preparative HPLC to give 7- (4-bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro- 50 mg (61.3% yield) of indolizin-8-carboxylic acid (2-hydroxy-ethoxy) -amide were obtained as the desired product.

Example: 84

Steps 1 to 12 were performed in a similar manner as described for Example 81.

Step: 5

5- (4-Bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclo Synthesis of penta [a] indene-4-carboxylic acid cyclobutylmethoxy-amide.

EDCI (262.4 mg, 1.369 mmol), HOBt (61 mg, 0.456 mmol), TEA (279 mg, 2.736 mmol) and O-cyclobutylmethyl-hydroxylamine (138 mg, 1.369 mmol) were diluted with DMF (5 mL) and 5- (4-Bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydro-1,3-dioxa in DCM (5 mL) To a stirred solution of -7a-aza-cyclopenta [a] indene-4-carboxylic acid (200 mg, 0.456 mmol) was added. The reaction mixture was stirred at rt for 16 h. The reaction mixture was partitioned between water and ethyl acetate (2x25 mL). The organic layer was washed with saturated NaHCO ₃ , brine solution, dried over Na ₂ SO ₄ and concentrated. The concentrate was purified by column chromatography (silica gel, 2% methanol in DCM as eluent) to afford 5- (4-bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo- 140 mg (61.4% yield) of the desired product of 3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylic acid cyclobutylmethoxy-amide Obtained as.

Steps: 6

7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclobutyl Synthesis of Methoxy-amide.

Concentrated HCl (3 mL) dissolved in methanol (3 mL) 5- (4-bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo-3a, 7,8,8a To a solution of -tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylic acid cyclobutylmethoxy-amide (130 mg, 0.249 mmol), the resulting mixture was added Stir at room temperature for 3 hours. The reaction mixture was concentrated and the concentrate was triturated with ethyl acetate. The precipitate formed was collected and purified by preparative HPLC to give 7- (4-bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5- 35 mg (29.1% yield) of tetrahydro-indoligin-8-carboxylic acid cyclobutylmethoxy-amide were obtained as the desired product.

Example: 85

Steps 1 to 12 were performed in a similar manner as described for Example 81.

Step: 5

5- (4-Bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclo Synthesis of penta [a] indene-4-carboxylic acid (3-tert-butoxy-2-methyl-propoxy) -amide.

EDCI (262.4 mg, 1.369 mmol), HOBt (186.6 mg, 1.369 mmol), TEA (279 mg, 2.736 mmol) and O- (3-tert-butoxy-2-methyl-propyl) -hydroxylamine (220 mg , 1.369 mmol) was diluted with 5- (4-bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo-3a, 7,8, in DMF (5 mL) and DCM (5 mL). To a stirred solution of 8a-tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylic acid (200 mg, 0.456 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated NaHCO ₃ , brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated. The concentrate was purified by column chromatography (silica gel, using 0-2% methanol in DCM as eluent) to give 5- (4-bromo-2-fluoro-phenylamino) -2,2-dimethyl-7- Oxo-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylic acid (3-tert-butoxy-2-methyl-propoxy 100 mg (37.8% yield) of) amide were obtained as the desired product.

Steps: 6

7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (3 Synthesis of hydroxy-2-methyl-propoxy) -amide.

Concentrated HCl (3 mL) dissolved in methanol (3 mL) 5- (4-bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo-3a, 7,8,8a -Tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylic acid (3-tert-butoxy-2-methyl-propoxy) -amide (120 mg, 0.21 mmol ) And the resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated and the concentrate was triturated with ethyl acetate to give a precipitate. Purification by preparative HPLC gave 7- (4-bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indoligin-8 50 mg (48.5% yield) of -carboxylic acid (3-hydroxy-2-methyl-propoxy) -amide were obtained as the desired product.

Scheme 17

Steps 1-4 are the same as Example 8

Example: 86

Steps 1 to 4 were carried out in a similar manner as described for Example 8.

Step: 5

4-fluoro-3- (2-fluoro-4-iodo-phenyl) -1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2, Synthesis of 5-dione

TEA (1.30 mL, 9.259 mmol) and DPPA (2.0 mL, 9.259 mmol) were added to 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo- in DMF (30 mL). To a stirred solution of 1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (4.0 g, 9.259 mmol) was added at 0 ° C. and the reaction mixture was stirred for 4 hours at room temperature under a nitrogen atmosphere. The reaction mixture was heated to 65 ° C. overnight. The reaction was monitored by TLC (15% MeOH in DCM). The resulting reaction mixture was cooled, water was added to promote the formation of a precipitate, which was collected and dried under reduced pressure to give 3.65 g (91% yield) of product.

Steps: 6

1- (1-allyl-cyclopropanesulfonyl) -4-fluoro-3- (2-fluoro-4-iodo-phenyl) -1,6,7,8-tetrahydro-3H-1,3 Synthesis of, 5a-triaza-as-indacene-2,5-dione

60% NaH (0.37 g, 9.324 mol) was added 4-fluoro-3- (2-fluoro-4-iodo-phenyl) -1,6,7,8-tetrahydro- in dry DMF (20 mL). To a stirred solution of 3H-1,3,5a-triaza-as-indacene-2,5-dione (2.0 g, 4.662 mmol) was added at 0 ° C. under a nitrogen atmosphere and the resulting mixture was stirred at 0 ° C. for 20 minutes. Was stirred. This was followed by addition of 1-allyl-cyclopropanesulfonyl chloride (1.26 g, 6.993 mol) at 0 ° C. and stirring continued at room temperature for the next 18 hours. The reaction was monitored by TLC (10% MeOH in DCM). The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with water, dried over Na ₂ S0 ₄ and concentrated. Purification by column chromatography on silica gel (60% ethyl acetate in hexanes) gave 1.22 g (46% yield) of the product.

Steps: 7

1-allyl-cyclopropanesulfonic acid [6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8- Synthesis of Il] -amide

Potassium trimethyl silanoate (0.23 g, 1.776 mmol) was diluted with 1- (1-allyl-cyclopropanesulfonyl) -4-fluoro-3- (2-fluoro-4-iodo-) in THF (10 mL). Phenyl) -1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2,5-dione (0.50 g, 0.888 mmol). The reaction mixture was refluxed at 65 ° C. for 30 minutes. The reaction was monitored by TLC (10% MeOH in DCM). The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over Na ₂ S0 ₄ and concentrated. The concentrate was washed with ether to give 405 mg (83% yield) of product.

Steps: 8

1- (2,3-Dihydroxy-propyl) -cyclopropanesulfonic acid [6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3, Synthesis of 5-tetrahydro-indolizin-8-yl] -amide.

N-methyl-morpholine-N-oxide (0.078 g, 0.676 mmol) and OsO ₄ (0.02 g, 0.067 mmol) was diluted with 1-allyl-cyclopropanesulfonic acid [6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1, in THF (10 mL). To a stirred solution of 2,3,5-tetrahydro-indolizin-8-yl] -amide (0.37 g, 0.676 mmol) was added and the resulting mixture was stirred at rt overnight. The reaction was monitored by TLC (10% MeOH in DCM). The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with water, brine solution, dried over Na ₂ S0 ₄ and concentrated. Purification by column chromatography on silica gel (5% methanol in chloroform) gave 86 mg (22% yield) of the product.

Example: 87

Steps 1 to 3 were performed in a manner similar to that described for Example 14, and step 4 was performed in a similar manner to that described for Example 15.

Step-5

3- (4-bromo-2-fluoro-phenyl) -4-methyl-1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2,5 Synthesis of Dion.

Using the same reaction conditions as for step 5 of Example 86, 7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2 in DMF (20 mL) , 3,5-tetrahydro-indoligin-8-carboxylic acid (2.75 g, 7.21784 mmol) was reacted with TEA (1.0 mL, 7.218 mmol) and DPPA (1.55 mL, 7.218 mmol) to give 2.2 g (80%) of the product. Yield).

Step-6

1- (1-allyl-cyclopropanesulfonyl) -3- (4-bromo-2-fluoro-phenyl) -4-methyl-1,6,7,8-tetrahydro-3H-1,3, Synthesis of 5a-triaza-as-indacene-2,5-dione.

TEA (0.15 mL, 1.06 mmol) was added 3- (4-bromo-2-fluoro-phenyl) -4-methyl-1,6,7,8-tetrahydro-3H-1 in DCM (8 mL), To a stirred solution of 3,5a-triaza-as-indacene-2,5-dione (0.20 g, 0.531 mmol) was added at 0 ° C. This was followed by addition of 1-allyl-cyclopropanesulfonyl chloride (0.196 g, 1.06 mmol) and DMAP (0.013 g, 0.106 mmol) at 0 ° C. and the resulting mixture was stirred at rt overnight. The reaction was monitored by TLC (10% MeOH in DCM). The reaction mixture was partitioned between water and DCM. The organic layer was washed with water, brine solution, dried over Na ₂ S0 ₄ and concentrated. Purification by column chromatography on silica gel (70% ethyl acetate in hexanes) gave 70 mg (25% yield) of the product.

Step-7

1-allyl-cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl ] -Amide synthesis

Using the same reaction conditions as in step 7 of Example 86, 1- (1-allyl-cyclopropanesulfonyl) -3- (4-bromo-2-fluoro-phenyl) in THF (4.0 mL) 4-methyl-1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2,5-dione (0.065 g, 0.124 mmol) was added to potassium trimethyl silanoate. Reaction with (0.032 g, 0.249 mmol) gave 40 mg (59% yield) of the product.

Step-8

1- (2,3-Dihydroxy-propyl) -cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5 Synthesis of Tetrahydro-indolizin-8-yl] -amide.

1-allyl-cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-methyl in THF (4.0 mL) using the same reaction conditions as for step 8 of Example 86 -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide (0.025 g, 0.050 mmol) was added N-methyl-morpholine-N-oxide (0.006 g, 0.050 mmol ), OsO ₄ (0.001 g, 0.005 mmol) to give the crude product. Purification by column chromatography on silica gel (5% methanol in DCM) followed by preparative HPLC gave 8 mg (26% yield) of the product.

Example: 88

Steps 1 to 3 were performed in a similar manner to that described for Example 8, step 4 was performed in a similar manner to that described for Example 11, and step 5 was performed in a similar manner to that described for Example 61 Was performed.

Step-6

1- (1-allyl-cyclopropanesulfonyl) -3- (4-bromo-2-fluoro-phenyl) -4-fluoro-1,6,7,8-tetrahydro-3H-1,3 Synthesis of, 5a-triaza-as-indacene-2,5-dione

Using the same reaction conditions as for step 6 of Example 86, 3- (4-bromo-2-fluoro-phenyl) -4-fluoro-1,6,7,8 in DMF (12 mL) -Tetrahydro-3H-1,3,5a-triaza-as-indacene-2,5-dione (1.0 g, 2.624 mmol) with NaH (0.21 g, 5.249 mmol) and 1-allyl-cyclopropanesulfonyl Reaction with chloride (0.71 g, 3.937 mmol) gave the crude product. Purification by column chromatography on silica gel (5% methanol in DCM) gave 300 mg (21% yield) of the product.

Step-7

1-allyl-cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8- Synthesis of Il] -amide

Using the same reaction conditions as in step 7 of Example 86, 1- (1-allyl-cyclopropanesulfonyl) -3- (4-bromo-2-fluoro-phenyl) in THF (8 mL) 4-Fluoro-1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2,5-dione (0.26 g, 0.494 mmol) was added to potassium trimethyl silano Reaction with ate (0.12 g, 0.989 mmol) gave 195 mg (79.2% yield) of product.

Step-8

1- (2,3-Dihydroxy-propyl) -cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3, Synthesis of 5-tetrahydro-indolizin-8-yl] -amide.

1-allyl-cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro in THF (4.0 mL) using the same reaction conditions as for step 8 of Example 86 Rho-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide (0.19 g, 0.38 mmol) was added N-methyl-morpholine-N-oxide (0.045 g, 0.380 mmol), OsO ₄ (0.01 g, 0.038 mmol) to give the crude product. Purification by column chromatography on silica gel (7% methanol in chloroform) gave 68 mg (34% yield) of the product.

Example: 89

Steps 1 to 4 were carried out in a similar manner as described for Example 8.

Step-5

6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2,2- Synthesis of Dimethyl- [1,3] dioxolan-4-ylmethoxy) -amide

EDCI (1.45 mg, 0.008 mol) and HOBt (1.03 g, 0.008 mol) were added to 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo- in DMF (20 mL). To a solution of 1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (1.1 g, 0.003 mol). The reaction mixture was stirred at room temperature for 1 hour. This was followed by addition of O- (2,2-dimethyl- [1,3] dioxolan-4-ylmethyl) -hydroxylamine (1.12 g, 0.008 mol) and TEA (0.77 g, 0.008 mol). The resulting mixture was stirred at rt for 18 h. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (150 mL). The organic layer was washed with saturated NaHCO ₃ solution (50 mL), NH ₄ Cl, brine solution, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 780 mg of crude compound which was used in the next step without further purification. It was.

Step-6

6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2,3- Synthesis of Dihydroxy-propoxy) -amides.

2N HCl (5 mL) was added to 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1, 2, 3, 5-tetrahydro- in methanol (20 mL). To a solution of indolizin-8-carboxylic acid (2, 3-dihydroxy-propoxy) -amide (780 mg, 0.001 mol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, then 1N NaOH was added until the pH was about 8 and extracted with ethyl acetate (2X100 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 250 mg of crude product. Purification by preparative HPLC gave 18 mg (2.4% yield) of the product.

Example: 90

Scheme 18

Step 1 was carried out in a similar manner as described for Example 18.

Step-2

Synthesis of 7-chloro-6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester

Phosphorous oxychloride (5.8 g, 0.038 mol) was dissolved in 7-hydroxy-6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid in toluene (75 mL). To a solution of ester (2 g, 0.008 mol) was added at room temperature. The reaction mixture was stirred at 110 ° C. for 2 hours. The reaction was monitored by TLC (60% ethyl acetate in hexanes). The reaction mixture was concentrated under reduced pressure, then ice water (50 mL) and saturated K ₂ CO ₃ solution (75 mL) (pH = 10) were added. The resulting reaction mixture was extracted with ethyl acetate (3X50 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 1.6 g of crude compound. Purification by recrystallization with hexanes gave 1.54 g (% yield) of the product.

Step-3

Synthesis of 7-chloro-6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid

1N LiOH solution (25 mL) was added 7-chloro-6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid in 75 mL of THF: MeOH (4: 1). To a solution of ethyl ester (1.5 g, 0.006 mol) was added. The reaction mixture was stirred at rt for 18 h. The reaction was monitored by TLC (20% methanol in DCM). The reaction mixture was concentrated under reduced pressure, then 1N HCl (100 mL) was added until the pH was about 1. The precipitate was collected and dried under reduced pressure to yield 1.12 g (84% yield) of product.

Step-4

Synthesis of 7- (2-fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid

LDA (1.86 g, 0.017 mol) was added to a solution of 2-fluoro-4-iodo-phenylamine (2.9 g, 0.012 mol) in dry THF (20 mL) at -78 ° C. The reaction mixture was stirred at -78 ° C for 45 minutes. This was followed by 7-chloro-6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (1.1 g, 0.005 mol) in THF (90 mL). Add at 78 ° C. and continue stirring for an additional 20 hours at room temperature. The reaction was monitored by TLC (20% methanol in DCM). The reaction mixture was concentrated under reduced pressure, then 2N HCl solution (50 mL) and diethyl ether (50 mL) were added. The reaction mixture was stirred for 15 minutes. The precipitate was collected, washed with diethyl ether (2X20 mL) and dried under reduced pressure to give 820 mg (41% yield) of product.

Step-5

Of 7- (2-fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropyl methoxy amide synthesis.

EDCI (334 mg, 0.002 mol) and HOBt (236 mg, 0.002 mol) were added to 7- (2-fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1 in DMF (10 mL). To a solution of 2,3,5-tetrahydro-indoligin-8-carboxylic acid (250 mg, 0.001 mol). The reaction mixture was stirred at room temperature for 1 hour. This was followed by addition of O-cyclopropylmethyl-hydroxylamine hydrochloride (216 mg, 0.002 mol) and TEA (176 mg, 0.002 mol). The resulting mixture was stirred at rt for 2 h. The reaction was monitored by TLC (10% methanol in DCM). The reaction mixture was partitioned between ethyl acetate (75 mL) and water (125 mL). The organic layer was washed with saturated NH ₄ Cl (50 mL), NaHCO ₃ , brine solution, dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford 210 mg of crude compound. Purification by recrystallization with methanol (2 mL) and diethyl ether (20 mL) gave 140 mg (48.2% yield) of the product.

Example: 91

Step 1 was performed in a similar manner to that described for Example 14, and steps 2 to 4 were performed in a similar manner to that described for Example 90.

Step-5

7- (2-Fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-tert-part Synthesis of oxy-ethoxy) -amide

EDCI (334 mg, 0.002 mol) and HOBt (236 mg, 0.002 mol) were added to 7- (2-fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1 in DMF (10 mL). To a solution of 2,3,5-tetrahydro-indoligin-8-carboxylic acid (250 mg, 0.001 mol). The reaction mixture was stirred at rt for 30 min. This was followed by addition of O- (2-tert-butoxy-ethyl) -hydroxylamine (233 mg, 0.002 mol) and TEA (176 mg, 0.002 mol). The resulting mixture was stirred at rt for 16 h. The reaction was monitored by TLC (10% methanol in DCM). The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was washed with saturated NH ₄ Cl (50 mL), NaHCO ₃ , brine solution, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 300 mg of crude compound. Purification by column chromatography on silica gel (2% methanol in DCM) gave 228 mg (71% yield) of product.

Step-6

7- (2-Fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-hydroxy- Synthesis of Ethoxy) -amide.

Trifluoro acetic acid (2.5 mL) was added 7- (2-fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro in DCM (2.5 mL). To a solution of indolizin-8-carboxylic acid (2-tert-butoxy-ethoxy) -amide (220 mg, 0.0004 mol) was added at 0 ° C. The reaction mixture was stirred for 2 hours. The reaction was monitored by TLC (10% methanol in DCM). The reaction mixture was concentrated under reduced pressure, then NaHCO ₃ was added until the pH was about 8 and extracted with ethyl acetate. The combined organic layers were washed with 5% NaHCO ₃ solution, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The concentrate was washed with diethyl ether and ethyl acetate to give 89 mg (45% yield) of product.

Example: 92

Step 1 was performed in a similar manner to that described for Example 14, and steps 2 to 4 were performed in a similar manner to that described for Example 90.

Step-5

7- (2-Fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclobutylmethoxy-amide Synthesis.

EDCI (167 mg, 0.001 mol) and HOBt (118 mg, 0.001 mol) were added to 7- (2-fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1 in DMF (8 mL). To a solution of 2,3,5-tetrahydro-indoligin-8-carboxylic acid (125 mg, 0.0003 mol). The reaction mixture was stirred at room temperature for 1 hour. This was followed by addition of O-cyclobutylmethyl-hydroxylamine (88 mg, 0.001 mol) and TEA (88 mg, 0.001 mol). The resulting mixture was stirred at rt for 2 h. The reaction was monitored by TLC (10% methanol in DCM). The reaction mixture was partitioned between ethyl acetate (50 mL) and water (75 mL). The organic layer was washed with saturated NH ₄ Cl (50 mL), NaHCO ₃ , brine solution, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 150 mg of crude compound. Purification by recrystallization with ethyl acetate (10 mL) and diethyl ether (50 mL) gave 85 mg (57% yield) of product.

Example: 93

Steps 3 and 3 were performed in a similar manner to that described for Example 14, and step 4 was performed in a similar manner to that described for Example 15.

Step-5

3- (2-fluoro-4-iodo-phenyl) -4-methyl-1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2,5 Synthesis of Dion

Using the same reaction conditions as for step 5 of Example 86, 7- (2-fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2 in DMF (30 mL) , 3,5-tetrahydro-indoligin-8-carboxylic acid (3.14 g, 7.34 mmol) was reacted with TEA (1.03 mL, 7.34 mmol) and DPPA (1.59 mL, 7.34 mmol) to yield 1.85 g (59%) of the product. Yield).

Step-6

1- (1-allyl-cyclopropanesulfonyl) -3- (2-fluoro-4-iodo-phenyl) -4-methyl-1,6,7,8-tetrahydro-3H-1,3, Synthesis of 5a-triaza-as-indacene-2,5-dione.

Using the same reaction conditions as for step 6 of Example 109 (current set), 3- (2-fluoro-4-iodo-phenyl) -4-methyl-1,6, in DMF (20 mL), 7,8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2,5-dione (1.80 g, 4.24 mmol) was dissolved in NaH (0.34 g, 8.47 mmol) and 1-allyl-cyclo Reaction with propanesulfonyl chloride (1.14 g, 6.35 mmol) gave the crude product. Purification by column chromatography on silica gel (50% ethyl acetate in hexanes) gave 490 mg (20% yield) of the product.

Step-7

1-allyl-cyclopropanesulfonic acid [7- (2-fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl ] -Amide synthesis

Example 1- (1-allyl-cyclopropanesulfonyl) -3- (2-fluoro-4-io) in THF (12 mL) using the same reaction conditions as for step 7 of Example 109 (current set) Do-phenyl) -4-methyl-1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2,5-dione (0.48 g, 0.84 mmol) is potassium Reaction with trimethyl silanoate (0.21 g, 1.69 mmol) gave 310 mg (63% yield) of product.

Step-8

1- (2,3-Dihydroxy-propyl) -cyclopropanesulfonic acid [7- (2-fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5 Synthesis of Tetrahydro-indolizin-8-yl] -amide.

1-allyl-cyclopropanesulfonic acid [7- (2-fluoro-4-iodo-phenylamino) in THF (10 mL) using the same reaction conditions as for step 8 of Example 109 (current set). -6-Methyl-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide (0.25 g, 0.46 mmol) was added to N-methyl-morpholine-N-oxide (0.054 g, 0.46 mmol), OsO ₄ (0.01 g, 0.046 mmol) to give the crude product. Purification by column chromatography on silica gel (5% methanol in CHCl ₃ ) followed by preparative HPLC gave 95 mg (36% yield) of the product.

Scheme 19

Example: 94

Steps 1 to 3 were performed in a manner similar to that described for Example 14, step 4 was performed in a manner similar to that described for Example 15, and step 5 was performed in a similar manner to that described for Example 87 Was performed.

Step-6

3- (4-bromo-2-fluoro-phenyl) -1-cyclopropanesulfonyl-4-methyl-1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as Synthesis of indacene-2,5-dione.

Sodium hydride (0.04 g, 0.001 mol) was added to 3- (4-bromo-2-fluoro-phenyl) -4-methyl-1,6,7,8-tetrahydro-3H- in dry DMF (3 mL). To a solution of 1,3,5a-triaza-as-indacene-2,5-dione (0.2 g, 0.0005 mol) was added at 0 ° C. Subsequently, cyclopropanesulfonyl chloride (0.11 g, 0.0008 mol) was added at 0 ° C. and the reaction mixture was stirred at rt overnight. The reaction was monitored by TLC (5% MeOH in CHCl ₃ ). Ice was added, neutralized with dilute HCl, extracted with ethyl acetate and then concentrated to afford 0.25 g of crude product, which was used in the next step without further purification.

Step-7

Of cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide synthesis.

6 mL of 1N NaOH solution was added 3- (4-bromo-2-fluoro-phenyl) -1-cyclopropanesulfonyl-4-methyl-1,6,7,8-tetrahydro-3H-1, in DMF. To 3,5a-triaza-as-indacene-2,5-dione (0.25 g), the mixture was heated to 65 ° C. for 1.30 h. Ice was added, neutralized with dilute HCl, extracted with ethyl acetate, then concentrated and purified by column chromatography on silica gel (2% methanol in CHCl ₃ ) to afford 0.090 g (37.34% yield) of the product.

The compounds of this example were evaluated as inhibitors of the MAP kinase pathway in the BRAF-MEK-ERK enzymatic cascade assay and cell viability assay, and the results are compared in Table 1. It is appreciated that other compounds described herein can be prepared by those skilled in the art using methods known to and / or using the methods described herein.

TABLE 1

The examples provided in the present description are only for illustrating the present invention, and therefore these should not be construed as limiting the scope of the present invention.

Claims (22)

Compounds of formula (I) and pharmaceutically acceptable salts thereof
<Formula I>

Where
X is C _{1 -3} - ^{alkylene, -N (R 6) -,} -O- or -S (O) _p - represents;
R ¹ represents aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein the ring is optionally substituted by one or more groups independently selected from List 1;
R ² represents H, cyano or the group -YR ⁷ ;
R ³ and R ⁴ are independently H, C _{1 -6} - alkyl, C _{1 -6} - haloalkyl, C _{1 -6} - hydroxyalkyl, hydroxyl, C _{1 -6} - alkoxy, amino, C _{1 -6} - alkylamino, di -C _{1 -6} - represents an alkyl or amino, or R ³ denotes a monocyclic cycloalkyl or monocyclic heterocycloalkyl further, where the ring is independently selected from the list 11 Optionally substituted by the above groups;
R ⁵ is H, halogen, C _{1 -3} - alkyl or C _{1 -3} - represents a haloalkyl;
Y represents a group selected from -D-, -E-, -DE- or -ED-;
D is -N (R ⁸ )-, -CO-, -CO _2- , -SO-, -SO _2- , CON (R ⁹ ) O-, -CON (R ¹⁰ )-, -N (R ¹¹ ) SO _2- , -N (R ²⁴ ) SO ₂ NR ^25- , -SO ₂ N (R ¹² )-, -N (R ¹³ ) CO-, -N (R ¹⁴ ) CON (R ¹⁵ )-, -N (R ¹⁶ ) represents a group selected from CO— or —C (═NH) N (R ¹⁷ ) —;
E represents monocyclic arylene, heteroarylene, cycloalkylene or heterocycloalkylene, wherein said ring is optionally substituted by one or more groups independently selected from List 1;
If alkynyl, cycloalkyl, aryl, heterocycloalkyl or a heteroaryl group represents a alkyl, wherein R ⁷ is other than H - R ⁷ is H, C _{1 -6} - alkyl, C _{2 -6} - alkenyl, C _{2 -6} halogen, cyano, hydroxyl, C _{1 -6} - alkoxy, C ₂ -C ₆ - alkenyloxy, C ₂ -C ₆ - alkynyloxy, C _{1 -6} - thioalkyl, C _{1 - 6} haloalkyl , amino, C _{1 - 6} alkylamino, di -C _{1 - 6} alkylamino, C _{1 - 6} acylamino, C _{1 - 6} acyl C _{1 - 6} alkyl, monocyclic cycloalkyl or monocyclic heterocycloalkyl by from one to selected independently from 1 to 3 groups is optionally substituted, where the ring is halogen, cyano, hydroxyl, C _{1 -6} - alkoxy, C ₂ -C ₆ - alkenyloxy, C ₂ -C ₆ - alkynyl aryloxy carbonyl, C _{1 -6} - thioalkyl, C _{1 -6} - haloalkyl, amino, C _{1 -6} - alkylamino, di -C _{1 -6} - alkylamino, C _{1 -6} - acylamino and C _{1 - 6} - acyl C _{1 -6-1} also independently selected from alkylamino Optionally two groups may be optionally substituted;
Z is O or N (R ¹⁸ );
List 1 is hydroxyl, cyano, nitro, C _{1 -6} - alkyl, C _{2 -6} - alkenyl, C _{2 -6} - alkynyl, C _{1 -6} - alkoxy, C _{2 -6} - alkenyloxy, C _{2 -6} - alkynyloxy, halogen, C _{1 -6} - alkyl-carbonyl, carboxy, C _{1 -6} - alkoxycarbonyl, amino, C _{1 -6} - alkylamino, di -C _{1 -6} - alkylamino , C _{1 -6} - alkyl-aminocarbonyl, di -C _{1 -6} - alkyl-aminocarbonyl, C _{1 -6} - alkylcarbonylamino, C _{1 -6} - alkyl-carbonyl (C _1-6 - alkyl) amino , C _{1 -6} - alkylsulfonylamino, C _{1 -6} - alkylsulfonyl (C _1-6 - alkyl) amino, C _{1 -6} - thioalkyl, C _{1 -6} - alkylsulfinyl, C _{1 -6} -alkyl-sulfanyl, C _{1-6-alkylsulfonyl,} aminosulfonyl, C _{1 -6-alkyl-aminosulfonyl} and di -C _{1 -6-alkyl} is selected from aminosulfonyl, wherein each of the above-mentioned hydrocarbon group one or more halogen, hydroxyl, C _{1 -6} - alkoxy, amino, C _{1 -6} - alkylamino, di -C _{1 -6} - alkylamino or by cyano, optionally Can be substituted;
R ²⁶ is H, C _{1 -6} - alkyl, C _{1 -6} - haloalkyl, C _{1 -6} - hydroxyalkyl, hydroxyl, C _{1 -6} - alkoxy, amino, C _{1 -6} - alkylamino or di -C _{1 -6} - represents an alkyl amino;
^{R 6, R 8, R 9} , R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17 R 18, R 24 and R ²⁵ are independently H or C _{1 -6} - Alkyl;
m and n are independently 0, 1, 2 or 3; m + n = 2 or 3;
p is 0, 1 or 2; here
Alkyl or alkylene means a straight chain, branched and / or cyclic hydrocarbon having 1 to 20 carbon atoms, wherein the alkyl moiety having 1 to 5 carbons is referred to as "lower alkyl", for example methyl, Ethyl, propyl, isopropyl, n-butyl, t-butyl and isobutyl;
Cycloalkyl or cycloalkylene represents a 3 to 14 membered monocyclic or bicyclic carbocyclic ring, wherein the monocyclic ring, or one of the bicyclic rings, is saturated or partially unsaturated, optionally -C (O) - may further comprise a ring member, other ring may be aromatic, saturated or partially unsaturated, -C (= O), -N (R 20) q -, -O- and S (O) _r ( wherein, r ²⁰ is H or C _{1 -6} - alkyl, q is from 0 to 1, r may comprise 0 to 2 1 to 3 ring members selected from Im);
Aryl or arylene represents a 6 to 14 membered monocyclic or bicyclic carbocyclic ring, wherein one of the monocyclic ring or bicyclic rings is aromatic and the other ring can be aromatic, saturated or partially unsaturated And -C (O), -N (R ¹⁹ ) _q- , -O- and S (O) _r , wherein R ¹⁹ is H or C _1-6 -alkyl, q is 0 to 1, r May comprise 0 to 2 ring members selected from 0 to 2;
Heteroaryl or heteroarylene represents a 5 to 14 membered monocyclic or bicyclic ring, wherein one of the monocyclic ring, or bicyclic rings is (a) 1 to 4 nitrogen atoms, (b) one Oxygen or one sulfur atom, or (c) an aromatic group comprising one oxygen atom or one sulfur atom and one or two nitrogen atoms, the other ring may be aromatic, saturated or partially unsaturated, and -C ( ^{O), -N (r 21)} q -, -O- and S (O) _r (wherein, r ²¹ is H or C _{1 -6} - alkyl, q is 0 to 1, r is from 0 to 2; May comprise 1 to 3 ring members selected from:
Heterocycloalkyl or heterocycloalkylene represents a 3 to 14 membered monocyclic or bicyclic ring, wherein one of the monocyclic ring, or bicyclic rings, is -N (R ²² )-, -O- and- A saturated or partially unsaturated group comprising one or two ring members selected from S (O) _r −, optionally further comprising a -C (O)-ring member, the other ring being aromatic, saturated or partially unsaturated And may include from 1 to 3 ring members selected from -C (= 0), -N (R ²³ ) _q- , -O- and S (O) _r (where R ²² or R ²³ is H or C _{1 -6} - alkyl, q is 0 to 1, r is from 0 to 2;). The compound of claim 1, wherein X represents -N (H)-. The compound of claim 1 or 2, wherein R ¹ represents substituted phenyl at the 2- and 4- positions. The compound of any of claims 1-3, wherein R ¹ represents 4-bromo-2-fluorophenyl or 4-iodo-2-fluorophenyl. The compound of any one of claims 1 to 4, wherein Y represents D, and D represents -C (O)-, -CO _2- , C (O) N (H) O-, -C (O). A group selected from N (C _1-6 -alkyl) O—, —C (O) N (H) — or —C (O) N (C _1-6 -alkyl)-. The compound of claim 1, wherein R ² is —COH—, —CO ₂ H, —CO ₂ Et, CON (H or CH ₃ ) OR ^7a , wherein R ^7a is methyl, ethyl, Cyclopropylmethyl, 2-ethenyloxyethyl, 2-hydroxyethyl or 2,3-dihydroxypropyl), -CON (H or CH ₃ ) -R ^7b , wherein R ^7b is H, methyl, Ethyl, cyclopropylmethyl, 2-methoxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, acetylaminomethyl, 2-dimethylaminoethyl, cyclopentyl or 2-thiazolyl), or R the compound ² is to represent an amino-oxadiazolyl. The compound of any one of claims 1-4 and 6, wherein R ² represents CONHOR ^7a , wherein R ^7a represents cyclopropylmethyl or 2-hydroxyethyl. The compound of any of claims 1-4, wherein -E- represents cycloalkyl, 5-membered heteroarylene or 5-membered heterocycloalkylene, which may be substituted or unsubstituted. The compound of any one of claims 1-4 and 8, wherein E represents cyclopentyl, thiazole or oxadiazole, which may be substituted or unsubstituted. The compound of claim 1, wherein R ³ and R ⁴ represent H. 11. The compound of any one of claims 1-10, wherein R ⁵ is H, methyl, ethyl, chloro or fluoro. The compound of any one of claims 1-8, wherein R ⁵ is methyl. The compound of any one of claims 1-12, wherein Z is O. The compound of any one of claims 1-13, wherein m and n are both 1 or one of m and n is 1 and the other is 2. 15. The compounds of formula (Id) and salts thereof.
<Formula Id>

Where
Rd ¹ represents H, halogen, C _{1 -3} - alkyl or C _{1 -3} - represents a haloalkyl;
Rd ² represents H, cyano or the group -Y-Rd ⁵ ;
Rd ³ and Rd ⁴ is independently hydroxyl, cyano, nitro, C _{1 -6} - alkenyl, C _{2 -6} - - alkyl, C _{2 -6-alkynyl,} C _{1 -6} - alkoxy, C _{2 -6} - alkenyloxy, C _{2 -6-alkynyloxy,} halogen, C _{1 -6-alkyl-carbonyl,} carboxy, C _{1 -6-alkoxy-carbonyl,} amino, C _{1 -6-alkylamino,} di -C _{1 6} - alkylamino, C _{1 -6-alkyl-aminocarbonyl,} di -C _{1 -6-alkyl-aminocarbonyl,} C _{1 -6-alkyl-carbonylamino,} C _{1 -6-alkyl-carbonyl} (C _{1- 6-alkyl)} amino, C _{1 -6-alkyl-sulfonyl-amino,} C _{1 -6-alkyl-sulfonyl} (C _1-6 -alkyl) amino, C _{1 -6-alkyl} thio, C _{1 -6-alkylsulfinyl} , C _{1 -6} - alkyl sulfanyl, C _{1 -6} - alkylsulfonyl, aminosulfonyl, C _{1 -6} - alkyl aminosulfonyl, and di -C _{1 -6} - alkyl represents an amino-sulfonyl, wherein each for alkylamino or cyano-the above-mentioned hydrocarbon group is one or more halogen, hydroxyl, C _{1 -6-alkoxy,} amino, C _{1 -6-alkylamino,} di -C _{1 -6} Optionally substituted by;
Y represents a group selected from -D-, -E-, -DE- or -ED-;
D is -N (Rd ⁸ )-, -CO-, -CO _2- , -SO-, -SO _2- , CON (Rd ⁹ ) O-, -CON (Rd ¹⁰ )-, -N (Rd ¹¹ ) SO _2- , -N (Rd ¹² ) SO ₂ NRd ^13- , -SO ₂ N (Rd ¹⁴ )-, -N (Rd ¹⁵ ) CO-, -N (Rd ¹⁶ ) CON (Rd ¹⁷ )-, -N A group selected from (Rd ¹⁸ ) CO- or -C (= NH) N (Rd ¹⁹ )-;
E represents monocyclic arylene, heteroarylene, cycloalkylene or heterocycloalkylene, wherein said ring is optionally substituted by one or more groups independently selected from list 1 as defined herein;
Rd ⁵ is H, C _{1 -6} - For non-alkynyl, cycloalkyl, aryl, heterocycloalkyl or a heteroaryl group represents a alkyl, where Rd is ⁵ H - alkyl, C _{2 -6} - alkenyl, C _{2 -6} halogen, cyano, hydroxyl, C _{1 -6} - alkoxy, C ₂ -C ₆ - alkenyloxy, C ₂ -C ₆ - alkynyloxy, C _{1 -6} - thioalkyl, C _{1 - 6} haloalkyl , amino, C _{1 - 6} alkylamino, di -C _{1 - 6} alkylamino, C _{1 - 6} acylamino, C _{1 - 6} acyl C _{1 - 6} alkyl, monocyclic cycloalkyl or monocyclic heterocycloalkyl by from one to selected independently from 1 to 3 groups is optionally substituted, where the ring is halogen, cyano, hydroxyl, C _{1 -6} - alkoxy, C ₂ -C ₆ - alkenyloxy, C ₂ -C ₆ - alkynyl aryloxy carbonyl, C _{1 -6} - thioalkyl, C _{1 -6} - haloalkyl, amino, C _{1 -6} - alkylamino, di -C _{1 -6} - alkylamino, C _{1 -6} - acylamino and C _{1 - 6} - acyl C _{1 -6-1} also independently selected from alkylamino May be optionally substituted by two groups;
Rd Rd ⁶ and ⁷ is independently a hydroxyl, cyano, nitro, C _{1 -6} - alkyl, C _{2 -6} - alkenyl, C _{2 -6} - alkynyl, C _{1 -6} - alkoxy, C _{2 -6} - alkenyloxy, C _{2 -6-alkynyloxy,} halogen, C _{1 -6-alkyl-carbonyl,} carboxy, C _{1 -6-alkoxy-carbonyl,} amino, C _{1 -6-alkylamino,} di -C _{1 6} - alkylamino, C _{1 -6-alkyl-aminocarbonyl,} di -C _{1 -6-alkyl-aminocarbonyl,} C _{1 -6-alkyl-carbonylamino,} C _{1 -6-alkyl-carbonyl} (C _{1- 6-alkyl)} amino, C _{1 -6-alkyl-sulfonyl-amino,} C _{1 -6-alkyl-sulfonyl} (C _1-6 -alkyl) amino, C _{1 -6-alkyl} thio, C _{1 -6-alkylsulfinyl} , C _{1 -6} - alkyl sulfanyl, C _{1 -6} - alkylsulfonyl, aminosulfonyl, C _{1 -6} - alkyl aminosulfonyl, and di -C _{1 -6} - alkyl represents an amino-sulfonyl, wherein each for alkylamino or cyano-the above-mentioned hydrocarbon group is one or more halogen, hydroxyl, C _{1 -6-alkoxy,} amino, C _{1 -6-alkylamino,} di -C _{1 -6} Optionally substituted by;
j and g independently represent 0, 1, 2 or 3;
^{Rd 8, Rd 9, Rd 10} , Rd 11, Rd 12, Rd 13, Rd 14, Rd 15, Rd 16, Rd 17, Rd 18 ¹⁹ and Rd are independently H or C _{1 -6} - alkyl;
Alkyl or alkylene means a straight chain, branched and / or cyclic hydrocarbon having 1 to 20 carbon atoms, wherein the alkyl moiety having 1 to 5 carbons is referred to as "lower alkyl", for example methyl, Ethyl, propyl, isopropyl, n-butyl, t-butyl and isobutyl;
Cycloalkyl or cycloalkylene represents a 3 to 14 membered monocyclic or bicyclic carbocyclic ring, wherein the monocyclic ring, or one of the bicyclic rings, is saturated or partially unsaturated, optionally -C (O) - may further comprise a ring member, other ring may be aromatic, saturated or partially unsaturated, -C (= O), -N (R 20) q -, -O- and S (O) _r ( wherein, r ²⁰ is H or C _{1 -6} - alkyl, q is from 0 to 1, r may comprise 0 to 2 1 to 3 ring members selected from Im);
Aryl or arylene represents a 6 to 14 membered monocyclic or bicyclic carbocyclic ring, wherein one of the monocyclic ring or bicyclic rings is aromatic and the other ring can be aromatic, saturated or partially unsaturated And -C (O), -N (R ¹⁹ ) _q- , -O- and S (O) _r , wherein R ¹⁹ is H or C _1-6 -alkyl, q is 0 to 1, r May comprise 0 to 2 ring members selected from 0 to 2;
Heteroaryl or heteroarylene represents a 5 to 14 membered monocyclic or bicyclic ring, wherein one of the monocyclic ring, or bicyclic rings is (a) 1 to 4 nitrogen atoms, (b) one Oxygen or one sulfur atom, or (c) an aromatic group comprising one oxygen atom or one sulfur atom and one or two nitrogen atoms, the other ring may be aromatic, saturated or partially unsaturated, and -C ( ^{O), -N (r 21)} q -, -O- and S (O) _r (wherein, r ²¹ is H or C _{1 -6} - alkyl, q is 0 to 1, r is from 0 to 2; May comprise 1 to 3 ring members selected from:
Heterocycloalkyl or heterocycloalkylene represents a 3 to 14 membered monocyclic or bicyclic ring, wherein one of the monocyclic ring, or bicyclic rings, is -N (R ²² )-, -O- and- A saturated or partially unsaturated group comprising one or two ring members selected from S (O) _r −, optionally further comprising a -C (O)-ring member, the other ring being aromatic, saturated or partially unsaturated And may include from 1 to 3 ring members selected from -C (= 0), -N (R ²³ ) _q- , -O- and S (O) _r (where R ²² or R ²³ is H or C _{1 -6} - alkyl, q is 0 to 1, r is from 0 to 2;). The compound of any one of claims 1-15 for use in therapy. A subject in need of treatment of a disease, disorder or syndrome associated with MEK inhibition is a compound according to any one of claims 1 to 15 or a prodrug thereof, or a compound of formula (I) or a prodrug thereof and a pharmaceutically acceptable excipient. A method of treating a disease, disorder, or syndrome associated with inhibition of MEK comprising administering a pharmaceutical composition comprising. The method of claim 17, wherein the disease, disorder or syndrome is hyperproliferative in a subject that is an animal, including humans, and is selected from the group comprising cancer and inflammation. A method of treating a compound of Formula (I), a disease, disorder, or syndrome associated with inhibition of MEK, substantially as described herein in connection with the Examples. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 15 and a pharmaceutically acceptable carrier or excipient. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 15 in combination with a second active agent and a pharmaceutically acceptable carrier or excipient. 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester;
7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropyl-methoxy-amide;
7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid dimethyl amide;
7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methoxyl amide;
7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid amide;
7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethoxy amide;
7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-hydroxy ethyl) amide;
7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methyl amide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methoxy-ethyl-amide;
7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carbaldehyde;
6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropyl methoxy- amides;
6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid amide;
7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid;
7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropyl methoxy- amides;
7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropyl methoxy-amide ;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-vinyloxy- Ethoxy) -amide;
7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methoxy-amide;
7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethoxy-amide;
2- (4-bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-1-carboxylic acid ethyl ester;
2- (4-Bromo-2-fluoro-phenyl-amino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-1-carboxylic acid;
2- (4-Bromo-2-fluoro-phenyl-amino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-1-carboxylic acid-cyclopropyl-methoxy amides;
2- (4-bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-1-carboxylic acid amide;
2- (4-Bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-1-carboxylic acid- (2-vinyloxy- Ethoxy) -amide;
2- (4-bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-1-carboxylic acid methoxy amide;
2- (4-bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-1-carboxylic acid ethoxy amide;
7- (4-Bromo-2-fluorophenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-hydroxyethoxy )amides;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (3-hydroxy-propyl) -amide ;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-methoxy-ethyl) -amide ;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-acetylamino-ethyl) -amide ;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-dimethylamino-ethyl) -amide ;
6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-hydroxy -Ethoxy) -amide;
7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopentylamide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethylamide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (3-methoxy- Propyl) -amide;
7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid;
7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid amide;
7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy-amide;
7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester;
7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-hydroxy-ethoxy)- amides;
7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methoxy-amide;
7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2,3-dihydroxy-pro Foxy) -amide;
7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid;
7- (4-Bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy-amide ;
7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methoxy-amide;
7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid amide;
7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2,3-di Hydroxy-propoxy) -amide;
6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid;
6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy-amide ;
6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methoxy-amide;
6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid amide;
6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethoxy-amide;
6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2,3-di Hydroxy-propoxy) -amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizin-8-carboxylic acid thiazol-2-yl amides;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (3-hydroxy- Propyl) -amide;
7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid dimethylamide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-methoxy- Ethyl) -amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-acetylamino- Ethyl) -amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (pyridin-2-yl Methyl) -amide;
6-fluoro-7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid;
6-Fluoro-7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylme Oxy-amide;
6-Fluoro-7- (2-fluoro-4-methylsulfanyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy -amides;
7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-8- [5- (2-hydroxy-ethylamino)-[1,3,4] oxadiazole-2- Sun] -2,3-dihydro-1H-indolizin-5-one;
7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid methoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-hydroxy -Ethoxy) -amide;
7- (4-Bromo-2-methyl-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid;
7- (4-Bromo-2-methyl-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy-amide ;
7- (4-bromo-2-methyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid;
7- (4-bromo-2-methyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy-amide;
6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -8- (3-hydroxy-3-piperidin-2-yl-azetidine-1-carbonyl) -2 , 3-dihydro-1H-indolizin-5-one hydrochloride;
7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-8- (3-hydroxy-3-piperidin-2-yl-azetidine-1-carbonyl) -2 , 3-dihydro-1H-indolizin-5-one;
6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -8- (3-hydroxy-3-piperidin-2-yl-azetidine-1-carbonyl) -2 , 3-dihydro-1H-indolizin-5-one;
Cyclopropanesulfonic acid [7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide ;
N- [7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -N, N-dimethyl-amino-sulfonamide;
2,3-dihydroxy-propane-amino-sulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro -Indolizin-8-yl] -amide;
1- [7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-ylsulfamoyl]- Pyrrolidine-2-carboxylic acid;
2-hydroxymethyl-pyrrolidine-1-sulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro -Indolizin-8-yl] -amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-8- (1-hydroxy-but-3-enyl) -2,3-dihydro-1H-indolizin-5 -On;
7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-8- (1-hydroxy-allyl) -2,3-dihydro-1H-indolizin-5-one;
7- (4-Bromo-2-fluoro-phenylamino) -8- (2,3-dihydroxy-propionyl) -6-fluoro-2,3-dihydro-1H-indolizin-5 -On;
7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-8- (2-hydroxy-acetyl) -2,3-dihydro-1H-indolizin-5-one;
7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester;
7- (2-Fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid;
7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy-amide;
7- (2-Fluoro-4-methoxy-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropylmethoxy-amide;
7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carbaldehyde oxime;
7- (4-Bromo-2-fluoro-phenylamino) -8- (3-hydroxy-3-pyridin-2-yl-azetidine-1-carbonyl) -2,3-dihydro-1H Indolizin-5-one;
7- (4-bromo-2-fluoro-phenylamino) -8- (3-hydroxy-azetidin-1-carbonyl) -2,3-dihydro-1H-indolizin-5-one;
3- (4-bromo-2-fluoro-phenyl) -1-methanesulfonyl-1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2 , 5-dione;
Cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide;
N- [7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -4-fluoro-benzenesulphone amides;
[7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -carbamic acid tert-butyl ester;
Cyclohexanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide;
N- [7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -4-trifluoromethyl- Benzenesulfonamide;
N- [7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -N, N-dimethylaminosulfone amides;
5- (4-Bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclo Penta [a] indene-4-carboxylic acid;
7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid ethyl ester ;
7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropyl Methoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2 -Hydroxy-ethoxy) -amide;
7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclobutyl Methoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (3 -Hydroxy-2-methyl-propoxy) -amide;
1- (2,3-Dihydroxy-propyl) -cyclopropanesulfonic acid [6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3, 5-tetrahydro-indolizin-8-yl] -amide;
1- (2,3-Dihydroxy-propyl) -cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5 -Tetrahydro-indolizin-8-yl] -amide;
1- (2,3-Dihydroxy-propyl) -cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3, 5-tetrahydro-indolizin-8-yl] -amide;
6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2,3- Dihydroxy-propoxy) -amide;
7- (2-fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclopropyl methoxy amide;
7- (2-Fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid (2-hydroxy- Ethoxy) -amide;
7- (2-Fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indoligin-8-carboxylic acid cyclobutylmethoxy-amide ;
1- (2,3-Dihydroxy-propyl) -cyclopropanesulfonic acid [7- (2-fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5 -Tetrahydro-indolizin-8-yl] -amide; And
Cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide,
Or pharmaceutically acceptable salts thereof.