JP2012524114A - Heterocyclic compounds as MEK inhibitors - Google Patents

Abstract

の化合物および薬学的に許容される塩に関する。これらの化合物は、癌および炎症のような過増殖性疾患の処置において強力なＭＥＫ阻害剤として作用できる。本発明またその製造方法にも関する。The present invention relates to a compound of formula (I)

And pharmaceutically acceptable salts thereof. These compounds can act as potent MEK inhibitors in the treatment of hyperproliferative diseases such as cancer and inflammation. The present invention also relates to a manufacturing method thereof.

Description

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

  Providing benefits from the treatment of hyperproliferative diseases such as cancer and inflammation is a concern for scientists. For this reason, efforts are being made to identify and target specific mechanisms involved in disease growth.

  It is known that overactivation of the mitogen-activated protein (MAP) kinase cascade plays 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 an ERK-mediated phosphorylation cascade from MEK (MAP kinase kinase). Inhibition of this pathway is known to be advantageous for hyperproliferative diseases. MEK is an attractive therapeutic target because the only known substrates for MEK phosphorylation are the MAP kinases, ERK1 and ERK2. Constitutive activation of MEK / ERK has been seen in primary tumor samples of pancreas, colon, lung, kidney and ovary.

  The phosphorylation of MEK appears to increase its affinity for ERK and its catalytic activity while at the same time being affinity for ATP. The present invention describes compounds that inhibit MEK activity by modulation of ATP binding, MEK-ERK binding by mechanisms that are competitive and / or allosteric and / or non-competitive.

Activation of MEK has been demonstrated in many disease models, thus suggesting that inhibition of MEK may have benefit in the treatment of various diseases such as:
・ Pain: Evidence of effects 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 effects in stroke models, marked neuroprotection against ischemic brain injury by MEK inhibition ( J. Pharmacol. Exp. Ther. 304: 172, 2003; Brain Res. 996: 55, 2004)
Diabetes: Evidence for effects on diabetic complications (Am. J. Physiol. Renal. 286, F120 2004)
・ Inflammation: Evidence of effects in inflammation models ( Biochem Biophy. Res. Com. 268: 647, 2000)
Arthritis: Evidence for effects in experimental osteoarthritis ( Arthritis & (J. Clin. Invest. 116: 163. 2006)

  Inhibition of MEK has been shown to have therapeutic benefit in several experiments.

〔式中、
ＸはＣ_１−３アルキレン、−Ｎ(Ｒ^６)−、−Ｏ−、または−Ｓ(Ｏ)_ｐ−であり；
Ｒ^１はアリール、ヘテロアリール、シクロアルキルまたはヘテロシクロアルキルであり、ここで、該環は場合によりリスト１から独立して選択される１個以上の基で置換されていてよく；
Ｒ^２はＨ、シアノ、または基−Ｙ−Ｒ^７であり；
Ｒ^３およびＲ^４は独立してＨ、Ｃ_１−６アルキル、Ｃ_１−６ハロアルキル、Ｃ_１−６ヒドロキシアルキル、ヒドロキシル、Ｃ_１−６アルコキシ、アミノ、Ｃ_１−６アルキルアミノまたはジＣ_１−６アルキルアミノであるか、またはＲ^３はさらに単環式シクロアルキルまたは単環式ヘテロシクロアルキルであり、ここで、該環は場合によりリスト１から独立して選択される１個以上の基で置換されていてよく；
Ｒ^５はＨ、ハロゲン、Ｃ_１−３アルキル、Ｃ_１−３アルコキシ、−ＳＣ_１−３アルキル、またはＣ_１−３ハロアルキルであり；
Ｙは−Ｄ−、−Ｅ−、−Ｄ−Ｅ−、または−Ｅ−Ｄ−から選択される基であり；
Ｄは−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_２ＮＲ^２５−、−ＳＯ_２Ｎ(Ｒ^１２)−、−Ｎ(Ｒ^１３)ＣＯ−、−Ｎ(Ｒ^１４)ＣＯＮ(Ｒ^１５)−、−Ｎ(Ｒ^１６)ＣＯ−、または−Ｃ(＝ＮＨ)Ｎ(Ｒ^１７)−から選択される基であり；
Ｅは単環式アリーレン、ヘテロアリーレン、シクロアルキレンまたはヘテロシクロアルキレンであり、ここで、該環は場合によりリスト１から独立して選択される１個以上の基で置換されていてよく；
Ｒ^７はＨ、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、シクロアルキル、アリール、ヘテロシクロアルキル、またはヘテロアリールであり、Ｒ^７は、Ｈ以外であるとき、場合により、ハロゲン、シアノ、ヒドロキシル、Ｃ_１−６アルコキシ、Ｃ_２−Ｃ_６−アルケニルオキシ、Ｃ_２−Ｃ_６−アルキニルオキシ、Ｃ_１−６チオアルキル、Ｃ_１−６ハロアルキル、アミノ、Ｃ_１−６アルキルアミノ、ジ−Ｃ_１−６アルキルアミノ、Ｃ_１−６アシルアミノ、Ｃ_１−６アシルＣ_１−６アルキルアミノ、単環式シクロアルキルまたは単環式ヘテロシクロアルキルから独立して選択される１〜３個の基で置換されていてよく、ここで、該環は、場合により、ハロゲン、シアノ、ヒドロキシル、Ｃ_１−６アルコキシ、Ｃ_２−Ｃ_６−アルケニルオキシ、Ｃ_２−Ｃ_６−アルキニルオキシ、Ｃ_１−６チオアルキル、Ｃ_１−６ハロアルキル、アミノ、Ｃ_１−６アルキルアミノ、ジ−Ｃ_１−６アルキルアミノ、Ｃ_１−６アシルアミノおよびＣ_１−６アシルＣ_１−６アルキルアミノから独立して選択される１個または２個の基で置換されていてよく；
ＺはＯまたはＮ(Ｒ^１８)であり；
リスト１はヒドロキシル、シアノ、ニトロ、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_１−６アルコキシ、Ｃ_２−６アルケニルオキシ、Ｃ_２−６アルキニルオキシ、ハロゲン、Ｃ_１−６アルキルカルボニル、カルボキシ、Ｃ_１−６アルコキシカルボニル、アミノ、Ｃ_１−６アルキルアミノ、ジ−Ｃ_１−６アルキルアミノ、Ｃ_１−６アルキルアミノカルボニル、ジ−Ｃ_１−６アルキルアミノカルボニル、Ｃ_１−６アルキルカルボニルアミノ、Ｃ_１−６アルキルカルボニル(Ｃ_１−６アルキル)アミノ、Ｃ_１−６アルキルスルホニルアミノ、Ｃ_１−６アルキルスルホニル(Ｃ_１−６アルキル)アミノ、Ｃ_１−６チオアルキル、Ｃ_１−６アルキルスルフィニル、Ｃ_１−６アルキルスルファニル、Ｃ_１−６アルキルスルホニル、アミノスルホニル、Ｃ_１−６アルキルアミノスルホニルおよびジ−Ｃ_１−６アルキルアミノスルホニルから選択され、ここで、上記炭化水素基の各々は、場合により１個以上のハロゲン、ヒドロキシル、Ｃ_１−６アルコキシ、アミノ、Ｃ_１−６アルキルアミノ、ジ−Ｃ_１−６アルキルアミノまたはシアノで置換されていてよく；
Ｒ^２６はＨ、Ｃ_１−６アルキル、Ｃ_１−６ハロアルキル、Ｃ_１−６ヒドロキシアルキル、ヒドロキシル、Ｃ_１−６アルコキシ、アミノ、Ｃ_１−６アルキルアミノ、またはジＣ_１−６アルキルアミノであり；
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、およびＲ^２５は独立してＨまたはＣ_１−６アルキルであり；
ｍおよびｎは独立して０、１、２、または３であり；かつｍ＋ｎ＝２または３であり；
ｐは０、１、または２であり；ここで Therefore, as a first aspect, the present invention provides a compound of formula (I)

[Where,
X is C _1-3 alkylene, —N (R ⁶ ) —, —O—, or —S (O) _p —;
R ¹ is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein the ring is optionally substituted with one or more groups independently selected from List 1;
R ² is H, cyano, or a 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 or diC _{1 -6} alkylamino or R ³ is further monocyclic cycloalkyl or monocyclic heterocycloalkyl, wherein the ring is optionally one or more groups independently selected from list 1 May be substituted with;
R ⁵ is H, halogen, C _1-3 alkyl, C _1-3 alkoxy, —SC _1-3 alkyl, or C _1-3 haloalkyl;
Y is a group selected from -D-, -E-, -D-E-, 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 A group selected from (R ¹⁶ ) CO—, or —C (═NH) N (R ¹⁷ ) —;
E is a monocyclic arylene, heteroarylene, cycloalkylene or heterocycloalkylene, wherein the ring is optionally substituted with one or more groups independently selected from List 1;
R ⁷ is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, and when R ⁷ is other than H, optionally , 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 alkyl 1 to independently selected from amino, di-C _1-6 alkylamino, C _1-6 acylamino, C _1-6 acyl C _1-6 alkylamino, monocyclic cycloalkyl or monocyclic heterocycloalkyl good three optionally substituted by a group, wherein said ring is optionally 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 And optionally substituted by one or two groups independently selected from C _1-6 acylC _1-6 alkylamino;
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 alkylcarbonyl, carboxy, C _1-6 alkoxycarbonyl, amino, C _1-6 alkylamino, di-C _1-6 alkylamino, C _1-6 alkylaminocarbonyl, di-C _1-6 alkylaminocarbonyl C _1-6 alkylcarbonylamino, C _1-6 alkylcarbonyl (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 alkylsulfanyl, C 1-6} alkyl Ruhoniru, aminosulfonyl, is selected from C _1-6 alkylaminosulfonyl and di -C _1-6 alkylaminosulfonyl, wherein said each of the hydrocarbon groups, optionally substituted by one or more halogen, hydroxyl, C _1- Optionally substituted with ₆ alkoxy, amino, C _1-6 alkylamino, di-C _1-6 alkylamino or cyano;
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 diC _1-6 alkylamino Yes;
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 Is -6} alkyl;
m and n are independently 0, 1, 2, or 3; and m + n = 2 or 3.
p is 0, 1, or 2; where

Alkyl or alkylene means straight, branched and / or cyclic hydrocarbons of 1 to 20 carbon atoms. Alkyl moieties having 1 to 5 carbons are termed “lower alkyl” and examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl;
Cycloalkyl or cycloalkylene is a 3-14 membered monocyclic or bicyclic carbocycle, wherein one of the monocycle or bicycle is saturated or partially unsaturated, optionally further —C ( O) - may include ring members, and the remaining ring in aromatic, may be either partially saturated or unsaturated, -C (= O), - N (R 20) q -, - O- and S 1 to 3 ring members selected from (O) r, wherein R ²⁰ is H or C _1-6 alkyl, q is 0-1 and r is 0-2. May include;
Aryl or arylene is a 6-14 membered monocyclic or bicyclic carbocycle, wherein one of the monocycle or bicycle is aromatic and the remaining ring is aromatic or saturated. It may be partially unsaturated, —C (O), —N (R ¹⁹ ) q—, —O— and S (O) r, wherein R ¹⁹ is H or C _1-6 alkyl, and q is 0-1 and r is 0-2) may comprise 1 to 3 ring members selected from;
Heteroaryl or heteroarylene is a 5-14 membered monocyclic or bicyclic ring, wherein one of the monocyclic or bicyclic rings is (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom. Or an aromatic group containing one sulfur atom or (c) one oxygen atom or one sulfur atom and one or two nitrogen atoms, the remaining rings being aromatic, saturated or partially -C (O), -N (R ²¹ ) q-, -O- and S (O) r, wherein R ²¹ is H or C _1-6 alkyl and q is 0 -1 and r is 0-2) may contain 1 to 3 ring members; and heterocycloalkyl or heterocycloalkylene is a 3-14 membered monocyclic or bicyclic ring There, wherein one of the monocyclic or bicyclic ^{ring, -N (R 22) -,} - O- and -S (O) _r - is selected from A saturated or partially unsaturated group containing one or two ring members and optionally further containing —C (O) — ring members, the remaining rings being aromatic, saturated or partially May be unsaturated, —C (═O), —N (R ²³ ) q—, —O— and S (O) r, wherein R ²² or R ²³ is H or C _1-6 alkyl; q may be 0-1 and r is 0-2). ]
And a pharmaceutically acceptable salt thereof.

Any number of the specific embodiments of the invention according to the following formula (I) may be incorporated and combined into the definition of formula (I) in any suitable manner.
In one embodiment, X is —N (H) —.
In other embodiments, R ¹ is an optionally substituted phenyl.

In other embodiments, optionally present substituents on R ¹ are halogen, such as fluoro, bromo or iodo, C _1-6 alkyl, such as ethyl, C _2-6 alkynyl, such as ethynyl, C _1-6 haloalkyl, For example, 1 to 3 groups independently selected from trifluoromethyl and C _1-6 thioalkyl, such as thiomethyl.

In another embodiment, R ¹ is phenyl substituted at the 2-position, 4-position and optionally the 6-position, preferably the 2-position and 4-position. In a further embodiment, R ¹ is phenyl substituted with 2-fluoro and 4-bromo, or 4-iodo-2-fluorophenyl, or iodo, trifluoromethyl, thiomethyl, ethynyl, or ethyl 2-position and 4 A phenyl substituted with any combination of positional substitutions.

から選択される環である。 In other embodiments,-D-is _{-C (O) -, - CO} 2 -, C (O) N (H) O -, - C (O) N (C 1-6 alkyl) O -, - C It is a group selected from (O) N (H)-and -C (O) N (C _1-6 alkyl)-.
In other embodiments, -E- is a 5-membered heteroarylene or 5-membered heterocycloalkylene. In a further aspect, E is;

A ring selected from

In other embodiments, when Y is -D-E-, -D- can be -C (O) N (H)-and -E- can be an optionally substituted cycloalkyl; For example, it may be cyclopentyl or optionally substituted heteroaryl, such as thiazole.
In other embodiments, when Y is -ED-, -E- can be an optionally substituted heteroaryl, such as oxadiazole, and -D- is -C (O) N. (H)-.

In other embodiments, Y is a group -D- or -E-.
In other embodiments, R ⁷ is H, C _1-6 alkyl, such as methyl or ethyl, such as hydroxyl, including di-hydroxyl, C _1-6 alkoxy, such as methoxy, C ₂ -C ₆ -alkenyloxy, such as ethenyloxy. Di-C _1-6 alkylamino, such as dimethylamino, C _1-6 acylamino, such as acetylamino, and optionally substituted monocyclic cycloalkyl, such as 1-3 selected from cyclopropyl, In another embodiment it is C _1-6 alkyl substituted with 1-2.

In other embodiments, R ⁷ is H, methyl, ethyl, cyclopropylmethyl, 2-hydroxyethyl, 2-ethenyloxyethyl, 3-hydroxypropyl, 2-methoxyethyl, acetylaminomethyl, 2-dimethylaminoethyl or 2,3-dihydroxypropyl.

In other embodiments, 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, cyclopropylmethyl, 2-methoxy Ethyl, 2-hydroxyethyl, 3-hydroxypropyl, acetylaminomethyl, 2-dimethylaminoethyl, cyclopentyl or 2-thiazolyl), or R ² is oxadiazolylamino.

In other embodiments, the present invention includes compounds of Formula (I) where R ² is CONHOR ^7a (wherein R ^{7 is} cyclopropylmethyl or 2-hydroxyethyl).
In other embodiments, m and n are both 1 or one of m and n is 1 and the other is 2.
In other embodiments, R ³ and R ⁴ are H.

In other embodiments, R ⁵ is H, halogen, such as fluoro or chloro, C _1-3 alkoxy, such as methoxy, or ethoxy, —SC _1-3 alkyl, such as SCH ₃ , or C _1-3 alkyl, such as Methyl or ethyl. In a further aspect, R ⁵ is fluoro. In a further aspect, R ⁵ is methyl.
In another embodiment, Z is O.

In other embodiments, aryl or arylene are each optionally substituted phenyl or phenylene.
In other embodiments, cycloalkyl or cycloalkylene is an optionally substituted 3-7 membered saturated monocyclic carbocycle, such as cyclopropyl or cyclopentyl.

In other embodiments, the heteroaryl or heteroarylene is optionally substituted (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulfur atom, or (c) 1 5-6 membered monocyclic aromatic groups containing one oxygen atom or one sulfur atom and one or two nitrogen atoms, such as tetrazolyl, thiazolyl or oxadiazolyl.
In other embodiments, the heterocycloalkyl or heterocycloalkylene optionally contains 1 or 2 ring members selected from —N (R ²² ) —, —O—, and —S (O) _r —. It is a 5-6 membered saturated monocycle which may be substituted.

In yet another aspect of the invention, the compound forms a pharmaceutically acceptable salt selected from the group consisting of acid addition salts and base addition salts.
In another embodiment, the invention includes a pharmaceutical composition comprising a compound of formula (I) or (Id) and a pharmaceutically acceptable carrier or additive. In other embodiments, the invention includes a pharmaceutical composition comprising a compound of formula (I) or (Id) in combination with a second active agent, and a pharmaceutically acceptable carrier or additive.

〔式中、
Ｒｄ^１はＨ、ハロゲン、Ｃ_１−３アルキル、またはＣ_１−３ハロアルキルであり；
Ｒｄ^２はＨ、シアノ、または基−Ｙ−Ｒｄ^５であり；
Ｒｄ^３およびＲｄ^４は独立してヒドロキシル、シアノ、ニトロ、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_１−６アルコキシ、Ｃ_２−６アルケニルオキシ、Ｃ_２−６アルキニルオキシ、ハロゲン、Ｃ_１−６アルキルカルボニル、カルボキシ、Ｃ_１−６アルコキシカルボニル、アミノ、Ｃ_１−６アルキルアミノ、ジ−Ｃ_１−６アルキルアミノ、Ｃ_１−６アルキルアミノカルボニル、ジ−Ｃ_１−６アルキルアミノカルボニル、Ｃ_１−６アルキルカルボニルアミノ、Ｃ_１−６アルキルカルボニル(Ｃ_１−６アルキル)アミノ、Ｃ_１−６アルキルスルホニルアミノ、Ｃ_１−６アルキルスルホニル(Ｃ_１−６アルキル)アミノ、Ｃ_１−６チオアルキル、Ｃ_１−６アルキルスルフィニル、Ｃ_１−６アルキルスルファニル、Ｃ_１−６アルキルスルホニル、アミノスルホニル、Ｃ_１−６アルキルアミノスルホニルまたはジ−Ｃ_１−６アルキルアミノスルホニルであり、ここで、上記炭化水素基の各々は、場合により１個以上のハロゲン、ヒドロキシル、Ｃ_１−６アルコキシ、アミノ、Ｃ_１−６アルキルアミノ、ジ−Ｃ_１−６アルキルアミノまたはシアノで置換されていてよく；
Ｙは−Ｄ−、−Ｅ−、−Ｄ−Ｅ−、または−Ｅ−Ｄ−から選択される基であり；
Ｄは−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_２ＮＲｄ^１３−、−ＳＯ_２Ｎ(Ｒｄ^１４)−、−Ｎ(Ｒｄ^１５)ＣＯ−、−Ｎ(Ｒｄ^１６)ＣＯＮ(Ｒｄ^１７)−、−Ｎ(Ｒｄ^１８)ＣＯ−、または−Ｃ(＝ＮＨ)Ｎ(Ｒｄ^１９)−から選択される基であり；
Ｅは単環式アリーレン、ヘテロアリーレン、シクロアルキレンまたはヘテロシクロアルキレンであり、ここで、該環は場合によりここで定義するリスト１から独立して選択される１個以上の基で置換されていてよく；
Ｒｄ^５はＨ、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、シクロアルキル、アリール、ヘテロシクロアルキル、またはヘテロアリールであり、ここで、Ｒｄ^５は、Ｈではないとき、場合により、ハロゲン、シアノ、ヒドロキシル、Ｃ_１−６アルコキシ、Ｃ_２−Ｃ_６−アルケニルオキシ、Ｃ_２−Ｃ_６−アルキニルオキシ、Ｃ_１−６チオアルキル、Ｃ_１−６ハロアルキル、アミノ、Ｃ_１−６アルキルアミノ、ジ−Ｃ_１−６アルキルアミノ、Ｃ_１−６アシルアミノ、Ｃ_１−６アシルＣ_１−６アルキルアミノ、単環式シクロアルキルまたは単環式ヘテロシクロアルキルから独立して選択される１〜３個の基で置換されていてよく、ここで、該環は、場合により、ハロゲン、シアノ、ヒドロキシル、Ｃ_１−６アルコキシ、Ｃ_２−Ｃ_６−アルケニルオキシ、Ｃ_２−Ｃ_６−アルキニルオキシ、Ｃ_１−６チオアルキル、Ｃ_１−６ハロアルキル、アミノ、Ｃ_１−６アルキルアミノ、ジ−Ｃ_１−６アルキルアミノ、Ｃ_１−６アシルアミノおよびＣ_１−６アシルＣ_１−６アルキルアミノから独立して選択される１個または２個の基で置換されていてよく；
Ｒｄ^６およびＲｄ^７は独立してヒドロキシル、シアノ、ニトロ、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_１−６アルコキシ、Ｃ_２−６アルケニルオキシ、Ｃ_２−６アルキニルオキシ、ハロゲン、Ｃ_１−６アルキルカルボニル、カルボキシ、Ｃ_１−６アルコキシカルボニル、アミノ、Ｃ_１−６アルキルアミノ、ジ−Ｃ_１−６アルキルアミノ、Ｃ_１−６アルキルアミノカルボニル、ジ−Ｃ_１−６アルキルアミノカルボニル、Ｃ_１−６アルキルカルボニルアミノ、Ｃ_１−６アルキルカルボニル(Ｃ_１−６アルキル)アミノ、Ｃ_１−６アルキルスルホニルアミノ、Ｃ_１−６アルキルスルホニル(Ｃ_１−６アルキル)アミノ、Ｃ_１−６チオアルキル、Ｃ_１−６アルキルスルフィニル、Ｃ_１−６アルキルスルファニル、Ｃ_１−６アルキルスルホニル、アミノスルホニル、Ｃ_１−６アルキルアミノスルホニルまたはジ−Ｃ_１−６アルキルアミノスルホニルであり、ここで、上記炭化水素基の各々は、場合により１個以上のハロゲン、ヒドロキシル、Ｃ_１−６アルコキシ、アミノ、Ｃ_１−６アルキルアミノ、ジ−Ｃ_１−６アルキルアミノまたはシアノで置換されていてよく；
ｊおよびｇは独立して０、１、２、または３であり；そして
Ｒｄ^８、Ｒｄ^９、Ｒｄ^１０、Ｒｄ^１１、Ｒｄ^１２、Ｒｄ^１３、Ｒｄ^１４、Ｒｄ^１５、Ｒｄ^１６、Ｒｄ^１７、Ｒｄ^１８、およびＲｄ^１９は独立してＨまたはＣ_１−６アルキルである。〕
の化合物、およびその塩を含む。 In another embodiment, the present invention provides compounds of formula (Id):

[Where,
Rd ¹ is H, halogen, C _1-3 alkyl, or C _1-3 haloalkyl;
Rd ² is H, cyano, or a group -Y-Rd ^5,;
Rd ³ and Rd ⁴ are independently 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 alkylcarbonyl, carboxy, C _1-6 alkoxycarbonyl, amino, C _1-6 alkylamino, di-C _1-6 alkylamino, C _1-6 alkylaminocarbonyl, di-C _1-6 alkylaminocarbonyl, C _1-6 alkylcarbonylamino, C _1-6 alkylcarbonyl (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} alkylsulfanyl C _1-6 alkylsulfonyl, _{aminosulfonyl,} a _{C 1-6} alkylaminosulfonyl or di _{-C 1-6} alkyl aminosulfonyl, wherein each of the hydrocarbon groups, optionally substituted by one or more halogen, hydroxyl Optionally substituted with C _1-6 alkoxy, amino, C _1-6 alkylamino, di-C _1-6 alkylamino or cyano;
Y is a group selected from -D-, -E-, -D-E-, 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 is a monocyclic arylene, heteroarylene, cycloalkylene or heterocycloalkylene, wherein the ring is optionally substituted with one or more groups selected independently from List 1 as defined herein. Often;
Rd ⁵ is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein when Rd ⁵ is not H, Optionally 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- Independently selected from ₆ alkylamino, di-C _1-6 alkylamino, C _1-6 acylamino, C _1-6 acyl C _1-6 alkylamino, monocyclic cycloalkyl or monocyclic heterocycloalkyl It may be substituted with 1 to 3 groups, wherein the ring is optionally halogen, cyano, hydroxyl, C _1-6 alkoxy. _Shi, 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, Optionally substituted with one or two groups independently selected from C _1-6 acylamino and C _1-6 acylC _1-6 alkylamino;
Rd ⁶ and Rd ⁷ are independently 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 alkylcarbonyl, carboxy, C _1-6 alkoxycarbonyl, amino, C _1-6 alkylamino, di-C _1-6 alkylamino, C _1-6 alkylaminocarbonyl, di-C _1-6 alkylaminocarbonyl, C _1-6 alkylcarbonylamino, C _1-6 alkylcarbonyl (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} alkylsulfanyl C _1-6 alkylsulfonyl, _{aminosulfonyl,} a _{C 1-6} alkylaminosulfonyl or di _{-C 1-6} alkyl aminosulfonyl, wherein each of the hydrocarbon groups, optionally substituted by one or more halogen, hydroxyl Optionally substituted with C _1-6 alkoxy, amino, C _1-6 alkylamino, di-C _1-6 alkylamino or cyano;
j and g are independently 0, 1, 2, or 3; and Rd ⁸ , Rd ⁹ , Rd ¹⁰ , Rd ¹¹ , Rd ¹² , Rd ¹³ , Rd ¹⁴ , Rd ¹⁵ , Rd ¹⁶ , Rd ¹⁷ , Rd ¹⁸ and Rd ¹⁹ are independently H or C _1-6 alkyl. ]
And the salts thereof.

  In one embodiment, j and g are independently 0, 1, 2, or 3 and j + g = 2, 3, or 4. In other embodiments, j is 0, 1, or 2, and g is 1, 2, or 3. In a further embodiment, 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 requisite 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 means an alkyl group substituted with up to 7 halogen groups, for example fluoro groups. For example, when the substituent is fluoro, common haloalkyl groups are trifluoroalkyl groups, 2,2,2-trifluoroethyl groups, or 2,2,2,1,1-pentafluoroethyl groups.

The term “alkenyl” means a monovalent radical derived from a hydrocarbon having at least one carbon-carbon double bond. The term “C ₂ -C ₆ -alkenyl” means a monovalent radical derived from a hydrocarbon having 2 to 6 carbon atoms and containing at least one carbon-carbon double bond.

The term “alkynyl” refers to a monovalent radical derived from a hydrocarbon having at least one carbon-carbon triple bond. The term “C ₂ -C ₆ -alkynyl” means a monovalent radical derived from a hydrocarbon having 2 to 6 carbon atoms and containing at least one carbon-carbon triple bond.
The term “alkoxy” means a group in which an alkyl group is attached to oxygen, where alkyl is as defined above.

The term C (O) means a —C═O group, where it should be interpreted as a ketone, aldehyde or acid or acid derivative. Similarly, S (O) means a —S═O group.
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) are [1,3] dioxolane, [1,4] dioxane, oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholino , Thiomorpholinyl, piperazinyl, azepinyl, oxapinyl, oxazepinyl and diazepinyl.

  Examples of monocyclic heteroaryl groups as defined in formula (I) include pyridyl, thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl. Examples of bicyclic heteroaryl groups include indolyl, benzofuranyl, quinolyl, isoquinolyl, indazolyl, indolinyl, isoindolyl, indolizinyl, benzimidazolyl, and quinolinyl.

Throughout this specification and the appended claims, unless the context requires otherwise, the term “comprising”, or “including” or variations thereof such as “comprising” It is intended to include individuals or groups of processes, but it should be understood that it does not exclude any other individual or process or group of individuals or processes.
In yet another aspect of the invention, the compound is a stereoisomer or tautomer.

Suitable individual compounds of the invention are selected from:
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropyl-methoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid dimethylamide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylic acid methoxylamide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylic acid amide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylic acid ethoxyamide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylic acid (2-hydroxyethyl) amide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid methylamide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-ethyl-amide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carbaldehyde 6-fluoro-7- (2-fluoro-4-iodo -Phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid;
7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-vinyloxy-ethoxy) -amide;

7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethoxy-amide;
2- (4-Bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolidine-1-carboxylic acid ethyl ester;
2- (4-Bromo-2-fluoro-phenyl-amino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolidine-1-carboxylic acid;
2- (4-Bromo-2-fluoro-phenyl-amino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-1-carboxylic acid-cyclopropyl-methoxyamide;
2- (4-Bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolidine-1-carboxylic acid amide;
2- (4-Bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolidine-1-carboxylic acid- (2-vinyloxy-ethoxy) -amide;
2- (4-Bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolidine-1-carboxylic acid methoxyamide;
2- (4-Bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolidine-1-carboxylic acid ethoxyamide;
7- (4-Bromo-2-fluorophenylamino) -6-methyl-5-oxo-1,2,3,5-tetra (tetyra) hydro-indolizine-8-carboxylic acid (2-hydroxyethoxy) amide ;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (3-hydroxy-propyl) -amide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-methoxy-ethyl) -amide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-acetylamino-ethyl) -amide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-dimethylamino-ethyl) -amide;
6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy) -amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopentylamide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethylamide;

7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (3-methoxy-propyl) -amide;
7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid;
7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid amide;
7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester;
7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy) -amide;
7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-amide;
7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2,3-dihydroxy-propoxy) -amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid;
7- (4-Bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2,3-dihydroxy-propoxy)- An amide;
6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid;
6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-amide;
6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid amide;

6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethoxy-amide;
6-Chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2,3-dihydroxy-propoxy)- An amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid thiazol-2-ylamide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (3-hydroxy-propyl) -amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid dimethylamide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-methoxy-ethyl) -amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-acetylamino-ethyl) -amide ;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (pyridin-2-ylmethyl) -amide;
6-fluoro-7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid;
6-fluoro-7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
6-fluoro-7- (2-fluoro-4-methylsulfanyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-8- [5- (2-hydroxy-ethylamino)-[1,3,4] oxadiazol-2-yl] -2 , 3-dihydro-1H-indolizin-5-one;
7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy) -amide;
7- (4-Bromo-2-methyl-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid;
7- (4-Bromo-2-methyl-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
7- (4-Bromo-2-methyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid;
7- (4-Bromo-2-methyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-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-India Lysine-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-India Lysine-5-one;
6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -8- (3-hydroxy-3-piperidin-2-yl-azetidine-1-carbonyl) -2,3-dihydro-1H-India Lysine-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-indolizine- 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-indolizine-8- Yl] -amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-8- (1-hydroxy-but-3-enyl) -2,3-dihydro-1H-indolizin-5-one;
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-one;
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-indolizine-8-carboxylic acid ethyl ester;
7- (2-Fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid;
7- (2-Fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
7- (2-Fluoro-4-methoxy-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carbaldehyde oxime;
7- (4-Bromo-2-fluoro-phenylamino) -8- (3-hydroxy-3-pyridin-2-yl-azetidine-1-carbonyl) -2,3-dihydro-1H-indolizine-5 on;
7- (4-Bromo-2-fluoro-phenylamino) -8- (3-hydroxy-azetidine-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-benzenesulfonamide;
[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-dimethylaminosulfonamide;
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;
7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester;
7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)- An amide;
7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclobutylmethoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indolizine-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- Indolizine-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- Indolizine-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- Indolizine-8-yl] -amide;
6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2,3-dihydroxy-propoxy)- An amide;
7- (2-Fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxyamide;
7- (2-Fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy) -amide;
7- (2-Fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-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- Indolizine-8-yl] -amide; and cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-india Lysine-8-yl] -amide, or a pharmaceutically acceptable salt thereof.

  Many of the compounds of formula (I) and (Id) are capable of forming acid addition salts, particularly pharmaceutically acceptable acid addition salts. Pharmaceutically acceptable acid addition salts of the compounds of formula (I) are inorganic acids such as hydrohalic acids such as hydrochloric acid, hydrobromic acid or hydroiodic acid, 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 carboxylic acids For example, 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-hydroxy Naphthalene-2-carboxylic acid, and sulfonic acids such as methanesulfonic acid or benzenesulfonic acid. These salts can be prepared from the compounds of formula (I) and (Id) by known salt forming methods.

  Compounds of formula (I) and (Id) containing acidic groups, such as carboxyl groups, can 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 metal or alkaline earth metal salts such as sodium, potassium, magnesium or calcium salts, or ammonia or pharmaceutically acceptable organic amines or heterocyclic bases such as ethanolamines, Including salts with benzylamines or pyridine. These salts can be prepared from the compounds of formula (I) and (Id) by known salt forming methods.

  In such compounds where asymmetric carbon atoms are present, these compounds may exist as individual optically active isomeric forms or mixtures thereof, for example racemic or diastereomeric mixtures. The present invention includes both the individual optically active R and S isomers and mixtures thereof, for example racemic or diastereomeric mixtures.

  The invention relates to any pharmaceutically acceptable wherein one or more atoms have the same atomic number but the atomic mass or mass number is replaced with an atom that is different from the atomic mass or mass number normally found in nature. Isotope-labelled compounds of formula (I) and (Id).

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

Substitution with heavy isotopes such as deuterium, i.e. ² H, can lead to certain therapeutic benefits due to great metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may be preferred in certain situations There is.

  Isotopically-labelled compounds of formulas (I) and (Id) were generally used earlier by conventional methods known to those skilled in the art or according to the methods described in the appended Examples and Preparation chapters. It can be produced by using a suitable isotope-labeled reaction material in place of the reaction material that is not isotope-labeled.

  The present invention in another aspect provides a process for the preparation of compounds of formula (I) and (Id). The scheme detailed below is a general scheme for the synthesis of compounds of formula (I) and (Id). It should be appreciated that the compound corresponding to the Roman numeral in the scheme does not match the Roman numeral of the claimed compound.

Compounds of formula (II) may be prepared using literature methods described in J. Org. Chem., 1995, 60, 2912 and Tetrahedron, 2002, 58, 2821.
By reacting a compound of formula (II) with a halogenating agent such as phosphorus oxybromide, undiluted or in a suitable solvent such as toluene, at a temperature ranging from room temperature to 140 ° C. Can be converted to a compound.

  Alternatively, the compound of formula (II) is reacted with nonafluorobutanesulfonyl fluoride in the presence of a base such as diisopropylethylamine and a catalyst such as N, N-dimethyl-4-aminopyridine in a solvent such as dichloromethane at room temperature. Or reacting with N-phenyltrifluoromethanesulfonimide in the presence of a base such as diisopropylethylamine in a suitable solvent such as 1,2-dimethoxyethane at a temperature ranging from room temperature to the reflux temperature of the solvent. Good. In addition, the compound of formula (II) is treated with trifluromethane sulfonic anhydride in the presence of a base, for example pyridine, in a solvent, for example dichloromethane, at a temperature ranging from −20 ° C. to ambient temperature. .

  Reacting a compound of formula (IV) from a compound of formula (III) with an appropriate aniline or phenol or thiophenol using Buchwald-Hartwig CN / S / O coupling conditions Can be obtained. The Buchwald-Hartwig reaction can be carried out using a catalyst such as tris (dibenzylideneacetone) dipalladium (0) or palladium acetate, a base such as potassium phosphate, sodium tert-butoxide, 1.8-diazobicyclo [5.4.1] undec- 7-ene or cesium carbonate, ligands such as 9,9′-dimethyl-4,5-bis (diphenylphosphino) -xanthene, 2,2′-bis (diphenylphosphino) -1-1′-binaphthyl, 2 -Dicyclohexylphosphino-2 '-(N, N-dimethylamino) biphenyl, 2-dicyclohexylphosphino-2', 6 '-(dimethoxy) biphenyl or tributylphosphine in the presence of a suitable solvent such as toluene, Reflux of solvent from room temperature in 2-dimethoxyethane, tetrahydrofuran or dioxane At temperatures ranging degrees, or 70 to 150 may be carried out under microwave irradiation, at a range of temperatures ° C..

  The compound of formula (V) is reacted from a compound of formula (IV) 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. Obtainable.

  The compound of formula (V) is converted to a functionalized hydroxylamine or amine and a suitable coupling agent such as O- (7-azabenzo-triazol-1-yl) -N, N, N ′, N′-tetra-methyluro. N-Hexafluorophosphate, N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride or N, N-dicyclohexylcarbodiimide, N-hydroxybenzotriazole and a suitable base such as diisopropylethylamine or triethylamine Can be treated in an aprotic solvent such as tetrahydrofuran, N, N-dimethylformamide, or dichloromethane at temperatures ranging from 0 ° C. to room temperature to give compounds of formula (VI). Alternatively, a compound of formula (VI) can be obtained directly from a compound of formula (IV) with an amine or hydroxylamine in the presence of a Lewis acid, such as trimethylaluminum, from a solvent, such as dichloromethane, from room temperature to the reflux temperature of the solvent. It can be obtained by reaction in a range of temperatures.

  A compound of formula (III) is converted to a compound of formula (VII) with [1- (chloromethyl) -4-fluoro-1,4-diazoniabicyclo [2.2.2] octane-bis (tetrafluoroborate). Can be converted by electrophilic halogenation using, for example, a suitable solvent such as acetonitrile at a temperature ranging from room temperature to 70 ° C.

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

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

A compound of formula (XI) from a compound of formula (II), the latter being a base such as NaH and an alkylating agent such as methyl iodide or a halogenating agent such as deoxyfluor, NCS, NBS, NIS and a suitable solvent, For example, it can be produced by reacting in THF or DMF at a temperature ranging from room temperature to 100 ° C.
Compounds of formula (XI) can be converted to compounds of formula (VII) using the same conditions described for the preparation of compounds of formula (II) (Scheme 1).

A compound of formula (XII) is prepared from a compound of formula (VII) in a base such as sodium hydroxide or lithium hydroxide and a protic solvent such as ethanol or methanol at a temperature ranging from room temperature to the reflux temperature of the solvent. It can be obtained by reacting.
The compound of formula (XII) can then be converted to the compound of formula (IX) using the S _N AR reaction. The latter is performed using an amide base such as LDA, LiHMDS, NaHMDS, or KHMDS in a suitable solvent such as THF, typically at a suitable temperature 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).

  Using a compound of formula (IX), a compound of formula (XIII), hydrazine and a reagent such as EDCI or PyBOP in the presence of HOBt in a suitable organic solvent such as DMF, THF or dichloromethane Can be converted by standard coupling methods.

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

Compound of formula (XV) is converted from compound of formula (XIV) with addition of the appropriate amine and recyclization of the intermediate acyl hydrazide using triphenylphosphine, triethylamine, and CCl ₄ in dichcloromethane. Can be obtained.

Aldehydes and ketones of formula (XVI) can be prepared from acids of formula (IX) using standard methods such as converting the acid to the corresponding wine levamide and treating with a suitable organometallic reagent.
Oxadiazoles of formula (XVII) can be prepared by acylating each amidoxime followed by dehydrative cyclization.
Acyl azides of formula (XVIII) can be prepared from compounds of general formula (IX) via acid halides, for example acid chloride, using standard conditions. The compound of formula (XVIII) can then be converted via the Curtius rearrangement to give the compound of general formula (XIX).
According to standard methods, the acid of formula (IX) is converted to the corresponding amides which are then dehydrated to give the corresponding nitriles of formula (XX). Treatment of the compound of formula (XX) with trimethylsilyl azide or NaN ₃ in a suitable aprotic solvent such as N, N-dimethylformamide at a temperature ranging from room temperature to 100 ° C. obtain.

The inhibitory properties of compounds of formula (I) and (Id) may be demonstrated using the following test methods:
The BRAF-MEK-ERK cascade assay is used to evaluate the effectiveness of these compounds as inhibitors of the MAP kinase pathway. Enzymatic cascade assays were performed using recombinant human activated BRAF (V599E) kinase (Cat No. 14-557), human full length inactivated MEK1 kinase (Cat No. 14-706) and human full length inactivated obtained from Upstate. Prepared using MAP kinase 2 / ERK2 (Cat No. 14-536) enzyme group. TR-FRET (time-resolved fluorescence-fluorescence resonance energy transfer) detection technique is used for reading. Assay buffer 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 500 nM in 384 well format. Contains a long chain biotin-peptide substrate (LCB-FFKNIVTPRTPPP). 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 (Cat. No. AD0176-Perkin Elmer), 20 nM SA-APC (Cat No. CR130-100- The TR-FRET signal (excitation 340 nm, emission 615 nm and 665 nm) is read on a Victor3 V fluorometer with a 50 μs delay time The data is calculated using a ratio of 665 nm to 615 nm reading The final DMSO concentration is 2.5% in this assay.
Each individual IC ₅₀ uses a 10-point dose response curve generated by GraphPad Prism software Version 4 (San Diego, California, USA) using a non-linear regression curve fit for sigmoidal dose response (variable slope) And decide.

An in vitro MAP kinase assay is constructed using activated MAP kinase 2 / ERK2 (Cat. No. 14-550) obtained from Upstate. TR-FRET detection technology is used for reading.
The assay buffer was 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. Including. The kinase reaction was stopped after 90 minutes with 10 mM EDTA, and a Lance detection mix (2 nM Eu labeled phospho-serine / threonine antibody (Cat. No. AD0176-Perkin Elmer), 20 nM SA-APC (Cat. No. CR130-100- The TR-FRET signal (excitation 340 nm, emission 615 nm and 665 nm) is read on a Victor3 V fluorometer with a 50 μs delay time The data is calculated using a ratio of 665 nm to 615 nm reading Final DMSO concentration is 2.5% in this assay.Compounds are screened by enzyme pre-incubation at 10 μM concentration in the presence of test compound for 45 minutes.

The radioactive filter binding assay is standardized with recombinant human activated BRAF (V599E) kinase (Cat No. 14-557) and kinase killed MEK1 (K97R) (Cat. No. 14-737) obtained from Upstate. Incorporation of ³² P into MEK1 (K97R) by BRAF (V599E) was performed using 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 μCi [γ ³² P] ATP and Measure with final assay buffer conditions of 500 mg MEK1 kinase killed 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 and washed 4 times with 0.75% orthophosphoric acid and finally with acetone. Read the dried P81 filter paper on a Micro-beta Trilux scintillation counter. The final DMSO concentration is 1% during the assay. Compounds are screened at a concentration of 10 μM by enzyme preincubation for 45 minutes in the presence of the test compound.

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

The cell viability assay with A375 cells is set up in a 96 well plate format using XTT.
XTT is a yellow tetrazolium salt that is cleaved to orange formazan pigment by mitochondria of metabolically active cells. A method that allows rapid determination with a microtiter to obtain reproducible and sensitive results.

  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 are allowed to adhere overnight, compounds are added to the wells at the following final concentrations: 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.001 μM, and 0.001 μM. 0001 μM. The assay is set up in triplicate for each concentration. Maintain DMSO concentration at 0.5% / well. XTT assay is performed 3 days after compound addition. The wells are washed once with PBS. 100 μL of DMEM medium without phenol red or FBS is added to each well. Prepare a working solution of XTT containing 1 mg / ml XTT and 100 μL / 5 ml PMS (stock concentration 0.383 mg / ml). Add 50 μL of XTT working solution to each well. The absorbance of the plate is read at 465 nm using a Spectramax 190 (Molecular Devices). Absorbance from media and XTT alone, without cells, is considered a blank and is subtracted from each well reading.

Percent viability is calculated assuming blank minus values from wells treated with DMSO alone are considered 100% viable. GI ₅₀ values are calculated using Graphpad Prism using a non-linear regression curve fit for sigmoidal dose response (slope with change).
Cell viability assays are further 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 for both prophylactic and therapeutic treatment of diseases or conditions associated with MEK overactivity and diseases or conditions modulated by the Raf / Ras / Mek pathway.

  Therefore, as a further aspect, the present invention provides a method of treating a disease or condition associated with MEK overactivity, or a disease or condition modulated by the MEK cascade, comprising a therapeutically effective amount of formula (I) or (Id ) Or a pharmaceutically acceptable salt thereof.

  In a further aspect, the present invention is a method of treating a proliferative disease, such as cancer, comprising administering an effective amount of a compound of formula (I) or (Id) or a pharmaceutically acceptable salt thereof, Regarding the method.

  Examples of cancer include, but are not limited to: hemangiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyosarcoma, fibroma, lipoma, teratoma; bronchogenic Carcinoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, alveolar (bronchiole) carcinoma, bronchial adenoma, lymphoma, chondroma hamartoma, inesothelioma, esophageal squamous cell carcinoma , Leiomyosarcoma, ductal adenocarcinoma, insulinoma, glucagon-producing tumor, gastrin-producing tumor, VIP-producing tumor, stomach and small intestine carcinoid tumor, adenocarcinoma, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma , Tubular adenoma, chorionic adenoma, hamartoma, Wilms tumor [nephroblastoma], leukemia, bladder and urethral squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, seminoma, teratocarcinoma, embryonal carcinoma, teratocareinoma ), Choriocarcinoma, interstitial Alveolar carcinoma, fibroadenoma, adenomatous tumor, hepatocellular carcinoma (hepatocellular carcinoma), hepatobiliary carcinoma, hepatoblastoma, hepatocellular adenoma, hemangioma, osteogenic sarcoma (osteosarcoma), malignant fibrous histiocytoma, Chondrosarcoma, Ewing sarcoma, malignant lymphoma (lyinphoma sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteochondro-exostoma), benign chondroma, chondroblast Cytomas, chondromyxoid fibromas, osteoid and giant cell tumors, osteomas, granulomas, xanthomas, osteoarthritis, meningiomas, meningiosarcomas, gliomatosis, astrocytomas, medulloblasts Tumor, glioma, ependymoma, germinoma [pineoloma], glioblastoma multiforme, oligodendroglioma, Schwannoma, retinoblastoma, congenital tumor, spinal neurofibroma, marrow Melanoma, glioma, endometrial carcinoma, cervical carcinoma, precancerous cervical glandular dysplasia, ovarian carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, granulosa-capsular cell tumor Tumor, Sertoli-Leydig cell tumor, anaplastic germoma, malignant teratoma, intraepithelial carcinoma, adenocarcinoma, melanoma), clear cell carcinoma of the vagina, grapevine sarcoma (embryonic rhabdomyosarcoma), Fallopian tube carcinoma Acute and chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma, malignant lymphoma, malignant melanoma, basal Cell carcinoma, mole, dysplastic nevi, hemangioma, dermal fibroma, keloid, psoriasis, and neuroblastoma.

  The compounds of the invention may also be useful in the treatment of diseases or conditions associated with other MEK overactivity. Therefore, as a further aspect, the present invention relates to a method of treating a disorder selected from: xenograft (cellos, skin, limb, organ or bone marrow transplant) rejection; osteoarthritis; rheumatic Cystic fibrosis; diabetic complications (including diabetic retinopathy and diabetic nephropathy); hepatomegaly; cardiac hypertrophy; stroke (eg acute focal ischemic stroke and global cerebral ischemia); heart failure; septic Asthma; chronic obstructive pulmonary disorder; Alzheimer's disease; and chronic or neuropathic pain.

  The term “chronic pain” for 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 many conditions, including but not limited to inflammation, and postoperative pain.

  As used herein, the term “neuropathic pain” refers to inflammation, postoperative pain, phantom limb pain, burn pain, gout, trigeminal neuralgia, acute herpes and postherpetic pain, burning pain, diabetic neuropathy, plexus detachment Associated with many conditions including, but not limited to, neuroma, vasculitis, viral infection, crash injury, stenosis injury, tissue injury, limb amputation, and nerve injury between the peripheral and central nervous systems .

  The compounds of the present invention may be used as antiviral agents for viral infections such as HIV, hepatitis (B) virus (HBV), human papilloma virus (HPV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV). Useful for treatment.

  The compounds of the present invention may also be useful in 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 useful in combination with one other pharmacologically active compound or in combination with two or more pharmacologically active compounds, particularly in the treatment of cancer. For example, a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, can be converted into a chemotherapeutic agent such as a mitotic inhibitor, such as taxanes, vinca alkaloids, paclitaxel, docetaxel, vincristine, vinblastine. Simultaneously with one or more drugs selected from vinorelbine or vinflunine and other anticancer agents such as cisplatin, 5-fluorouracil or 5-fluoro-2-4 (1H, 3H) -pyrimidinedione (5FU), flutamide or gemcitabine May be administered sequentially or separately.
Such a combination may provide considerable benefits including synergistic activity in therapy.

  The compounds of formula (I) or (Id) can also be utilized in combination with other antiproliferative compounds. Such antiproliferative compounds include: aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors, such as LBH589; A cyclooxygenase inhibitor; an MMP inhibitor; an mTOR inhibitor such as RAD001; an anti-neoplastic antimetabolite; a platin compound; a compound that targets / reduces protein or lipid kinase activity and an additional anti-angiogenic compound; Compounds that target, decrease or inhibit activity; gonadorelin agonists; antiandrogens; methionine aminopeptidase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; Inhibitors; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, decrease or inhibit the activity of Flt-3, eg PKC412; Hsp90 inhibitors; For example, 17-AAG (17-allylamino-geldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (Conforma Therapeutics ) And AUY922; temozolomide (TEMODAL); kinesin spindle protein inhibitors such as SB715992 or SB743921 (GlaxoSmithKline), or pentamidine / chlorpromazine (CombinatoRx); PI3K inhibitors such as BEZ235; RAF inhibitors such as RAF265; EDG binders; Anti-leukemic compound, ribonucleotide redac Over peptidase inhibitors, S- adenosylmethionine decarboxylase inhibitors, including antiproliferative antibodies or other chemotherapeutic compounds, but are not limited to. In addition to or in addition to these, they may be used in combination with surgery, ionizing radiation, photodynamic therapy, eg implants containing corticosteroids, other tumor treatment methods including hormonal agents. Or they may be used as radiosensitizers. Combinations with anti-inflammatory agents are also included in anti-inflammatory and / or anti-proliferative treatments. Combinations with antihistamines, bronchodilatatory drugs, NSAIDs or chemokine receptor antagonists are also possible.

  The term “aromatase inhibitor” as used herein relates to compounds which inhibit estrogen production, ie the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term refers to steroids, especially atamestan, exemestane and formestane, and especially non-steroids, especially aminoglutethimide, logretimide, pyridoglutethimide, trirostan, test lactone, ketoconazole, borozole, fadrazole, anastrozole and letrozole Including, but not limited to. Exemestane can be administered, eg, in the form as it is marketed, eg under the trademark AROMASIN. Formestane 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. Aminoglutethimide can be administered, eg, in the form as it is marketed, eg under the trademark ORIMETEN. A combination of the invention comprising a chemotherapeutic agent that is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, particularly breast tumors.

  The term “antiestrogens” as used herein is based on compounds that antagonize the action of estrogens 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 described in US 4,659,516, or can be administered, eg, in the form as it is marketed, eg under the trademark FASLODEX. A combination of the invention comprising a chemotherapeutic agent that is an anti-estrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors.

  The term “anti-androgen” as used herein refers to any substance capable of inhibiting the biological properties of androgen, including but not limited to bicalutamide (CASODEX) which can be formulated as disclosed in US Pat. No. 4,636,505, for example.

  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.

  As used herein, the term “topoisomerase I inhibitor” refers to compound A1) of topotecan, gimatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin and macromolecular camptothecin conjugate PNU-166148 (WO 99/17804). Including, but 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.

  The term “topoisomerase II inhibitor” refers to anthracyclines such as doxorubicin (including liposomal formulations such as CAELYX), daunorubicin, epirubicin, idarubicin and nemorubicin, anthraquinones mitoxantrone and rosoxanthrone, and podophyllotoxins. Including but not limited to 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” relates to microtubule stabilization, microtubule destabilization compounds and microtubule polymerization inhibitors and relates to taxanes such as paclitaxel and docetaxel, vinca alkaloids such as vinblastine, especially vinblastine sulfate, vincristine and particularly sulfate. Vincristine, and vinorelbine, discodermrides, cochicine and epothilones and derivatives thereof, including but not limited to epothilone B or D or derivatives thereof. Paclitaxel can be administered, eg, in the form as it is marketed, eg, taxol. Docetaxel can be administered, eg, in the form as it is marketed, eg under the trademark Taxotere. Vinblastine sulfate 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. Discodemolide can be obtained, for example, as disclosed in US 5,010,099. Also included are the epothilone derivatives disclosed in WO 98/10121, US 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO 00/31247. Particularly preferred is epothilone A and / or B.

  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 has antiproliferative activity. This is the LDH589 disclosed in sodium butyrate, 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 its pharmaceutically acceptable salts, particularly lactate, but not limited to. In addition, suberoylanilide hydroxamic acid (SAHA), MS275, FK228 (formerly FR901228), trichostatin A and the compounds disclosed in US 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 antimetabolite” includes 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylated compounds such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folate antagonists such as pemetrexed. It is not limited to. 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.

  The term “platin compound” as used herein includes, but is not limited to carboplatin, cisplatin, cisplastin 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.

The terms “compounds that target / reduce protein or lipid kinase activity”; or “protein or lipid phosphatase activity”; or “further anti-angiogenic compounds” are protein tyrosine kinases and / or serine and / or threonine kinase inhibitors or Lipid kinase inhibitors, including but not limited to the following:
a) a compound that targets, decreases or inhibits the activity of platelet derived growth factor receptor (PDGFR), eg a compound which targets, decreases or inhibits the activity of PDGFR, in particular a compound which inhibits the PDGF receptor, eg N -Phenyl-2-pyrimidin-amine derivatives such as imatinib, SU101, SU6668 and GFB-111;
b) a compound that targets, decreases or inhibits the activity of fibroblast growth factor receptor (FGFR);
c) a compound which targets, decreases or inhibits the activity of insulin-like growth factor receptor I (IGF-IR), eg a compound which targets, decreases or inhibits the activity of IGF-IR, in particular a kinase of the IGF-I receptor A compound that inhibits the activity, such as a compound disclosed in WO 02/092599, or an antibody targeting the extracellular domain of the IGF-I receptor or a growth factor thereof;
d) a compound that targets, decreases or inhibits the activity of the Trk receptor tyrosine kinase family, or an ephrin B4 inhibitor;
e) a compound that targets, decreases or inhibits the activity of the Axl receptor tyrosine kinase family;
f) a compound that targets, decreases or inhibits the activity of the Ret receptor tyrosine kinase;
g) Compounds that target, decrease or inhibit the activity of Kit / SCFR receptor tyrosine kinases, ie, C-kit receptor tyrosine kinases— (part of the PDGFR family), such as those of the c-Kit receptor tyrosine kinase family Compounds that target, decrease or inhibit activity, in particular compounds which inhibit the c-Kit receptor, such as imatinib;
h) Compounds that target, reduce or inhibit the activity of c-Abl family members, their gene fusion products (eg, BCR-Abl kinase) and variants, eg, c-AbI family members and their gene fusion product activities Compounds that target, reduce or inhibit, eg N-phenyl-2-pyrimidin-amine derivatives such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 (ParkeDavis); or dasatinib (BMS-354825)
i) Raf family of protein kinase C (PKC) and serine / threonine kinases, members of MEK, SRC, JAK, FAK, PDK1, PKB / Akt, and Ras / MAPK family members, and / or the cyclin dependent kinase family ( Compounds that target, reduce or inhibit the activity of members of CDK), in particular the staurosporine derivatives disclosed in US 5,093,330, eg midostaurin; examples of further compounds are eg UCN-01, saphingol, BAY 43-9006, Bryostatin 1, Perifosine; Ilmofosin; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531 / LY379196; Isoquinoline compounds as disclosed in WO 00/09495; FTIs; BEZ235 (P13K inhibitor) Or AT7519 (a CDK inhibitor);
j) Targeting, reducing or inhibiting the activity of protein-tyrosine kinase inhibitors, including compounds which target, reduce or inhibit the activity of protein-tyrosine kinase inhibitors, for example imatinib mesylate (GLEEVEC) or tyrophostin. Compound. Tyrophostin is preferably a compound selected from low molecular weight (mw <1500) compounds, or pharmaceutically acceptable salts thereof, in particular benzylidene malonitrile class or S-arylbenzene malonitrile or bisubstrate quinoline class), More specifically Tyrophostin A23 / RG-50810; AG 99; Tyrophostin AG 213; Tyrophostin AG 1748; Tyrophostin AG 490; Tyrophostin B44; Tyrophostin B44 (+) enantiomer; Tyrophostin AG 555; AG 494; Tyrophostin AG 556, AG957 and A compound selected from the group consisting of adaphostin (4-{[(2,5-dihydroxyphenyl) methyl] amino} -benzoic acid adamantyl ester; NSC 680410, adaphostin);
k) Compounds that target, decrease or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their variants, such as epidermal growth factor Compounds that target, decrease or inhibit the activity of the receptor family are compounds that specifically inhibit EGF receptor tyrosine kinase family members such as EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF-related ligands , Proteins or antibodies, in particular compounds of WO 97/02266 (eg Example 39)), or EP 0564409, WO 99/03854, EP 0 520 722, EP 0 566 226, EP 0 787 722, EP 0 870663, US 5 , 747,498, WO 98/10767, WO 97/30034, WO 97/49688, WO 97/38983, and in particular compounds of WO 96/30347 (eg known as compound CP 358774), WO 96/33980 (eg compound ZD 1839) and WO 95 / 03283 (eg compound ZM105180) compounds and proteins or monoclonal antibodies generally and specifically disclosed; eg Traceptumab (Herceptin), Cetuximab (Erbitux), Iressa, 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- disclosed in WO03 / 013541 Pyrrolo- [2,3-d] pyrimidine derivatives; and l) compounds that target, decrease or inhibit the activity of c-Met receptors, eg, target and decrease the activity of c-Met Or compound that inhibits, in particular c-Met receptor kinase active compounds that inhibit, or c-Met antibodies of the extracellular domain that binds to or HGF targets.

  Additional anti-angiogenic compounds include compounds having another mechanism for their activity, eg, independent of protein or lipid kinase inhibition, such as thalidomide (THALOMID) and TNP-470.

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

  The compound that induces the cell differentiation process is, for example, retinoic acid, or tocopherol or tocotrienol.

  As used herein, the term cyclooxygenase inhibitor includes, for example, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenyl acetic acids and derivatives such as celecoxib (CELEBREX), rofecoxib (VIOXX), etoroxixib, valdecoxib or 5-alkyl-2 -Arylaminophenylacetic acid, including but not limited to, 5-methyl-2- (2'-chloro-6'-fluoroanilino) phenylacetic acid, lumiracoxib.

  The term “bisphosphonates” as used herein includes, but is not limited to, etidolone, clodrone, tiludron, pamidron, alendron, ibandron, risedron and zoledronic acid. “Etridonic acid” can be administered, eg, in the form as it is marketed, eg under the trademark DIDRONEL. “Clodronic 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. “Pamidronic 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. “Risedronic 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 mammalian target of rapamycin (mTOR) and have antiproliferative activity, such as Rapamune, Everticus, CCI-779 and ABT578.

  The term “heparanase inhibitor” as used herein means a compound that targets, decreases or inhibits heparin sulfate degradation. The term includes, but is not limited to PI-88.

  The term “biological response modifier” as used herein refers to lymphokines or interferons, such as interferons.

  As used herein, the term “Ras carcinogenic isoform, eg, an inhibitor of H-Ras, K-Ras, or N-Ras” refers to a compound that targets, decreases or inhibits the oncogenic activity of Ras, eg, “farnesyl. “Transferase inhibitor” means for example L-744832, DK8G557 or R115777 (Zarnestra).

  The term “telomerase inhibitor” as used herein means a compound that targets, decreases or inhibits the activity of telomerase. Compounds that target, reduce or inhibit the activity of telomerase are in particular compounds which inhibit the telomerase receptor, for example telomestatin.

  The term “methionine aminopeptidase inhibitor” as used herein means a compound that targets, decreases or inhibits the activity of methionine aminopeptidase. A compound that targets, decreases or inhibits the activity of methionine aminopeptidase is, for example, benamide or a derivative 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, reduce or inhibit the activity of the proteasome include, for example, Bortezomid (Velcade) and MLN 341.

  The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) refers to collagen peptidomimetic and non-peptidomimetic inhibitors, tetracycline derivatives, such as the hydroxamate peptidomimetic inhibitor batimastat and its oral bioavailable analogs Including, but not limited to, marimastat (BB-2516), purino mustat (AG3340), metastat (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

  As used herein, the term “compound used in the treatment of hematological malignancies” targets, decreases or inhibits the activity of an FMS-like tyrosine kinase inhibitor, eg, FMS-like tyrosine kinase receptor (Flt-3R). Interferon, 1-bD-arabinofuranosyl (aras-c) and bisulfan; and ALK inhibitors such as compounds that target, decrease or inhibit anaplastic lymphoma kinase However, it is not limited to these.

  Compounds that target, decrease or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R) are in particular compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, eg PKC412, TKI258, midostaurin , Staurosporine derivatives, SU11248 and MLN518.

  As used herein, the term “HSP90 inhibitor” includes compounds that target, decrease or inhibit the endogenous ATPase activity of HSP90; compounds that target, decrease or inhibit HSP90 client proteins via the proteosome pathway, It is not limited to. Compounds that target, decrease or inhibit the endogenous ATPase activity of HSP90 include compounds, proteins or antibodies that specifically inhibit the ATPase activity of HSP90, eg, 17-allylamino, 17-demethoxygeldanamycin (17AAG), gel Danamycin derivatives; other geldanamycin-related compounds, and radicicol.

  The term “anti-proliferative antibody” as used herein includes, but is not limited to, Traceptumab (Herceptin), Trastuzumab-DM1, Erbitux, Bevacizumab (Avastin), Rituximab (Rituxan), PRO64553 (anti-CD40) and 2C4 antibody. . Antibody refers to antibody fragments as long as they exhibit, for example, intact monoclonal antibodies, polyclonal antibodies, multi-characteristic regressions made from at least two intact antibodies, and the desired biological activity.

  For the treatment of acute myeloid leukemia (AML), the compound of formula (I) can be used in combination with standard leukemia therapy, particularly in combination with the therapy used for AML. In particular, the compounds of formula (I) are for example farnesyltransferase inhibitors and / or other agents useful for the treatment of AML, such as daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, Can be administered in combination with carboplatin and PKC412.

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

  As used herein, a somatostatin receptor antagonist refers to a compound that targets, decreases or inhibits the somatostatin receptor, such as octreotide, and SOM230 (pasireotide).

  Tumor cytotoxicity means a method like ionizing radiation. The term “ionizing radiation” means ionizing radiation that occurs either as electromagnetic waves (eg, X-rays and gamma rays) or particles (eg, alpha and beta particles), as described above and hereinafter. Ionizing radiation is provided as, but not limited to, radiation therapy and is known in the art. See 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 group of immunosuppressants that regulate lymphocyte recirculation, such as FTY720.

  The term “ribonucleotide reductase inhibitor” refers to fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C for ALL) ) And / or pyrimidine or purine nucleoside analogs including but not limited to pentostatin. Ribonucleotide reductase inhibitors are particularly hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives such as Nandy et al., Acta Oncologica, Vol. 33, No. 8, pp. 953-961 ( 1994), PL-1, PL-2, PL-3, PL-4, PL-5, PL-6, PL-7 or PL-8.

  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.

  In particular, compounds disclosed in WO 98/35958, proteins or monoclonal antibodies of VEGF such as 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine or pharmaceutically acceptable salts thereof such as succinate Or WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO 00/27819 and EP 0769947; Pretwett et al, Cancer Res, Vol. 59, pp. 5209-5218 (1999); Yuan et al., Proc Natl Acad Sci USA, 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); disclosed in WO00 / 37502 and WO94 / 10202; O'Reilly et al., Cell, Vol. 79, pp. 315-328 (1994) Angiostatin as described in O'Reilly et endostatin described by al., Cell, Vol. 88, pp. 277-285 (1997); anthranilic amides; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibody or anti-VEGF receptor antibody Also included are, for example, rhuMAb and RHUFab, VEGF aptamers such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgG1 antibodies, Angiozyme (RPI 4610) and bevacizumab (Avastin).

  Photodynamic therapy as used herein refers to therapy using certain chemicals known as photosensitizing compounds for the treatment or prevention of cancer. Examples of photodynamic therapy include treatment using compounds such as VISUDYNE and porfimer sodium.

  As used herein, angiogenesis-inhibiting steroids are, for example, blood vessels such as anecortab, triamcinolone, hydrocortisone, 11-epihydrocortisol, cortexolone, 17-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone. A compound that blocks or prevents formation.

  Corticosteroid-containing implants mean compounds such as fluocinolone, dexamethasone.

  “Other chemotherapeutic compounds” include plant alkaloids, hormone compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNAs or siRNAs; or miscellaneous compounds Or a compound having an unknown mechanism of action, but not limited thereto.

  The structure of the active compounds identified by code number, generic name or trade name can be taken from the current edition of the standard introduction “The Merck Index” or from databases such as Patents International (eg IMS World Publications).

  None of the references cited herein should be construed as an admission that these references have a negative impact on 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 agents, For example: Anakinra; anti-cytokine and anti-cytokine receptor agents such as anti-IL-6RAb, anti-IL-15Ab, anti-IL-17Ab, anti-IL-12Ab; B cell and T cell modulators such as anti-CD20Ab; CTL4-Ig, Disease-modifying anti-rheumatic agents (DMARDs) such as methotrexate, leflunamide, sulfasalazine; gold salts, penicillamine, hydroxychloroquine and chloroquine, azathioprine, glucocorticoids and nonsteroidal anti-inflammatory drugs (NSAIDs) such as cyclooxygenase inhibitors, selective COX-2 inhibitor regulates immune cell migration Agents, such as chemokine receptor antagonists, modulators of adhesion molecules, such as inhibitors of LFA-1, VLA-4.

The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) or (Id) or a prodrug thereof and a pharmaceutically acceptable additive.
In yet 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 carriers that release an active compound of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of the present invention may be obtained by modifying functional groups present on the compounds of the present invention in such a way that the modification is cleaved to the parent compound of the present invention by routine manipulation or in vivo. Can be manufactured.

  In yet another aspect of the invention, the additive is a binder, anti-adhesive, disintegrant, extender, diluent, flavoring agent, dye, glidant, lubricant, preservative, adsorbent and sweetener or Selected from the group consisting of:

  In yet another embodiment of the present invention, the composition is applied to tablets, troches, lozenges, aqueous or oily suspensions, ointments, patches, gels, lotions, toothpastes, capsules, emulsions. Formulated in a variety of dosage forms selected from the group comprising creams, sprays, drops, dispersible powders or granules, emulsions in hard or soft gel capsules, syrups and elixirs.

  The dosage of the inventive agent used in the practice of the invention will depend, for example, on the particular condition being treated, the effect desired and the mode of administration. In general, a suitable daily dosage for suitable oral administration is 0.1 to 10 mg / kg.

The invention is further illustrated by the following non-limiting examples, in which 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] octanebis (tetrafluoroborate)
Dess-martin periodinane: 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one DCM: dichloromethane THF: tetrahydrofuran DMF: dimethylformamide DIBAL-H: diisobutyl Aluminum hydride EtOH: Ethanol EtOAc: Ethyl acetate Triflic anhydride: Trifluro methanesulfonic anhydride;
DCM: dichloromethane;
Pd (OAc) ₂ : palladium acetate;
Cs ₂ CO ₃ : cesium carbonate;
BINAP: 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl;
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-d ₆ : deuterated dimethyl sulfoxide,
CDCl ₃ : deuterated chloroform,
LC-MS: liquid chromatography-mass spectrometry,
HPLC: High performance liquid chromatography or high performance liquid chromatography.

  The examples described herein are only illustrative of the present invention and therefore should not be construed as limiting the scope of the invention.

ピロリジン−２−オン(８５ｇ、１mol)を、２時間かけて、撹拌している硫酸ジメチル(１２６ｇ、１mol)溶液に、窒素雰囲気下滴下する。反応混合物を１６時間、６０℃で撹拌する。反応混合物を氷に注ぎ、飽和炭酸カリウム溶液、ジエチルエーテル(２×５００ml)で抽出し、塩水で洗浄し、乾燥させる(無水硫酸ナトリウム)。有機抽出物を減圧下、２０℃で除去して、７３ｇの粗５−メトキシ−３,４−ジヒドロ−２Ｈ−ピロールを明黄色液体として得る。この化合物を次工程にさらに精製せずに使用する。表題化合物のＮＭＲスペクトルは理論値に従う。
¹H NMR (CDCl₃, 300 MHZ): δ 3.80 (s, 3H), 3.66 (t, 2H), 2.48 (t, 2H), 2.08-1.95 (m,2H)。 Example 1
Process 1
The compounds of steps I and II can be prepared according to the methods 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) is added dropwise over 2 hours to the stirring solution of dimethyl sulfate (126 g, 1 mol) under a nitrogen atmosphere. The reaction mixture is stirred for 16 hours at 60 ° C. The reaction mixture is poured onto ice, extracted with saturated potassium carbonate solution, diethyl ether (2 × 500 ml), washed with brine and dried (anhydrous sodium sulfate). The organic extract is removed under reduced pressure at 20 ° C. to give 73 g of crude 5-methoxy-3,4-dihydro-2H-pyrrole as a light yellow liquid. This compound is used in the next step without further purification. The NMR spectrum of the title compound follows the theoretical value.
¹ H NMR (CDCl ₃ , 300 MHZ): δ 3.80 (s, 3H), 3.66 (t, 2H), 2.48 (t, 2H), 2.08-1.95 (m, 2H).

トリエチルアミンを、５−メトキシ−３,４−ジヒドロ−２Ｈ−ピロール(７３ｇ、０.７３mmol)および３−オキソペンタンジオイック酸ジエチルエステル(２００ｇ、０.９９mmol)の混合物に室温で添加する。得られた溶液を５日間撹拌し、反応混合物を濾過して、３９ｇ(２４％収率)の７−ヒドロキシ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エチルエステルを白色固体として得る。表題化合物のＮＭＲスペクトルは理論値に従う。
¹H NMR (CDCl₃, 300 MHZ): δ 11.4 (s, 1H), 5.80 (s, 1H), 4.40 (q, 2H), 4.15 (t, 2H), 3.50 (t, 2H), 2.3-2.15 (m, 2H), 1.40 (t, 3H)。 Process 2
Synthesis of 7-hydroxy-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester

Triethylamine is added to a mixture of 5-methoxy-3,4-dihydro-2H-pyrrole (73 g, 0.73 mmol) and 3-oxopentanedioic acid diethyl ester (200 g, 0.99 mmol) at room temperature. The resulting solution was stirred for 5 days and the reaction mixture was filtered to give 39 g (24% yield) of 7-hydroxy-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid. The ethyl ester is obtained as a white solid. The NMR spectrum of the title compound follows the theoretical value.
¹ H NMR (CDCl ₃ , 300 MHZ): δ 11.4 (s, 1H), 5.80 (s, 1H), 4.40 (q, 2H), 4.15 (t, 2H), 3.50 (t, 2H), 2.3-2.15 (m, 2H), 1.40 (t, 3H).

撹拌している７−ヒドロキシ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エチルエステル(６０mg、０.２mmol)およびトリエチルアミン(３０mg、０.４mmol)の５mlのジクロロメタン溶液を−７８℃に冷却する。トリフル酸無水物(９１mg、０.３２mmol)を２０分間かけて滴下し、得られた反応混合物を２時間、環境温度でＴＬＣモニタリングしながら撹拌する(１００％ＥｔＯＡｃ)。反応混合物を水性重炭酸ナトリウム溶液(４ml)および水(４ml)で洗浄する。有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮し、得られた生成物を溶離剤として１５％酢酸エチルのヘキサン溶液を使用するシリカゲルカラムクロマトグラフィー(６０−１２０メッシュ)で精製して、４０mg(４８％収率)の表題化合物を得る。
LC-MS純度: 95%, m/z 356 (M+1)。
¹H NMR (CDCl₃, 300 MHZ): δ 6.15 (s, 1H), 4.40 (q, 2H), 4.20 (t, 2H), 3.58 (t, 2H), 2.32-2.2 (m, 2H), 1.40 (t, 3H)。 Process 3
Synthesis of 5-oxo-7-trifluoromethanesulfonyloxy-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester

5 ml of stirring 7-hydroxy-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester (60 mg, 0.2 mmol) and triethylamine (30 mg, 0.4 mmol) Cool the dichloromethane solution to -78 ° C. Triflic anhydride (91 mg, 0.32 mmol) is added dropwise over 20 minutes and the resulting reaction mixture is stirred for 2 hours at ambient temperature with TLC monitoring (100% EtOAc). The reaction mixture is 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 purified the product obtained by silica gel column chromatography using hexane to 15% ethyl acetate as eluent (60-120 mesh), 40 mg (48% yield) of the title compound is obtained.
LC-MS purity: 95%, m / z 356 (M + 1).
¹ H NMR (CDCl ₃ , 300 MHZ): δ 6.15 (s, 1H), 4.40 (q, 2H), 4.20 (t, 2H), 3.58 (t, 2H), 2.32-2.2 (m, 2H), 1.40 (t, 3H).

撹拌している５−オキソ−７−トリフルオロメタンスルホニルオキシ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エチルエステル(２.３ｇ、６.４mmol)、２−フルオロ−４−ブロモ−アニリン(１.２５ｇ、６.５mmol)、炭酸セシウム(３.１７ｇ、９.７mmol)、ＢＩＮＡＰ(０.６ｇ、０.９７mmol)およびＰｄ(ＯＡｃ)_２(０.１５ｇ、０.６４mmol)のトルエン(１００ml)懸濁液を、８０℃で、１６時間加熱する。反応をＴＬＣ(９：１ ＣＨＣｌ_３−ＭｅＯＨ ｖ／ｖ)でモニターする。反応混合物を酢酸エチル(６０ml)で希釈し、濾過する。濾液を水(１００ml)で洗浄し、水性層を酢酸エチル(３０ml)で再抽出する。合わせた有機抽出物を乾燥させ(無水Ｎａ_２ＳＯ_４)、濃縮し、粗生成物を０.１−０.５％ＭｅＯＨのクロロホルム溶液を使用するシリカゲルカラムクロマトグラフィー(６０−１２０メッシュ)で精製して、３３６mg(１３％収率)の表題化合物を得る。
LC-MS純度: 98%, m/z 395, 397(M+, Brパターン)。
¹H NMR (DMSO-D₆, 300 MHZ): δ 9.48 (s, 1H), 7.70 (d, 1H), 7.49-7.39 (m, 2H), 5.32 (s, 1H), 4.30 (q, 2H), 3.95 (t, 2H), 3.48 (t, 2H), 2.14-2.0 (m, 2H), 1.30 (t, 3H)。 Process 4
Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester

Stirring 5-oxo-7-trifluoromethanesulfonyloxy-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester (2.3 g, 6.4 mmol), 2-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) A toluene (100 ml) suspension of is heated at 80 ° C. for 16 hours. The reaction is monitored by TLC (9: 1 CHCl ₃ -MeOH v / v). The reaction mixture is diluted with ethyl acetate (60 ml) and filtered. The filtrate is washed with water (100 ml) and the aqueous layer is re-extracted with ethyl acetate (30 ml). Dry the organic extracts combined (anhydrous _Na 2 SO _4), concentrated, purified by silica gel column chromatography of the crude product using a chloroform solution of 0.1-0.5% MeOH (60-120 mesh) To give 336 mg (13% yield) of the title compound.
LC-MS purity: 98%, m / z 395, 397 (M +, Br pattern).
¹ H NMR (DMSO-D ₆ , 300 MHZ): δ 9.48 (s, 1H), 7.70 (d, 1H), 7.49-7.39 (m, 2H), 5.32 (s, 1H), 4.30 (q, 2H) , 3.95 (t, 2H), 3.48 (t, 2H), 2.14-2.0 (m, 2H), 1.30 (t, 3H).

７−(４−ブロモ−２−フルオロ−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エチルエステル(２８０mg、０.７１mmol)のＴＨＦ：ＭｅＯＨ(４：１、ｖ／ｖ、６ml)溶液に、１Ｎ 水性ＬｉＯＨ溶液(２ml)を添加する。得られた混合物を３時間、室温でＴＬＣモニタリングしながら撹拌する(ＣＨＣｌ_３−ＭｅＯＨ、８：２)。反応混合物のｐＨを１０％水性ＨＣｌ溶液で１に調節し、得られた沈殿を濾過し、水(２０ml)および酢酸エチル(１０ml)で洗浄して、２４０mg(９２％収率)の表題化合物を得る。
LC-MS純度: 96%, m/z 367, 369(M+, Brパターン)。
¹H NMR (DMSO-D₆, 300 MHZ): δ 13.40 (s, 1H), 9.90 (s, 1H) 7.70 (d, 1H), 7.45 (s, 2H), 5.35 (s, 1H), 3.95 (t, 2H), 3.49 (t, 2H), 2.15-2.0 (m, 2H)。 Example 2
Synthesis of 7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid

7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester (280 mg, 0.71 mmol) in THF: MeOH ( 4: 1, v / v, 6 ml) To the solution is added 1N aqueous LiOH solution (2 ml). The resulting mixture is 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 with 10% aqueous HCl solution and 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. obtain.
LC-MS purity: 96%, m / z 367, 369 (M +, Br pattern).
¹ H NMR (DMSO-D ₆ , 300 MHZ): δ 13.40 (s, 1H), 9.90 (s, 1H) 7.70 (d, 1H), 7.45 (s, 2H), 5.35 (s, 1H), 3.95 ( t, 2H), 3.49 (t, 2H), 2.15-2.0 (m, 2H).

撹拌している７−(４−ブロモ−２−フルオロ−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(１４０mg、０.３８mmol)の１０mlの乾燥ＤＭＦ溶液に、ＥＤＣＩ(２２０mg、１.１４mmol)およびＨＯＢｔ(１６０mg、１.１４mmol)を添加する。反応混合物を３０分間撹拌し、Ｏ−シクロプロピルメチルヒドロキシルアミン(１４１mg、１.１４mmol)およびＴＥＡ(２３２mg、１.１４mmol)で処理する。得られた反応混合物を１６時間ＴＬＣモニタリングしながら撹拌する(ＭｅＯＨ−ＣＨＣｌ_３ ２：８、ｖ／ｖ)。反応混合物を酢酸エチル(２０ml)で希釈し、飽和水性ＮＨ_４Ｃｌ溶液(２５ml)、飽和水性ＮａＨＣＯ_３溶液(２５ml)および塩水(２５ml)で洗浄する。合わせた有機抽出物を乾燥させ(無水Ｎａ_２ＳＯ_４)、濃縮する。残留物質をシリカゲルカラムクロマトグラフィー(１％ＭｅＯＨのＣＨＣｌ_３溶液)で精製して、表題化合物を３６％収率で得る。
LC-MS純度: 97%, m/z 436, 438 (M+, Brパターン)。
¹H NMR (DMSO-D₆, 300 MHZ): δ 11.20 (s, 1H), 8.25 (s, 1H), 7.65 (d,1H), 7.45-7.3 (m, 2H), 5.38 (s, 1H), 3.91 (t, 2H), 3.72 (d, 2H), 3.25 (t, 2H), 2.15-2.0 (m, 2H), 1.18-1.02 (m, 1H), 0.6-0.5 (m, 2H), 0.31-0.25 (m, 2H)。 Example 3
Synthesis of 7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropyl-methoxy-amide

10 ml of stirring 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (140 mg, 0.38 mmol) To the dry DMF solution, EDCI (220 mg, 1.14 mmol) and HOBt (160 mg, 1.14 mmol) are added. The reaction mixture is stirred for 30 minutes and treated with O-cyclopropylmethylhydroxylamine (141 mg, 1.14 mmol) and TEA (232 mg, 1.14 mmol). The resulting reaction mixture is stirred for 16 h with TLC monitoring (MeOH—CHCl ₃ 2: 8, v / v). The reaction mixture is 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 are dried (anhydrous Na ₂ SO ₄ ) and concentrated. The residual material is purified by silica gel column chromatography (1% MeOH in CHCl ₃ ) to give the title compound in 36% yield.
LC-MS purity: 97%, m / z 436, 438 (M +, Br pattern).
¹ H NMR (DMSO-D ₆ , 300 MHZ): δ 11.20 (s, 1H), 8.25 (s, 1H), 7.65 (d, 1H), 7.45-7.3 (m, 2H), 5.38 (s, 1H) , 3.91 (t, 2H), 3.72 (d, 2H), 3.25 (t, 2H), 2.15-2.0 (m, 2H), 1.18-1.02 (m, 1H), 0.6-0.5 (m, 2H), 0.31 -0.25 (m, 2H).

実施例３と同じ反応条件を使用して、７−(４−ブロモ−２−フルオロ−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロインドリジン−８−カルボン酸(０.２ｇ、０.５４４mmol)をメトキシルアミンヒドロクロライド(１３６mg、１.６３mmol)を反応させて、粗生成物を得る。生成物のシリカゲルカラムクロマトグラフィー(４％メタノールのＣＨＣｌ_３溶液)および分取ＨＰＬＣによる精製により、表題化合物を１６％収率で得る。
LC-MS純度: 99.27%, m/z= 396, 398.9, (M⁺ Brパターン)。
¹H NMR: (DMSO-D₆ 300 MHZ): 11.4 (s, 1H), 8.4 (s, 1H), 7.7-7.6 (m, 1H), 7.5-7.3 (m, 2H), 7.223 (t, 1H), 5.3 (s, 1H), 3.9 (t, 2H), 3.3-3.1 (m, 4H), 3.0 (s, 3H), 2.1 (t, 2H)。 Example 4
Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylic acid methoxylamide

Using the same reaction conditions as in Example 3, 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylic acid (0. 2 g, 0.544 mmol) is reacted with methoxylamine hydrochloride (136 mg, 1.63 mmol) to give the crude product. Purification of the product by silica gel column chromatography (4% methanol in CHCl ₃ ) and preparative HPLC affords the title compound in 16% yield.
LC-MS purity: 99.27%, m / z = 396, 398.9, (M ⁺ Br pattern).
¹ H NMR: (DMSO-D ₆ 300 MHZ): 11.4 (s, 1H), 8.4 (s, 1H), 7.7-7.6 (m, 1H), 7.5-7.3 (m, 2H), 7.223 (t, 1H ), 5.3 (s, 1H), 3.9 (t, 2H), 3.3-3.1 (m, 4H), 3.0 (s, 3H), 2.1 (t, 2H).

実施例３と同じ反応条件を使用して、７−(４−ブロモ−２−フルオロ−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロインドリジン−８−カルボン酸(０.２ｇ、０.５４４mmol)を、塩化アンモニウムおよびトリエチルアミンを用いて表題化合物に変換する。試験用化合物は、シリカゲルカラムクロマトグラフィー(５％メタノールのＣＨＣｌ_３溶液)の後、白色固体として３０％収率で得られる。
LC-MS純度: 98.74%, m/z= 366, 368, (M⁺ Brパターン)
¹H NMR: (DMSO-D₆ 300 MHZ): 9.0 (s, 1H), 7.7-7.6 (m, 2H), 7.4 (t, 2H), 5.3 (s, 1H), 3.9 (t, 2H), 3.2-3.1 (m, 2H), 3.0 (s, 3H), 2.1 (t, 2H) Example 5
Synthesis of 7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylic acid amide

Using the same reaction conditions as in Example 3, 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylic acid (0. 2 g, 0.544 mmol) is converted to the title compound using ammonium chloride and triethylamine. The test compound is obtained in 30% yield as a white solid after silica gel column chromatography (5% methanol in CHCl ₃ ).
LC-MS purity: 98.74%, m / z = 366, 368, (M ⁺ Br pattern)
¹ H NMR: (DMSO-D ₆ 300 MHZ): 9.0 (s, 1H), 7.7-7.6 (m, 2H), 7.4 (t, 2H), 5.3 (s, 1H), 3.9 (t, 2H), 3.2-3.1 (m, 2H), 3.0 (s, 3H), 2.1 (t, 2H)

実施例３と同じ反応条件を使用して、７−(４−ブロモ−２−フルオロ−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロインドリジン−８−カルボン酸(０.２ｇ、０.５４mmol)をエトキシルアミンヒドロクロライドを用いて表題化合物に変換する。生成物のシリカゲルカラムクロマトグラフィー(５％メタノールのＣＨＣｌ_３溶液)および分取ＨＰＬＣによる精製により、試験用化合物を白色固体として２８％収率で得る。
LC-MS純度: 99.27%, m/z= 410, 412, (M⁺ Brパターン)。
¹H NMR: (DMSO-D₆ 300 MHZ): 11.4 (s, 1H), 8.3 (s, 1H), 7.7-7.5 (m, 1H), 7.5-7.3 (m, 2H), 5.3 (s, 1H), 4.0-3.8 (m, 4H), 3.4-3.2 (m, 2H), 2.1 (t, 2H), 1.2 (t, 3H)。 Example 6
Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylic acid ethoxyamide

Using the same reaction conditions as in Example 3, 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylic acid (0. 2 g, 0.54 mmol) is converted to the title compound using ethoxylamine hydrochloride. Purification of the product by silica gel column chromatography (5% methanol in CHCl ₃ ) and preparative HPLC affords the test compound as a white solid in 28% yield.
LC-MS purity: 99.27%, m / z = 410, 412, (M ⁺ Br pattern).
¹ H NMR: (DMSO-D ₆ 300 MHZ): 11.4 (s, 1H), 8.3 (s, 1H), 7.7-7.5 (m, 1H), 7.5-7.3 (m, 2H), 5.3 (s, 1H ), 4.0-3.8 (m, 4H), 3.4-3.2 (m, 2H), 2.1 (t, 2H), 1.2 (t, 3H).

７−(４−ブロモ−２−フルオロ−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸メトキシメチルアミド(０.１ｇ、０.２５mmol)の５ml 乾燥ＴＨＦ溶液に、窒素下、０.７６ml(０.７６mmol)のＤＩＢＡＨ−Ｈ(ジエチルエーテル中１.０Ｍ溶液)を５分間かけて、−７８℃で滴下する。反応混合物を−７８℃で４時間撹拌し、飽和水性塩化アンモニウム溶液(１０ml)でクエンチする。反応混合物を酢酸エチルで抽出し、合わせた有機抽出物を水および塩水で洗浄し、乾燥させ(無水硫酸ナトリウム)、濃縮する。表題化合物を、シリカゲルカラムクロマトグラフィー(２％メタノールのＣＨ_２Ｃｌ_２溶液)後、４１％収率で得る。
LC-MS純度: 90%, m/z= 350, (M+2 Brパターン)
HPLC: 92%
¹H NMR: (DMSO-D₆,, 300 MHZ): δ 10.0 (s, 1 H), 9.56 (s, 1H), 7.54 (d, 1H), 7.50 (s, 2H), 5.35 (s, 1H), 4.0 (t, 2H), 3.55 (t, 2 H), 2.4-2.2 (m, 2H)。 Example 7
Synthesis of 7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carbaldehyde

5 ml of 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxymethylamide (0.1 g, 0.25 mmol) To the dry THF solution, 0.76 ml (0.76 mmol) of DIBAH-H (1.0 M solution in diethyl ether) is added dropwise at −78 ° C. over 5 minutes under nitrogen. The reaction mixture is stirred at −78 ° C. for 4 hours and quenched with saturated aqueous ammonium chloride solution (10 ml). The reaction mixture is extracted with ethyl acetate and the combined organic extracts are washed with water and brine, dried (anhydrous sodium sulfate) and concentrated. The title compound is obtained in 41% yield after silica gel column chromatography (2% methanol in CH ₂ Cl ₂ ).
LC-MS purity: 90%, m / z = 350, (M + 2 Br pattern)
HPLC: 92%
¹ H NMR: (DMSO-D ₆ ,, 300 MHZ): δ 10.0 (s, 1 H), 9.56 (s, 1H), 7.54 (d, 1H), 7.50 (s, 2H), 5.35 (s, 1H ), 4.0 (t, 2H), 3.55 (t, 2 H), 2.4-2.2 (m, 2H).

７−ヒドロキシ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エチルエステル(５００mg、２.２mmol)のＰＯＣｌ_３(２ｇ、１３.４mmol)懸濁液に、ＴＥＡ(０.２２６ｇ、２.２mmol)を添加し、反応混合物を１４時間撹拌する。反応塊を氷水に注ぎ、混合物のｐＨを水性Ｋ_２ＣＯ_３溶液で７に調節する。反応混合物をＥｔＯＡｃで抽出し、合わせた有機抽出物を乾燥させ(無水Ｎａ_２ＳＯ_４)、濃縮する。表題化合物を、シリカゲルカラムクロマトグラフィー(１：１ ＥｔＯＡｃ−ヘキサン、ｖ／ｖ)後、７４％収率で得る。
LC-MS純度: 100%, m/z= 242, (M+)
¹H NMR (CDCl₃, 300 MHZ): 6.60 (s,1H), 4.40 (q, 2H), 4.12 (t, 2H), 3.50 (t, 2H), 2.32-2.19 (m, 2H), 1.40 (t, 3H)。 Example 8
Process 1
Synthesis of 7-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester

To a suspension of 7-hydroxy-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester (500 mg, 2.2 mmol) in POCl ₃ (2 g, 13.4 mmol) was added TEA. (0.226 g, 2.2 mmol) is added and the reaction mixture is stirred for 14 h. The reaction mass is poured into ice water and the pH of the mixture is adjusted to 7 with aqueous K ₂ CO ₃ solution. The reaction mixture is extracted with EtOAc and the combined organic extracts are dried (anhydrous Na ₂ SO ₄ ) and concentrated. The title compound is obtained in 74% yield after silica gel column chromatography (1: 1 EtOAc-hexane, v / v).
LC-MS purity: 100%, m / z = 242, (M +)
¹ H NMR (CDCl ₃ , 300 MHZ): 6.60 (s, 1H), 4.40 (q, 2H), 4.12 (t, 2H), 3.50 (t, 2H), 2.32-2.19 (m, 2H), 1.40 ( t, 3H).

７−クロロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エチルエステル(１４.５ｇ、０.０６mol)および１−(クロロメチル)−４−フルオロ−１,４−ジアゾニアビシクロ[２.２.２]オクタン−ビス(テトラフルオロボレート)(４４.７ｇ、０.１３mol)の７００mlのＣＨ_３ＣＮ中の混合物を、撹拌しながら５−１０分間８０℃で加熱する；熱源を外す。揮発性成分を減圧下除去し、残留物質を水に溶解し、ＥｔＯＡｃで抽出する。合わせた有機抽出物を乾燥させ(無水Ｎａ_２ＳＯ_４)、濃縮して、１４ｇの粗生成物を得る。表題化合物を、シリカゲルカラムクロマトグラフィー(４０％ＥｔＯＡｃのヘキサン溶液)後３３％収率で得て、次工程にさらに精製せずに使用する。
LC-MS純度: 87%, m/z =260, (M+)。 Process 2
Synthesis of 7-chloro-6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester

7-Chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester (14.5 g, 0.06 mol) and 1- (chloromethyl) -4-fluoro-1, A mixture of 4-diazoniabicyclo [2.2.2] octane-bis (tetrafluoroborate) (44.7 g, 0.13 mol) in 700 ml CH ₃ CN is stirred for 5-10 minutes at 80 ° C. Heat; remove heat source. Volatiles are removed under reduced pressure and the residual material is dissolved in water and extracted with EtOAc. The combined organic extracts are dried (anhydrous Na ₂ SO ₄ ) and concentrated to give 14 g of crude product. The title compound is obtained in 33% yield after silica gel column chromatography (40% EtOAc in hexane) and used in the next step without further purification.
LC-MS purity: 87%, m / z = 260, (M +).

５.２ｇの７−クロロ−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エチルエステル(０.０２mol)を含む１２０mlのＴＨＦ：ＭｅＯＨ(４：１、ｖ／ｖ)溶液に３０mlの１Ｎ 水性ＬｉＯＨ溶液を添加し、全体を環境温度で３時間撹拌する。反応混合物のｐＨを１に調節し、それをＥｔＯＡｃで抽出する。合わせた有機抽出物を乾燥させ(無水Ｎａ_２ＳＯ_４)、濃縮して、粗生成物を得る。ＥｔＯＡｃでの摩砕により、表題化合物を７８％収率で灰色固体として得る。
LC-MS純度: 95%, m/z= 232, (M+)
¹H NMR (DMSO-D₆, 300 MHZ): 13.4 (s, 1H),s 4.08 (t, 2H), 3.30 (t, 2H), 2.18-2.06 (m, 2H)。 Process 3
Synthesis of 7-chloro-6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid

120 ml THF: MeOH (4: 5 g) containing 5.2 g 7-chloro-6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester (0.02 mol) 1, v / v) Add 30 ml of 1N aqueous LiOH solution to the solution and stir the whole at ambient temperature for 3 hours. The pH of the reaction mixture is adjusted to 1 and it is extracted with EtOAc. The combined organic extracts are dried (anhydrous Na ₂ SO ₄ ) and concentrated to give the crude product. Trituration with EtOAc gives the title compound as a gray solid in 78% yield.
LC-MS purity: 95%, m / z = 232, (M +)
¹ H NMR (DMSO-D ₆ , 300 MHZ): 13.4 (s, 1H), s 4.08 (t, 2H), 3.30 (t, 2H), 2.18-2.06 (m, 2H).

撹拌している２−フルオロ−４−ヨード−フェニルアミン(６.４ｇ、０.０２７mol)の６０ml ＴＨＦ溶液を、ＬＤＡ(４ｇ、０.０３７mol)で、−７８℃で窒素下処理する。２０分間後、７−クロロ−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２.５ｇ、０.０１１mol)を含むＴＨＦ(３３０ml)溶液を添加する。反応混合物をさらに３０分間、−７８℃で撹拌し、環境温度に温める。反応混合物を３日間撹拌し、揮発性成分を減圧下除去する。残留物質を５０mlの３Ｎ ＨＣｌ溶液および５０mlのジエチルエーテルに分配する。１５分間撹拌後、得られた固体を回収して、７２％収率の表題化合物を明褐色固体として得る。
LC-MS純度: 96%, m/z =433, (M+)
¹H NMR (DMSO-D₆, 300MHZ): δ 13.8-13.6 (br s, 1H), 9.42 (s, 1H), 7.62 (d, 1H), 7.48 (d, 1H), 6.9-6.8 (m, 1H), 4.04 (t, 2H), 3.46 (t, 2H), 2.18-2.04 (m, 2H)。 Process 4
Synthesis of 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid

A stirred solution of 2-fluoro-4-iodo-phenylamine (6.4 g, 0.027 mol) in 60 ml THF is treated with LDA (4 g, 0.037 mol) at −78 ° C. under nitrogen. After 20 minutes, a THF (330 ml) solution containing 7-chloro-6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2.5 g, 0.011 mol) was added. Added. The reaction mixture is stirred for an additional 30 minutes at −78 ° C. and warmed to ambient temperature. The reaction mixture is stirred for 3 days and volatile components are removed under reduced pressure. The residual material is partitioned between 50 ml of 3N HCl solution and 50 ml of diethyl ether. After stirring for 15 minutes, the resulting solid is collected to give a 72% yield of the title compound as a light brown solid.
LC-MS purity: 96%, m / z = 433, (M +)
¹ H NMR (DMSO-D ₆ , 300MHZ): δ 13.8-13.6 (br s, 1H), 9.42 (s, 1H), 7.62 (d, 1H), 7.48 (d, 1H), 6.9-6.8 (m, 1H), 4.04 (t, 2H), 3.46 (t, 2H), 2.18-2.04 (m, 2H).

実施例３と同じ反応条件を使用して、６−フルオロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(１００mg、０.２３mmol)、ＥＤＣＩ(１３３mg、０.６９mmol)およびＨＯＢｔ(９３mg、０.６９mmol)の６mlの乾燥ＤＭＦ中の混合物を３０分間撹拌し、Ｏ−シクロプロピルメチル−ヒドロキシルアミン(８６mg、０.６９mmol)およびＴＥＡ(７０mg、０.６９mmol)を合わせて、表題化合物を、シリカゲルカラムクロマトグラフィー(０−２％ＭｅＯＨのＣＨＣｌ_３溶液)の後、灰色固体として、３４％収率で得る。
LC-MS純度: 91%, m/z 500, (M-)
¹H NMR (DMSO-D₆, 300 MHZ): δ 11.40 (s, 1H), 8.08 (s, 1H), 7.58 (d, 1H), 7.42 (d, 1H), 6.86-6.76 (m, 1H), 4.00 (t, 2H), 3.52 (d, 2H), 3.18 (t, 2H), 2.2-2.0 (m, 2H), 1.08-0.98 (m, 1H), 0.57-0.47 (m, 2H), 0.27-0.19 (m, 2H)。 Example 9
Synthesis of 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide

Using the same reaction conditions as in Example 3, 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8- A mixture of carboxylic acid (100 mg, 0.23 mmol), EDCI (133 mg, 0.69 mmol) and HOBt (93 mg, 0.69 mmol) in 6 ml dry DMF was stirred for 30 min and O-cyclopropylmethyl-hydroxylamine ( 86 mg, 0.69 mmol) and TEA (70 mg, 0.69 mmol) were combined to give the title compound as a gray solid in 34% yield after silica gel column chromatography (0-2% MeOH in CHCl ₃ ). obtain.
LC-MS purity: 91%, m / z 500, (M-)
¹ H NMR (DMSO-D ₆ , 300 MHZ): δ 11.40 (s, 1H), 8.08 (s, 1H), 7.58 (d, 1H), 7.42 (d, 1H), 6.86-6.76 (m, 1H) , 4.00 (t, 2H), 3.52 (d, 2H), 3.18 (t, 2H), 2.2-2.0 (m, 2H), 1.08-0.98 (m, 1H), 0.57-0.47 (m, 2H), 0.27 -0.19 (m, 2H).

実施例５に記載するのと同じ反応条件および反応材を使用して、６−フルオロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(３００mg、０.６９mmol)を、２００mgの粗表題化合物に変換する。ＥｔＯＡｃおよびジエチルエーテルでの摩砕により、試験用化合物を４０％収率で、薄黄色固体として得る。
LC-MS純度: 96%, m/z 432, (M+)
¹H NMR (DMSO-D₆, 300 MHZ): δ 8.58 (s, 1H), 7.75 (d, 2H), 7.60 (d, 1H), 7.45 (d, 1H) 6.82-6.7 (m, 1H), 4.02 (t, 2H), 3.3 (t, 2H), 2.2-2.08 (m, 2H)。 Example 10
Synthesis of 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid amide

Using the same reaction conditions and reactants as described in Example 5, 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5- Tetrahydro-indolizine-8-carboxylic acid (300 mg, 0.69 mmol) is converted to 200 mg of the crude title compound. Trituration with EtOAc and diethyl ether gives the test compound as a pale yellow solid in 40% yield.
LC-MS purity: 96%, m / z 432, (M +)
¹ H NMR (DMSO-D ₆ , 300 MHZ): δ 8.58 (s, 1H), 7.75 (d, 2H), 7.60 (d, 1H), 7.45 (d, 1H) 6.82-6.7 (m, 1H), 4.02 (t, 2H), 3.3 (t, 2H), 2.2-2.08 (m, 2H).

実施例８、工程４のものと同一の反応条件および反応材を使用して、４−ブロモ−２−フルオロ−フェニルアミン(９２５mg、４.８mmol)を７−クロロ−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(４５０mg、１.９４mol)と合わせて、表題化合物を６０％収率で明褐色固体として得る。
LC-MS純度: 94%, m/z= 385, 387 (M+, Brパターン)
¹H NMR (DMSO-D₆, 300 MHZ): δ 13.9-13.80 (br s, 1H), 9.44 (s, 1H), 7.56 (d, 1H), 7.34 (d, 1H), 7.18-6.9 (m, 1H), 4.04 (t, 2H), 3.48 (t, 2H), 2.18-2.05 (m, 2H)。 Example 11
Synthesis of 7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid

Using the same reaction conditions and reactants as in Example 8, Step 4, 4-bromo-2-fluoro-phenylamine (925 mg, 4.8 mmol) was converted to 7-chloro-6-fluoro-5-oxo. Combine with -1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (450 mg, 1.94 mol) to give the title compound as a light brown solid in 60% yield.
LC-MS purity: 94%, m / z = 385, 387 (M +, Br pattern)
¹ H NMR (DMSO-D ₆ , 300 MHZ): δ 13.9-13.80 (br s, 1H), 9.44 (s, 1H), 7.56 (d, 1H), 7.34 (d, 1H), 7.18-6.9 (m , 1H), 4.04 (t, 2H), 3.48 (t, 2H), 2.18-2.05 (m, 2H).

実施例９のものと同一の反応条件および反応材を使用して、７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン(ndolizine)−８−カルボン酸(１００mg、０.２５mmol)を変換して、シリカゲルクロマトグラフィー(０−２％ＭｅＯＨのＣＨＣｌ_３溶液)の後、表題化合物を白色固体として３２％収率で得る。
LC-MS純度: 98%, m/z= 454, 456 (M+, Brパターン)。
¹H NMR (DMSO-D₆, 300 MHZ): δ 11.40 (s, 1H), 8.06 (s, 1H), 7.54 (d,1H), 7.28 (d, 1H), 7.04-6.94 (m, 1H), 4.00 (t, 2H), 3.52 (d, 2H), 3.20 (t, 2H), 2.18-2.04 (m, 2H), 1.08-0.98 (m, 1H), 0.55-0.45 (m, 2H), 0.28-0.19 (m, 2H)。 Example 12
Synthesis of 7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide

Using the same reaction conditions and reactants as in Example 9, 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro -After conversion of ndolizine-8-carboxylic acid (100 mg, 0.25 mmol) and chromatography on silica gel (0-2% MeOH in CHCl ₃ ), the title compound as a white solid, 32% yield Get in.
LC-MS purity: 98%, m / z = 454, 456 (M +, Br pattern).
¹ H NMR (DMSO-D ₆ , 300 MHZ): δ 11.40 (s, 1H), 8.06 (s, 1H), 7.54 (d, 1H), 7.28 (d, 1H), 7.04-6.94 (m, 1H) , 4.00 (t, 2H), 3.52 (d, 2H), 3.20 (t, 2H), 2.18-2.04 (m, 2H), 1.08-0.98 (m, 1H), 0.55-0.45 (m, 2H), 0.28 -0.19 (m, 2H).

実施例５に記載するのと同じ反応条件および反応材を使用して、７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２５０mg、０.６４mmol)を１４０mgの粗表題化合物に変換する。ＥｔＯＡｃおよびジエチルエーテルでの摩砕により、試験用化合物を２５％収率で明黄色固体として得る。
LC-MS純度: 99%, m/z 384, 386 (M+, Brパターン)。
¹H NMR (DMSO-D₆, 300 MHZ): δ 8.58 (s, 1H), 7.74 (d, 2H), 7.54 (d, 1H), 7.29 (d, 1H) 7.0-6.9 (m, 1H), 4.00 (t, 2H), 3.3 (t, 2H), 2.19-2.08 (m, 2H)。 Example 13
Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid amide

Using the same reaction conditions and reactants as described in Example 5, 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5- Tetrahydro-indolizine-8-carboxylic acid (250 mg, 0.64 mmol) is converted to 140 mg of the crude title compound. Trituration with EtOAc and diethyl ether gives the test compound as a light yellow solid in 25% yield.
LC-MS purity: 99%, m / z 384, 386 (M +, Br pattern).
¹ H NMR (DMSO-D ₆ , 300 MHZ): δ 8.58 (s, 1H), 7.74 (d, 2H), 7.54 (d, 1H), 7.29 (d, 1H) 7.0-6.9 (m, 1H), 4.00 (t, 2H), 3.3 (t, 2H), 2.19-2.08 (m, 2H).

７−ヒドロキシ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エチルエステル(７.５ｇ、３３.６mmol)のＴＨＦ溶液を、０℃で、撹拌している水素化ナトリウムのＴＨＦ懸濁液に、不活性雰囲気下滴下する。反応混合物を環境温度に温め、ヨードメタンで処理する。得られた反応混合物を２日間撹拌し(ＴＬＣモニタリング、１００％ＥｔＯＡｃ)、氷でクエンチする。揮発物を減圧下除去し、残った水性相を酢酸エチルで抽出する。合わせた有機抽出物を塩水で洗浄し、濃縮する。粗生成物のシリカゲルカラムクロマトグラフィー(７０％酢酸エチルのヘキサン溶液)により、３８％の収率で表題化合物を得る。
¹H NMR (DMSO-D₆): δ 11.5 (s, 1H), 4.3 (q, 2H), 4.0 (t, 2H), 3.48 (t, 2H), 2.1 (q, 2H), 1.8, (s, 3H), 1.3 (t, 3H)。 Example 14
Process 1
Synthesis of 7-hydroxy-6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester

A solution of 7-hydroxy-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester (7.5 g, 33.6 mmol) in THF at 0 ° C. with stirring hydrogen. Add dropwise to a THF suspension of sodium chloride under inert atmosphere. The reaction mixture is warmed to ambient temperature and treated with iodomethane. The resulting reaction mixture is stirred for 2 days (TLC monitoring, 100% EtOAc) and quenched with ice. Volatiles are removed under reduced pressure and the remaining aqueous phase is extracted with ethyl acetate. The combined organic extracts are washed with brine and concentrated. Silica gel column chromatography of the crude product (70% ethyl acetate in hexane) gives the title compound in 38% yield.
¹ H NMR (DMSO-D ₆ ): δ 11.5 (s, 1H), 4.3 (q, 2H), 4.0 (t, 2H), 3.48 (t, 2H), 2.1 (q, 2H), 1.8, (s , 3H), 1.3 (t, 3H).

実施例１、工程３に記載するのと同じ反応条件を使用して、７−ヒドロキシ−６−メチル−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エチルエステル(０.７５ｇ、３.１６mmol)を、トリフル酸無水物(１.０６ｇ、３.７９mmol)を用いて、１２時間、環境温度後、表題化合物に変換する。試験用化合物を、シリカゲルカラムクロマトグラフィー(２５％酢酸エチルのヘキサン溶液)後、４０％収率で得る。
¹H NMR (DMSO-D₆): 4.40 (q, 2H), 4.20 (t, 2H), 3.5 (t, 2H), 2.3-2.2 (m, 2H), 2.05 (s,3H), 1.35 (t, 3H)。 Process 2
Synthesis of 6-methyl-5-oxo-7-trifluoromethanesulfonyloxy-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester

7-Hydroxy-6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester using the same reaction conditions as described in Example 1, Step 3. (0.75 g, 3.16 mmol) is converted to the title compound with triflic anhydride (1.06 g, 3.79 mmol) after 12 hours at ambient temperature. The test compound is obtained in 40% yield after silica gel column chromatography (25% ethyl acetate in hexane).
¹ H NMR (DMSO-D ₆ ): 4.40 (q, 2H), 4.20 (t, 2H), 3.5 (t, 2H), 2.3-2.2 (m, 2H), 2.05 (s, 3H), 1.35 (t , 3H).

撹拌している６−メチル５−オキソ−７−トリフルオロメタンスルホニルオキシ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エチルエステル(０.４７ｇ、１.２６mmol)、２−フルオロ−４−ブロモ−アニリン(０.２８７ｇ、１.２６mmol)、炭酸セシウム(０.６１７ｇ、１.８９mmol)、ＢＩＮＡＰ(０.６ｇ、０.１９mmol)およびＰｄ(ＯＡｃ)_２(０.０２８ｇ、０.１２６mmol)を含むトルエン(１００ml)を、４時間、９０℃で加熱する。反応混合物を濾過し、濾液を濃縮する。残留物質を酢酸エチルに取り込み、２回塩水で洗浄し、乾燥させ(無水Ｎａ_２ＳＯ_４)、濃縮する。粗生成物のシリカゲルカラムクロマトグラフィー(７５％酢酸エチルのヘキサン溶液)により、表題化合物を１９％収率で得る。
LC-MS純度: 96.24%, m/z 409, (M+, Brパターン)。
¹H NMR (DMSO-D₆): δ 8.5 (s, 1H), 7.50 (d, 1H), 7.25 (d, 1H), 6.6 (t,1H), 4.2-4.0 (m, 4H), 3.45 (d, 2H), 2.2-2.1 (m, 2H), 1.70 (t, 3H), 1.3 (t, 3H)。 Process 3
Synthesis of 7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester

Stirring 6-methyl 5-oxo-7-trifluoromethanesulfonyloxy-1,2,3,5-tetrahydro-indolizine-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) in toluene (100 ml) is heated at 90 ° C. for 4 hours. The reaction mixture is filtered and the filtrate is concentrated. The residual material is taken up in ethyl acetate, washed twice with brine, dried (anhydrous Na ₂ SO ₄ ) and concentrated. Silica gel column chromatography (75% ethyl acetate in hexane) gives the title compound in 19% yield.
LC-MS purity: 96.24%, m / z 409, (M +, Br pattern).
¹ H NMR (DMSO-D ₆ ): δ 8.5 (s, 1H), 7.50 (d, 1H), 7.25 (d, 1H), 6.6 (t, 1H), 4.2-4.0 (m, 4H), 3.45 ( d, 2H), 2.2-2.1 (m, 2H), 1.70 (t, 3H), 1.3 (t, 3H).

水性ＮａＯＨ溶液(１ml、１Ｎ)を、ＴＨＦ：ＭｅＯＨ(３：１、ｖ／ｖ)溶媒混合物中の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−メチル−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エチルエステル(４０mg、０.１０mmol)に添加する。得られた反応混合物を３時間、室温で撹拌する。反応混合物のｐＨを１Ｎ 水性ＨＣｌ溶液で１.５に調節し、得られた沈殿を濾過し、水(２０ml)および酢酸エチル(１０ml)で洗浄して、表題化合物を５３％収率で得る。
LC-MS純度: 99.2%, m/z 381 (M+, Brパターン)。
¹H NMR (DMSO-D₆): δ 13.30 (s, 1H), 9.10 (s, 1H) 7.5 (d, 1H) 7.20 (d, 1H), 6.5 (s, 1H), 4.05 (t, 2H), 3.5 (t, 2H), 2.10 (t, 2H), 1.6 (s, 3H)。 Example 15
Synthesis of 7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid

Aqueous NaOH solution (1 ml, 1N) was added to 7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1 in THF: MeOH (3: 1, v / v) solvent mixture. , 2,3,5-Tetrahydro-indolizine-8-carboxylic acid ethyl ester (40 mg, 0.10 mmol). The resulting reaction mixture is stirred for 3 hours at room temperature. The pH of the reaction mixture is adjusted to 1.5 with 1N aqueous HCl solution and the resulting precipitate is filtered and washed with water (20 ml) and ethyl acetate (10 ml) to give the title compound in 53% yield.
LC-MS purity: 99.2%, m / z 381 (M +, Br pattern).
¹ H NMR (DMSO-D ₆ ): δ 13.30 (s, 1H), 9.10 (s, 1H) 7.5 (d, 1H) 7.20 (d, 1H), 6.5 (s, 1H), 4.05 (t, 2H) , 3.5 (t, 2H), 2.10 (t, 2H), 1.6 (s, 3H).

実施例９と同一の反応条件および反応材を使用して、７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−メチル−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(３００mg、０.７８７mmol)を、Ｏ−シクロプロピルメチルヒドロキシルアミンを用いて表題化合物に変換し、シリカゲルクロマトグラフィー(１％ＭｅＯＨのＣＨＣｌ_３溶液)による精製後、８％収率で得る。
LC-MS純度: 92.7%, m/z 450 (M+, Brパターン)。
¹H NMR (DMSO-D₆): δ 11.20 (s, 1H), 7.7 (s, 1H), 7.5 (d, 1H), 7.2 (d, 1H), 6.56 (t, 1H), 4.0 (t, 2H), 3.5 (d, 2H), 3.2 (t, 2H), 2.18 (q, 2H), 1.78 (s, 3H), 1.0 (s,1H), 0.5 (d, 2H), 0.2 (d, 2H)。 Example 16
Synthesis of 7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide

Using the same reaction conditions and reactants as in Example 9, 7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-india Lysine-8-carboxylic acid (300 mg, 0.787 mmol) was converted to the title compound using O-cyclopropylmethylhydroxylamine and after purification by silica gel chromatography (1% MeOH in CHCl ₃ ), 8% yield. Get at a rate.
LC-MS purity: 92.7%, m / z 450 (M +, Br pattern).
¹ H NMR (DMSO-D ₆ ): δ 11.20 (s, 1H), 7.7 (s, 1H), 7.5 (d, 1H), 7.2 (d, 1H), 6.56 (t, 1H), 4.0 (t, 2H), 3.5 (d, 2H), 3.2 (t, 2H), 2.18 (q, 2H), 1.78 (s, 3H), 1.0 (s, 1H), 0.5 (d, 2H), 0.2 (d, 2H ).

撹拌している７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−メチル−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(３００mg、０.７８７mmol)の６mlの乾燥ＤＭＦおよび２mlのジクロロメタン中の溶液に、ＥＤＣＩ(１６５mg、０.８６５mmol)およびＨＯＢｔ(１１６mg、０.８６５mmol)を０℃で添加する。得られた反応混合物を２時間、０℃で撹拌し、連続的にＯ−(２−ビニルオキシ−エチル)−ヒドロキシルアミン(７１mg、０.７８７mmol)およびＴＥＡ(１５８mg、１.５７mmol)で処理する。１２時間後、反応混合物を酢酸エチルで希釈し、飽和水性ＮａＨＣＯ_３溶液で洗浄する。有機相を乾燥させ(無水Ｎａ_２ＳＯ_４)、減圧下濃縮する。残留物質をシリカゲルクロマトグラフィー(１％ＭｅＯＨのＣＨＣｌ_３溶液)して、１８０mgの表題化合物を低純度で得る。
LC MS: 31.7%, m/z= 466, (M+ Brパターン) Example 17
Process 1
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-vinyloxy-ethoxy) -amide Composition

Stirring 7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (300 mg, 0.787 mmol) ) In 6 ml dry DMF and 2 ml dichloromethane are added EDCI (165 mg, 0.865 mmol) and HOBt (116 mg, 0.865 mmol) at 0 ° C. The resulting reaction mixture is stirred for 2 hours at 0 ° C. and treated sequentially with O- (2-vinyloxy-ethyl) -hydroxylamine (71 mg, 0.787 mmol) and TEA (158 mg, 1.57 mmol). After 12 hours, the reaction mixture is diluted with ethyl acetate and washed with saturated aqueous NaHCO ₃ solution. The organic phase is dried (anhydrous Na ₂ SO ₄ ) and concentrated under reduced pressure. The residual material is chromatographed on silica gel (1% MeOH in CHCl ₃ ) to give 180 mg of the title compound in low purity.
LC MS: 31.7%, m / z = 466, (M + Br pattern)

粗７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２−ビニルオキシ−エトキシ)−アミド(１８０mg、０.３８６mmol)を、１mlの１Ｎ ＨＣｌ含有エタノールに溶解し、１６時間、室温で撹拌する。反応混合物を濃縮し、残留物を酢酸エチルに溶解する。有機相を塩水で洗浄し、濃縮し、残留物をシリカゲルカラムクロマトグラフィー(２％ＭｅＯＨのＣＨＣｌ_３溶液)して、表題化合物を３０％収率で得る。
LC MS: 96.5%, m/z= 440, (M+ Brパターン)
HPLC: 94.05%
¹H NMR (DMSO-D₆): δ 11.20 (s, 1H), 7.65 (s, 1H), 7.48 (d, 1H), 7.18 (d, 1H), 6.5 (t, 1H), 4.0 (t, 2H), 3.7 (t, 2H), 3.5 (s, 3H), 3.2 (t, 2H), 2.14 (quin, 2H), 1.72 (s, 3H)。 Process 2
Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy) -amide

Crude 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-vinyloxy-ethoxy) -amide (180 mg, 0.386 mmol) is dissolved in 1 ml of ethanol containing 1N HCl and stirred for 16 hours at room temperature. The reaction mixture is concentrated and the residue is dissolved in ethyl acetate. The organic phase is washed with brine, concentrated and the residue is chromatographed on silica gel (2% MeOH in CHCl ₃ ) to give the title compound in 30% yield.
LC MS: 96.5%, m / z = 440, (M + Br pattern)
HPLC: 94.05%
¹ H NMR (DMSO-D ₆ ): δ 11.20 (s, 1H), 7.65 (s, 1H), 7.48 (d, 1H), 7.18 (d, 1H), 6.5 (t, 1H), 4.0 (t, 2H), 3.7 (t, 2H), 3.5 (s, 3H), 3.2 (t, 2H), 2.14 (quin, 2H), 1.72 (s, 3H).

７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−メチル−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２００mg、０.５２４mmol)の６ml ＴＨＦ溶液に、ＴＢＴＵ(２９２mg、０.７８７mmol)およびＴＥＡ(７９mg、０.７８７mmol)含有ＴＨＦ溶液を０℃で添加する。反応混合物をゆっくりと室温に温め、１時間撹拌する。塩化アンモニウムを添加し、反応混合物をさらに環境温度で１２時間撹拌する。反応混合物を濃縮し、残留物を酢酸エチルに溶解する。有機相を水性ＮａＨＣＯ_３溶液で洗浄し、濃縮する。表題化合物を、中性アルミナカラムクロマトグラフィー(２％ＭｅＯＨのＣＨＣｌ_３溶液)後、２５％収率で得る。
LC MS: 93.7%, m/z= 380, (M+ Brパターン)。
HPLC: 98.7%
¹H NMR (DMSO-D₆): δ 7.7 (s,1H), 7.5 (dd, 1H), 7.2 (d, 1H), 6.5 (t, 1H), 4.0 (t, 2H), 3.3 (s, 2H), 2.1 (quin, 2H), 1.78 (s, 3H)。 Example 18
Synthesis of 7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid amide

7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (200 mg, 0.524 mmol) in 6 ml THF To the solution is added a solution of TBTU (292 mg, 0.787 mmol) and TEA (79 mg, 0.787 mmol) in THF at 0 ° C. The reaction mixture is slowly warmed to room temperature and stirred for 1 hour. Ammonium chloride is added and the reaction mixture is further stirred at ambient temperature for 12 hours. The reaction mixture is concentrated and the residue is dissolved in ethyl acetate. The organic phase is washed with aqueous NaHCO ₃ solution and concentrated. The title compound is obtained in 25% yield after neutral alumina column chromatography (2% MeOH in CHCl ₃ ).
LC MS: 93.7%, m / z = 380, (M + Br pattern).
HPLC: 98.7%
¹ H NMR (DMSO-D ₆ ): δ 7.7 (s, 1H), 7.5 (dd, 1H), 7.2 (d, 1H), 6.5 (t, 1H), 4.0 (t, 2H), 3.3 (s, 2H), 2.1 (quin, 2H), 1.78 (s, 3H).

実施例４と同じ反応条件および反応材を使用して、７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−メチル−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２００mg、０.５２５mmol)を、メトキシルアミンヒドロクロライド(４５mg、０.５５mmol)を用いて表題化合物に変換する。試験用化合物を、シリカカラムクロマトグラフィー(１％ＭｅＯＨのＣＨＣｌ_３溶液)により１９％収率で得る。
LC-MS純度: 96.42%, m/z= 410, (M+ Brパターン)。
HPLC: 97.8%
¹H NMR (DMSO-D₆): δ 11.20 (s, 1H), 7.7 (s, 1H), 7.5-7.4 (dd, 1H), 7.2 (d, 1H), 6.5 (t, 1H), 4.0 (t, 2H), 3.5 (s, 3H), 3.2 (t, 2H), 2.1 (quin, 2H), 1.78 (s, 3H)。 Example 19
Synthesis of 7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-amide

Using the same reaction conditions and reactants as in Example 4, 7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine The -8-carboxylic acid (200 mg, 0.525 mmol) is converted to the title compound using methoxylamine hydrochloride (45 mg, 0.55 mmol). The test compound is obtained in 19% yield by silica column chromatography (1% MeOH in CHCl ₃ ).
LC-MS purity: 96.42%, m / z = 410, (M + Br pattern).
HPLC: 97.8%
¹ H NMR (DMSO-D ₆ ): δ 11.20 (s, 1H), 7.7 (s, 1H), 7.5-7.4 (dd, 1H), 7.2 (d, 1H), 6.5 (t, 1H), 4.0 ( t, 2H), 3.5 (s, 3H), 3.2 (t, 2H), 2.1 (quin, 2H), 1.78 (s, 3H).

実施例３と同じ反応条件を使用して、７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−メチル−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２００mg、０.５２３mmol)をエトキシルアミンヒドロクロライド(５３mg、０.５５mmol)と反応させて、表題化合物を得る。試験用サンプルを、シリカゲルカラムクロマトグラフィー(１％ＭｅＯＨのＣＨＣｌ_３溶液)後、２３％収率で得る。
LC-MS純度: 95.58%, m/z=424, (M+ Brパターン)
HPLC: 98.61%
¹H NMR (DMSO-D₆): δ 11.20 (s, 1H), 7.7 (s, 1H), 7.5-7.4 (dd, 1H), 7.2 (d, 1H) 6.5 (t, 1H), 4.0 (t, 2H), 3.7 (q, 2H), 3.2 (t, 2H), 2.1 (quin, 2H), 1.78 (s, 3H), 1.1(t, 3H)。 Example 20
Synthesis of 7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethoxy-amide

Using the same reaction conditions as in Example 3, 7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8- Carboxylic acid (200 mg, 0.523 mmol) is reacted with ethoxylamine hydrochloride (53 mg, 0.55 mmol) to give the title compound. Test samples are obtained in 23% yield after silica gel column chromatography (1% MeOH in CHCl ₃ ).
LC-MS purity: 95.58%, m / z = 424, (M + Br pattern)
HPLC: 98.61%
¹ H NMR (DMSO-D ₆ ): δ 11.20 (s, 1H), 7.7 (s, 1H), 7.5-7.4 (dd, 1H), 7.2 (d, 1H) 6.5 (t, 1H), 4.0 (t , 2H), 3.7 (q, 2H), 3.2 (t, 2H), 2.1 (quin, 2H), 1.78 (s, 3H), 1.1 (t, 3H).

実施例３に記載する方法に従い１５０mgの２−(４−ブロモ−２−フルオロ−フェニルアミノ)−４−オキソ−６,７,８,９−テトラヒドロ−４Ｈ−キノリジン−１−カルボン酸(０.３９mmol)を、をＯ−シクロプロピルメチルヒドロキシルアミン用いて表題化合物に変換する。表題化合物を、シリカゲルカラムクロマトグラフィー(３％メタノールのＣＨＣｌ_３溶液)後、２９％収率で得る。
LC-MS純度: 99.3%, m/z = 451, (M+ Brパターン)
¹H NMR (DMSO-D₆): δ 11.8 (s, 1H), 7.64 (d, 1H), 7.54 (s, 1H), 7.4 (d, 1H), 7.3 (t, 1H), 5.2 (s, 1H), 3.8 (t, 2H), 3.7 (d, 2H), 2.7 (t, 2H), 1.85-1.65 (m, 4H), 1.1-1.0 (m, 1H), 0.55-0.45 (m, 2H), 0.3-0.2 (m, 2H)。 Example 21
Synthesis of 2- (4-bromo-2-fluoro-phenyl-amino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolizin-1-carboxylic acid-cyclopropyl-methoxyamide

According to the method described in Example 3, 150 mg of 2- (4-bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolidine-1-carboxylic acid (0. 39 mmol) is converted to the title compound using O-cyclopropylmethylhydroxylamine. The title compound is obtained in 29% yield after silica gel column chromatography (3% methanol in CHCl ₃ ).
LC-MS purity: 99.3%, m / z = 451, (M + Br pattern)
¹ H NMR (DMSO-D ₆ ): δ 11.8 (s, 1H), 7.64 (d, 1H), 7.54 (s, 1H), 7.4 (d, 1H), 7.3 (t, 1H), 5.2 (s, 1H), 3.8 (t, 2H), 3.7 (d, 2H), 2.7 (t, 2H), 1.85-1.65 (m, 4H), 1.1-1.0 (m, 1H), 0.55-0.45 (m, 2H) , 0.3-0.2 (m, 2H).

実施例１７、工程１と同一の反応条件を使用して、２−(４−ブロモ−２−フルオロ−フェニルアミノ)−４−オキソ−６,７,８,９−テトラヒドロ−４Ｈ−キノリジン−１−カルボン酸(２００mg、０.５２mmol)の５ml ＤＭＦ溶液を、Ｏ−(２−ビニルオキシ−エチル)−ヒドロキシルアミン(６４mg、０.６２mmol)を用いて表題化合物に変換する。精製生成物をシリカゲルカラムクロマトグラフィー(メタノール：クロロホルム)により、６２％収率で得る。 Example 22
Process 1
Synthesis of 2- (4-bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolidine-1-carboxylic acid- (2-vinyloxy-ethoxy) -amide

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

実施例１７、工程２と同一の反応条件を使用して、２−(４−ブロモ−２−フルオロ−フェニルアミノ)−４−オキソ−６,７,８,９−テトラヒドロ−４Ｈ−キノリジン−１−カルボン酸−(２−ビニルオキシ−エトキシ)−アミド(１５０mg、０.０３２mmol)を表題化合物に変換して、それを、分取ＨＰＬＣ後１２％収率で得る。
LC-MS純度: 98.7%, m/z = 441, (M+ Brパターン)。
¹H NMR (DMSO-D₆): δ 11.6 (s, 1H), 7.68-7.58 (dd, 2H), 7.46-7.42 (dd, 1H), 7.3 (t, 1H), 5.2 (s, 1H), 4.85 (t, 1H), 4.0 (t, 2H), 3.8 (t, 2H), 3.6 (q, 2H), 2.7 (t, 2H), 1.85-1.65 (m, 4H)。 Process 2
Synthesis of 2- (4-bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-1-carboxylic acid- (2-hydroxy-ethoxy) -amide

Using the same reaction conditions as in Example 17, Step 2, 2- (4-bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-1 -Carboxylic acid- (2-vinyloxy-ethoxy) -amide (150 mg, 0.032 mmol) is converted to the title compound, which is obtained in 12% yield after preparative HPLC.
LC-MS purity: 98.7%, m / z = 441, (M + Br pattern).
_{^{1 H NMR (DMSO-D 6}} ): δ 11.6 (s, 1H), 7.68-7.58 (dd, 2H), 7.46-7.42 (dd, 1H), 7.3 (t, 1H), 5.2 (s, 1H), 4.85 (t, 1H), 4.0 (t, 2H), 3.8 (t, 2H), 3.6 (q, 2H), 2.7 (t, 2H), 1.85-1.65 (m, 4H).

実施例５と同じ反応条件および反応材を使用して、２−(４−ブロモ−２−フルオロ−フェニルアミノ)−４−オキソ−６,７,８,９−テトラヒドロ−４Ｈ−キノリジン−１−カルボン酸(２００mg、０.５２mmol)を、メトキシルアミンヒドロクロライド(１３１mg、１.５２mmol)を用いて表題化合物に変換する。生成物のシリカゲルカラムクロマトグラフィー(３.５％ＭｅＯＨのＣＨＣｌ_３溶液)、分取ＨＰＬＣにより、２５mgの試験用化合物を得る。
LC-MS純度: 96.4%, m/z = 409.9, (M+ Brパターン)。
¹H NMR (DMSO-D₆): δ 11.65 (s, 1H), 7.64 (d, 1H), 7.59 (s, 1H), 7.4 (d, 1H), 7.3 (t, 1H), 5.2 (s, 1H), 3.8 (t, 2H), 3.7 (s, 3H), 2.7 (t, 2H), 1.85-1.65 (m, 4H)。 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 reactants as in Example 5, 2- (4-bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolidine-1- Carboxylic acid (200 mg, 0.52 mmol) is converted to the title compound using methoxylamine hydrochloride (131 mg, 1.52 mmol). Silica gel column chromatography of the product (3.5% MeOH in CHCl ₃ ), preparative HPLC yields 25 mg of the test compound.
LC-MS purity: 96.4%, m / z = 409.9, (M + Br pattern).
¹ H NMR (DMSO-D ₆ ): δ 11.65 (s, 1H), 7.64 (d, 1H), 7.59 (s, 1H), 7.4 (d, 1H), 7.3 (t, 1H), 5.2 (s, 1H), 3.8 (t, 2H), 3.7 (s, 3H), 2.7 (t, 2H), 1.85-1.65 (m, 4H).

実施例３と同じ反応条件および反応材を使用して、２−(４−ブロモ−２−フルオロ−フェニルアミノ)−４−オキソ−６,７,８,９−テトラヒドロ−４Ｈ−キノリジン−１−カルボン酸(２００mg、０.５２mmol)をエトキシルアミンヒドロクロライド(１５３mg、１.５mmol)と反応させて、５５mg(２５％収率)の表題化合物を分取ＨＰＬＣ後に得る。
LC-MS純度: 97.9%, m/z = 425.8, (M+ Brパターン)。
¹H NMR (DMSO-D₆): δ 11.6 (s, 1H), 7.64 (d, 1H), 7.52 (s, 1H), 7.4 (d, 1H), 7.3 (t, 1H), 5.2 (s, 1H), 4.0 (q, 2H), 3.8 (t, 2H), 2.7 (t, 2H), 1.85-1.65 (m, 4H), 1.3-1.15 (m, 3H)。 Example 24
Synthesis of 2- (4-bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolidine-1-carboxylic acid ethoxy-amide

Using the same reaction conditions and reactants as in Example 3, 2- (4-bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolidine-1- Carboxylic acid (200 mg, 0.52 mmol) is reacted with ethoxylamine hydrochloride (153 mg, 1.5 mmol) to give 55 mg (25% yield) of the title compound after preparative HPLC.
LC-MS purity: 97.9%, m / z = 425.8, (M + Br pattern).
¹ H NMR (DMSO-D ₆ ): δ 11.6 (s, 1H), 7.64 (d, 1H), 7.52 (s, 1H), 7.4 (d, 1H), 7.3 (t, 1H), 5.2 (s, 1H), 4.0 (q, 2H), 3.8 (t, 2H), 2.7 (t, 2H), 1.85-1.65 (m, 4H), 1.3-1.15 (m, 3H).

Example 25
Steps 1-4 were performed according to the method described in Example 1, and Step 5 was performed according to the method described in Example 2.

ＥＤＣＩ(３９０mg、０.００２mol)およびＨＯＢｔ(１６２mg、０.００２mol)を、撹拌している７−(４−ブロモ−２−フルオロ−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロインドリジン−８−カルボン酸(２５０mg、０.００１mol)のＤＭＦ(６mL)溶液に０℃で添加した。反応混合物を１時間、０℃で撹拌した。これに３−アミノ−プロパノール(０.１５６ml、０.００２mol)、ＴＥＡ(１mL、０.０１２mol)を添加した。反応混合物を、一夜、ＲＴで撹拌した。反応混合物を酢酸エチルおよび冷水(２０mL)に分配した。有機層をＮａＨＣＯ_３溶液で洗浄し、濃縮した。分取ＨＰＬＣによる精製により、４１mg(１４.１３％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(３−ヒドロキシ−プロピル)−アミドを得た。
LC-MS純度: 97.2%, m/z = 426, 428 (M+ Brパターン)
¹H NMR (DMSO-D₆, 300 MHZ) δ 8.68 (s, 1H), 8.28 (t, 1H), 7.7-7.6 (m, 1H), 7.5-7.3 (m, 2H), 5.49 (s, 1H), 3.9 (t, 2H), 3.5 (t, 2H), 3.4-3.1 (m, 4H), 2.1 (quin, 2H), 1.7-1.5 (q, 2H) Step 6
Synthesis of 7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (3-hydroxy-propyl) -amide

EDCI (390 mg, 0.002 mol) and HOBt (162 mg, 0.002 mol) were stirred with 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5- Tetrahydroindolizine-8-carboxylic acid (250 mg, 0.001 mol) was added to a solution of DMF (6 mL) at 0 ° C. The reaction mixture was stirred for 1 hour at 0 ° C. To this was added 3-amino-propanol (0.156 ml, 0.002 mol), TEA (1 mL, 0.012 mol). The reaction mixture was stirred overnight at RT. 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 41 mg (14.13% yield) of 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8. -Carboxylic acid (3-hydroxy-propyl) -amide was obtained.
LC-MS purity: 97.2%, m / z = 426, 428 (M + Br pattern)
¹ H NMR (DMSO-D ₆ , 300 MHZ) δ 8.68 (s, 1H), 8.28 (t, 1H), 7.7-7.6 (m, 1H), 7.5-7.3 (m, 2H), 5.49 (s, 1H ), 3.9 (t, 2H), 3.5 (t, 2H), 3.4-3.1 (m, 4H), 2.1 (quin, 2H), 1.7-1.5 (q, 2H)

Example 26
Steps 1 to 4 were performed according to the method described in Example 8.

ＥＤＣＩ(５３０mg、０.００３mol)およびＨＯＢｔ(３６４mg、０.００３mol)を、撹拌している６−フルオロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２００mg、０.４６mmol)のＤＭＦ(２０mL)およびＤＣＭ(１０mL)溶液に０℃で添加した。反応混合物を、２時間、０℃で撹拌した。Ｏ−(２−ビニルオキシ−エチル)−ヒドロキシルアミン(２８０mg、０.００３mol)、ＴＥＡ(２７２mg、０.００３mol)を反応フラスコに添加し、撹拌を２０時間、ＲＴで続けた。反応混合物を水および酢酸エチル(２０mL)に分配し、有機層を飽和ＮａＨＣＯ_３(２０mL)、ＮＨ_４Ｃｌ(２０mL)および塩水溶液(２０mL)で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。残留粗生成物(４５０mg)をさらに精製せずに次工程に使用した。
LCMS純度: 25%, m/z=518, (M+) Process 5
Of 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-vinyloxy-ethoxy) -amide Composition

EDCI (530 mg, 0.003 mol) and HOBt (364 mg, 0.003 mol) were stirred with 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2, To a solution of 3,5-tetrahydro-indolizine-8-carboxylic acid (200 mg, 0.46 mmol) in DMF (20 mL) and DCM (10 mL) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 2 hours. O- (2-vinyloxy-ethyl) -hydroxylamine (280 mg, 0.003 mol), TEA (272 mg, 0.003 mol) was added to the reaction flask and stirring was continued for 20 h at RT. The reaction mixture was partitioned between water and ethyl acetate (20 mL) and the organic layer was washed with saturated NaHCO ₃ (20 mL), NH ₄ Cl (20 mL) and brine solution (20 mL), dried over Na ₂ SO ₄ and concentrated. . The residual crude product (450 mg) was used in the next step without further purification.
LCMS purity: 25%, m / z = 518, (M +)

１Ｎ ＨＣｌ(３mL)を、撹拌しているＴＨＦおよびＥｔＯＨの１：１混合物(１２mL)中の６−フルオロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２−ビニルオキシ−エトキシ)−アミド(４５０mg、０.２２mmol)の溶液に添加した。反応混合物を９０分間撹拌した。反応混合物からの溶媒を留去し、反応混合物を水(３mL)に溶解し、ｐＨを２Ｎ ＮａＯＨ溶液で６に調節し、ＥｔＯＡｃとの間で分液した。有機層をＮａ_２ＳＯ_４で乾燥させ、濃縮した。分取ＨＰＬＣによる精製により、６１mg(２６％収率)の６−フルオロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２−ヒドロキシ−エトキシ)−アミドを白色固体として得た。
LCMS純度: 95%, m/z= 491.9, (M+)
HPLC: 96.6%
¹H NMR (DMSO-D₆, 300 MHz) 11.5-11.4 (br s, 1H), 8.2-8.0 (br s, 1H), 7.6 (d, 1H), 7.4 (d, 1H), 6.82-6.72 (m, 1H), 4.0 (t, 2H), 3.8 (t, 2H), 3.6 (t, 2H), 3.2 (t, 2H), 2.2-2.0 (m, 2H) Step 6
Of 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy) -amide Composition

1N HCl (3 mL) was added to 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2 in a stirring 1: 1 mixture of THF and EtOH (12 mL). , 3,5-tetrahydro-indolizine-8-carboxylic acid (2-vinyloxy-ethoxy) -amide (450 mg, 0.22 mmol) was added. The reaction mixture was stirred for 90 minutes. The solvent from the reaction mixture was distilled off, the reaction mixture was dissolved in water (3 mL), the pH was adjusted to 6 with 2N NaOH solution and partitioned between EtOAc. The organic layer was dried over Na ₂ SO ₄ and concentrated. Purification by preparative HPLC gave 61 mg (26% yield) of 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine. -8-carboxylic acid (2-hydroxy-ethoxy) -amide was obtained as a white solid.
LCMS purity: 95%, m / z = 491.9, (M +)
HPLC: 96.6%
¹ H NMR (DMSO-D ₆ , 300 MHz) 11.5-11.4 (br s, 1H), 8.2-8.0 (br s, 1H), 7.6 (d, 1H), 7.4 (d, 1H), 6.82-6.72 ( m, 1H), 4.0 (t, 2H), 3.8 (t, 2H), 3.6 (t, 2H), 3.2 (t, 2H), 2.2-2.0 (m, 2H)

Scheme 7

ＴＥＡ(５８.２７mmol、８.４mL)を、撹拌している７−ヒドロキシ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エチルエステル(１３ｇ、５８.２７mmol)の蒸留ＰＯＣｌ_３(３２ml、３４９mmol)溶液に添加した。反応混合物を１６時間、ＲＴで、窒素雰囲気下に撹拌した。ＰＯＣｌ_３を反応混合物から留去し、残留物を氷冷水に注ぎ、飽和Ｋ_２ＣＯ_３溶液で塩基性化した(ｐＨ＝８.５)。反応混合物をＥｔＯＡｃで抽出した。有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮し、濃縮物をカラムクロマトグラフィー(シリカゲルおよび溶離剤として７５％酢酸エチルのヘキサン溶液を使用)により精製して、７.５mg(５３.５％収率)の７−クロロ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エチルエステルを黄色固体として得た。
¹H NMR (DMSO-D₆, 300 MHz): δ 6.6-6.5 (br s, 1H), 4.4-4.3 (m, 2H), 4.2-4.1 (m, 2H), 3.5-3.3 (t, 2H), 2.3-2.2 (m, 2H), 1.4-1.3 (t, 2H) Example 27
Process 1
Synthesis of 7-chloro-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester

TEA (58.27 mmol, 8.4 mL) was stirred with 7-hydroxy-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester (13 g, 58.27 mmol). To a distilled POCl ₃ (32 ml, 349 mmol) solution. The reaction mixture was stirred for 16 h at RT under a nitrogen atmosphere. POCl ₃ was distilled off 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 and concentrated, and the concentrate was purified by column chromatography (silica gel and using 75% ethyl acetate in hexane as eluent) to give 7.5 mg (53.5% Yield) of 7-chloro-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester as a yellow solid.
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 6.6-6.5 (br s, 1H), 4.4-4.3 (m, 2H), 4.2-4.1 (m, 2H), 3.5-3.3 (t, 2H) , 2.3-2.2 (m, 2H), 1.4-1.3 (t, 2H)

１Ｎ ＬｉＯＨ(４０mL)を、撹拌している７−ヒドロキシ−５−オキソ−１,２,３,５−テトラヒドロ−インドリン−８−カルボン酸エチルエステル(７.５ｇ、３１.１mmol)の(４：１)ＴＨＦ：ＭｅＯＨ(７５mL)溶液に添加した。反応混合物を１５時間、室温で撹拌した。反応混合物を濃縮し、１Ｎ ＨＣｌで酸性化し、形成した沈殿を回収して、５.２ｇ(７８.７％収率)の７−クロロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸を白色固体として得た。
LC-MS純度: 99%, m/z=212, (M-1)
¹H NMR (DMSO-D₆, 300 MHz): δ 13.25-13.15 (br s, 1H), 6.4 (s, 1H), 4.0 (t, 3H), 2.15-2.05 (m, 3H)。 Process 2
Synthesis of 7-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid

1N LiOH (40 mL) was added to stirred 7-hydroxy-5-oxo-1,2,3,5-tetrahydro-indoline-8-carboxylic acid ethyl ester (7.5 g, 31.1 mmol) (4: 1) Added to THF: MeOH (75 mL) solution. The reaction mixture was stirred for 15 hours at room temperature. The reaction mixture was concentrated and acidified with 1N HCl and the precipitate formed was collected and 5.2 g (78.7% yield) of 7-chloro-5-oxo-1,2,3,5-tetrahydro- Indolizine-8-carboxylic acid was obtained as a white solid.
LC-MS purity: 99%, m / z = 212, (M-1)
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 13.25-13.15 (br s, 1H), 6.4 (s, 1H), 4.0 (t, 3H), 2.15-2.05 (m, 3H).

リチウムジイソプロピルアミド(１６.５ml、３２.８mmol)を、撹拌している２−フルオロ−４−ヨードアニリン(５.６ｇ、２３.４７mmol)の乾燥ＴＨＦ(４０mL)溶液に、−７８℃で窒素雰囲気下添加した。続いて７−クロロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２ｇ、９.３８mmol)の乾燥ＴＨＦ(１５０mL)溶液を添加し、得られた混合物を最初に３０分間、−７８℃およびＲＴで５日間撹拌した。反応混合物を濃縮し、１Ｎ ＨＣｌでｐＨが約２になるまで酸性化した。形成した沈殿を回収し、ジエチルエーテルで洗浄して、２.５ｇ(６５.７％収率)の７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸を白色固体として得た。
LC-MS純度: 92.8%, m/z=414.8, (M+1)
¹H NMR (DMSO-D₆, 300 MHz) δ 13.45-13.35 (br s, 1H), 10.05-9.95 (br s, 1H), 7.8 (dd, 1H), 7.6 (d, 1H), 7.4-7.2 (t, 1H), 5.4-5.3 (s, 1H), 4.0 (t, 2H), 3.5-3.4 (t, 2H), 2.1-2.0 (m, 2H) Process 3
Synthesis of 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-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 a nitrogen atmosphere. Added under. Subsequently, 7-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2 g, 9.38 mmol) in dry THF (150 mL) was added and the resulting mixture was added. Initially stirred for 30 minutes at −78 ° C. and RT for 5 days. The reaction mixture was concentrated and acidified with 1N HCl until the pH was about 2. The precipitate that formed was collected, washed with diethyl ether, and 2.5 g (65.7% yield) of 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3. , 5-tetrahydro-indolizine-8-carboxylic acid was obtained as a white solid.
LC-MS purity: 92.8%, m / z = 414.8, (M + 1)
¹ H NMR (DMSO-D ₆ , 300 MHz) δ 13.45-13.35 (br s, 1H), 10.05-9.95 (br s, 1H), 7.8 (dd, 1H), 7.6 (d, 1H), 7.4-7.2 (t, 1H), 5.4-5.3 (s, 1H), 4.0 (t, 2H), 3.5-3.4 (t, 2H), 2.1-2.0 (m, 2H)

Example 28
Steps 1 to 3 were performed according to the method described in Example 27.

ＥＤＣＩ(０.４１５mg、２.１７mmol)およびＨＯＢｔ(０.２９３mg、１.７mmol)を、撹拌している７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(０.３００mg、０.７２mmol)のＤＭＦ(５mL)およびＴＥＡ(０.０５mL)溶液に０℃で添加した。反応混合物を３０分間、０℃で窒素雰囲気下撹拌した。続いてＮＨ_４Ｃｌ(０.１１５mg、２.１７mmol)、ＴＥＡ(０.３ml、２.１７mmol)を添加し、反応混合物を６時間、ＲＴで撹拌した。反応混合物を水で希釈し、ＥｔＯＡｃで抽出した。有機層を水および塩水で洗浄し溶液。形成した沈殿を回収して、０.０４０mg(１３％収率)の７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸アミドを白色固体として得た。
LC-MS純度: 98.7%, m/z=412, (M-1)
¹H NMR (DMSO-D₆, 300 MHz) δ 9.0 (br s, 2H), 7.7 (dd, 1H), 7.7-7.6 (d, 1H), 7.3-7.2 (t, 1H), 5.5 (s, 1H), 3.9 (t, 2H), 2.1-2.0 (m, 2H) Process 4
Synthesis of 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid amide

EDCI (0.415 mg, 2.17 mmol) and HOBt (0.293 mg, 1.7 mmol) were stirred with 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2, To a solution of 3,5-tetrahydro-indolizine-8-carboxylic acid (0.300 mg, 0.72 mmol) in DMF (5 mL) and TEA (0.05 mL) was added at 0 ° C. The reaction mixture was stirred for 30 minutes at 0 ° C. under nitrogen atmosphere. Subsequently NH ₄ Cl (0.115 mg, 2.17 mmol), TEA (0.3 ml, 2.17 mmol) were added and the reaction mixture was stirred for 6 h at RT. The reaction mixture was diluted with water and extracted with EtOAc. Wash the organic layer with water and brine to give a solution. The precipitate that formed was collected and 0.040 mg (13% yield) of 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine- 8-Carboxamide was obtained as a white solid.
LC-MS purity: 98.7%, m / z = 412, (M-1)
¹ H NMR (DMSO-D ₆ , 300 MHz) δ 9.0 (br s, 2H), 7.7 (dd, 1H), 7.7-7.6 (d, 1H), 7.3-7.2 (t, 1H), 5.5 (s, 1H), 3.9 (t, 2H), 2.1-2.0 (m, 2H)

Example 29
Steps 1 to 3 were performed according to the method described in Example 27.

ＥＤＣＩ(０.１０１mg、０.５３mmol)およびＨＯＢｔ(０.０７２mg、０.５３mmol)を、撹拌している７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(０.２００mg,０.４８mmol)のＤＭＦ(４mL)およびＴＥＡ(０.１ml、１.４４mmol)溶液に、ＲＴで添加した。反応混合物を３０分間、ＲＴで窒素雰囲気下撹拌した。続いてＯ−シクロプロピルメチル−ヒドロキシルアミンヒドロクロライド(０.０７２mg、０.５７mol)、ＴＥＡ(０.４ml、１.４４mmol)を添加し、反応混合物を１８時間、ＲＴで撹拌した。反応混合物を水で希釈し、ＥｔＯＡｃで抽出した。有機層を水、ＮａＨＣＯ_３および塩水溶液で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。残留物をＤＣＭ(５mL)およびメタノール(１mL)から再結晶して、０.０５９mg(２５％収率)の７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸シクロプロピルメトキシ−アミドを褐色固体として得た。
LC-MS純度: 97%, m/z=481.9, (M-1)
¹H NMR (DMSO-D₆, 300 MHz) δ 11.4-11.3 (br s, 1H), 8.3-8.2 (br s, 1H) 7.7 (dd, 1H) 7.6-7.5, (d, 1H), 7.2 (t, 1H), 5.4 (s, 1H), 3.9 (t, 2H), 3.7-3.6 (d, 2H), 3.2-3.1 (m, 2H), 2.1-2.0 (m, 2H), 1.1-1.0 (m, 1H), 0.5-0.4 (m, 2H), 0.3-0.2 (m, 2H) Process 4
Synthesis of 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide

EDCI (0.101 mg, 0.53 mmol) and HOBt (0.072 mg, 0.53 mmol) were stirred with 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2, To a solution of 3,5-tetrahydro-indolizine-8-carboxylic acid (0.200 mg, 0.48 mmol) in DMF (4 mL) and TEA (0.1 mL, 1.44 mmol) was added at RT. The reaction mixture was stirred for 30 minutes at RT under a nitrogen atmosphere. Subsequently O-cyclopropylmethyl-hydroxylamine hydrochloride (0.072 mg, 0.57 mol), TEA (0.4 ml, 1.44 mmol) were added and the reaction mixture was stirred for 18 h at RT. 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 0.059 mg (25% yield) of 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2 , 3,5-Tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide was obtained as a brown solid.
LC-MS purity: 97%, m / z = 481.9, (M-1)
¹ H NMR (DMSO-D ₆ , 300 MHz) δ 11.4-11.3 (br s, 1H), 8.3-8.2 (br s, 1H) 7.7 (dd, 1H) 7.6-7.5, (d, 1H), 7.2 ( t, 1H), 5.4 (s, 1H), 3.9 (t, 2H), 3.7-3.6 (d, 2H), 3.2-3.1 (m, 2H), 2.1-2.0 (m, 2H), 1.1-1.0 ( m, 1H), 0.5-0.4 (m, 2H), 0.3-0.2 (m, 2H)

Example 30
Steps 1 to 3 were performed according to the method described in Example 27.

濃Ｈ_２ＳＯ_４(０.６mL)を、ＥｔＯＨ(５mL)に溶解した撹拌している７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(０.３００mg、０.７２mol)溶液に添加し、反応混合物を３日間、８５℃で窒素雰囲気下撹拌した。反応混合物を濃縮し、ＥｔＯＡｃおよび水に分配した。有機層をＮａＨＣＯ_３、塩水溶液で洗浄し、濃縮し、ジエチルエーテルで洗浄した。カラムクロマトグラフィー(シリカゲルおよび溶離剤として１.５％メタノールのクロロホルム溶液を使用)による精製により、０.０９５mg、(２９.６％収率)の７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エチルエステルを白色固体として得た。
LC-MS純度: 96%, m/z=443, (M+1)
¹H NMR (DMSO-D₆, 300 MHz) δ 9.5-9.4 (br s, 1H), 7.8 (dd, 1H) 7.6 (d, 1H) 7.3-7.2 (m, 1H), 5.4-5.3 (br s, 1H), 4.4-4.2 (m, 2H), 3.9 (t, 2H), 3.5 (t, 2H), 2.1-2.0 (m, 2H), 1.4-1.2 (m, 3H) Process 4
Synthesis of 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester

Concentrated H ₂ SO ₄ (0.6 mL) was dissolved in EtOH (5 mL) with stirring 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5- Tetrahydro-indolizine-8-carboxylic acid (0.300 mg, 0.72 mol) was added to the solution and the reaction mixture was stirred for 3 days at 85 ° C. under 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. Purification by column chromatography (using silica gel and 1.5% methanol in chloroform as eluent) gave 0.095 mg, (29.6% yield) of 7- (2-fluoro-4-iodo-phenylamino). ) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester was obtained as a white solid.
LC-MS purity: 96%, m / z = 443, (M + 1)
¹ H NMR (DMSO-D ₆ , 300 MHz) δ 9.5-9.4 (br s, 1H), 7.8 (dd, 1H) 7.6 (d, 1H) 7.3-7.2 (m, 1H), 5.4-5.3 (br s , 1H), 4.4-4.2 (m, 2H), 3.9 (t, 2H), 3.5 (t, 2H), 2.1-2.0 (m, 2H), 1.4-1.2 (m, 3H)

Example 31
Steps 1 to 3 were performed according to the method described in Example 27.

ＥＤＣＩ(０.１３８mg、０.７２mmol)およびＨＯＢｔ(０.０９７mg、０.７２mmol)を撹拌している７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(０.２００mg、０.４８mmol)のＤＭＦ(５mL)およびＴＥＡ(０.１３ml、０.９６mmol)溶液にＲＴで添加した。続いてＯ−(２−ビニルオキシ−エチル)−ヒドロキシルアミン(０.９９mg、０.９６mmol)、ＴＥＡ(０.１３ml、０.９６mmol)を添加し、反応フラスコを５時間、ＲＴで窒素雰囲気下撹拌した。反応混合物を水で希釈し、ＥｔＯＡｃとの間で分液した。有機層をＮＨ_４Ｃｌ、ＮａＨＣＯ_３、塩水溶液で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。分取ＨＰＬＣによる精製により、１３５mg(５６％収率)の７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２−ビニルオキシ−エトキシ)−アミドを褐色ガム状固体として得た。 Process 4
Synthesis of 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-vinyloxy-ethoxy) -amide

7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3 stirring EDCI (0.138 mg, 0.72 mmol) and HOBt (0.097 mg, 0.72 mmol) , 5-tetrahydro-indolizine-8-carboxylic acid (0.200 mg, 0.48 mmol) in DMF (5 mL) and TEA (0.13 ml, 0.96 mmol) was added at RT. Subsequently, O- (2-vinyloxy-ethyl) -hydroxylamine (0.99 mg, 0.96 mmol), TEA (0.13 ml, 0.96 mmol) were added and the reaction flask was stirred at RT under nitrogen atmosphere for 5 hours. did. The reaction mixture was diluted with water and partitioned between 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 135 mg (56% yield) of 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carvone The acid (2-vinyloxy-ethoxy) -amide was obtained as a brown gummy solid.

１Ｎ ＨＣｌ(１.５mL)およびＥｔＯＨ(３mL)を、撹拌している７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸−(２−ビニルオキシ−エトキシ)−アミド(０.１３５mg、０.２７mmol)溶液に添加し、反応混合物を３時間、ＲＴで撹拌した。ｐＨを２Ｎ ＮａＯＨ溶液で５−７に調節した。反応混合物をＥｔＯＡｃで抽出した。有機層を水、塩水溶液で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。分取ＨＰＬＣによる精製により、１２mg(１０％収率)の７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２−ヒドロキシ−エトキシ)−アミドを白色固体として得た。
LC-MS純度: 98.9%, m/z=473.9, (M+1)
¹H NMR (DMSO-D₆, 300 MHz) 11.4-11.3 (br s, 1H), 8.3-8.2 (br s, 1H), 7.8-7.7 (dd, 1H) 7.6-7.5 (d, 1H) 7.2-7.1 (m, 1H), 5.4-5.3 (br s, 1H), 4.0-3.8 (m, 4H), 3.6 (t, 2H), 3.2 (t, 2H), 2.1-2.0 (m, 2H) Process 5
Synthesis of 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy) -amide

1N HCl (1.5 mL) and EtOH (3 mL) are stirred with 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine- To a solution of 8-carboxylic acid- (2-vinyloxy-ethoxy) -amide (0.135 mg, 0.27 mmol) was added and the reaction mixture was stirred for 3 h at RT. 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 12 mg (10% yield) of 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carvone The acid (2-hydroxy-ethoxy) -amide was obtained as a white solid.
LC-MS purity: 98.9%, m / z = 473.9, (M + 1)
¹ H NMR (DMSO-D ₆ , 300 MHz) 11.4-11.3 (br s, 1H), 8.3-8.2 (br s, 1H), 7.8-7.7 (dd, 1H) 7.6-7.5 (d, 1H) 7.2- 7.1 (m, 1H), 5.4-5.3 (br s, 1H), 4.0-3.8 (m, 4H), 3.6 (t, 2H), 3.2 (t, 2H), 2.1-2.0 (m, 2H)

Example 32
Steps 1 to 3 were performed according to the method described in Example 27.

ＥＤＣＩ(０.２８０mg、０.００１mol)およびＨＯＢｔ(０.１９７mg、０.００１mmol)を、撹拌している７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(０.２００mg、０.０００５mol)のＤＭＦ(５mL)、ＴＥＡ(０.００５mL)およびクロロホルム(２mL)中の溶液に０℃で添加した。反応混合物を１.３０時間、０℃で窒素雰囲気下で撹拌した。続いてＯ−メトキシ−ヒドロキシルアミンヒドロクロライド(０.１２１mg、０.００１mol)、ＴＥＡ(０.２ml、０.００１mol)を添加し、反応混合物を１８時間、ＲＴで撹拌した。反応混合物を水で希釈し、ＥｔＯＡｃで抽出した。有機層を水、ＮａＨＣＯ_３および塩水溶液で洗浄した。反応混合物を無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。濃縮物を分取ＨＰＬＣで精製して、６mg(２.８％収率)の７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸メトキシ−アミドを白色固体として得た。
LC-MS純度: 98%, m/z=443.8, (M+1)
¹H NMR (DMSO-D₆, 300 MHz) δ 11.4-11.3 (br s, 1H), 8.3-8.2 (br s, 1H) 7.7 (dd, 1H) 7.5, (d, 1H), 7.2-7.1 (t, 1H), 5.3 (s, 1H), 3.9 (t, 2H), 3.8-3.6 (br s, 2H), 3.3-3.2 (m, 2H), 2.1-2.0 (m, 2H) Process 4
7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-amide

EDCI (0.280 mg, 0.001 mol) and HOBt (0.197 mg, 0.001 mmol) were stirred with 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2, To a solution of 3,5-tetrahydro-indolizine-8-carboxylic acid (0.200 mg, 0.0005 mol) in DMF (5 mL), TEA (0.005 mL) and chloroform (2 mL) at 0 ° C. The reaction mixture was stirred for 1.30 hours at 0 ° C. under a nitrogen atmosphere. Subsequently O-methoxy-hydroxylamine hydrochloride (0.121 mg, 0.001 mol), TEA (0.2 ml, 0.001 mol) was added and the reaction mixture was stirred for 18 h at RT. 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 6 mg (2.8% yield) of 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro- Indolizine-8-carboxylic acid methoxy-amide was obtained as a white solid.
LC-MS purity: 98%, m / z = 443.8, (M + 1)
¹ H NMR (DMSO-D ₆ , 300 MHz) δ 11.4-11.3 (br s, 1H), 8.3-8.2 (br s, 1H) 7.7 (dd, 1H) 7.5, (d, 1H), 7.2-7.1 ( t, 1H), 5.3 (s, 1H), 3.9 (t, 2H), 3.8-3.6 (br s, 2H), 3.3-3.2 (m, 2H), 2.1-2.0 (m, 2H)

Example 33
Steps 1 to 3 were performed according to the method described in Example 27.

ＥＤＣＩ(０.２７７mg、０.００１mol)およびＨＯＢｔ(０.２００mg、０.００１mmol)を、撹拌している７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(０.２００mg、０.０００５mol)のＤＭＦ(５mL)、ＴＥＡ(０.１mL)およびＤＣＭ(２mL)中の溶液に０℃で添加した。反応混合物を１.３０時間、０℃で窒素雰囲気下で撹拌した。続いてＯ−エトキシ−ヒドロキシルアミンヒドロクロライド(０.１４１mg、０.００１mol)、ＴＥＡ(０.２ml、０.００１mol)を添加し、反応混合物を１８時間、ＲＴで撹拌した。反応混合物を水で希釈し、ＥｔＯＡｃで抽出した。有機層を水、ＮａＨＣＯ_３および塩水溶液で洗浄した。反応混合物を無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。分取ＨＰＬＣによる精製により、１３mg(６％収率)の７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エトキシ−アミドを白色固体として得た。
LC-MS純度: 98%, m/z=457.8, (M+1)
¹H NMR (DMSO-D₆, 300 MHz) δ 11.4-11.3 (br s, 1H), 8.3-8.25 (br s, 1H) 7.8-7.7 (d, 1H) 7.6-7.5, (d, 1H), 7.3-7.1 (t, 1H), 5.4 (s, 1H), 4.0-3.8 (m, 4H), 3.3-3.0 (m, 2H), 2.1-2.0 (t, 2H), 1.3-1.1(t, 3H) Process 4
Synthesis of 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethoxy-amide

EDCI (0.277 mg, 0.001 mol) and HOBt (0.200 mg, 0.001 mmol) were stirred with 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2, To a solution of 3,5-tetrahydro-indolizine-8-carboxylic acid (0.200 mg, 0.0005 mol) in DMF (5 mL), TEA (0.1 mL) and DCM (2 mL) at 0 ° C. The reaction mixture was stirred for 1.30 hours at 0 ° C. under a nitrogen atmosphere. Subsequently O-ethoxy-hydroxylamine hydrochloride (0.141 mg, 0.001 mol), TEA (0.2 ml, 0.001 mol) were added and the reaction mixture was stirred for 18 h at RT. 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 13 mg (6% yield) of 7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carvone The acid ethoxy-amide was obtained as a white solid.
LC-MS purity: 98%, m / z = 457.8, (M + 1)
¹ H NMR (DMSO-D ₆ , 300 MHz) δ 11.4-11.3 (br s, 1H), 8.3-8.25 (br s, 1H) 7.8-7.7 (d, 1H) 7.6-7.5, (d, 1H), 7.3-7.1 (t, 1H), 5.4 (s, 1H), 4.0-3.8 (m, 4H), 3.3-3.0 (m, 2H), 2.1-2.0 (t, 2H), 1.3-1.1 (t, 3H )

Example 34
Steps 1 to 4 were performed according to the method described in Example 1, and Step 5 was performed according to the method described in Example 2.

ＥＤＣＩ(１５５mg、０.８１６mmol)およびＨＯＢｔ(１１０mg、０.８１６mmol)を、撹拌している７−(４−ブロモ−２−フルオロ−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(０.２ｇ、０.５４４mmol)のＤＭＦ(６mL)溶液に０℃で添加した。反応混合物を１時間、０℃で撹拌した。続いてＯ−(４,４−ジメチル−[１,３]ジオキソラン−２−イルメチル)−ヒドロキシルアミン(１８０mg、０.６５３mmol)、ＴＥＡ(０.４５ml、３.２６４mmol)を添加した。反応混合物をＲＴで一夜撹拌した。反応混合物を酢酸エチル(５０mL)および冷水(５０mL)に分配した。有機層を飽和ＮａＨＣＯ_３溶液で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。カラムクロマトグラフィー(シリカゲル、溶離剤として５％メタノールのクロロホルム溶液を使用)による精製により、５０mg(１９.１３％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２,２−ジメチル−[１,３]ジオキソラン−４−イルメトキシ)−アミドを、望む生成物として得た。 Step 6
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2,2-dimethyl- [1,3] dioxolane- Synthesis of 4-ylmethoxy) -amide

EDCI (155 mg, 0.816 mmol) and HOBt (110 mg, 0.816 mmol) were stirred with 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5- Tetrahydro-indolizine-8-carboxylic acid (0.2 g, 0.544 mmol) was added to a solution of DMF (6 mL) at 0 ° C. The reaction mixture was stirred for 1 hour at 0 ° C. Then O- (4,4-dimethyl- [1,3] dioxolan-2-ylmethyl) -hydroxylamine (180 mg, 0.653 mmol), TEA (0.45 ml, 3.264 mmol) were added. The reaction mixture was stirred overnight at RT. 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. Purification by column chromatography (silica gel, using 5% methanol in chloroform as eluent) gave 50 mg (19.13% yield) of 7- (4-bromo-2-fluoro-phenylamino) -5-oxo. -1,2,3,5-Tetrahydro-indolizine-8-carboxylic acid (2,2-dimethyl- [1,3] dioxolan-4-ylmethoxy) -amide was obtained as the desired product.

１Ｎ ＨＣｌ(１mL)を、エタノール(２mL)に溶解した撹拌している７−(４−ブロモ−２−フルオロ−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２,２−ジメチル−[１,３]ジオキソラン−４−イルメトキシ)−アミド(５０mg、０.０１０mmol)溶液に添加した。反応混合物を３時間、ＲＴで撹拌した。エタノールを留去し、反応混合物を水および酢酸エチル(２０mL)に分配した。有機層をＮａ_２ＳＯ_４で乾燥させ、濃縮し、濃縮物をＤＣＭを使用する再結晶により精製して、２５mg(１７.３５％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２,３−ジヒドロキシ−プロポキシ)−アミドを、望む生成物として得た。
LC-MS: 95.8%; m/z=456 (M+1), 458 (M+2)
HPLC: 97.3%
¹H NMR (DMSO-D₆, 300 MHz): δ 11.2 (br s, 1H), 8.3-8.2 (br s, 1H), 7.6-7.5 (d, 1H), 7.5-7.3 (m, 2H), 5.3 (s,1H), 4.9 (d, 1H), 4.6-4.4 (t, 1H), 4.0-3.8 (m, 3H), 3.8-3.5 (m, 2H), 3.4 (m, 2H), 3.3-3.2 (m, 2H), 2.1-2.0 (m, 2H) Step 7
Synthesis of 7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2,3-dihydroxy-propoxy) -amide

Stirring 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine- dissolved in 1N HCl (1 mL) in ethanol (2 mL) To a 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 for 3 h at RT. 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 and concentrated, and the concentrate was purified by recrystallization using DCM to yield 25 mg (17.35% yield) of 7- (4-bromo-2-fluoro-phenyl). Amino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2,3-dihydroxy-propoxy) -amide was obtained as the desired product.
LC-MS: 95.8%; m / z = 456 (M + 1), 458 (M + 2)
HPLC: 97.3%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 11.2 (br s, 1H), 8.3-8.2 (br s, 1H), 7.6-7.5 (d, 1H), 7.5-7.3 (m, 2H), 5.3 (s, 1H), 4.9 (d, 1H), 4.6-4.4 (t, 1H), 4.0-3.8 (m, 3H), 3.8-3.5 (m, 2H), 3.4 (m, 2H), 3.3- 3.2 (m, 2H), 2.1-2.0 (m, 2H)

Scheme 8:

ＴＥＡ(５８.２７mmol、８.４mL)を、蒸留ＰＯＣｌ_３(３２ml、３４９mmol)に溶解した撹拌している７−ヒドロキシ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エチルエステル(１３ｇ、５８.２７mmol)溶液に添加し、反応混合物を１６時間、室温で窒素雰囲気下に撹拌した。ＰＯＣｌ_３を留去し、反応混合物を氷冷水に注ぎ、飽和Ｋ_２ＣＯ_３溶液で約８.５のｐＨまで塩基性化した。反応混合物をＥｔＯＡｃで抽出した。有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。濃縮物をカラムクロマトグラフィー(シリカゲル、溶離剤として７５％酢酸エチルのヘキサン溶液を使用)で精製して、７.５mg(５３.５％収率)の７−クロロ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エチルエステルを黄色固体として得た。
¹H NMR (DMSO-D₆, 300 MHz): δ 6.6-6.5 (br s, 1H), 4.4-4.3 (m, 2H), 4.2-4.1 (m, 2H), 3.5-3.3 (t, 2H), 2.3-2.2 (m, 2H), 1.4-1.3 (t, 2H) Example 35
Process 1
Synthesis of 7-chloro-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester

TEA (58.27 mmol, 8.4 mL) is dissolved in distilled POCl ₃ (32 mL, 349 mmol) and stirred with 7-hydroxy-5-oxo-1,2,3,5-tetrahydro-indolizine-8-. Carboxylic acid ethyl ester (13 g, 58.27 mmol) was added to the solution and the reaction mixture was stirred for 16 hours at room temperature under a nitrogen atmosphere. POCl ₃ was distilled off and the reaction mixture was poured into ice-cold water and basified with saturated K ₂ CO ₃ solution to a pH of about 8.5. The reaction mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated. The concentrate was purified by column chromatography (silica gel, using 75% ethyl acetate in hexane as eluent) to give 7.5 mg (53.5% yield) of 7-chloro-1,2,3,5. -Tetrahydro-indolizine-8-carboxylic acid ethyl ester was obtained as a yellow solid.
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 6.6-6.5 (br s, 1H), 4.4-4.3 (m, 2H), 4.2-4.1 (m, 2H), 3.5-3.3 (t, 2H) , 2.3-2.2 (m, 2H), 1.4-1.3 (t, 2H)

ＮＣＳ(３０４mg、０.００２２８２mol)を、ＤＭＦに溶解した７−クロロ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エチルエステル(５００mg、０.００２０１mol)溶液に添加し、反応混合物を１８時間、ＲＴで窒素雰囲気下撹拌した。反応混合物を酢酸エチルで抽出し、水および塩水溶液で洗浄した。有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮して、４００mg(７０％収率)の６,７−ジクロロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エチルエステルを、望む生成物として得た。
¹H NMR (DMSO-D₆, 300 MHz): δ 4.3-4.2 (m, 2H), 4.1-4.0 (t, 2H), 3.3 (t, 2H), 2.2-2.1 (m, 2H), 1.3 (t, 3H)
LCMS: 78%; m/z=278, M+2
HPLC: 89% Process 2
Synthesis of 6,7-dichloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester

NCS (304 mg, 0.0000222 mol) was added to a solution of 7-chloro-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester (500 mg, 0.00011 mol) dissolved in DMF and reacted. The mixture was stirred for 18 hours at RT 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 give 400 mg (70% yield) of 6,7-dichloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carvone. The acid ethyl ester was obtained as the desired product.
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 4.3-4.2 (m, 2H), 4.1-4.0 (t, 2H), 3.3 (t, 2H), 2.2-2.1 (m, 2H), 1.3 ( t, 3H)
LCMS: 78%; m / z = 278, M + 2
HPLC: 89%

１Ｎ ＬｉＯＨ(１０mL)を、撹拌している６,７−ジクロロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エチルエステル(４００mg、０.００１mol)の(４：１)ＴＨＦ：ＭｅＯＨ(１０mL)溶液に添加し、反応混合物を３時間、ＲＴで撹拌した。反応混合物を濃縮し、１Ｎ ＨＣｌで約２のｐＨまで酸性化した。沈殿を減圧下回収して、３７５mg(１００％収率)の６,７−ジクロロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸を、望む生成物として得た。
¹H NMR (DMSO-D₆, 300 MHZ): δ 13.2 (s, 1H), 4.1-4.0 (t, 2H), 3.3 (t, 2H), 2.2-2.1 (m, 2H)
LCMS: 92%; m/z=248, M+1; 249.7, M+2
HPLC: 90.8% Process 3
Synthesis of 6,7-dichloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid

1N LiOH (10 mL) was added to a stirred 6,7-dichloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester (400 mg, 0.001 mol) of (4 1) To a THF: MeOH (10 mL) solution was added and the reaction mixture was stirred for 3 h at RT. The reaction mixture was concentrated and acidified with 1N HCl to a pH of about 2. The precipitate was collected under reduced pressure to give 375 mg (100% yield) of 6,7-dichloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid as the desired product. It was.
¹ H NMR (DMSO-D ₆ , 300 MHZ): δ 13.2 (s, 1H), 4.1-4.0 (t, 2H), 3.3 (t, 2H), 2.2-2.1 (m, 2H)
LCMS: 92%; m / z = 248, M + 1; 249.7, M + 2
HPLC: 90.8%

ｎ−ブチルリチウム(２ml、０.００３mol)を、撹拌しているジイソプロピルアミン(０.６５ml、０.００５mol)の乾燥ＴＨＦ(４０mL)溶液に、５分間かけて−７８℃で添加し、反応混合物を３０分間撹拌し、乾燥ＴＨＦ(５mL)に溶解した４−ブロモ−２−フルオロ−フェニルアミン(４６２mg、０.００２mol)を−７８℃で添加した。反応混合物をさらに３０分間撹拌し、乾燥ＴＨＦ(１０mL)に溶解した６,７−ジクロロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２００mg、０.００１mol)を、−７８℃で、撹拌しながら３０分間かけて添加した。撹拌をさらに１６時間、ＲＴで続けた。ＴＨＦを留去し、残留塊を１Ｎ ＨＣｌの添加により酸性化し、エーテルを１０分間撹拌しながら添加した。形成した沈殿を回収し、エーテルで洗浄し、乾燥させて、２３２mg(７２％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−クロロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸を、望む生成物として得た。
¹H NMR (DMSO-D₆, 300 MHz) δ 13.3 (s, 1H), 9.6-9.5 (br s, 1H), 7.6-7.5 (dd, 1H), 7.3 (d, 1H), 6.9 (t, 1H), 4.1-4.0 (t, 2H), 3.5-3.4 (t, 2H), 2.2-2.1 (m, 2H)
LCMS: 96%; m/z=400.9, M+1
HPLC=95.5% Process 4
Synthesis of 7- (4-Bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid

n-Butyllithium (2 ml, 0.003 mol) was added to a stirred solution of diisopropylamine (0.65 ml, 0.005 mol) in dry THF (40 mL) at −78 ° C. over 5 min. Was stirred for 30 min and 4-bromo-2-fluoro-phenylamine (462 mg, 0.002 mol) dissolved in dry THF (5 mL) was added at −78 ° C. The reaction mixture was stirred for an additional 30 minutes and 6,7-dichloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (200 mg, 0.001 mol) dissolved in dry THF (10 mL). ) Was added at −78 ° C. over 30 minutes with stirring. Stirring was continued for an additional 16 hours at RT. The THF was distilled off, the residual mass was acidified by addition of 1N HCl and ether was added with stirring for 10 minutes. The precipitate that formed was collected, washed with ether, dried and 232 mg (72% yield) of 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2 1,3,5-Tetrahydro-indolizine-8-carboxylic acid was obtained as the desired product.
¹ H NMR (DMSO-D ₆ , 300 MHz) δ 13.3 (s, 1H), 9.6-9.5 (br s, 1H), 7.6-7.5 (dd, 1H), 7.3 (d, 1H), 6.9 (t, 1H), 4.1-4.0 (t, 2H), 3.5-3.4 (t, 2H), 2.2-2.1 (m, 2H)
LCMS: 96%; m / z = 400.9, M + 1
HPLC = 95.5%

方法：
ＥＤＣＩ(１４３mg、０.００１mol)およびＨＯＢｔ(１０２mg、０.００１mol)を、撹拌している７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−クロロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(１００mg、０.０００２mol)のＤＭＦ(３mL)溶液に０℃で添加した。反応混合物を１.５時間、０℃で撹拌した。続いてＯ−シクロプロピルメチル−ヒドロキシルアミンヒドロクロライド(９２mg、０.００１mol)、ＴＥＡ(０.１ml、０.００１mol)を０℃で添加した。反応混合物を１８時間、ＲＴで撹拌した。反応混合物を酢酸エチルおよび水に分配した。有機層を飽和ＮＨ_４Ｃｌ溶液、ＮａＨＣＯ_３溶液および塩水溶液で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。分取ＨＰＬＣによる精製により、４２mg(３６％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−クロロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸シクロプロピルメトキシ−アミドを、望む生成物として得た。
¹H NMR (DMSO-D₆, 300 MHz) δ 11.4-11.2 (br s, 1H), 8.04-7.96 (br s, 1H), 7.5 (d, 1H), 7.3 (d, 1H), 6.9 (t, 1H), 4.1-4.0 (t, 2H), 3.2 (d, 2H), 3.1 (t, 2H), 2.2-2.1 (m, 2H), 1.0 -0.9(m, 1H), 0.5 (d, 2H), 0.3 (s, 2H)
LCMS: 100%; m/z=471.7, M+1
HPLC=99% Example 36
Process 5
Synthesis of 7- (4-Bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide

Method:
EDCI (143 mg, 0.001 mol) and HOBt (102 mg, 0.001 mol) are stirred with 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2, To a solution of 3,5-tetrahydro-indolizine-8-carboxylic acid (100 mg, 0.0002 mol) in DMF (3 mL) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1.5 hours. Subsequently, O-cyclopropylmethyl-hydroxylamine hydrochloride (92 mg, 0.001 mol) and TEA (0.1 ml, 0.001 mol) were added at 0 ° C. The reaction mixture was stirred for 18 hours at RT. 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 gave 42 mg (36% yield) of 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine -8-carboxylic acid cyclopropylmethoxy-amide was obtained as the desired product.
¹ H NMR (DMSO-D ₆ , 300 MHz) δ 11.4-11.2 (br s, 1H), 8.04-7.96 (br s, 1H), 7.5 (d, 1H), 7.3 (d, 1H), 6.9 (t , 1H), 4.1-4.0 (t, 2H), 3.2 (d, 2H), 3.1 (t, 2H), 2.2-2.1 (m, 2H), 1.0 -0.9 (m, 1H), 0.5 (d, 2H ), 0.3 (s, 2H)
LCMS: 100%; m / z = 471.7, M + 1
HPLC = 99%

Example 37
Steps 1 to 4 were performed according to the method described in Example 1.

ＥＤＣＩ(２８６mg、０.００１mol)およびＨＯＢｔ(２０２mg、０.００１mol)を、撹拌している７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−クロロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２００mg、０.０００５mol)の乾燥ＤＭＦ(５mL)溶液に、０℃で添加した。反応混合物を１.３０時間、０℃で撹拌した。続いてＯ−メトキシ−ヒドロキシルアミンヒドロクロライド(１２５mg、０.００１mol)、ＴＥＡ(０.２１ml、０.００１mol)を０℃で添加した。反応混合物を１６時間、ＲＴで、窒素雰囲気下に撹拌した。反応混合物をＥｔＯＡｃおよび水に分配した。有機層を水、飽和ＮａＨＣＯ_３溶液および塩水溶液で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮し、粗生成物をメタノールで洗浄して、０.０２０ｇ(９.３％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−クロロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸メトキシ−アミドを白色固体として得た。
¹H NMR (DMSO-D₆, 300 MHz) δ 11.4-11.2 (br s, 1H), 8.0 (br s, 1H), 7.5 (dd, 1H), 7.3 (d, 1H), 6.9 (t, 1H), 4.0 (t, 2H), 3.4 (s, 3H), 3.1 (t, 2H), 2.1-2.0 (m, 2H)
LCMS: 90%; m/z=431.9, M+1
HPLC: 99% Process 5
Synthesis of 7- (4-Bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-amide

EDCI (286 mg, 0.001 mol) and HOBt (202 mg, 0.001 mol) are stirred with 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2, To a solution of 3,5-tetrahydro-indolizine-8-carboxylic acid (200 mg, 0.0005 mol) in dry DMF (5 mL) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1.30 hours. Subsequently, O-methoxy-hydroxylamine hydrochloride (125 mg, 0.001 mol) and TEA (0.21 ml, 0.001 mol) were added at 0 ° C. The reaction mixture was stirred for 16 h at RT 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 crude product washed with methanol to give 0.020 g (9.3% yield). 7- (4-Bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-amide was obtained as a white solid.
¹ H NMR (DMSO-D ₆ , 300 MHz) δ 11.4-11.2 (br s, 1H), 8.0 (br s, 1H), 7.5 (dd, 1H), 7.3 (d, 1H), 6.9 (t, 1H ), 4.0 (t, 2H), 3.4 (s, 3H), 3.1 (t, 2H), 2.1-2.0 (m, 2H)
LCMS: 90%; m / z = 431.9, M + 1
HPLC: 99%

Example 38
Steps 1 to 4 were performed according to the method described in Example 1.

ＥＤＣＩ(２８６mg、０.００１mol)およびＨＯＢｔ(２０２mg、０.０.００１mol)を、撹拌している７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−クロロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２００mg、０.００５mol)の乾燥ＤＭＦ(５mL)溶液に０℃で添加した。反応混合物を１.３０時間、０℃で撹拌した。続いてＮＨ_４Ｃｌ(８０mg、０.００１mol)、ＴＥＡ(０.２ml、０.００１mol)を０℃で添加した。反応混合物を１６時間、ＲＴで撹拌した。反応混合物をＥｔＯＡｃおよび水に分配した。有機層を水、飽和ＮａＨＣＯ_３溶液および塩水溶液で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮して、０.０２０ｇ(９.３％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−クロロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸アミドを、望む生成物として得た。
¹H NMR (DMSO-D₆, 300 MHz) δ 8.44-8.4 (br s, 1H), 7.64-7.58 (br s, 2H), 7.5 (dd, 1H), 7.2 (d, 1H), 6.9-6.8 (t, 1H), 4.0 (t, 2H), 3.3-3.2 (t, 2H), 2.1-2.0 (m, 2H)
LCMS: 94.2%; m/z=401.9, M+1
HPLC: 94.5% Process 5
Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid amide

EDCI (286 mg, 0.001 mol) and HOBt (202 mg, 0.001 mol) are stirred with 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1, To a solution of 2,3,5-tetrahydro-indolizine-8-carboxylic acid (200 mg, 0.005 mol) in dry DMF (5 mL) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1.30 hours. Subsequently NH ₄ Cl (80 mg, 0.001 mol) and TEA (0.2 ml, 0.001 mol) were added at 0 ° C. The reaction mixture was stirred for 16 h at RT. 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 and concentrated to give 0.020 g (9.3% yield) of 7- (4-Bromo-2- Fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid amide was obtained as the desired product.
¹ H NMR (DMSO-D ₆ , 300 MHz) δ 8.44-8.4 (br s, 1H), 7.64-7.58 (br s, 2H), 7.5 (dd, 1H), 7.2 (d, 1H), 6.9-6.8 (t, 1H), 4.0 (t, 2H), 3.3-3.2 (t, 2H), 2.1-2.0 (m, 2H)
LCMS: 94.2%; m / z = 401.9, M + 1
HPLC: 94.5%

Example 39
Steps 1 to 4 were performed according to the method described in Example 1.

ＥＤＣＩ(２８６mg、０.００１mol)およびＨＯＢｔ(２０２mg、０.００１mol)を、撹拌している７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−クロロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２００mg、０.０００５mol)の乾燥ＤＭＦ(５mL)溶液に０℃で添加した。反応混合物を１.３０時間、０℃で撹拌した。続いてＯ−エトキシ−ヒドロキシルアミンヒドロクロライド(１４５mg、０.００１mol)、ＴＥＡ(０.２ml、０.００１mol)を０℃で添加した。反応混合物を１８時間、ＲＴで窒素雰囲気下撹拌した。反応混合物をＥｔＯＡｃおよび水に分配した。有機層を水、飽和ＮａＨＣＯ_３溶液および塩水溶液で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮し、粗生成物をメタノールを使用して再結晶して、５２ｇ(２３.６％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−クロロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エトキシ−アミドを、望む生成物として得た。
¹H NMR (DMSO-D₆, 300 MHz) δ 11.4-11.2 (br s, 1H), 8.1-7.9 (br s, 1H), 7.5 (dd, 1H), 7.3 (d, 1H), 6.9 (t, 1H), 4.0 (t, 2H), 3.6-3.5 (m, 2H), 3.1 (t, 2H), 2.2-2.0 (m, 2H), 1.1 (t, 3H)
LCMS: 100%; m/z=445.7, M+1; 443.8, M-1
HPLC: 96% Process 5
Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethoxy-amide

EDCI (286 mg, 0.001 mol) and HOBt (202 mg, 0.001 mol) are stirred with 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2, To a solution of 3,5-tetrahydro-indolizine-8-carboxylic acid (200 mg, 0.0005 mol) in dry DMF (5 mL) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1.30 hours. Subsequently, O-ethoxy-hydroxylamine hydrochloride (145 mg, 0.001 mol) and TEA (0.2 ml, 0.001 mol) were added at 0 ° C. The reaction mixture was stirred for 18 hours at RT 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 crude product was recrystallized using methanol to give 52 g (23.6% yield). 7- (4-Bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethoxy-amide of the desired product Got as.
¹ H NMR (DMSO-D ₆ , 300 MHz) δ 11.4-11.2 (br s, 1H), 8.1-7.9 (br s, 1H), 7.5 (dd, 1H), 7.3 (d, 1H), 6.9 (t , 1H), 4.0 (t, 2H), 3.6-3.5 (m, 2H), 3.1 (t, 2H), 2.2-2.0 (m, 2H), 1.1 (t, 3H)
LCMS: 100%; m / z = 445.7, M + 1; 443.8, M-1
HPLC: 96%

Example 40
Steps 1 to 4 were performed according to the method described in Example 1.

ＥＤＣＩ(５７２mg、０.００３mol)およびＨＯＢｔ(１９１.７mg、０.００３mol)を、撹拌している７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−クロロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(４００mg、０.００１６mol)の乾燥ＤＭＦ(１０mL)溶液に０℃で添加した。反応混合物を１.３０時間、０℃で撹拌した。続いてＯ−(２,２−ジメチル−[１,３]ジオキソラン−４−イルメチル)−ヒドロキシルアミン(４４０mg、０.００３mol)、ＴＥＡ(０.４ml、０.００３mol)を０℃で添加し、撹拌を１６時間、ＲＴで続けた。反応混合物をＥｔＯＡｃおよび水に分配した。有機層を水、飽和ＮａＨＣＯ_３溶液および塩水溶液で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。カラムクロマトグラフィー(シリカゲル、溶離剤として２％メタノールおよびクロロホルムを使用)での精製により、０.３ｇ(５６.８％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−クロロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２,２−ジメチル−[１,３]ジオキソラン−４−イルメトキシ)−アミドを、望む生成物として得た。
¹H NMR (DMSO-D₆, 300 MHz) δ 11.4 (br s, 1H), 7.94-8.06 (br s, 1H), 7.5 (dd, 1H), 7.3-7.24 (d, 1H), 6.9 (t, 1H), 4.2-4.1 (m, 1H), 4.1-4.0 (m, 3H), 3.6-3.5 (m, 3H), 3.1 (t, 2H), 2.1-2.0 (m, 2H), 0.8-0.7 (s, 6H)
LCMS: 65%; m/z=529.9 M+1 Process 5
7- (4-Bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2,2-dimethyl- [1, 3] Synthesis of dioxolan-4-ylmethoxy) -amide

EDCI (572 mg, 0.003 mol) and HOBt (191.7 mg, 0.003 mol) were stirred with 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1, To a solution of 2,3,5-tetrahydro-indolizine-8-carboxylic acid (400 mg, 0.0016 mol) in dry DMF (10 mL) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1.30 hours. Subsequently, O- (2,2-dimethyl- [1,3] dioxolan-4-ylmethyl) -hydroxylamine (440 mg, 0.003 mol), TEA (0.4 ml, 0.003 mol) were added at 0 ° C. Stirring was continued for 16 hours at RT. 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 and concentrated. Purification by column chromatography (silica gel, using 2% methanol and chloroform as eluent) gave 0.3 g (56.8% yield) of 7- (4-bromo-2-fluoro-phenylamino) -6. -Chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2,2-dimethyl- [1,3] dioxolan-4-ylmethoxy) -amide as the desired product Obtained.
¹ H NMR (DMSO-D ₆ , 300 MHz) δ 11.4 (br s, 1H), 7.94-8.06 (br s, 1H), 7.5 (dd, 1H), 7.3-7.24 (d, 1H), 6.9 (t , 1H), 4.2-4.1 (m, 1H), 4.1-4.0 (m, 3H), 3.6-3.5 (m, 3H), 3.1 (t, 2H), 2.1-2.0 (m, 2H), 0.8-0.7 (s, 6H)
LCMS: 65%; m / z = 529.9 M + 1

１Ｎ ＨＣｌ(０.６mL)を、ＥｔＯＨ(１２mL)に溶解した撹拌している７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−クロロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２,２−ジメチル−[１,３]ジオキソラン−４−イルメトキシ)−アミド(３００mg、０.００１mol)溶液に添加した。反応混合物を２時間、室温で撹拌した。エタノールを留去し、残留塊をＥｔＯＡｃで抽出した。有機層を水、飽和ＮａＨＣＯ_３溶液、塩水溶液で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。メタノールからの再結晶により、５０mg(１８.５％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−クロロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２,３−ジヒドロキシ−プロポキシ)−アミドを白色固体として得た。
¹H NMR (DMSO-D₆, 300 MHz) δ 11.4 (br s, 1H), 8.0 (br s, 1H), 7.5-7.4 (dd, 1H), 7.3-7.2 (d, 1H), 6.9 (t, 1H), 4.8 (d, 1H), 4.6-4.5 (t, 1H), 4.0 (t, 2H), 3.7-3.5 (m, 2H), 3.5-3.4 (m, 1H), 3.2-3.1 (t, 2H), 2.1-2.0 (m, 2H)。
LCMS: 85%; m/z=491.7, M+1
HPLC=96% Step 6
7- (4-Bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2,3-dihydroxy-propoxy)- Synthesis of amide

1N HCl (0.6 mL) is dissolved in EtOH (12 mL) with stirring 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5 -Tetrahydro-indolizine-8-carboxylic acid (2,2-dimethyl- [1,3] dioxolan-4-ylmethoxy) -amide (300 mg, 0.001 mol) was added to the solution. The reaction mixture was stirred for 2 hours at room temperature. Ethanol was distilled off and the residual mass 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 gave 50 mg (18.5% yield) of 7- (4-bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro- Indolizine-8-carboxylic acid (2,3-dihydroxy-propoxy) -amide was obtained as a white solid.
¹ H NMR (DMSO-D ₆ , 300 MHz) δ 11.4 (br s, 1H), 8.0 (br s, 1H), 7.5-7.4 (dd, 1H), 7.3-7.2 (d, 1H), 6.9 (t , 1H), 4.8 (d, 1H), 4.6-4.5 (t, 1H), 4.0 (t, 2H), 3.7-3.5 (m, 2H), 3.5-3.4 (m, 1H), 3.2-3.1 (t , 2H), 2.1-2.0 (m, 2H).
LCMS: 85%; m / z = 491.7, M + 1
HPLC = 96%

Example 41
Steps 1 to 3 were performed according to the method described in Example 1.

ｎ−ブチルリチウム(２０ml、０.０３２mol)を、５分間かけて、撹拌しているジイソプロピルアミン(４.５ml、０.０３２mol)の乾燥ＴＨＦ(５mL)溶液に−７８℃で滴下し、反応混合物を３０分間撹拌した。続いて乾燥ＴＨＦ(１０mL)に溶解した２−フルオロ−４−ヨード−フェニルアミン(５.７５ｇ、０.００２mol)を−７８℃で添加した。反応混合物をさらに３０分間撹拌し、続いて乾燥ＴＨＦ(１３０mL)に溶解した６,７−ジクロロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２ｇ、０.００８mol)を、−７８℃で、撹拌しながら３０分間にわたり添加した。撹拌を、さらに２日間、ＲＴで窒素雰囲気下続けた。ＴＨＦを留去し、残留反応混合物を１Ｎ ＨＣｌの添加により酸性化した。ジエチルエーテルを添加し、１０分間撹拌して、沈殿が生じ、それを回収し、ジエチルエーテルで洗浄し、乾燥させて、２.３ｇ(６３.８％収率)の６−クロロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸を、望む生成物として得た。
¹H NMR (DMSO-D₆, 300 MHz) δ 13.6 (s, 1H), 9.5 (br s, 1H), 7.6 (dd, 1H), 7.4 (d, 1H), 6.7 (t, 1H), 4.1-4.0 (t, 2H), 3.5-3.4 (t, 2H), 2.2-2.1 (m, 2H)
LCMS: 92%; m/z=448.7
HPLC: 98% Process 4
Synthesis of 6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid

n-Butyllithium (20 ml, 0.032 mol) was added dropwise over 5 minutes to a stirred solution of diisopropylamine (4.5 ml, 0.032 mol) in dry THF (5 mL) at −78 ° C. Was stirred for 30 minutes. Subsequently, 2-fluoro-4-iodo-phenylamine (5.75 g, 0.002 mol) dissolved in dry THF (10 mL) was added 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-indolizine-8-carboxylic acid (2 g, 0) dissolved in dry THF (130 mL). 0.008 mol) was added at -78 ° C over 30 minutes with stirring. Stirring was continued for an additional 2 days at RT under a nitrogen atmosphere. The THF was distilled off and the residual reaction mixture was acidified by the addition of 1N HCl. Diethyl ether was added and stirred for 10 minutes to form a precipitate which was collected, washed with diethyl ether and dried to give 2.3 g (63.8% yield) of 6-chloro-7- ( 2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid was obtained as the desired product.
¹ H NMR (DMSO-D ₆ , 300 MHz) δ 13.6 (s, 1H), 9.5 (br s, 1H), 7.6 (dd, 1H), 7.4 (d, 1H), 6.7 (t, 1H), 4.1 -4.0 (t, 2H), 3.5-3.4 (t, 2H), 2.2-2.1 (m, 2H)
LCMS: 92%; m / z = 448.7
HPLC: 98%

ＥＤＣＩ(２５６mg、０.００１mol)およびＨＯＢｔ(１８１mg、０.００１mol)を、撹拌している６−クロロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２００mg、０.０００４mol)の乾燥ＤＭＦ(５mL)溶液に０℃で添加した。反応混合物を１.３０時間、０℃で撹拌した。続いてＯ−シクロプロピルメチル−ヒドロキシルアミンヒドロクロライド(１６５mg、０.００１mol)、ＴＥＡ(０.２ml、０.００１mol)を０℃で添加した。反応混合物を１６時間、ＲＴで、窒素雰囲気下に撹拌した。反応混合物をＥｔＯＡｃおよび水に分配した。有機層を水、飽和ＮＨ_４Ｃｌ、飽和ＮａＨＣＯ_３溶液および塩水溶液で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮し、濃縮物をメタノールで洗浄して、５５mg(２４％収率)の６−クロロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸シクロプロピルメトキシ−アミドを、望む生成物として得た。
¹H NMR (DMSO-D₆, 300 MHz) δ 11.25-11.2 (br s, 1H), 8.0-7.94 (br s, 1H), 7.6-7.5 (dd, 1H), 7.4 (d, 1H), 6.8-6.7 (t, 1H), 4.0 (t, 2H), 3.2 (d, 2H), 3.1 (t, 2H), 2.1 (t, 2H), 1.0-0.9 (m, 1H), 0.5 (d, 2H), 0.3 (s, 2H)
LCMS: 94.5%; m/z=517.6
HPLC: 94.79% Example 42
Process 5
Synthesis of 6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide

EDCI (256 mg, 0.001 mol) and HOBt (181 mg, 0.001 mol) were stirred with 6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2, To a solution of 3,5-tetrahydro-indolizine-8-carboxylic acid (200 mg, 0.0004 mol) in dry DMF (5 mL) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1.30 hours. Subsequently, O-cyclopropylmethyl-hydroxylamine hydrochloride (165 mg, 0.001 mol) and TEA (0.2 ml, 0.001 mol) were added at 0 ° C. The reaction mixture was stirred for 16 h at RT 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 and concentrated, and the concentrate was washed with methanol to give 55 mg (24% yield). 6-Chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide Got as.
¹ H NMR (DMSO-D ₆ , 300 MHz) δ 11.25-11.2 (br s, 1H), 8.0-7.94 (br s, 1H), 7.6-7.5 (dd, 1H), 7.4 (d, 1H), 6.8 -6.7 (t, 1H), 4.0 (t, 2H), 3.2 (d, 2H), 3.1 (t, 2H), 2.1 (t, 2H), 1.0-0.9 (m, 1H), 0.5 (d, 2H ), 0.3 (s, 2H)
LCMS: 94.5%; m / z = 517.6
HPLC: 94.79%

Example 43
Steps 1-3 were performed according to the method described in Example 1, and Step 4 was performed according to the method described in Example 6.

ＥＤＣＩ(２５６mg、０.００１mol)およびＨＯＢｔ(１８１mg、０.００１mol)を、撹拌している６−クロロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２００mg、０.０００４mol)の乾燥ＤＭＦ(１０mL)溶液に０℃で添加した。反応混合物を１.３０時間、０℃で撹拌した。続いてＯ−メチル−ヒドロキシルアミンヒドロクロライド(１１１mg、０.００１mol)、ＴＥＡ(０.２ml、０.００１mol)を０℃で添加した。反応混合物を１６時間、ＲＴで、窒素雰囲気下に撹拌した。反応混合物をＥｔＯＡｃおよび水に分配した。有機層を水、飽和ＮａＨＣＯ_３溶液および塩水溶液で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮し、濃縮物をメタノールで洗浄して、１０５mg(４８％収率)の６−クロロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸メトキシ−アミドを、望む生成物として得た。
¹H NMR (DMSO-D₆, 300 MHz) δ 11.4-11.2 (br s, 1H), 8.02-7.96 (br s, 1H), 7.6-7.5 (dd, 1H), 7.4 (d, 1H), 6.8-6.7 (t, 1H), 4.0 (t, 2H), 3.4 (s, 3H), 3.1 (t, 2H), 2.1-2.0 (m, 2H)
LCMS: 90%; m/z=477.9
HPLC: 96.6% Process 5
Synthesis of 6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-amide

EDCI (256 mg, 0.001 mol) and HOBt (181 mg, 0.001 mol) were stirred with 6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2, To a solution of 3,5-tetrahydro-indolizine-8-carboxylic acid (200 mg, 0.0004 mol) in dry DMF (10 mL) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1.30 hours. Subsequently, O-methyl-hydroxylamine hydrochloride (111 mg, 0.001 mol) and TEA (0.2 ml, 0.001 mol) were added at 0 ° C. The reaction mixture was stirred for 16 h at RT 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 and concentrated, the concentrate was washed with methanol to give 105 mg (48% yield) of 6-chloro-7. -(2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-amide was obtained as the desired product.
¹ H NMR (DMSO-D ₆ , 300 MHz) δ 11.4-11.2 (br s, 1H), 8.02-7.96 (br s, 1H), 7.6-7.5 (dd, 1H), 7.4 (d, 1H), 6.8 -6.7 (t, 1H), 4.0 (t, 2H), 3.4 (s, 3H), 3.1 (t, 2H), 2.1-2.0 (m, 2H)
LCMS: 90%; m / z = 477.9
HPLC: 96.6%

Example 44
Steps 1-3 were performed according to the method described in Example 1, and Step 4 was performed according to the method described in Example 6.

ＥＤＣＩ(２５６mg、０.００１mol)およびＨＯＢｔ(１８１mg、０.００１mol)を、撹拌している６−クロロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２００mg、０.０００４mol)の乾燥ＤＭＦ(５mL)溶液に０℃で添加した。反応混合物を１.３０時間、０℃で窒素雰囲気下で撹拌した。続いてＮＨ_４Ｃｌ(０.０７１ｇ、０.００１mol)、ＴＥＡ(０.２ml、０.００１mol)を０℃で添加した。反応混合物を１６時間、ＲＴで撹拌した。反応混合物をＥｔＯＡｃおよび水に分配した。有機層を水、飽和ＮａＨＣＯ_３溶液および塩水溶液で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮し、濃縮物をメタノールで洗浄して、６０mg(３０％収率)の６−クロロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸アミドを、望む生成物として得た。
¹H NMR (DMSO-D₆, 300 MHz) δ 8.46-8.4 (br s, 1H), 7.68-7.52 (m, 3H), 7.4 (d, 1H), 6.7 (t, 1H), 4.0 (t, 2H), 3.3-3.2 (t, 2H), 2.1-2.0 (m, 2H)
LCMS: 98.68%; m/z=447.8
HPLC: 97.5% Process 5
Synthesis of 6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid amide

EDCI (256 mg, 0.001 mol) and HOBt (181 mg, 0.001 mol) were stirred with 6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2, To a solution of 3,5-tetrahydro-indolizine-8-carboxylic acid (200 mg, 0.0004 mol) in dry DMF (5 mL) was added at 0 ° C. The reaction mixture was stirred for 1.30 hours at 0 ° C. under a nitrogen atmosphere. Subsequently, NH ₄ Cl (0.071 g, 0.001 mol) and TEA (0.2 ml, 0.001 mol) were added at 0 ° C. The reaction mixture was stirred for 16 h at RT. 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 and concentrated, the concentrate was washed with methanol to give 60 mg (30% yield) of 6-chloro-7. -(2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid amide was obtained as the desired product.
¹ H NMR (DMSO-D ₆ , 300 MHz) δ 8.46-8.4 (br s, 1H), 7.68-7.52 (m, 3H), 7.4 (d, 1H), 6.7 (t, 1H), 4.0 (t, 2H), 3.3-3.2 (t, 2H), 2.1-2.0 (m, 2H)
LCMS: 98.68%; m / z = 447.8
HPLC: 97.5%

Example 45
Steps 1-3 were performed according to the method described in Example 1, and Step 4 was performed according to the method described in Example 6.

ＥＤＣＩ(２５６mg、０.００１mol)およびＨＯＢｔ(１８１mg、０.００１mol)を、撹拌している６−クロロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２００mg、０.０００４４６mol)の乾燥ＤＭＦ(５mL)溶液に０℃で添加した。反応混合物を１.３０時間、０℃で窒素雰囲気下で撹拌した。続いてＯ−エチル−ヒドロキシルアミンヒドロクロライド(１３０mg、０.００１mol)、ＴＥＡ(０.２ml、０.００１mol)を０℃で添加した。反応混合物を１８時間、ＲＴで撹拌した。反応混合物をＥｔＯＡｃおよび水に分配した。有機層を水、飽和ＮａＨＣＯ_３溶液および塩水溶液で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮し、濃縮物をメタノールで洗浄して、１０５mg(４８％収率)の６−クロロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エトキシ−アミドを、望む生成物として得た。
¹H NMR (DMSO-D₆, 300 MHz) δ 11.25-11.2 (br s, 1H), 8.02-7.94 (br s, 1H), 7.6-7.5 (d, 1H), 7.4 (d, 1H), 6.8-6.7 (t, 1H), 4.0 (t, 2H), 3.6-3.5 (m, 2H), 3.1 (t, 2H), 2.1-2.0 (m, 2H), 1.1 (t, 3H)
LCMS: 99%; m/z=491.6
HPLC: 96% Process 5
Synthesis of 6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethoxy-amide

EDCI (256 mg, 0.001 mol) and HOBt (181 mg, 0.001 mol) were stirred with 6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2, To a solution of 3,5-tetrahydro-indolizine-8-carboxylic acid (200 mg, 0.004646 mol) in dry DMF (5 mL) was added at 0 ° C. The reaction mixture was stirred for 1.30 hours at 0 ° C. under a nitrogen atmosphere. Subsequently, 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 for 18 hours at RT. 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 and concentrated, the concentrate was washed with methanol to give 105 mg (48% yield) of 6-chloro-7. -(2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethoxy-amide was obtained as the desired product.
¹ H NMR (DMSO-D ₆ , 300 MHz) δ 11.25-11.2 (br s, 1H), 8.02-7.94 (br s, 1H), 7.6-7.5 (d, 1H), 7.4 (d, 1H), 6.8 -6.7 (t, 1H), 4.0 (t, 2H), 3.6-3.5 (m, 2H), 3.1 (t, 2H), 2.1-2.0 (m, 2H), 1.1 (t, 3H)
LCMS: 99%; m / z = 491.6
HPLC: 96%

Example 46
Steps 1-3 were performed according to the method described in Example 1, and Step 4 was performed according to the method described in Example 6.

ＥＤＣＩ(２５６mg、０.００１mol)およびＨＯＢｔ(１８０mg、０.００１mol)を、撹拌している６−クロロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２００mg、０.０００４mol)の乾燥ＤＭＦ(５mL)溶液に０℃で添加した。反応混合物を１.３０時間、０℃で窒素雰囲気下で撹拌した。続いてＯ−(２,２−ジメチル−[１,３]ジオキソラン−４−イルメチル)−ヒドロキシルアミン(１９６mg、０.００１mol)、ＴＥＡ(０.２ml、０.００１mol)を０℃で添加した。反応混合物を１８時間、ＲＴで撹拌した。反応混合物をＥｔＯＡｃおよび水に分配した。有機層を水、飽和ＮａＨＣＯ_３溶液および塩水溶液で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮して、１７０mg(６６％収率)の６−クロロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２,２−ジメチル−[１,３]ジオキソラン−４−イルメトキシ)−アミドを、望む生成物として得た。
LCMS: 61%; m/z=577.8, M+1 Process 5
6-Chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2,2-dimethyl- [1, 3] Synthesis of dioxolan-4-ylmethoxy) -amide

EDCI (256 mg, 0.001 mol) and HOBt (180 mg, 0.001 mol) were stirred with 6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2, To a solution of 3,5-tetrahydro-indolizine-8-carboxylic acid (200 mg, 0.0004 mol) in dry DMF (5 mL) was added at 0 ° C. The reaction mixture was stirred for 1.30 hours at 0 ° C. under a nitrogen atmosphere. Subsequently, O- (2,2-dimethyl- [1,3] dioxolan-4-ylmethyl) -hydroxylamine (196 mg, 0.001 mol) and TEA (0.2 ml, 0.001 mol) were added at 0 ° C. The reaction mixture was stirred for 18 hours at RT. 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 170 mg (66% yield) of 6-chloro-7- (2-fluoro-4- Iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2,2-dimethyl- [1,3] dioxolan-4-ylmethoxy) -amide is desired Obtained as product.
LCMS: 61%; m / z = 577.8, M + 1

１Ｎ ＨＣｌ(０.６mL)を、ＥｔＯＨ(６mL)に溶解した撹拌している６−クロロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２,２−ジメチル−[１,３]ジオキソラン−４−イルメトキシ)−アミド(１７０mg、０.０００３mol)溶液に添加した。反応混合物を２時間、室温で撹拌した。エタノールを留去し、粗生成物をメタノールを使用する再結晶により精製して、２５mg(１７.３５％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−クロロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２,３−ジヒドロキシ−プロポキシ)−アミドを白色固体として得た。
¹H NMR (DMSO-D₆, 300 MHz) δ 11.4-11.35 (br s, 1H), 8.0-7.96 (br s, 1H), 7.6-7.5 (dd, 1H), 7.4 (dd, 1H), 7.4 (d, 1H), 6.8 (t, 1H), 4.8 (d, 1H), 4.6 (t, 1H), 4.0 (t, 2H), 3.7-3.4 (m, 1H), 3.1 (t, 2H), 2.1-2.0 (m, 2H)
LCMS: 85%; m/z=491.7, M+1
HPLC: 96% Step 6
6-Chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2,3-dihydroxy-propoxy)- Synthesis of amide

1N HCl (0.6 mL) is dissolved in EtOH (6 mL) with stirring 6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5. -Tetrahydro-indolizine-8-carboxylic acid (2,2-dimethyl- [1,3] dioxolan-4-ylmethoxy) -amide (170 mg, 0.0003 mol) was added to the solution. The reaction mixture was stirred for 2 hours at room temperature. Ethanol was distilled off and the crude product was purified by recrystallization using methanol to give 25 mg (17.35% yield) of 7- (4-bromo-2-fluoro-phenylamino) -6-chloro- 5-Oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2,3-dihydroxy-propoxy) -amide was obtained as a white solid.
¹ H NMR (DMSO-D ₆ , 300 MHz) δ 11.4-11.35 (br s, 1H), 8.0-7.96 (br s, 1H), 7.6-7.5 (dd, 1H), 7.4 (dd, 1H), 7.4 (d, 1H), 6.8 (t, 1H), 4.8 (d, 1H), 4.6 (t, 1H), 4.0 (t, 2H), 3.7-3.4 (m, 1H), 3.1 (t, 2H), 2.1-2.0 (m, 2H)
LCMS: 85%; m / z = 491.7, M + 1
HPLC: 96%

Example 47
Steps 1 to 3 were performed according to the method described in Example 8.

ＬＤＡ(４１６mg、０.００４mol)を、２−フルオロ−４−トリフルオロメチル−フェニルアミン(４８４mg、０.００３mol)のＴＨＦ(１０mL)溶液に−７８℃で添加し、得られた混合物を１時間、−７８℃で撹拌した。続いて７−クロロ−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２５０mg、０.００１mol)のＴＨＦ(３０mL)を−７８℃で添加し、撹拌をさらに１８時間、ＲＴで続けた。反応混合物からのＴＨＦを留去し、続いて１Ｎ ＨＣｌ(５mL)およびエーテル(１０mL)を添加した。反応混合物を１５分間撹拌し、沈殿を回収して、１５０mg(３７％収率)の６−フルオロ−７−(２−フルオロ−４−トリフルオロメチル−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸を、望む生成物として得た。
LC-MS純度: 100%, m/z=375, (M+)
HPLC: 91.4%
¹H NMR (DMSO-D₆, 300 MHz): δ 13.8-13.6 (br s, 1H), 9.6 (s, 1H), 7.7 (d, 1H), 7.52 (d, 1H), 7.15 (q, 1H), 4.1 (t, 2H), 3.5 (t, 2H), 2.2-2.1 (m, 2H)。 Process 4
Synthesis of 6-fluoro-7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-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 for 1 hour. , And stirred at -78 ° C. Subsequently, 7-chloro-6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (250 mg, 0.001 mol) in THF (30 mL) was added at -78 ° C. Stirring was continued for an additional 18 hours at RT. The THF from the reaction mixture was distilled off, followed by addition of 1N HCl (5 mL) and ether (10 mL). The reaction mixture was stirred for 15 minutes and the precipitate collected and 150 mg (37% yield) of 6-fluoro-7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2 1,3,5-Tetrahydro-indolizine-8-carboxylic acid was obtained as the desired product.
LC-MS purity: 100%, m / z = 375, (M +)
HPLC: 91.4%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 13.8-13.6 (br s, 1H), 9.6 (s, 1H), 7.7 (d, 1H), 7.52 (d, 1H), 7.15 (q, 1H ), 4.1 (t, 2H), 3.5 (t, 2H), 2.2-2.1 (m, 2H).

Example 48
Steps 1-3 were performed according to the method described in Example 8, and Step 4 was performed according to the method described in Example 47.

ＥＤＣＩ(１３８mg、０.００１mol)およびＨＯＢｔ(９８mg、０.００１mol)を、撹拌している６−フルオロ−７−(２−フルオロ−４−トリフルオロメチル−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(９０mg、０.０００２mol)のＤＭＦ(６mL)溶液に添加し、反応混合物を３０分間、ＲＴで撹拌した。続いてＯ−シクロプロピルメチル−ヒドロキシルアミンヒドロクロライド(９０mg、０.００１mol)およびＴＥＡ(７３mg、０.００１mol)を添加した。反応混合物を２０時間、ＲＴで撹拌した。反応混合物を水および酢酸エチル(２０mL)に分配した。有機層を飽和ＮａＨＣＯ_３(２０mL)、ＮＨ_４Ｃｌ(２０mL)および塩水溶液(２０mL)で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮し、濃縮物をメタノール(０.５mL)およびジエチルエーテル(１０mL)に溶解した。形成した沈殿を回収して、３５mg(３３％収率)の６−フルオロ−７−(２−フルオロ−４−トリフルオロメチル−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸シクロプロピルメトキシ−アミドを、望む生成物として得た。
LCMS純度: 100%, m/z=443, (M+)
HPLC: 94.3%
¹H NMR (DMSO-D₆, 300 MHz): δ 11.40 (s, 1H), 8.4 (s, 1H), 7.65 (d,1H), 7.43 (d, 1H), 7.12-7.02 (m, 1H), 4.1 (t, 2H), 3.5 (d, 2H), 3.2 (t, 2H), 2.2-2.1 (m, 2H), 1.05-0.95 (m, 1H), 0.52-0.42 (m, 2H), 0.25-0.15 (m, 2H)。 Process 5
Synthesis of 6-fluoro-7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide

EDCI (138 mg, 0.001 mol) and HOBt (98 mg, 0.001 mol) were stirred with 6-fluoro-7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1, 2,3,5-Tetrahydro-indolizine-8-carboxylic acid (90 mg, 0.0002 mol) in DMF (6 mL) was added and the reaction mixture was stirred for 30 min at RT. Subsequently, O-cyclopropylmethyl-hydroxylamine hydrochloride (90 mg, 0.001 mol) and TEA (73 mg, 0.001 mol) were added. The reaction mixture was stirred for 20 h at RT. The reaction mixture was partitioned between water and ethyl acetate (20 mL). The organic layer was washed with saturated NaHCO ₃ (20 mL), NH ₄ Cl (20 mL) and brine solution (20 mL), dried over Na ₂ SO ₄ and concentrated, and the concentrate was methanol (0.5 mL) and diethyl ether ( 10 mL). The formed precipitate was collected and 35 mg (33% yield) of 6-fluoro-7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro -Indolizine-8-carboxylic acid cyclopropylmethoxy-amide was obtained as the desired product.
LCMS purity: 100%, m / z = 443, (M +)
HPLC: 94.3%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 11.40 (s, 1H), 8.4 (s, 1H), 7.65 (d, 1H), 7.43 (d, 1H), 7.12-7.02 (m, 1H) , 4.1 (t, 2H), 3.5 (d, 2H), 3.2 (t, 2H), 2.2-2.1 (m, 2H), 1.05-0.95 (m, 1H), 0.52-0.42 (m, 2H), 0.25 -0.15 (m, 2H).

Example 49
Steps 1 to 3 were performed according to the method described in Example 8.

２−フルオロ−フェニルアミン(２ｇ、０.０１８mol)を、Selectfluor試薬(５.９ｇ、０.０１７mol)およびＫＳＣＮ(１.８１ｇ、０.０１９mol)のアセトニトリル溶液に添加し、得られた反応塊を７０時間、ＲＴで撹拌した。溶媒を留去し、反応塊を水(３００mL)に溶解し、２回ＤＣＭ(７５mL)で抽出し、有機層を水(１００mL)および塩水溶液(１００mL)で洗浄した。反応混合物をＮａ_２ＳＯ_４で乾燥させ、濃縮し、濃縮物をカラムクロマトグラフィー(シリカゲル、溶離剤として５−１０％の酢酸エチルのヘキサン溶液を使用)で精製して、７４０mg(２５％収率)の２−フルオロ−４−チオシアナト−フェニルアミンを薄黄色液体として得た。
¹H NMR (DMSO-D₆, 300 MHz): δ 7.3-7.15 (m, 2H), 6.8 (t, 1H), 4.15-4.0 (br s, 2H) Step 3a
Synthesis of 2-fluoro-4-thiocyanato-phenylamine

2-Fluoro-phenylamine (2 g, 0.018 mol) was added to a solution of Selectfluor reagent (5.9 g, 0.017 mol) and KSCN (1.81 g, 0.019 mol) in acetonitrile and the reaction mass obtained was Stir for 70 hours at RT. The solvent was removed and the reaction mass was dissolved in water (300 mL) and extracted twice with DCM (75 mL), and the organic layer was washed with water (100 mL) and brine solution (100 mL). The reaction mixture was dried over Na ₂ SO ₄ and concentrated, and the concentrate was purified by column chromatography (silica gel, using 5-10% ethyl acetate in hexane as eluent) to give 740 mg (25% yield). Of 2-fluoro-4-thiocyanato-phenylamine as a pale yellow liquid.
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 7.3-7.15 (m, 2H), 6.8 (t, 1H), 4.15-4.0 (br s, 2H)

Ｎａ_２Ｓ(１.０４ｇ、０.０１１mol)の水(２.２mL)溶液を、２−フルオロ−４−チオシアナト−フェニルアミン(７３０mg、０.００４mol)のエタノール(１２mL)溶液に添加し、反応混合物を２時間、５０℃で撹拌した。続いてＣＨ_３Ｉ(６８３mg、０.００４７mol)のエタノール(２mL)溶液を添加し、撹拌をさらに３時間続けた。反応塊を酢酸エチルで希釈し、続いて水(５０mL)を添加し、酢酸エチルで抽出した。有機層を水(２０mL)、塩水溶液(２０mL)で洗浄し、濃縮して、６１０mg(８９％収率)の２−フルオロ−４−メチルスルファニル−フェニルアミンを、望む生成物として得た。
¹H NMR (DMSO-D₆, 300 MHz): δ 7.2-6.92 (m, 2H), 6.72 (t, 1H), 3.8-3.6 (br s, 2H), 2.4 (s, 3H) Step 3b
Synthesis of 2-fluoro-4-methylsulfanyl-phenylamine

A solution of Na ₂ S (1.04 g, 0.011 mol) in water (2.2 mL) was added to a solution of 2-fluoro-4-thiocyanato-phenylamine (730 mg, 0.004 mol) in ethanol (12 mL) and reacted. The mixture was stirred at 50 ° C. for 2 hours. Subsequently, a solution of CH ₃ I (683 mg, 0.0035 mol) in ethanol (2 mL) was added and stirring was continued for another 3 hours. The reaction mass was diluted with ethyl acetate, followed by addition of water (50 mL) and extraction 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.
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 7.2-6.92 (m, 2H), 6.72 (t, 1H), 3.8-3.6 (br s, 2H), 2.4 (s, 3H)

ＬＤＡ(３１６mg、０.００２９６mol)を、２−フルオロ−４−メチルスルファニル−フェニルアミン(３２２mg、０.００２mol)のＴＨＦ(１０mL)溶液に−７８℃で添加し、得られた混合物を１.３０時間、−７８℃撹拌した。続いて７−クロロ−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(１９０mg、０.００１mol)のＴＨＦ(３０mL)溶液を−７８℃で添加し、撹拌をさらに２４時間、ＲＴで続けた。ＴＨＦを反応混合物から留去し、続いて１Ｎ ＨＣｌ(１２mL)およびエーテル(１０mL)を添加した。反応混合物を１５分間撹拌し、沈殿を回収して、１２８mgの６−フルオロ−７−(２−フルオロ−４−メチルスルファニル−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸を出発物質と共に得て、それをさらに精製せずに次工程に使用した。
LC-MS純度: 50%, m/z=353, (M+) Process 4
Synthesis of 6-fluoro-7- (2-fluoro-4-methylsulfanyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid

LDA (316 mg, 0.0026 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 1.30. Stir for -78 ° C. for hours. Subsequently, 7-chloro-6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (190 mg, 0.001 mol) in THF (30 mL) was added at -78 ° C. And stirring was continued at RT for an additional 24 hours. THF was distilled off from the reaction mixture followed by addition of 1N HCl (12 mL) and ether (10 mL). The reaction mixture was stirred for 15 minutes and the precipitate was collected and 128 mg of 6-fluoro-7- (2-fluoro-4-methylsulfanyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro- Indolizine-8-carboxylic acid was obtained with the starting material and used in the next step without further purification.
LC-MS purity: 50%, m / z = 353, (M +)

ＥＤＣＩ(２２７mg、０.００１mol)およびＨＯＢｔ(１６０mg、０.００１mol)を、撹拌している６−フルオロ−７−(２−フルオロ−４−メチルスルファニル−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(１２０mg、０.０００３mol)のＤＭＦ(５mL)溶液に添加し、反応混合物を１時間、ＲＴで撹拌した。続いてＯ−シクロプロピルメチル−ヒドロキシルアミンヒドロクロライド(１４７mg、０.００１mol)およびＴＥＡ(１２０mg、０.００１mol)を添加した。反応混合物を１６時間、ＲＴで撹拌した。反応混合物を酢酸エチルおよび水に分配した。有機層を飽和ＮａＨＣＯ_３、ＮＨ_４Ｃｌ、塩水溶液で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。濃縮物をメタノール(０.５mL)およびジエチルエーテル(１０mL)に溶解した。沈殿を回収して、７mg(９.８％収率)の６−フルオロ−７−(２−フルオロ−４−メチルスルファニル−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸シクロプロピルメトキシ−アミドを、望む生成物として得た。
LCMS純度: 89.5%, m/z=422, (M+)
HPLC: 91%
¹H NMR (DMSO-D₆, 300 MHz): δ 11.4 (s, 1H), 8.0 (s, 1H), 7.2 (d,1H), 7.0 (s, 2H), 4.0 (t, 2H), 3.5 (d, 2H), 3.2 (t, 2H), 2.5 (s, 3H), 2.14-2.04 (m, 2H), 1.05-0.95 (m, 1H), 0.55-0.45 (m, 2H), 0.25-0.15 (m, 2H)。 Process 5
Synthesis of 6-fluoro-7- (2-fluoro-4-methylsulfanyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide

EDCI (227 mg, 0.001 mol) and HOBt (160 mg, 0.001 mol) were stirred with 6-fluoro-7- (2-fluoro-4-methylsulfanyl-phenylamino) -5-oxo-1,2 , 3,5-Tetrahydro-indolizine-8-carboxylic acid (120 mg, 0.0003 mol) in DMF (5 mL) was added and the reaction mixture was stirred for 1 h at RT. Subsequently, O-cyclopropylmethyl-hydroxylamine hydrochloride (147 mg, 0.001 mol) and TEA (120 mg, 0.001 mol) were added. The reaction mixture was stirred for 16 h at RT. 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 and 7 mg (9.8% yield) of 6-fluoro-7- (2-fluoro-4-methylsulfanyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro- Indolizine-8-carboxylic acid cyclopropylmethoxy-amide was obtained as the desired product.
LCMS purity: 89.5%, m / z = 422, (M +)
HPLC: 91%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 11.4 (s, 1H), 8.0 (s, 1H), 7.2 (d, 1H), 7.0 (s, 2H), 4.0 (t, 2H), 3.5 (d, 2H), 3.2 (t, 2H), 2.5 (s, 3H), 2.14-2.04 (m, 2H), 1.05-0.95 (m, 1H), 0.55-0.45 (m, 2H), 0.25-0.15 (m, 2H).

Example 50
Steps 1-3 were performed according to the method described in Example 8, and Step 4 was performed according to the method described in Example 11.

Scheme 9

２,３,４,５,６−ペンタフルオロ−安息香酸トリフルオロメチルエステル(１３６mg、０.０００５mol)およびピリジン(３８mg、０.０００５mol)を、７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(１７０mg、０.０００４mol)のＤＭＦ(３mL)溶液に添加し、反応混合物を４時間、ＲＴで撹拌した。反応混合物を酢酸エチルおよび水に分配した。有機層をＮａＨＣＯ_３、２回１Ｍ ＨＣｌ溶液および塩水溶液で洗浄した。有機層をＮａ_２ＳＯ_４で乾燥させ、濃縮して、２５６mgの７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸ペンタフルオロフェニルエステルを粗生成物として得て、それをさらに精製せずに次工程に使用した。 Process 5
Synthesis of 7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid pentafluorophenyl ester

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

ＴＥＡ(９８mg、０.００１mol)を、撹拌しているヒドラジンヒドロクロライド(３５mg、０.００１mol)のＤＣＭ(５mL)溶液に添加し、反応混合物を１時間撹拌した。続いて７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸ペンタフルオロフェニルエステル(２５１mg、０.０００５mol)を添加し、撹拌をさらに８時間続けた。反応混合物を酢酸エチルおよび水に分配した。有機層を２回水、飽和ＮａＨＣＯ_３および２回塩水溶液で洗浄した。有機層をＮａ_２ＳＯ_４で乾燥させ、濃縮して、１３８mg(５５％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸ヒドラジドを、望む生成物として得た。
LCMS純度: 78%, m/z=399, 401, (M+) Step 6
Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid hydrazide

TEA (98 mg, 0.001 mol) was added to a stirring solution of hydrazine hydrochloride (35 mg, 0.001 mol) in DCM (5 mL) and the reaction mixture was stirred for 1 hour. Then 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid pentafluorophenyl ester (251 mg, 0 .0005 mol) was added and stirring was continued for another 8 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with water, saturated NaHCO ₃ and twice with brine solution. The organic layer was dried over Na ₂ SO ₄ and concentrated to give 138 mg (55% yield) of 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2, 3,5-Tetrahydro-indolizine-8-carboxylic acid hydrazide was obtained as the desired product.
LCMS purity: 78%, m / z = 399, 401, (M +)

イミダゾール(２３.４ｇ、０.３４４mol)を、２−アミノ−エタノール(２０ｇ、０.３２７mol)のＤＭＦ(４００mL)溶液に添加し、反応混合物を０℃に冷却した。続いてｔｅｒｔ−ブチル−クロロ−ジメチル−シラン(５１.８ｇ、０.３４４mol)を添加し、反応混合物を３時間、ＲＴで撹拌した。残留塊を水(１Ｌ)で希釈し、２回酢酸エチル(３００mL)で抽出した。酢酸エチル層を水、０.１Ｎ ＨＣｌ(１００mL)および塩水溶液(１００mL)で洗浄した。有機層をＮａ_２ＳＯ_４で乾燥させ、濃縮し、粗生成物をカラムクロマトグラフィー(シリカゲル、溶出系として３０−４０％酢酸エチルのヘキサン溶液を使用)で精製して、１８.１ｇ(３１％収率)の２−(ｔｅｒｔ−ブチル−ジメチル−シラニルオキシ)−エチルアミンを、望む生成物として得た。
LCMS純度: 92%, m/z=176, (M+) 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. Subsequently tert-butyl-chloro-dimethyl-silane (51.8 g, 0.344 mol) was added and the reaction mixture was stirred for 3 h at RT. The residual mass 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 yield 18.1 g (31% Yield) of 2- (tert-butyl-dimethyl-silanyloxy) -ethylamine was obtained as the desired product.
LCMS purity: 92%, m / z = 176, (M +)

２−(ｔｅｒｔ−ブチル−ジメチル−シラニルオキシ)−エチルアミン(７.３ｇ、０.０４２mol)のＤＣＭ(１５０mL)溶液を、ＣＤＩ(１０.１１ｇ、０.０６２mol)のＴＨＦ(６０mL)溶液にＲＴで添加し、反応混合物を８時間、５０℃で撹拌した。反応混合物からの溶媒を留去し、残留粗生成物をカラムクロマトグラフィー(シリカゲル、溶出系として２０−４０％酢酸エチルのヘキサン溶液を使用)で精製して、２.１ｇ(１９％収率)のイミダゾール−１−カルボン酸[２−(ｔｅｒｔ−ブチル−ジメチル−シラニルオキシ)−エチル]−アミドを、望む生成物として得た。
LCMS純度: 94.5%, m/z=270, (M+) 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 RT. The reaction mixture was stirred at 50 ° C. for 8 hours. The solvent from the reaction mixture was distilled off, and the residual crude product was purified by column chromatography (silica gel, using 20-40% ethyl acetate in hexane as elution system) to obtain 2.1 g (19% yield). Of imidazole-1-carboxylic acid [2- (tert-butyl-dimethyl-silanyloxy) -ethyl] -amide was obtained as the desired product.
LCMS purity: 94.5%, m / z = 270, (M +)

酢酸(６３mg、０.０００３mol)および７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸ヒドラジド(１３５mg、０.０００３mol)を、イミダゾール−１−カルボン酸[２−(ｔｅｒｔ−ブチル−ジメチル−シラニルオキシ)−エチル]−アミド(９１mg、０.０００３mol)のＴＨＦ(１０mL)溶液に添加し、反応混合物を１４時間、ＲＴで撹拌した。反応混合物からの溶媒を蒸留して、２１３mgの７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸Ｎ’−２−(ｔｅｒｔ−ブチル−ジメチル−シラニルオキシ)−エチル−アミノ−カルボニル−ヒドラジドを粗生成物として得て、それをさらに精製せずに次工程に使用した。
ＬＣＭＳ純度：４９％、ｍ／ｚ＝６００、(Ｍ＋) Step 7
7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid N′-2- (tert-butyl- Synthesis of (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-indolizine-8-carboxylic acid hydrazide (135 mg, 0.0003 mol) was added to a solution of imidazole-1-carboxylic acid [2- (tert-butyl-dimethyl-silanyloxy) -ethyl] -amide (91 mg, 0.0003 mol) in THF (10 mL) and reacted. The mixture was stirred for 14 hours at RT. The solvent from the reaction mixture was distilled to give 213 mg of 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8- The carboxylic acid N′-2- (tert-butyl-dimethyl-silanyloxy) -ethyl-amino-carbonyl-hydrazide was obtained as a crude product, which was used in the next step without further purification.
LCMS purity: 49%, m / z = 600, (M +)

トシルクロライド(６３mg、０.０００３mol)およびＴＥＡ(８４mg、０.０００８mol)を、撹拌している７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸Ｎ’−２−(ｔｅｒｔ−ブチル−ジメチル−シラニルオキシ)−エチル−アミノ−カルボニル−ヒドラジド(２００mg、０.０００３mol)のＤＣＭ(８mL)溶液に添加し、反応混合物を１２時間、ＲＴで撹拌した。反応混合物からのＤＣＭを留去し、残留混合物を水で希釈し、酢酸エチルで抽出した。有機層をＮａ_２ＳＯ_４で乾燥させ、濃縮して、１８.１ｇ(３１％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−８−{５−[２−(ｔｅｒｔ−ブチル−ジメチル−シラニルオキシ)−エチルアミノ]−[１,３,４]オキサジアゾール−２−イル}−６−フルオロ−２,３−ジヒドロ−１Ｈ−インドリジン−５−オンを粗生成物として得て、それをさらに精製せずに次工程に使用した。 Process 8
7- (4-Bromo-2-fluoro-phenylamino) -8- {5- [2- (tert-butyl-dimethyl-silanyloxy) -ethylamino]-[1,3,4] oxadiazole-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 stirred with 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2 1,3,5-tetrahydro-indolizine-8-carboxylic acid N′-2- (tert-butyl-dimethyl-silanyloxy) -ethyl-amino-carbonyl-hydrazide (200 mg, 0.0003 mol) in DCM (8 mL) Was added and the reaction mixture was stirred for 12 h at RT. DCM from the reaction mixture was distilled off and the residual mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over Na ₂ SO ₄ and concentrated to give 18.1 g (31% yield) of 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-indolidin-5-one Which was used in the next step without further purification.

酢酸(２５mg、０.０００４mol)およびテトラブチルアンモニウムフルオライド(１６８mg、０.０００６mol)を、７−(４−ブロモ−２−フルオロ−フェニルアミノ)−８−{５−[２−(ｔｅｒｔ−ブチル−ジメチル−シラニルオキシ)−エチルアミノ]−[１,３,４]オキサジアゾール−２−イル}−６−フルオロ−２,３−ジヒドロ−１Ｈ−インドリジン−５−オン(２５０mg、０.０００４mol)のＴＨＦ(６mL)溶液に０℃で添加し、反応混合物を３時間、ＲＴで撹拌した。反応混合物を酢酸エチルおよび水で希釈した。有機層をＮａＨＣＯ_３溶液、１Ｍ ＨＣｌおよび塩水溶液で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。粗生成物をＤＣＭ(２mL)に溶解し、続いてジエチルエーテルを添加し、形成した沈殿を回収し、乾燥させて、２７.５mg(１４％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−８−[５−(２−ヒドロキシ−エチルアミノ)−[１,３,４]オキサジアゾール−２−イル]−２,３−ジヒドロ−１Ｈ−インドリジン−５−オンを、望む生成物として得た。
LCMS純度: 92.2%, m/z=468, 470 (M+)
HPLC: 95%
¹H NMR (DMSO-D₆, 300 MHz): δ 9.1 (s, 1H), 7.82 (t, 1H), 7.55 (d,1H), 7.32 (s, 1H), 7.12 (m, 1H), 4.8 (t, 1H), 4.1 (t, 2H), 3.6-3.5 (q, 12H), 3.4-3.2 (m, 4H), 2.3-2.1 (m, 2H)。 Step 9
7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-8- [5- (2-hydroxy-ethylamino)-[1,3,4] oxadiazol-2-yl] -2 Of 1,3-dihydro-1H-indolizin-5-one

Acetic acid (25 mg, 0.0004 mol) and tetrabutylammonium fluoride (168 mg, 0.0006 mol) were added 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 (250 mg, 0.0004 mol) ) In THF (6 mL) at 0 ° C. and the reaction mixture was stirred for 3 h at RT. 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 was dissolved in DCM (2 mL) followed by addition of diethyl ether and the formed precipitate was collected and dried to yield 27.5 mg (14% yield) of 7- (4-bromo-2- Fluoro-phenylamino) -6-fluoro-8- [5- (2-hydroxy-ethylamino)-[1,3,4] oxadiazol-2-yl] -2,3-dihydro-1H-indolizine -5-one was obtained as the desired product.
LCMS purity: 92.2%, m / z = 468, 470 (M +)
HPLC: 95%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 9.1 (s, 1H), 7.82 (t, 1H), 7.55 (d, 1H), 7.32 (s, 1H), 7.12 (m, 1H), 4.8 (t, 1H), 4.1 (t, 2H), 3.6-3.5 (q, 12H), 3.4-3.2 (m, 4H), 2.3-2.1 (m, 2H).

Example 51
Steps 1 to 4 were performed according to the method described in Example 8.

ＥＤＣＩ(２９６mg、０.００１５mol)およびＨＯＢｔ(２０９mg、０.００１５mol)を、撹拌している７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２００mg、０.０００５mol)のＤＭＦ(５mL)溶液に添加し、反応混合物を１時間、ＲＴで撹拌した。続いてＯ−メチル−ヒドロキシルアミン(１３０mg、０.００２mol)およびＴＥＡ(１５６mg、０.００２mol)を添加した。反応混合物を１９時間、ＲＴで撹拌した。反応混合物を水および酢酸エチルに分配した。有機層を飽和ＮａＨＣＯ_３、飽和ＮＨ_４Ｃｌおよび塩水溶液で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。濃縮物をＩＰＡ(２mL)に溶解し、ジエチルエーテル(１５mL)を添加した。形成した沈殿を回収して、５７mg(２７％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸メトキシ−アミドを、望む生成物として得た。
LCMS純度: 97%, m/z 413,415 (M+, Brパターン)
HPLC: 99%
¹H NMR (DMSO-D₆, 300 MHz): δ 11.42 (s, 1H), 8.1 (s, 1H), 7.5 (d, 1H), 7.3(d, 1H), 6.98 (m, 1H), 4.00 (t, 2H), 3.6(s, 3H), 3.3(t, 2H), 2.10 (m, 2H) Process 5
Synthesis of 7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-amide

EDCI (296 mg, 0.0015 mol) and HOBt (209 mg, 0.0015 mol) are stirred with 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2, 3,5-Tetrahydro-indolizine-8-carboxylic acid (200 mg, 0.0005 mol) in DMF (5 mL) was added and the reaction mixture was stirred for 1 h at RT. 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 for 19 hours at RT. 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) and diethyl ether (15 mL) was added. The formed precipitate was recovered and 57 mg (27% yield) of 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-india Lysine-8-carboxylic acid methoxy-amide was obtained as the desired product.
LCMS purity: 97%, m / z 413,415 (M +, Br pattern)
HPLC: 99%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 11.42 (s, 1H), 8.1 (s, 1H), 7.5 (d, 1H), 7.3 (d, 1H), 6.98 (m, 1H), 4.00 (t, 2H), 3.6 (s, 3H), 3.3 (t, 2H), 2.10 (m, 2H)

Example 52
Steps 1 to 4 were performed according to the method described in Example 8.

ＥＤＣＩ(２９６mg、０.００２mol)およびＨＯＢｔ(２０９mg、０.００２mol)を、撹拌している７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２００mg、０.０００５mol)のＤＭＦ(５mL)溶液に添加し、反応混合物を１時間、ＲＴで撹拌した。続いてＯ−エチル−ヒドロキシルアミン(１５２mg、０.００２mol)およびＴＥＡ(１５６mg、０.００２mol)を添加した。反応混合物を１８時間、ＲＴで撹拌した。反応混合物を水および酢酸エチルに分配した。有機層を飽和ＮａＨＣＯ_３、飽和ＮＨ_４Ｃｌおよび塩水溶液で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。濃縮物をメタノール(１mL)に溶解し、エーテル(１０mL)をそれに添加し、形成した沈殿を回収して、９７mg(４４％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エトキシ−アミドを、望む生成物として得た。
LCMS純度: 97%, m/z 428,430 (M+, Brパターン)
HPLC: 97.6%
¹H NMR (DMSO-D₆, 300 MHz): δ 11.4 (s, 1H), 8.08 (s, 1H), 7.52 (d, 1H), 7.28 (d, 1H), 6.98 (m, 1H), 4.00 (t, 2H), 3.8 (q, 2H), 3.2 (t, 2H), 2.10 (m, 2H), 1.12 (t, 3H) Process 5
Synthesis of 7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethoxy-amide

EDCI (296 mg, 0.002 mol) and HOBt (209 mg, 0.002 mol) were stirred with 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2, 3,5-Tetrahydro-indolizine-8-carboxylic acid (200 mg, 0.0005 mol) in DMF (5 mL) was added and the reaction mixture was stirred for 1 h at RT. Subsequently, O-ethyl-hydroxylamine (152 mg, 0.002 mol) and TEA (156 mg, 0.002 mol) were added. The reaction mixture was stirred for 18 hours at RT. 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 to it and the precipitate formed was collected to recover 97 mg (44% yield) of 7- (4-bromo-2-fluoro-phenylamino). -6-Fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethoxy-amide was obtained as the desired product.
LCMS purity: 97%, m / z 428,430 (M +, Br pattern)
HPLC: 97.6%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 11.4 (s, 1H), 8.08 (s, 1H), 7.52 (d, 1H), 7.28 (d, 1H), 6.98 (m, 1H), 4.00 (t, 2H), 3.8 (q, 2H), 3.2 (t, 2H), 2.10 (m, 2H), 1.12 (t, 3H)

Example 53
Steps 1 to 4 were performed according to the method described in Example 8.

ＥＤＣＩ(１４８mg、０.００１mol)およびＨＯＢｔ(１０４mg、０.００１mol)を撹拌している７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(１００mg、０.０００３mol)のＤＭＦ(３mL)溶液に添加し、反応混合物を１.３０時間、ＲＴで撹拌した。続いてＯ−(２−ビニルオキシ−エチル)−ヒドロキシルアミン(８０mg、０.００１mol)およびＴＥＡ(７８mg、０.００１mol)を添加した。反応混合物を１９時間、ＲＴで撹拌した。反応混合物を水および酢酸エチルに分配した。有機層を飽和ＮａＨＣＯ_３、飽和ＮＨ_４Ｃｌおよび塩水溶液で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮して、１１０mgの粗生成物を得て、それをさらに精製せずに次工程に使用した。 Process 5
7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-vinyloxy-ethoxy) -amide Composition

7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3 stirring EDCI (148 mg, 0.001 mol) and HOBt (104 mg, 0.001 mol) , 5-Tetrahydro-indolizine-8-carboxylic acid (100 mg, 0.0003 mol) in DMF (3 mL) was added and the reaction mixture was stirred for 1.30 h at RT. Subsequently O- (2-vinyloxy-ethyl) -hydroxylamine (80 mg, 0.001 mol) and TEA (78 mg, 0.001 mol) were added. The reaction mixture was stirred for 19 hours at RT. 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 that was used in the next step without further purification. did.

１Ｎ ＨＣｌ(１.６mL)を、撹拌している７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２−ビニルオキシ−エトキシ)−アミド(１１０mg、０.０００２mol)のＴＨＦおよびＥｔＯＨの１：１混合物(２mL)中の溶液に添加した。反応混合物を１時間撹拌した。反応混合物を酢酸エチルで希釈した；ｐＨを２Ｎ ＮａＯＨを使用して５に調節し、ＥｔＯＡｃで抽出した。有機層をＮａ_２ＳＯ_４で乾燥させ、濃縮した。濃縮物を２mLのＩＰＡに溶解し、１０mLのエーテルをこれに添加し、形成した沈殿を回収して、８mg(７％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２−ヒドロキシ−エトキシ)−アミドを、望む生成物として得た。
LCMS純度: 91.8%, m/z=443.9, 445.9 (M+, Brパターン)
HPLC: 98.2%
¹H NMR (DMSO-D₆, 300 MHz): δ 11.42 (s, 1H), 8.1 (s, 1H), 7.5 (d, 1H), 7.3 (d, 1H), 6.98 (m, 1H), 4.8 (t, 1H), 4.00 (t, 2H), 3.8 (t, 2H) 3.55 (t, 2H), 3.2 (t, 2H), 2.12 (m, 2H) Step 6
Of 7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy) -amide Composition

1N HCl (1.6 mL) was stirred with 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8. -To a solution of carboxylic acid (2-vinyloxy-ethoxy) -amide (110 mg, 0.0002 mol) in a 1: 1 mixture of THF and EtOH (2 mL). The reaction mixture was stirred for 1 hour. The reaction mixture was diluted with ethyl acetate; the pH was adjusted to 5 using 2N NaOH and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ and concentrated. The concentrate is dissolved in 2 mL of IPA, 10 mL of ether is added to it and the precipitate formed is collected to recover 8 mg (7% yield) of 7- (4-bromo-2-fluoro-phenylamino)- 6-Fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy) -amide was obtained as the desired product.
LCMS purity: 91.8%, m / z = 443.9, 445.9 (M +, Br pattern)
HPLC: 98.2%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 11.42 (s, 1H), 8.1 (s, 1H), 7.5 (d, 1H), 7.3 (d, 1H), 6.98 (m, 1H), 4.8 (t, 1H), 4.00 (t, 2H), 3.8 (t, 2H) 3.55 (t, 2H), 3.2 (t, 2H), 2.12 (m, 2H)

Example 54
Steps 1 to 3 were performed according to the method described in Example 8.

ＬＤＡ(２.３３ｇ、０.０１１mol)を、４−ブロモ−２−メチル−フェニルアミン(１.４mg、０.００８mol)のＴＨＦ(１０mL)溶液に−７８℃で添加し、得られた混合物を１時間、−７８℃で撹拌した。続いて７−クロロ−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(７００mg、０.００３mol)のＴＨＦ(５０mL)溶液を−７８℃で添加し、撹拌をさらに２０時間、ＲＴで続けた。ＴＨＦを留去し、続いて１Ｎ ＨＣｌ(２０mL)、水(２５mL)およびエーテル(１０mL)を添加した。形成した沈殿を回収して、２８１mg(２４％収率)の７−(４−ブロモ−２−メチル−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸を得た。
LCMS純度: 96%, m/z 380, 382 (M+, Brパターン)
HPLC: 95.89%
¹H NMR (DMSO-D₆, 300MHz): δ 13.70 (s, 1H), 9.4 (s, 1H), 7.4 (s, 1H), 7.3 (d, 1H), 6.8 (m, 1H), 4.04 (t, 2H), 3.48 (t, 2H), 2.25 (s, 3H), 2.10 (m, 2H)。 Process 4
Synthesis of 7- (4-bromo-2-methyl-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid

LDA (2.33 g, 0.011 mol) was 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 was added. Stir at -78 ° C for 1 hour. Subsequently, 7-chloro-6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (700 mg, 0.003 mol) in THF (50 mL) was added at −78 ° C. And stirring was continued at RT for an additional 20 hours. The THF was distilled off followed by addition of 1N HCl (20 mL), water (25 mL) and ether (10 mL). The precipitate that formed was collected and 281 mg (24% yield) of 7- (4-bromo-2-methyl-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-india. Lysine-8-carboxylic acid was obtained.
LCMS purity: 96%, m / z 380, 382 (M +, Br pattern)
HPLC: 95.89%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 13.70 (s, 1H), 9.4 (s, 1H), 7.4 (s, 1H), 7.3 (d, 1H), 6.8 (m, 1H), 4.04 ( t, 2H), 3.48 (t, 2H), 2.25 (s, 3H), 2.10 (m, 2H).

Example 55
Steps 1-3 were performed according to the method described in Example 8, and Step 4 was performed according to the method described in Example 54.

ＥＤＣＩ(３４６mg、０.００２mol)およびＨＯＢｔ(２４４mg、０.００２mol)を、撹拌している７−(４−ブロモ−２−メチル−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２３０mg、０.００１mol)のＤＭＦ(３mL)溶液に添加し、反応混合物を１時間、ＲＴで撹拌した。続いてＯ−シクロプロピルメチル−ヒドロキシルアミン(２２４mg、０.００２mol)およびＴＥＡ(１８３mg、０.００２mol)を添加した。反応混合物を２４時間、ＲＴで撹拌した。反応混合物を水および酢酸エチルに分配した。有機層を飽和ＮａＨＣＯ_３、飽和ＮＨ_４Ｃｌおよび塩水溶液で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。濃縮物を５mLのメタノールに溶解し、２５mLのジエチルエーテルをこれに添加し、形成した沈殿を回収して、４０mg(１４.７％収率)の７−(４−ブロモ−２−メチル−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸シクロプロピルメトキシ−アミドを、望む生成物として得た。
LCMS純度: 95%, m/z 450,452 (M+, Brパターン)
HPLC: 96.1%
¹H NMR (DMSO-D₆, 300MHz): δ 11.30 (s, 1H), 7.78 (s, 1H), 7. 4 (s, 1H), 7.22 (d, 1H), 6.88 (m, 1H), 4.00 (t, 2H), 3.4 (d, 2H), 3.20 (t, 2H), 2.2 (s, 3H) 2.10 (m, 2H), 1.00 (m, 1H), 0.50 (m, 2H), 0.20 (m, 2H) Process 5
Synthesis of 7- (4-Bromo-2-methyl-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide

EDCI (346 mg, 0.002 mol) and HOBt (244 mg, 0.002 mol) were stirred with 7- (4-bromo-2-methyl-phenylamino) -6-fluoro-5-oxo-1,2, 3,5-Tetrahydro-indolizine-8-carboxylic acid (230 mg, 0.001 mol) in DMF (3 mL) was added and the reaction mixture was stirred for 1 h at RT. 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 for 24 h at RT. 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 is dissolved in 5 mL of methanol, 25 mL of diethyl ether is added thereto, and the precipitate that forms is collected to recover 40 mg (14.7% yield) of 7- (4-bromo-2-methyl-phenyl). Amino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide was obtained as the desired product.
LCMS purity: 95%, m / z 450,452 (M +, Br pattern)
HPLC: 96.1%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 11.30 (s, 1H), 7.78 (s, 1H), 7.4 (s, 1H), 7.22 (d, 1H), 6.88 (m, 1H), 4.00 (t, 2H), 3.4 (d, 2H), 3.20 (t, 2H), 2.2 (s, 3H) 2.10 (m, 2H), 1.00 (m, 1H), 0.50 (m, 2H), 0.20 ( m, 2H)

Example 56
Steps 1 to 3 were performed according to the method described in Example 8.

ＬＤＡ(２.７ｇ、０.０２５３mol)を、４−ブロモ−２−メチル−フェニルアミン(３.２８mg、０.０１８mol)のＴＨＦ(３０mL)溶液に−７８℃で添加し、得られた混合物を４５分間、−７８℃で撹拌した。続いて７−クロロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(１.５ｇ、０.０１mol)のＴＨＦ(９０mL)溶液を−７８℃で添加し、撹拌をさらに２１時間、ＲＴで続けた。ＴＨＦを留去し、続いて６０mLの１Ｎ ＨＣｌ(ｐＨ＝１)、水(１１５mL)およびジエチルエーテル(１１５mL)を添加した。形成した沈殿を回収して、６１０mg(３６％収率)の７−(４−ブロモ−２−メチル−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸を得た。
LCMS純度: 93%, m/z 363,365(M+, Brパターン)
HPLC: 95.3%
¹H NMR (DMSO-D₆, 300 MHz): δ 13.30 (s, 1H), 9.8 (s, 1H), 7.6 (s, 1H), 7.42 (d, 1H), 7.2 (m, 1H), 5.08 (s, 1H), 3.8 (t, 2H), 3.48 (t, 2H), 2.35 (s, 3H), 2.15 (m, 2H)。 Process 4
Synthesis of 7- (4-Bromo-2-methyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-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 added. Stir for 45 minutes at -78 ° C. Subsequently, 7-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (1.5 g, 0.01 mol) in THF (90 mL) was added at −78 ° C., Stirring was continued for an additional 21 hours at RT. The THF was distilled off, followed by the addition of 60 mL of 1N HCl (pH = 1), water (115 mL) and diethyl ether (115 mL). The formed precipitate was recovered and 610 mg (36% yield) of 7- (4-bromo-2-methyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8- Carboxylic acid was obtained.
LCMS purity: 93%, m / z 363,365 (M +, Br pattern)
HPLC: 95.3%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 13.30 (s, 1H), 9.8 (s, 1H), 7.6 (s, 1H), 7.42 (d, 1H), 7.2 (m, 1H), 5.08 (s, 1H), 3.8 (t, 2H), 3.48 (t, 2H), 2.35 (s, 3H), 2.15 (m, 2H).

Example 57
Steps 1-3 were performed according to the method described in Example 8, and Step 4 was performed according to the method described in Example 56.

ＥＤＣＩ(４７３mg、０.００２mol)およびＨＯＢｔ(３３４mg、０.００２mol)を、撹拌している７−(４−ブロモ−２−メチル−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(３００mg、０.００１mol)のＤＭＦ(３mL)溶液に添加し、反応混合物を１時間、ＲＴで撹拌した。続いてＯ−シクロプロピルメチル−ヒドロキシルアミン(３０６mg、０.００２mol)およびＴＥＡ(２５０mg、０.００２mol)を添加した。反応混合物を２６時間、ＲＴで撹拌した。反応混合物をＥｔＯＡｃおよび水に分配した。有機層を飽和ＮＨ_４Ｃｌ、飽和ＮａＨＣＯ_３溶液および塩水溶液で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。濃縮物を２.５mLのメタノールに溶解し、１０mLのジエチルエーテルをこれに添加し、形成した沈殿を回収して、４７mg(１３％収率)の７−(４−ブロモ−２−メチル−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸シクロプロピルメトキシ−アミドを、望む生成物として得た。
LCMS純度: 96%, m/z 432,434 (M+, Brパターン)
HPLC: 92.1%
¹H NMR (DMSO-D₆, 300 MHz): δ 11.36 (s, 1H), 8.02 (s, 1H), 7. 58 (s, 1H), 7.4 (d, 1H), 7.15 (m, 1H), 5.02 (s, 1H) 3.8 (t, 2H), 3.7 (d, 2H), 3.20 (t, 2H), 2.2 (s, 3H) 2.16 (m, 2H), 1.10 (m, 1H), 0.52 (m, 2H), 0.30 (m, 2H) Process 5
Synthesis of 7- (4-Bromo-2-methyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide

EDCI (473 mg, 0.002 mol) and HOBt (334 mg, 0.002 mol) were stirred with 7- (4-bromo-2-methyl-phenylamino) -5-oxo-1,2,3,5- Tetrahydro-indolizine-8-carboxylic acid (300 mg, 0.001 mol) was added to a solution of DMF (3 mL) and the reaction mixture was stirred for 1 h at RT. This was followed by the addition of O-cyclopropylmethyl-hydroxylamine (306 mg, 0.002 mol) and TEA (250 mg, 0.002 mol). The reaction mixture was stirred for 26 hours at RT. 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 is dissolved in 2.5 mL of methanol, 10 mL of diethyl ether is added thereto, and the precipitate that forms is collected to recover 47 mg (13% yield) of 7- (4-bromo-2-methyl-phenyl). Amino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide was obtained as the desired product.
LCMS purity: 96%, m / z 432,434 (M +, Br pattern)
HPLC: 92.1%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 11.36 (s, 1H), 8.02 (s, 1H), 7.58 (s, 1H), 7.4 (d, 1H), 7.15 (m, 1H) , 5.02 (s, 1H) 3.8 (t, 2H), 3.7 (d, 2H), 3.20 (t, 2H), 2.2 (s, 3H) 2.16 (m, 2H), 1.10 (m, 1H), 0.52 ( m, 2H), 0.30 (m, 2H)

Example 58
Steps 1 to 4 were performed according to the method described in Example 8.

ＥＤＣＩ(１５４mg、０.００１mol)およびＨＯＢｔ(１００mg、０.００１mol)を、撹拌している６−フルオロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(１４０mg、０.０００３mol)のＤＭＦ(４mL)溶液に添加し、反応混合物を１時間、ＲＴで撹拌した。続いて２−(３−ヒドロキシ−アゼチジン−３−イル)−ピペリジン−１−カルボン酸ｔｅｒｔ−ブチルエステル(Ｓ異性体)(１６６mg、０.００１mol)およびＴＥＡ(９８mg、０.００１mol)を添加した。反応混合物を１６時間、ＲＴで撹拌した。反応混合物をＥｔＯＡｃおよび水に分配した。有機層を飽和ＮＨ_４Ｃｌ、飽和ＮａＨＣＯ_３溶液および塩水溶液で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。濃縮物をカラムクロマトグラフィー(シリカゲル、溶離剤として２−３％メタノールのＤＣＭ溶液を使用)で精製して、１８０mg(８２.９％収率)の２−{１−[６−フルオロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボニル]−３−ヒドロキシ−アゼチジン−３−イル}−ピペリジン−１−カルボン酸ｔｅｒｔ−ブチルエステル(Ｓ異性体)を、望む生成物として得た。 Process 5
2- {1- [6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carbonyl] -3-hydroxy Synthesis of -azetidin-3-yl} -piperidine-1-carboxylic acid tert-butyl ester

EDCI (154 mg, 0.001 mol) and HOBt (100 mg, 0.001 mol) were stirred with 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2, 3,5-Tetrahydro-indolizine-8-carboxylic acid (140 mg, 0.0003 mol) in DMF (4 mL) was added and the reaction mixture was stirred for 1 h at RT. Subsequently, 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) were added. . The reaction mixture was stirred for 16 h at RT. 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, using 2-3% methanol in DCM as eluent) to give 180 mg (82.9% yield) of 2- {1- [6-fluoro-7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carbonyl] -3-hydroxy-azetidin-3-yl} -piperidine-1- Carboxylic acid tert-butyl ester (S isomer) was obtained as the desired product.

ＨＣｌ中４Ｎ ジオキサン(２.５mL)を、２−{１−[６−フルオロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボニル]−３−ヒドロキシ−アゼチジン−３−イル}−ピペリジン−１−カルボン酸ｔｅｒｔ−ブチルエステル(Ｓ異性体)(５０mg、０.０００１mol)のメタノール(２mL)溶液に添加し、得られた混合物を１時間、ＲＴで撹拌した。溶媒を反応混合物から留去し、残留物をエーテルで摩砕して、３４mg(７５％収率)の６−フルオロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−８−(３−ヒドロキシ−３−ピペリジン−２−イル−アゼチジン−１−カルボニル)−２,３−ジヒドロ−１Ｈ−インドリジン−５−オンヒドロクロライド(Ｓ異性体)を、望む生成物として得た。 Step 6
6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -8- (3-hydroxy-3-piperidin-2-yl-azetidine-1-carbonyl) -2,3-dihydro-1H-India Synthesis of lysine-5-one hydrochloride

4N dioxane (2.5 mL) in HCl was added to 2- {1- [6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro- Indolizine-8-carbonyl] -3-hydroxy-azetidin-3-yl} -piperidine-1-carboxylic acid tert-butyl ester (S isomer) (50 mg, 0.0001 mol) in methanol (2 mL) was added. The resulting mixture was stirred for 1 h at RT. The solvent was removed from the reaction mixture and the residue was triturated with ether to give 34 mg (75% yield) of 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 (S isomer) was obtained as the desired product.

Example 59
Steps 1-3 were performed according to the method described in Example 8, and Step 4 was performed according to the method described in Example 11.

ＥＤＣＩ(１８５mg、０.００１mol)およびＨＯＢｔ(１３１mg、０.００１mol)を、撹拌している７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２５０mg、０.００１mol)のＤＭＦ(５mL)溶液に添加し、反応混合物を１時間、ＲＴで撹拌した。続いて２−(３−ヒドロキシ−アゼチジン−３−イル)−ピペリジン−１−カルボン酸ｔｅｒｔ−ブチルエステル(ラセミ混合物)(１９９mg、０.００１mol)およびＴＥＡ(１９６mg、０.００２mol)を添加した。反応混合物を１６時間、ＲＴで撹拌した。反応混合物をＥｔＯＡｃおよび水に分配した。有機層を飽和ＮＨ_４Ｃｌ(１０mL)、飽和ＮａＨＣＯ_３溶液(１０mL)および塩水溶液(１０mL)で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。濃縮物を３mLの酢酸エチルに溶解して沈殿を得て、それを回収して、２００mg(４９.６％収率)の２−{１−[７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボニル]−３−ヒドロキシ−アゼチジン−３−イル}−ピペリジン−１−カルボン酸ｔｅｒｔ−ブチルエステル(ラセミ混合物)を、望む生成物として得た。
HPLC: 98.4% Process 5
2- {1- [7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carbonyl] -3-hydroxy Synthesis of -azetidin-3-yl} -piperidine-1-carboxylic acid tert-butyl ester

EDCI (185 mg, 0.001 mol) and HOBt (131 mg, 0.001 mol) were stirred with 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2, 3,5-Tetrahydro-indolizine-8-carboxylic acid (250 mg, 0.001 mol) in DMF (5 mL) was added and the reaction mixture was stirred for 1 h at RT. Subsequently, 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) were added. The reaction mixture was stirred for 16 h at RT. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with saturated NH ₄ Cl (10 mL), saturated NaHCO ₃ 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 that was collected and collected in 200 mg (49.6% yield) of 2- {1- [7- (4-bromo-2-fluoro-phenyl]. Amino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carbonyl] -3-hydroxy-azetidin-3-yl} -piperidine-1-carboxylic acid tert-butyl ester (Racemic mixture) was obtained as the desired product.
HPLC: 98.4%

ＨＣｌ中４Ｎ ジオキサン(４mL)を、２−{１−[７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボニル]−３−ヒドロキシ−アゼチジン−３−イル}−ピペリジン−１−カルボン酸ｔｅｒｔ−ブチルエステル(ラセミ混合物)(７５mg、０.０００１mol)のメタノール(１mL)溶液に添加し、得られた混合物を１時間、ＲＴで撹拌した。溶媒を反応混合物から蒸留した。５mLのジエチルエーテルでの摩砕により沈殿を得て、それを回収して、４８mg(７１.６％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−８−(３−ヒドロキシ−３−ピペリジン−２−イル−アゼチジン−１−カルボニル)−２,３−ジヒドロ−１Ｈ−インドリジン−５−オン(ラセミ混合物)を、望む生成物として得た。
LC-MS純度: 97%, m/z 523, 525 (M+, Brパターン)
¹H NMR (DMSO-D₆): δ 8.3-8.2 (br s, 1H), 8.12 (s, 1H), 7.52 (d,1H), 7.3 (d, 1H), 7.16- 7.02 (m, 1H), 4.2-4.1 (m, 1H), 4.10-3.90 (m, 4H), 3.75-3.65 (m, 1H), 3.5-3.45 (m, 1H), 3.2-3.1 (m, 2H), 3.08 (t, 2H), 2.9-2.8 (m, 1H), 2.2-2.08 (m, 2H), 1.8-1. 5 (m, 4H), 1.45-1.3 (m, 2H) Step 6
7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-8- (3-hydroxy-3-piperidin-2-yl-azetidine-1-carbonyl) -2,3-dihydro-1H-India Synthesis of lysine-5-one

4N dioxane (4 mL) in HCl was added to 2- {1- [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine. -8-carbonyl] -3-hydroxy-azetidin-3-yl} -piperidine-1-carboxylic acid tert-butyl ester (racemic mixture) (75 mg, 0.0001 mol) in methanol (1 mL) to give The mixture was stirred for 1 h at RT. The solvent was distilled from the reaction mixture. Trituration with 5 mL of diethyl ether gave a precipitate that was collected and 48 mg (71.6% yield) of 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 (racemic mixture) was obtained as the desired product.
LC-MS purity: 97%, m / z 523, 525 (M +, Br pattern)
¹ H NMR (DMSO-D ₆ ): δ 8.3-8.2 (br s, 1H), 8.12 (s, 1H), 7.52 (d, 1H), 7.3 (d, 1H), 7.16- 7.02 (m, 1H) , 4.2-4.1 (m, 1H), 4.10-3.90 (m, 4H), 3.75-3.65 (m, 1H), 3.5-3.45 (m, 1H), 3.2-3.1 (m, 2H), 3.08 (t, 2H), 2.9-2.8 (m, 1H), 2.2-2.08 (m, 2H), 1.8-1.5 (m, 4H), 1.45-1.3 (m, 2H)

Example 60
Steps 1 to 4 were performed according to the method described in Example 8.

ＥＤＣＩ(１６５mg、０.００１mol)およびＨＯＢｔ(１７８mg、０.００１mol)を、撹拌している６−フルオロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２５０mg、０.００１mol)のＤＭＦ(５mL)溶液に添加し、反応混合物を１時間、ＲＴで撹拌した。続いて２−(３−ヒドロキシ−アゼチジン−３−イル)−ピペリジン−１−カルボン酸ｔｅｒｔ−ブチルエステル(ラセミ混合物)(１８０mg、０.００１mol)およびＴＥＡ(１７５mg、０.００２mol)を添加した。反応混合物を１６時間、ＲＴで撹拌した。反応混合物をＥｔＯＡｃおよび水に分配した。有機層を飽和ＮＨ_４Ｃｌ(１０mL)、飽和ＮａＨＣＯ_３溶液(１０mL)および塩水溶液(１０mL)で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。濃縮物(１００mg)をさらに精製せずに次工程に使用した。 Process 5
2- {1- [6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carbonyl] -3-hydroxy Synthesis of -azetidin-3-yl} -piperidine-1-carboxylic acid tert-butyl ester

EDCI (165 mg, 0.001 mol) and HOBt (178 mg, 0.001 mol) were stirred with 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2, 3,5-Tetrahydro-indolizine-8-carboxylic acid (250 mg, 0.001 mol) in DMF (5 mL) was added and the reaction mixture was stirred for 1 h at RT. Subsequently, 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) were added. The reaction mixture was stirred for 16 h at RT. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with saturated NH ₄ Cl (10 mL), saturated NaHCO ₃ solution (10 mL) and brine solution (10 mL), dried over Na ₂ SO ₄ and concentrated. The concentrate (100 mg) was used in the next step without further purification.

ＨＣｌ中４Ｎ ジオキサン(５mL)を、２−{１−[６−フルオロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボニル]−３−ヒドロキシ−アゼチジン−３−イル}−ピペリジン−１−カルボン酸ｔｅｒｔ−ブチルエステル(ラセミ混合物)(１００mg、０.０００１mol)のメタノール(１mL)溶液に添加し、得られた混合物を１時間、ＲＴで撹拌した。溶媒を反応混合物から蒸留して沈殿を得て、それを分取ＨＰＬＣで精製して、１５mg(１６.６％収率)の６−フルオロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−８−(３−ヒドロキシ−３−ピペリジン−２−イル−アゼチジン−１−カルボニル)−２,３−ジヒドロ−１Ｈ−インドリジン−５−オン(ラセミ混合物)を、望む生成物として得た。
LC-MS純度: 95%, m/z 571 (M+)
¹H NMR (DMSO-D₆): δ 8.6-8.4 (br s, 1H), 8.2 (s, 1H), 7.6 (d,1H), 7.44 (d, 1H), 6.98- 6.9 (m, 1H), 4.2-4.1 (m, 1H), 4.10-3.95 (m, 3H), 3.9-3.8 (m, 1H), 3.75-3.65 (m, 1H), 3.5-3.45 (m, 1H), 3.2-3.1 (m, 2H), 3.08 (t, 2H), 2.9-2.8 (m,1H), 2.2-2.08 (m, 2H), 1.75-1.65 (m, 4H), 1.5-1.35 (m, 2H) Step 6
6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -8- (3-hydroxy-3-piperidin-2-yl-azetidine-1-carbonyl) -2,3-dihydro-1H-India Synthesis of lysine-5-one

4N dioxane (5 mL) in HCl was added to 2- {1- [6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine. -8-carbonyl] -3-hydroxy-azetidin-3-yl} -piperidine-1-carboxylic acid tert-butyl ester (racemic mixture) (100 mg, 0.0001 mol) in methanol (1 mL) and obtained The mixture was stirred for 1 h at RT. The solvent was distilled from the reaction mixture to give a precipitate which was purified by preparative HPLC to give 15 mg (16.6% yield) of 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 (racemic mixture) was obtained as the desired product. .
LC-MS purity: 95%, m / z 571 (M +)
¹ H NMR (DMSO-D ₆ ): δ 8.6-8.4 (br s, 1H), 8.2 (s, 1H), 7.6 (d, 1H), 7.44 (d, 1H), 6.98-6.9 (m, 1H) , 4.2-4.1 (m, 1H), 4.10-3.95 (m, 3H), 3.9-3.8 (m, 1H), 3.75-3.65 (m, 1H), 3.5-3.45 (m, 1H), 3.2-3.1 ( m, 2H), 3.08 (t, 2H), 2.9-2.8 (m, 1H), 2.2-2.08 (m, 2H), 1.75-1.65 (m, 4H), 1.5-1.35 (m, 2H)

Example 61
Scheme 10 *

  Steps 1-3 were performed according to the method described in Example 8, and Step 4 was performed according to the method described in Example 11.

ＴＥＡ(０.１２mL、０.００１mol)およびＤＰＰＡ(０.１８mL、０.００１mol)を７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(３００mg、０.００１mol)のＤＭＦ(５mL)溶液に添加し、反応混合物を４時間、ＲＴで窒素雰囲気下撹拌した。続いてトルエン(５mL)を添加し、反応混合物を９０℃で、２時間加熱した。反応混合物を減圧下濃縮し、水を添加して沈殿を得て、それを回収し、乾燥させて、２５０mg(８４％収率)の３−(４−ブロモ−２−フルオロ−フェニル)−４−フルオロ−１,６,７,８−テトラヒドロ−３Ｈ−１,３,５ａ−トリアザ−ａｓ−インダセン−２,５−ジオンを、望む生成物として得た。 Process 5
Synthesis of 3- (4-bromo-2-fluoro-phenyl) -4-fluoro-1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2,5-dione

TEA (0.12 mL, 0.001 mol) and DPPA (0.18 mL, 0.001 mol) were combined with 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3 , 5-tetrahydro-indolizine-8-carboxylic acid (300 mg, 0.001 mol) in DMF (5 mL) was added and the reaction mixture was stirred for 4 h at RT under a nitrogen atmosphere. Toluene (5 mL) was then added and the reaction mixture was heated at 90 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and water was added to give a precipitate that was collected and dried to give 250 mg (84% yield) of 3- (4-bromo-2-fluoro-phenyl) -4. -Fluoro-1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2,5-dione was obtained as the desired product.

６０％ＮａＨ(３０mg、０.００１mol)を、撹拌している３−(４−ブロモ−２−フルオロ−フェニル)−４−フルオロ−１,６,７,８−テトラヒドロ−３Ｈ−１,３,５ａ−トリアザ−ａｓ−インダセン−２,５−ジオン(０.２ｇ、０.００１mol)の乾燥ＤＭＦ(４mL)溶液に、０−５℃で窒素雰囲気下添加し、得られた混合物を１時間、ＲＴで撹拌した。続いてシクロプロパンスルホニルクロライド(１１０mg、０.００１mol)の乾燥ＴＨＦ溶液を１０分間かけて、０℃で滴下し、撹拌を１６時間、ＲＴで続けた。粗生成物をさらに精製せずに次工程に使用した。 Step 6
3- (4-bromo-2-fluoro-phenyl) -1-cyclopropanesulfonyl-4-fluoro-1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2, Synthesis of 5-dione

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

１Ｎ 水性ＮａＯＨ(６mL)を３−(４−ブロモ−２−フルオロ−フェニル)−１−シクロプロパンスルホニル−４−フルオロ−１,６,７,８−テトラヒドロ−３Ｈ−１,３,５ａ−トリアザ−ａｓ−インダセン−２,５−ジオンに添加し、得られた混合物を６５℃で、４時間加熱した。氷冷水を反応混合物に添加し、５％氷冷ＨＣｌで約４のｐＨまで中和し、反応混合物を酢酸エチルおよび水に分配した。有機層をＮａ_２ＳＯ_４で乾燥させ、減圧下濃縮し、濃縮物をカラムクロマトグラフィー(シリカゲル、溶離剤として２％メタノールのＤＣＭ溶液を使用)で精製して、２１mg(８.５％収率)のシクロプロパンスルホン酸[７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−イル]−アミドを、望む生成物として得た。
LCMS純度: 98.89%, m/z=461.9 (M+)
HPLC: 93.6%
¹H NMR (DMSO-D₆, 300 MHz): δ 8.9 (s, 1H), 7.65-7.25 (m, 3H), 4.1 (t, 2H), 3.2 (t, 2H), 2.8-2.7 (m,1H), 2.2-2.1 (m, 2H), 0.95-0.85 (m, 4H) Step 7
Synthesis of cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide

1N aqueous NaOH (6 mL) was added to 3- (4-bromo-2-fluoro-phenyl) -1-cyclopropanesulfonyl-4-fluoro-1,6,7,8-tetrahydro-3H-1,3,5a-triaza -As-Indacene-2,5-dione was added and the resulting mixture was heated at 65 ° C for 4 hours. Ice cold water was added to the reaction mixture, neutralized with 5% ice cold HCl to a pH of about 4, and the reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure, and the concentrate was purified by column chromatography (silica gel, using 2% methanol in DCM as eluent) to give 21 mg (8.5% yield). ) Of cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide To give the desired product.
LCMS purity: 98.89%, m / z = 461.9 (M +)
HPLC: 93.6%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 8.9 (s, 1H), 7.65-7.25 (m, 3H), 4.1 (t, 2H), 3.2 (t, 2H), 2.8-2.7 (m, 1H), 2.2-2.1 (m, 2H), 0.95-0.85 (m, 4H)

Example 62
Steps 1-4 were performed according to the method described in Example 8, and Step 5 was performed according to the method described in Example 61.

６０％ＮａＨ(０.４ｇ、０.０１mol)を、撹拌している３−(４−ブロモ−２−フルオロ−フェニル)−４−フルオロ−１,６,７,８−テトラヒドロ−３Ｈ−１,３,５ａ−トリアザ−ａｓ−インダセン−２,５−ジオン(２.５ｇ、０.００７mol)の乾燥ＤＭＦ(２０mL)溶液に、ＲＴで窒素雰囲気下添加した。得られた混合物を３０分間撹拌した。続いてＢＯＣ無水物(１.９ｇ、０.００９mol)の乾燥ＴＨＦ溶液を、５分間かけて、０℃で滴下し、反応混合物を４時間、ＲＴで撹拌した。粗生成物をさらに精製せずに次工程に使用した。 Step 6
3- (4-Bromo-2-fluoro-phenyl) -4-fluoro-2,5-dioxo-2,3,5,6,7,8-hexahydro-1,3,5a-triaza-as-indacene- Synthesis of 1-carboxylic acid tert-butyl ester

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

１Ｎ 水性ＮａＯＨ(１５mL)を、３−(４−ブロモ−２−フルオロ−フェニル)−４−フルオロ−２,５−ジオキソ−２,３,５,６,７,８−ヘキサヒドロ−１,３,５ａ−トリアザ−ａｓ−インダセン−１−カルボン酸ｔｅｒｔ−ブチルエステルに０℃で添加し、得られた混合物をＲＴで６時間撹拌した。反応塊を酢酸エチルで抽出した。有機層を水で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、減圧下濃縮して、１.１５ｇ(２８％収率)の[７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−イル]−カルバミン酸ｔｅｒｔ−ブチルエステルを、望む生成物として得た。
¹H NMR (CDCl₃, 300MHz): δ 7.45-6.7 (m, 3H), 6.1 (s, 1H), 5.65 (s, 1H), 4.25 (t, 2H), 3.15 (t, 2H), 2.25-2.0 (m, 2H), 1.45 (s, 9H)。 Step 7
Synthesis of [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -carbamic acid tert-butyl ester

1N aqueous NaOH (15 mL) was added to 3- (4-bromo-2-fluoro-phenyl) -4-fluoro-2,5-dioxo-2,3,5,6,7,8-hexahydro-1,3, To 5a-triaza-as-indacene-1-carboxylic acid tert-butyl ester was added at 0 ° C. and the resulting mixture was stirred at RT for 6 h. The reaction mass was extracted with ethyl acetate. The organic layer was washed with water, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 1.15 g (28% yield) of [7- (4-bromo-2-fluoro-phenylamino) -6- Fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -carbamic acid tert-butyl ester was obtained as the desired product.
¹ H NMR (CDCl ₃ , 300MHz): δ 7.45-6.7 (m, 3H), 6.1 (s, 1H), 5.65 (s, 1H), 4.25 (t, 2H), 3.15 (t, 2H), 2.25- 2.0 (m, 2H), 1.45 (s, 9H).

１Ｎ濃ＨＣｌ(４mL)を、撹拌している[７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−イル]−カルバミン酸ｔｅｒｔ−ブチルエステル(０.９ｇ、０.００２mol)のＴＨＦ(１０mL)溶液に添加し、反応混合物を４時間、ＲＴで撹拌した。反応混合物を減圧下濃縮し、飽和ＮａＨＣＯ_３溶液を添加し、酢酸エチルで抽出した。有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、減圧下濃縮して、３６０mg(７２％収率)の８−アミノ−７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−２,３−ジヒドロ−１Ｈ−インドリジン−５−オンを、望む生成物として得た。
¹H NMR (DMSO, 300MHz): δ 7.85-6.85 (m, 3H), 4.2 (s, 2H), 4.12 (t, 2H), 3.1 (t, 2H), 2.25-2.0 (m, 2H) Process 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) is stirred with [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8. -Yl] -carbamic acid tert-butyl ester (0.9 g, 0.002 mol) in THF (10 mL) was added and the reaction mixture was stirred for 4 h at RT. The reaction mixture was concentrated under reduced pressure, saturated NaHCO ₃ solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 360 mg (72% yield) of 8-amino-7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-2. , 3-Dihydro-1H-indolizin-5-one was obtained as the desired product.
¹ H NMR (DMSO, 300MHz): δ 7.85-6.85 (m, 3H), 4.2 (s, 2H), 4.12 (t, 2H), 3.1 (t, 2H), 2.25-2.0 (m, 2H)

ピリジン(２mL)を、８−アミノ−７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−２,３−ジヒドロ−１Ｈ−インドリジン−５−オン(２００mg、０.００１mol)溶液に添加し、反応混合物を５分間、窒素雰囲気下に撹拌した。続いてＤＭＡＰ(５mg、０.０００４mol)を添加し、反応塊を０℃に冷却し、Ｎ,Ｎ−ジメチル−スルホニルクロライド(８５mg、０.００１mol)を添加し、撹拌を１６時間、ＲＴで続けた。反応をＴＬＣ(１００％酢酸エチル)でモニターし、それにより出発物質の存在が示された。反応混合物を５０℃で、２時間加熱した。反応混合物を酢酸エチル(３×５０mL)および水に分配した。有機層を飽和ＮＨ_４Ｃｌ溶液で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、減圧下濃縮し、濃縮物をカラムクロマトグラフィー(中性アルミナ、溶離剤として酢酸エチルを使用)で精製して、２２mg(８％収率)のＮ−[７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−イル]−Ｎ,Ｎ−ジメチル−アミノ−スルホンアミドを、望む生成物として得た。
LCMS純度: 96.189%, m/z=463 (M+)
HPLC: 98%
¹H NMR (DMSO-D₆, 300 MHz): δ 8.7 (s, 1H), 7.6-6.85 (m, 3H), 4.15 (t, 2H), 3.29 (t, 2H), 2.7 (s, 6H), 2.2-2.1 (m, 2H) Step 9
N- [7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -N, N-dimethyl- Synthesis of 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). To the solution, the reaction mixture was stirred for 5 minutes under a nitrogen atmosphere. Then DMAP (5 mg, 0.0004 mol) is added, the reaction mass is cooled to 0 ° C., N, N-dimethyl-sulfonyl chloride (85 mg, 0.001 mol) is added and stirring is continued for 16 h at RT. It was. The reaction was monitored by TLC (100% ethyl acetate), which indicated the presence of starting material. The reaction mixture was heated at 50 ° C. for 2 hours. The reaction mixture was partitioned between ethyl acetate (3 × 50 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 yield 22 mg (8% yield) N- [7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -N, N-dimethyl-amino-sulfonamide was obtained as the desired product.
LCMS purity: 96.189%, m / z = 463 (M +)
HPLC: 98%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 8.7 (s, 1H), 7.6-6.85 (m, 3H), 4.15 (t, 2H), 3.29 (t, 2H), 2.7 (s, 6H) , 2.2-2.1 (m, 2H)

Example 63
Steps 1-4 were performed according to the method described in Example 8, Step 5 was performed according to the method described in Example 61, and Steps 6-8 were performed according to the method described in Example 62. .

Ｃ−(２,２−ジメチル−[１,３]ジオキソラン−４−イル)−メチルアミン(３００mg、０.００２２９mol)およびＤＭＡＰ(２９５mg、０.００２４mol)の乾燥ＤＣＭ溶液を、撹拌している塩化スルフリル(３２０mg、０.００２３mol)のＤＣＭ溶液に−７８℃で添加し、得られた混合物を−７８℃で、１時間、−５０℃で、２時間そしてＲＴで２時間撹拌した。形成した生成物を次工程に使用した。 N- (2,2-Dimethyl- [1,3] dioxolan-4-ylmethyl) -chloro-sulfonamide step 8a
Synthesis of

A dry DCM solution of C- (2,2-dimethyl- [1,3] dioxolan-4-yl) -methylamine (300 mg, 0.000022 mol) and DMAP (295 mg, 0.0028 mol) was stirred with chloride. Sulfuryl (320 mg, 0.0027 mol) in DCM was added at −78 ° C. and the resulting mixture was stirred at −78 ° C. for 1 hour, −50 ° C. for 2 hours and RT at 2 hours. The product formed was used in the next step.

Ｎ−(２,２−ジメチル−[１,３]ジオキソラン−４−イルメチル)−クロロ−スルホンアミド(０.００１mol)を、撹拌している８−アミノ−７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−２,３−ジヒドロ−１Ｈ−インドリジン−５−オン(２００mg、０.００１mol)の乾燥ピリジン(３mL)およびＤＭＡＰ(５０mg、０.０００４mol)中の溶液に１０分間かけて、０℃で滴下し、反応混合物を４０℃で、１６時間加熱し、反応混合物を減圧下濃縮し、濃縮物を酢酸エチルおよび水に分配した。有機層を濃縮し、濃縮物をカラムクロマトグラフィー(中性アルミナ、溶離剤としてＤＣＭを使用)で精製して、２６mg(５％収率)のＮ−[７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−イル]−Ｃ−(２,２−ジメチル−[１,３]ジオキソラン−４−イル)−メチルアミン−スルホンアミドを、望む生成物として得た。
¹H NMR (DMSO, 300MHz): δ 8.7 (s, 1H), 7.6-6.7 (m, 3H), 4.1-3.8 (m, 4H), 3.65-3.5 (m, 1H), 3.3-3.2 (m, 1H), 3.2 (t, 2H), 3.1-2.9 (m, 1H), 2.9-2.6 (m, 1H), 2.1 (t, 2H), 1.2 (d, 6H) Step 9
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 synthesis

N- (2,2-dimethyl- [1,3] dioxolan-4-ylmethyl) -chloro-sulfonamide (0.001 mol) is stirred with 8-amino-7- (4-bromo-2-fluoro). -Phenylamino) -6-fluoro-2,3-dihydro-1H-indolizin-5-one (200 mg, 0.001 mol) in a solution in dry pyridine (3 mL) and DMAP (50 mg, 0.0004 mol). Over a period of time, dropwise at 0 ° C., the reaction mixture was heated at 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 yield 26 mg (5% yield) of 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 was obtained as the desired product.
¹ H NMR (DMSO, 300 MHz): δ 8.7 (s, 1H), 7.6-6.7 (m, 3H), 4.1-3.8 (m, 4H), 3.65-3.5 (m, 1H), 3.3-3.2 (m, 1H), 3.2 (t, 2H), 3.1-2.9 (m, 1H), 2.9-2.6 (m, 1H), 2.1 (t, 2H), 1.2 (d, 6H)

濃ＨＣｌ(１mL)を、撹拌しているＮ−[７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−イル]−Ｃ−(２,２−ジメチル−[１,３]ジオキソラン−４−イル)−メチルアミン−スルホンアミド(２６mg、０.００００５mol)のエタノール(４mL)溶液に２０℃で添加し、反応混合物を４時間、ＲＴで撹拌した。反応混合物を減圧下濃縮し、ジエチルエーテルを添加し、傾捨し、減圧下乾燥させて、１６mg(７０％収率)の２,３−ジヒドロキシ−プロパン−アミノ−スルホン酸−[７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−イル]−アミドを、望む生成物として得た。
LCMS純度: 97.1%, m/z=509 (M+)
HPLC: 96.8%
¹H NMR (DMSO-D₆, 300 MHz): δ 8.7 (s, 1H), 7.6-6.85 (m, 3H), 4.15 (t, 2H), 3.4 (t, 2H), 3.25-3.15 (m, 2H), 3.1-3.0 (m, 2H), 2.85-2.75 (m, 1H) Step 10
2,3-dihydroxy-propane-amino-sulfonic acid- [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine- Synthesis of 8-yl] -amide

Concentrated HCl (1 mL) is added to stirred N- [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine- Add 8-yl] -C- (2,2-dimethyl- [1,3] dioxolan-4-yl) -methylamine-sulfonamide (26 mg, 0.00005 mol) in ethanol (4 mL) at 20 ° C. The reaction mixture was stirred for 4 h at RT. The reaction mixture was concentrated under reduced pressure, diethyl ether was added, decanted, dried under reduced pressure, and 16 mg (70% yield) of 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 was obtained as the desired product.
LCMS purity: 97.1%, m / z = 509 (M +)
HPLC: 96.8%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 8.7 (s, 1H), 7.6-6.85 (m, 3H), 4.15 (t, 2H), 3.4 (t, 2H), 3.25-3.15 (m, 2H), 3.1-3.0 (m, 2H), 2.85-2.75 (m, 1H)

Example 64
Steps 1-4 were performed according to the method described in Example 8, Step 5 was performed according to the method described in Example 61, and Steps 6-8 were performed according to the method described in Example 62. .

Scheme 11

塩化チオニル(８mL)およびピロリジン−２−カルボン酸(３ｇ、０.０２６mol)を、ベンジルアルコール(２０mL)に、−１０℃で窒素雰囲気下に添加し、反応混合物をＲＴで１６時間撹拌した。反応塊を乾燥ジエチルエーテルで希釈し、ＲＴで２時間撹拌して沈殿を得て、それを過剰のジエチルエーテルで洗浄し、傾捨し、減圧下乾燥させて、４ｇ(６６％収率)のピロリジン−２−カルボン酸ベンジルエステルヒドロクロライドを、望む生成物として得た。
¹H NMR (CDCl₃, 300MHz): δ 10.9 (s, 1H), 9.2 (s, 1H), 7.2-7.6 (s, 5H), 5.2 (t, 2H), 4.9 (s, 1H), 4.5 (s, 1H), 3.5 (t, 2H), 2.4-2.3 (m, 1H), 2.2-2.1 (m, 2H) Step 8a
Synthesis of pyrrolidine-2-carboxylic acid benzyl ester hydrochloride

Thionyl chloride (8 mL) and pyrrolidine-2-carboxylic acid (3 g, 0.026 mol) were added to benzyl alcohol (20 mL) at −10 ° C. under a nitrogen atmosphere and the reaction mixture was stirred at RT for 16 h. The reaction mass is diluted with dry diethyl ether and stirred at RT for 2 h to give a precipitate which is washed with excess diethyl ether, decanted and dried under reduced pressure to give 4 g (66% yield). Pyrrolidine-2-carboxylic acid benzyl ester hydrochloride was obtained as the desired product.
¹ H NMR (CDCl ₃ , 300 MHz): δ 10.9 (s, 1H), 9.2 (s, 1H), 7.2-7.6 (s, 5H), 5.2 (t, 2H), 4.9 (s, 1H), 4.5 ( s, 1H), 3.5 (t, 2H), 2.4-2.3 (m, 1H), 2.2-2.1 (m, 2H)

ＤＭＡＰ(０.５ｇ、０.００４mol)およびＴＥＡ(１.６mg、０.０１６mol)を、撹拌しているピロリジン−２−カルボン酸ベンジルエステルヒドロクロライド(３ｇ、０.０１５mol)の乾燥トルエン(４０mL)溶液にＲＴで添加し、得られた混合物を２０分間撹拌した。反応混合物を−１０℃に冷却し、塩化スルフリル(２ｇ、０.０１５mol)を１５分間かけて滴下し、撹拌を３時間、ＲＴで続けた。反応塊を飽和ＮＨ_４Ｃｌ溶液でクエンチし、ＤＣＭで抽出し、有機層をＮａ_２ＳＯ_４で乾燥させ、濃縮して、１.２ｇの１−クロロスルホニル−ピロリジン−２−カルボン酸ベンジルエステルを粗生成物として得た。
¹H NMR (DMSO-D₆, 300 MHz): δ 10.9 (s, 1H), 9.2 (s, 1H), 7.6-7.2 (br s, 5H), 5.2 (t, 2H), 4.9 (s, 1H), 4.5 (s, 1H), 3.5 (t, 2H), 2.4 (m, 1H), 2.2 (m, 2H) 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 stirred with pyrrolidine-2-carboxylic acid benzyl ester hydrochloride (3 g, 0.015 mol) in dry toluene (40 mL). To the solution was added at RT and the resulting mixture was stirred for 20 minutes. The reaction mixture was cooled to −10 ° C., sulfuryl chloride (2 g, 0.015 mol) was added dropwise over 15 minutes and stirring was continued for 3 hours at RT. The reaction mass is quenched with saturated NH ₄ Cl solution, extracted with DCM, the organic layer is dried over Na ₂ SO ₄ and concentrated to give 1.2 g of 1-chlorosulfonyl-pyrrolidine-2-carboxylic acid benzyl ester. Obtained as a crude product.
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 10.9 (s, 1H), 9.2 (s, 1H), 7.6-7.2 (br s, 5H), 5.2 (t, 2H), 4.9 (s, 1H ), 4.5 (s, 1H), 3.5 (t, 2H), 2.4 (m, 1H), 2.2 (m, 2H)

ピリジン(３mL)およびＤＭＡＰ(２０mg、０.０００２mol)を、８−アミノ−７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−２,３−ジヒドロ−１Ｈ−インドリジン−５−オン(１１０mg、０.０００３mol)に、窒素雰囲気下添加し、反応混合物を０℃に冷却した。１−クロロスルホニル−ピロリジン−２−カルボン酸ベンジルエステル(３００mg、０.００１mol)のＤＣＭ溶液を１５分間かけて滴下し、ＲＴで１時間撹拌し、６０℃で、１６時間加熱した。反応塊を減圧下濃縮し、濃縮物を酢酸エチルおよび水に分配した。有機層をＮａ_２ＳＯ_４で乾燥させ、カラムクロマトグラフィー(シリカゲル、溶離剤として１００％酢酸エチルを使用)で精製して、６５mg(３３％収率)の１−[７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−イルスルファモイル]−ピロリジン−２−カルボン酸ベンジルエステルを、望む生成物として得た。
¹H NMR (DMSO-D₆, 300 MHz): δ 7.4-7.15 (m, 8H), 6.85-6.75 (m, 1H), 6.7-6.6 (s, 1H), 5.2 (q, 3H), 4.65-4.55 (m, 1H), 4.25-4.2 (m, 3H), 3.65-3.55 (m, 3H), 3.4 (t, 2H), 3.3 (t, 2H), 3.25-3.15 (m, 1H), 2.4 (t, 2H), 2.2 (t, 2H), 2.15-2.05 (m, 8H) Step 9
1- [7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-ylsulfamoyl] -pyrrolidine-2- Synthesis of 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-indolizine-5. To -one (110 mg, 0.0003 mol) was added under a nitrogen atmosphere and the reaction mixture was cooled to 0 ° C. A solution of 1-chlorosulfonyl-pyrrolidine-2-carboxylic acid benzyl ester (300 mg, 0.001 mol) in DCM was added dropwise over 15 minutes, stirred at RT for 1 hour and heated at 60 ° C. for 16 hours. The reaction mass 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 65 mg (33% yield) of 1- [7- (4-bromo- 2-Fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-ylsulfamoyl] -pyrrolidine-2-carboxylic acid benzyl ester as the desired product Obtained.
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 7.4-7.15 (m, 8H), 6.85-6.75 (m, 1H), 6.7-6.6 (s, 1H), 5.2 (q, 3H), 4.65- 4.55 (m, 1H), 4.25-4.2 (m, 3H), 3.65-3.55 (m, 3H), 3.4 (t, 2H), 3.3 (t, 2H), 3.25-3.15 (m, 1H), 2.4 ( t, 2H), 2.2 (t, 2H), 2.15-2.05 (m, 8H)

ＬｉＯＨ溶液(２０mg、０.０００４mol)を、撹拌している１−[７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−イルスルファモイル]−ピロリジン−２−カルボン酸ベンジルエステル(６５mg、０.０００１mol)のメタノール：ＴＨＦ(２：３)溶液に添加し、得られた混合物をＲＴで３時間撹拌した。反応塊を減圧下濃縮し、水で希釈し、１０％ＨＣｌでｐＨ約２まで中和し、形成した沈殿を回収し、乾燥させて、２０mg(３６％収率)の１−[７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−イルスルファモイル]−ピロリジン−２−カルボン酸を、望む生成物として得た。
HPLC: 91.17%
¹H NMR (DMSO-D₆, 300 MHz): 12.85 (s, 1H), 8.9 (s, 1H), 7.6-7.2 (m, 3H), 4.3-4.2 (m, 1H), 4.1 (t, 2H), 3.1 (t, 2H), 2.15-2.05 (m, 2H), 1.75-1.65 (m, 2H) Step 10
1- [7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-ylsulfamoyl] -pyrrolidine-2- Synthesis of carboxylic acid

LiOH solution (20 mg, 0.0004 mol) was stirred with 1- [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro -Indolizine-8-ylsulfamoyl] -pyrrolidine-2-carboxylic acid benzyl ester (65 mg, 0.0001 mol) in methanol: THF (2: 3) solution and the resulting mixture stirred at RT for 3 h did. The reaction mass was concentrated under reduced pressure, diluted with water, neutralized with 10% HCl to pH˜2, the precipitate formed was collected and dried to yield 20 mg (36% yield) of 1- [7- ( 4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-ylsulfamoyl] -pyrrolidine-2-carboxylic acid Obtained as a thing.
HPLC: 91.17%
¹ H NMR (DMSO-D ₆ , 300 MHz): 12.85 (s, 1H), 8.9 (s, 1H), 7.6-7.2 (m, 3H), 4.3-4.2 (m, 1H), 4.1 (t, 2H ), 3.1 (t, 2H), 2.15-2.05 (m, 2H), 1.75-1.65 (m, 2H)

Example 65
Steps 1-4 were performed according to the method described in Example 8, Step 5 was performed according to the method described in Example 61, and Steps 6-8 were performed according to the method described in Example 62. .

ＤＭＡＰ(０.５ｇ、０.００４０９mol)およびＴＥＡ(２.５４ｇ、０.０２５１mol)を、撹拌しているピロリジン−２−カルボン酸メチルエステルヒドロクロライド(４ｇ、０.０２４mol)の乾燥トルエン(５０mL)溶液にＲＴで添加し、得られた混合物を１０分間撹拌した。反応混合物を−２０℃に冷却し、塩化スルフリル(３.３ｇ、０.０２４mol)を３０分間かけて滴下し、撹拌を１時間、−１０℃で、さらに２時間、ＲＴで続けた。反応塊をＤＣＭで希釈し、水性ＮＨ_４Ｃｌ溶液で洗浄した。有機層を、Ｎａ_２ＳＯ_４で乾燥させ、濃縮して、１.２ｇ(２４％収率)の１−クロロスルホニル−ピロリジン−２−カルボン酸メチルエステルを、望む生成物として得た。 Process 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 stirred with pyrrolidine-2-carboxylic acid methyl ester hydrochloride (4 g, 0.024 mol) in dry toluene (50 mL). To the solution was added at RT and the resulting mixture was stirred for 10 minutes. The reaction mixture was cooled to −20 ° C., sulfuryl chloride (3.3 g, 0.024 mol) was added dropwise over 30 minutes and stirring was continued for 1 hour at −10 ° C. for an additional 2 hours at RT. The reaction mass 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.

ＤＭＡＰ(５０mg、０.０００４mol)を、撹拌している８−アミノ−７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−２,３−ジヒドロ−１Ｈ−インドリジン−５−オン(３００mg、０.００１mol)の乾燥ピリジン(５mL)溶液に添加し、窒素雰囲気下、反応混合物を０℃に冷却した。１１−クロロスルホニル−ピロリジン−２−カルボン酸メチルエステル(１ｇ、０.００４mol)のＤＣＭ溶液を１０分間かけて滴下し、得られた混合物をＲＴで４時間撹拌した。反応混合物を６５℃で、１６時間加熱した。反応塊を減圧下濃縮し、濃縮物を酢酸エチルおよび水に分配した。有機層を塩水で洗浄し溶液、減圧下濃縮し、濃縮物をカラムクロマトグラフィー(シリカゲル、溶離剤として７０％酢酸エチルのヘキサン溶液を使用)で精製して、１１０mg(２４％収率)の１−[７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−イルスルファモイル]−ピロリジン−２−カルボン酸メチルエステルを、望む生成物として得た。 Step 9
1- [7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-ylsulfamoyl] -pyrrolidine-2- Synthesis of carboxylic acid methyl ester

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

ＮａＢＨ_４(２５mg、０.０００６５mol)を、撹拌している１−[７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−イルスルファモイル]−ピロリジン−２−カルボン酸メチルエステル(１１０mg、０.０００２mol)の乾燥ＴＨＦ(３mL)溶液に窒素雰囲気下滴下し、得られた混合物を６０℃で加熱した。メタノール(２mL)を５分間かけて滴下し、その間温度を６０℃で、１時間維持した。反応塊を減圧下濃縮し、氷冷水を添加し、５％希ＨＣｌで中和し、酢酸エチルで抽出し、有機層をＮａ_２ＳＯ_４で乾燥させ、濃縮した。粗生成物を１：９ メタノール：ＤＣＭに溶解し、エーテルを添加し、形成した沈殿を回収して、７５ｇ(７０％収率)の２−ヒドロキシメチル−ピロリジン−１−スルホン酸[７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−イル]−アミドを、望む生成物として得た。
LCMS純度: 99.66%, m/z=521 (M+2)
HPLC: 95.4%
¹H NMR (DMSO-D₆, 300 MHz): δ 8.7 (s, 1H), 7.6-7.25 (m, 3H), 4.15 (t, 2H), 3.65 (m, 1H), 3.1-3.2 (m, 4H), 2.15-2.05 (m, 2H), 1.85-1.75 (m, 4H) Step 10
2-Hydroxymethyl-pyrrolidine-1-sulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8- Of yl] -amide

NaBH ₄ (25 mg, 0.0065 mol) was stirred with 1- [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro -Indolizine-8-ylsulfamoyl] -pyrrolidine-2-carboxylic acid methyl ester (110 mg, 0.0002 mol) in dry THF (3 mL) was added dropwise under a nitrogen atmosphere and the resulting mixture was heated at 60 ° C. . Methanol (2 mL) was added dropwise over 5 minutes while maintaining the temperature at 60 ° C. for 1 hour. The reaction mass was concentrated under reduced pressure, ice-cold water was added, neutralized with 5% diluted 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 to recover 75 g (70% yield) of 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 was obtained as the desired product.
LCMS purity: 99.66%, m / z = 521 (M + 2)
HPLC: 95.4%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 8.7 (s, 1H), 7.6-7.25 (m, 3H), 4.15 (t, 2H), 3.65 (m, 1H), 3.1-3.2 (m, 4H), 2.15-2.05 (m, 2H), 1.85-1.75 (m, 4H)

さらに：

Example 66
Scheme 12

further:

  Steps 1-3 were performed according to the method described in Example 8, and Step 4 was performed according to the method described in Example 11.

ＥＤＣＩ(０.９９ｇ、０.００５mol)およびＨＯＢｔ(０.７０２ｇ、０.００５mol)を、撹拌している７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(１ｇ、０.００３mol)のＤＭＦ(５０mL)溶液に添加し、反応混合物を１.３０時間、ＲＴで撹拌した。続いてＯ,Ｎ−ジメチル−ヒドロキシルアミンヒドロクロライド(０.５０６ｇ、０.００５mol)およびＴＥＡ(２.１６mL、０.０１６mol)を窒素雰囲気下添加した。反応混合物を１６時間、ＲＴで撹拌した。反応混合物を酢酸エチルおよび水に分配した。有機層を飽和ＮＨ_４Ｃｌ、塩水溶液で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮して、０.８００mg(７２.７％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸メトキシ−メチル−アミドを、望む生成物として得た。
LCMS純度: 96.9%, m/z=428 (M+1)
¹H NMR (DMSO-D₆, 300 MHz): δ 8.0-7.95 (br s, 1H), 7.5-7.4 (dd, 1H), 7.3-7.2 (dd, 1H), 7.0 (t, 1H), 4.1-3.9 (m, 2H), 3.6 (s, 3H), 3.4 (s, 3H), 3.0-2.9 (m, 2H), 2.15-2.05 (m, 2H) Process 5
Synthesis of 7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-methyl-amide

EDCI (0.99 g, 0.005 mol) and HOBt (0.702 g, 0.005 mol) were stirred with 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo- 1,2,3,5-Tetrahydro-indolizine-8-carboxylic acid (1 g, 0.003 mol) in DMF (50 mL) was added and the reaction mixture was stirred for 1.30 h at RT. Subsequently, O, N-dimethyl-hydroxylamine hydrochloride (0.506 g, 0.005 mol) and TEA (2.16 mL, 0.016 mol) were added under a nitrogen atmosphere. The reaction mixture was stirred for 16 h at RT. 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 give 0.800 mg (72.7% yield) of 7- (4-bromo-2-fluoro- Phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-methyl-amide was obtained as the desired product.
LCMS purity: 96.9%, m / z = 428 (M + 1)
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 8.0-7.95 (br s, 1H), 7.5-7.4 (dd, 1H), 7.3-7.2 (dd, 1H), 7.0 (t, 1H), 4.1 -3.9 (m, 2H), 3.6 (s, 3H), 3.4 (s, 3H), 3.0-2.9 (m, 2H), 2.15-2.05 (m, 2H)

ＤＩＢＡＬ−Ｈ(トルエン中１.０Ｍ溶液)(５.７mL、５.７mmol)を、７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸メトキシ−メチル−アミド(０.７ｇ、１.６３５mmol)の乾燥ＴＨＦ(２０mL)溶液に−７８℃で添加し、反応混合物を２時間、−７８℃で撹拌した。反応塊を飽和ＮＨ_４Ｃｌでクエンチし、酢酸エチルで抽出した。水性層を酢酸エチルで抽出し、有機層を水、塩水(１０mL)で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。濃縮物をカラムクロマトグラフィー(シリカゲル、溶離剤として２％メタノールのＤＣＭ溶液を使用)で精製して、０.２ｇ、(３３.１６％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボアルデヒドを、望む生成物として得た。
¹H NMR (DMSO-D₆, 300 MHz): δ 9.83-9.8 (d, 1H), 9.6 (d, 1H), 7.6 (dd, 1H), 7.4-7.3 (d, 1H), 7.2-7.15 (m, 1H), 4.1-4.0 (t, 2H), 3.5 (t, 2H), 2.2 (t, 2H) Step 6
Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carbaldehyde

DIBAL-H (1.0 M solution in toluene) (5.7 mL, 5.7 mmol) was added to 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3. , 5-tetrahydro-indolizine-8-carboxylic acid methoxy-methyl-amide (0.7 g, 1.635 mmol) in dry THF (20 mL) at −78 ° C. and the reaction mixture was added at −78 ° C. for 2 h. Stir with. The reaction mass 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 give 0.2 g, (33.16% yield) of 7- (4-bromo-2-fluoro- Phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carbaldehyde was obtained as the desired product.
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 9.83-9.8 (d, 1H), 9.6 (d, 1H), 7.6 (dd, 1H), 7.4-7.3 (d, 1H), 7.2-7.15 ( m, 1H), 4.1-4.0 (t, 2H), 3.5 (t, 2H), 2.2 (t, 2H)

アリルマグネシウムブロマイド(１１.６５mL、０.０１１６５３mol)を、７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボアルデヒド(０.４３０ｇ、０.００１mol)の乾燥ＴＨＦ(１０mL)溶液に、−７８℃で窒素雰囲気下添加した。反応混合物を２時間、ＲＴで撹拌した。反応混合物を飽和ＮＨ_４Ｃｌ溶液でクエンチし、酢酸エチルで抽出した。有機層を水、塩水溶液で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。濃縮物をカラムクロマトグラフィー(シリカゲル、溶離剤として１−１.５％メタノールのＤＣＭ溶液を使用)で精製して、０.２５０mg(５２.４％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−８−(１−ヒドロキシ−ブト−３−エニル)−２,３−ジヒドロ−１Ｈ−インドリジン−５−オンを、望む生成物として得た。
LCMS: 84.4%, m/z=411 (M+)
HPLC: 90%
¹H NMR (DMSO-D₆, 300 MHz): δ 8.2-8.1 (br s, 1H), 7.6-7.5 (dd, 1H), 7.3 (d, 1H), 6.8-6.7 (m, 1H), 6.4 (d, 1H), 5.7 (m, 1H), 5.0-4.8 (m, 2H), 4.7-4.6 (d, 1H), 4.0-3.9 (m, 2H), 3.1-2.9 (m, 2H), 3.0-2.9 (m, 1H), 2-5-2.4 (m 1H), 2.3-2.2 (m, 1H), 2.1 (t, 2H)。 Step 7
Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-8- (1-hydroxy-but-3-enyl) -2,3-dihydro-1H-indolidin-5-one

Allylmagnesium bromide (11.65 mL, 0.011653 mol) was added to 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine- To a solution of 8-carbaldehyde (0.430 g, 0.001 mol) in dry THF (10 mL) was added at −78 ° C. under a nitrogen atmosphere. The reaction mixture was stirred for 2 h at RT. 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 0.250 mg (52.4% yield) of 7- (4-bromo-2 -Fluoro-phenylamino) -6-fluoro-8- (1-hydroxy-but-3-enyl) -2,3-dihydro-1H-indolizin-5-one was obtained as the desired product.
LCMS: 84.4%, m / z = 411 (M +)
HPLC: 90%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 8.2-8.1 (br s, 1H), 7.6-7.5 (dd, 1H), 7.3 (d, 1H), 6.8-6.7 (m, 1H), 6.4 (d, 1H), 5.7 (m, 1H), 5.0-4.8 (m, 2H), 4.7-4.6 (d, 1H), 4.0-3.9 (m, 2H), 3.1-2.9 (m, 2H), 3.0 -2.9 (m, 1H), 2-5-2.4 (m 1H), 2.3-2.2 (m, 1H), 2.1 (t, 2H).

Example 67
Steps 1-3 were performed according to the method described in Example 8, Step 4 was performed according to the method described in Example 111, and Steps 5-6 were performed according to the method described in Example 66. .

ビニルマグネシウムブロマイド(ＴＨＦ中１Ｍ溶液)(１.６２mL、０.００２mol)を、７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボアルデヒド(０.１ｇ、０.０００３mol)の乾燥ＴＨＦ(１０mL)溶液に−７８℃で窒素雰囲気下添加した。反応混合物を２時間、ＲＴで撹拌した。反応混合物を飽和ＮＨ_４Ｃｌ溶液で−７８℃でクエンチし、酢酸エチルでＲＴで抽出した。有機層を水、塩水溶液で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。濃縮物を分取ＨＰＬＣで精製して、１０mg(９％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−８−(１−ヒドロキシ−アリル)−２,３−ジヒドロ−１Ｈ−インドリジン−５−オンを、望む生成物として得た。
LCMS: 96.4%, m/z=399 (M+2), 398 (M+1)
HPLC: 98%
¹H NMR (DMSO-D₆, 300 MHz): δ 8.0-7.8 (br s, 1H), 7.6-7.4 (d, 1H), 7.6-7.3 (d, 1H), 6.6 (t, 1H), 6.6-6.5 (br s, 1H), 5.8-6.0 (m, 1H), 5.2 (d, 2H), 5.0 (d, 1H), 4.0 (t, 2H), 3.1 (m, 2H), 2.1 (t, 2H)。 Step 7
Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-8- (1-hydroxy-allyl) -2,3-dihydro-1H-indolizin-5-one

Vinylmagnesium bromide (1M solution in THF) (1.62 mL, 0.002 mol) was added to 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5. -Tetrahydro-indolizine-8-carbaldehyde (0.1 g, 0.0003 mol) in dry THF (10 mL) was added at -78 ° C under nitrogen atmosphere. The reaction mixture was stirred for 2 h at RT. The reaction mixture was quenched with saturated NH ₄ Cl solution at −78 ° C. and extracted with ethyl acetate at RT. 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 10 mg (9% yield) of 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-8- (1-hydroxy-allyl) -2, 3-Dihydro-1H-indolizin-5-one was obtained as the desired product.
LCMS: 96.4%, m / z = 399 (M + 2), 398 (M + 1)
HPLC: 98%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 8.0-7.8 (br s, 1H), 7.6-7.4 (d, 1H), 7.6-7.3 (d, 1H), 6.6 (t, 1H), 6.6 -6.5 (br s, 1H), 5.8-6.0 (m, 1H), 5.2 (d, 2H), 5.0 (d, 1H), 4.0 (t, 2H), 3.1 (m, 2H), 2.1 (t, 2H).

Example 68
Steps 1-3 are performed according to the method described in Example 8, Step 4 is performed according to the method described in Example 11, Steps 5-6 are performed according to the method described in Example 66, and Step 7 was performed according to the method described in Example 67.

Dess-martinペルヨージナン(０.５８２ｇ、０.００１mol)を、撹拌している７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−８−(１−ヒドロキシ−アリル)−２,３−ジヒドロ−１Ｈ−インドリジン−５−オン(０.４４０ｇ、０.００１mol)のＤＣＭ(１０mL)溶液に添加し、反応混合物を１２時間、ＲＴで撹拌した。続いて１０mLの水に溶解した０.８ｇのＮａＨＣＯ_３および１０mlの水に溶解した２.４８ｇのチオ硫酸ナトリウム.５Ｈ_２Ｏを添加し、撹拌を５分間続けた。反応混合物をＤＣＭで抽出し、有機層を飽和ＮａＨＣＯ_３溶液、塩水で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮して、０.４００ｇの８−アクリロイル−７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−２,３−ジヒドロ−１Ｈ−インドリジン−５−オンを粗生成物として得て、それをさらに精製せずに次工程に使用した。 Process 8
Synthesis of 8-acryloyl-7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-2,3-dihydro-1H-indolizin-5-one

Dess-martin periodinane (0.582 g, 0.001 mol) was stirred with 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-8- (1-hydroxy-allyl) -2, 3-Dihydro-1H-indolizin-5-one (0.440 g, 0.001 mol) in DCM (10 mL) was added and the reaction mixture was stirred for 12 h at RT. Subsequently 0.8 g NaHCO ₃ dissolved in 10 mL water and 2.48 g sodium thiosulfate 0.5 H ₂ O dissolved in 10 mL water were added and stirring was continued for 5 minutes. The reaction mixture was extracted with DCM and the organic layer was washed with saturated NaHCO ₃ solution, brine, dried over anhydrous Na ₂ SO ₄ , concentrated and 0.400 g 8-acryloyl-7- (4-bromo-2 -Fluoro-phenylamino) -6-fluoro-2,3-dihydro-1H-indolizin-5-one was obtained as a crude product, which was used in the next step without further purification.

４−メチル−モルホリン−Ｎ−オキシド(０.１１８ｇ、０.００１０１２mol)およびオスミウムテトラオキシド(０.０２５ｇ、０.０００１mol)を、撹拌している８−アクリロイル−７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−２,３−ジヒドロ−１Ｈ−インドリジン−５−オン(０.４ｇ、０.００１mol)のＴＨＦ(１０mL)溶液に窒素雰囲気下添加し、得られた混合物を２時間、ＲＴで撹拌した。反応混合物を酢酸エチルおよび水に分配した。有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮し、濃縮物をカラムクロマトグラフィー(シリカゲル、溶離剤として１.５％メタノールのＤＣＭ溶液を使用)で精製して、黄色固体を得て、それをさらに分取ＨＰＬＣで精製して、１０mg(２.３％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−８−(２,３−ジヒドロキシ−プロピオニル)−６−フルオロ−２,３−ジヒドロ−１Ｈ−インドリジン−５−オンを、望む生成物として得た。
LCMS: m/z=431 (M+2)
HPLC: 90%
¹H NMR (DMSO-D₆, 300 MHz): δ 8.6-8.5 (br s, 1H), 7.5-7.4 (dd, 1H), 7.3-7.2 (dd, 1H), 6.9-6.8 (m, 1H), 5.3 (d, 1H), 5.0 (t, 1H), 4.5-4.4 (m, 1H), 4.1-4.0 (m, 2H), 3.5 (t, 2H), 3.3-3.2 (m, 1H), 3.1-3.0 (m, 1H), 2.1 (t, 2H) Step 9
Synthesis of 7- (4-Bromo-2-fluoro-phenylamino) -8- (2,3-dihydroxy-propionyl) -6-fluoro-2,3-dihydro-1H-indolizin-5-one

4-Methyl-morpholine-N-oxide (0.118 g, 0.000112 mol) and osmium tetraoxide (0.025 g, 0.0001 mol) were stirred with 8-acryloyl-7- (4-bromo-2- Fluoro-phenylamino) -6-fluoro-2,3-dihydro-1H-indolizin-5-one (0.4 g, 0.001 mol) in THF (10 mL) was added under a nitrogen atmosphere and the resulting mixture Was stirred for 2 h at RT. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous Na ₂ SO ₄ and 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 to yield 10 mg (2.3% yield) of 7- (4-bromo-2-fluoro-phenylamino) -8- (2,3-dihydroxy-propionyl) -6-fluoro. -2,3-Dihydro-1H-indolizin-5-one was obtained as the desired product.
LCMS: m / z = 431 (M + 2)
HPLC: 90%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 8.6-8.5 (br s, 1H), 7.5-7.4 (dd, 1H), 7.3-7.2 (dd, 1H), 6.9-6.8 (m, 1H) , 5.3 (d, 1H), 5.0 (t, 1H), 4.5-4.4 (m, 1H), 4.1-4.0 (m, 2H), 3.5 (t, 2H), 3.3-3.2 (m, 1H), 3.1 -3.0 (m, 1H), 2.1 (t, 2H)

Example 69
Steps 1 to 3 were performed according to the method described in Example 8, Step 4 was performed according to the method described in Example 11, and Steps 5 to 6 were performed according to the method described in Example 66.

ｎ−ブチルリチウム(ヘキサン中２.５Ｍ溶液)(６.６mL、６.７７５mmol)を、撹拌しているトリブチル−メトキシメトキシメチル−スタンナン(３.７２ｇ、１０.１７mmol)の乾燥ＴＨＦ溶液に、−７８℃で５分間かけて滴下し、得られた混合物を５分間撹拌した。続いて７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボアルデヒド(２５０mg、０.６７８mmol)のＴＨＦ溶液を−７８℃で添加し、撹拌をさらに４０分間、−７８℃で続けた。反応混合物を飽和ＮＨ_４Ｃｌ溶液で−７８℃でクエンチし、ＲＴに温め、酢酸エチルで希釈した。有機層を塩水で洗浄し溶液、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。濃縮物をさらに精製せずに次工程に使用した。 Step 7
Synthesis of 7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-8- (1-hydroxy-2-methoxymethoxy-ethyl) -2,3-dihydro-1H-indolizin-5-one

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

Dess-martinペルヨージナン(０.１８０ｇ、０.０００４mol)を、撹拌している７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−８−(１−ヒドロキシ−２−メトキシメトキシ−エチル)−２,３−ジヒドロ−１Ｈ−インドリジン−５−オン(０.１６０ｇ、０.０００４mol)のＤＣＭ(１０mL)溶液に添加し、反応混合物を１.３０時間、ＲＴで撹拌した。続いて３００mgのチオ硫酸ナトリウム.５Ｈ_２Ｏを含む１０mLの飽和ＮａＨＣＯ_３を添加し、撹拌を１０分間続けた。残留混合物を酢酸エチルで抽出し、有機層を飽和ＮａＨＣＯ_３溶液、塩水で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。濃縮物をカラムクロマトグラフィー(シリカゲル、溶離剤として６０−６５％酢酸エチルのヘキサン溶液を使用)で精製して、１００mg(６２.８％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−８−(２−メトキシメトキシ−アセチル)−２,３−ジヒドロ−１Ｈ−インドリジン−５−オンを、望む生成物として得た。
LCMS純度: 76.1%, m/z=444 (M+1), 445 (M+2)
HPLC: 80% Process 8
Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-8- (2-methoxymethoxy-acetyl) -2,3-dihydro-1H-indolizin-5-one

Dess-martin periodinane (0.180 g, 0.0004 mol) was stirred with 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-8- (1-hydroxy-2-methoxymethoxy-). Ethyl) -2,3-dihydro-1H-indolizin-5-one (0.160 g, 0.0004 mol) in DCM (10 mL) was added and the reaction mixture was stirred for 1.30 h at RT. Subsequently, 10 mL saturated NaHCO ₃ containing 300 mg sodium thiosulfate 0.5 H ₂ O was added and stirring was continued for 10 minutes. The residual 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 100 mg (62.8% yield) of 7- (4-bromo-2-fluoro- Phenylamino) -6-fluoro-8- (2-methoxymethoxy-acetyl) -2,3-dihydro-1H-indolizin-5-one was obtained as the desired product.
LCMS purity: 76.1%, m / z = 444 (M + 1), 445 (M + 2)
HPLC: 80%

１０％水性ＨＣｌ(４mL)および水(３mL)を、撹拌している７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−８−(２−メトキシメトキシ−アセチル)−２,３−ジヒドロ−１Ｈ−インドリジン−５−オン(１００mg、０.０００２mol)のメタノール(３mL)溶液に添加し、得られた混合物を１８時間、ＲＴで撹拌した。反応混合物を飽和ＮａＨＣＯ_３溶液で中和し、酢酸エチルで希釈し、有機層を塩水で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。濃縮物を分取ＨＰＬＣで精製して、１４mg(１５.７％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−８−(２−ヒドロキシ−アセチル)−２,３−ジヒドロ−１Ｈ−インドリジン−５−オンを、望む生成物として得た。
LCMS: 98.4%, m/z=401 (M+2)
HPLC: 98.7%
¹H NMR (DMSO-D₆, 300 MHz): δ 9.0-8.8 (br s, 1H), 7.5 (dd, 1H), 7.3 (d, 1H), 6.9-6.8 (m, 1H), 5.2 (t, 1H), 4.3-4.0 (m, 2H), 4.0 (t, 2H), 3.3-3.2 (m, 2H), 2.1 (t, 2H) Step 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 to stirred 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-8- (2-methoxymethoxy-acetyl) -2, 3-Dihydro-1H-indolizin-5-one (100 mg, 0.0002 mol) in methanol (3 mL) was added and the resulting mixture was stirred for 18 h at RT. 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 14 mg (15.7% yield) of 7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-8- (2-hydroxy-acetyl)- 2,3-Dihydro-1H-indolizin-5-one was obtained as the desired product.
LCMS: 98.4%, m / z = 401 (M + 2)
HPLC: 98.7%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 9.0-8.8 (br s, 1H), 7.5 (dd, 1H), 7.3 (d, 1H), 6.9-6.8 (m, 1H), 5.2 (t , 1H), 4.3-4.0 (m, 2H), 4.0 (t, 2H), 3.3-3.2 (m, 2H), 2.1 (t, 2H)

Scheme 13

ＴＥＡ(５.０８２ｇ、０.０５０２２４２mol)を、ＤＣＭ(７０mL)に溶解した７−ヒドロキシ−６−メチル−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エチルエステル(７.０ｇ、０.０３１mol)の溶液に添加し、反応混合物を−７８℃に冷却した。トリフル酸無水物(１１.５１ｇ、０.０４１mol)を反応混合物に添加し、反応混合物を１６時間、環境温度で撹拌した。反応混合物を重炭酸ナトリウム溶液(２０mL)で洗浄し、有機層を乾燥させ、濃縮した。濃縮物をカラムクロマトグラフィー(シリカゲル、溶離剤として５％ＭｅＯＨのＣＨＣｌ_３溶液を使用)で精製して、７.７８ｇ(７３.０％収率)の５−オキソ−７−トリフルオロメタンスルホニルオキシ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エチルエステルを、望む生成物として得た。
¹H NMR (CDCl₃, 300 MHz): 6.3 (s, 1H), 4.4 (q, 2H), 4.2 (t, 2H), 3.5 (t, 2H), 2.35 (q, 3H), 1.4 (t, 3H)。 Example 70
Process 1
Synthesis of 5-oxo-7-trifluoromethanesulfonyloxy-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester

TEA (5.082 g, 0.0502242 mol) was dissolved in DCM (70 mL) 7-hydroxy-6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid 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 for 16 hours at ambient temperature. 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 7.78 g (73.0% yield) of 5-oxo-7-trifluoromethanesulfonyloxy- 1,2,3,5-Tetrahydro-indolizine-8-carboxylic acid ethyl ester was obtained as the desired product.
¹ H NMR (CDCl ₃ , 300 MHz): 6.3 (s, 1H), 4.4 (q, 2H), 4.2 (t, 2H), 3.5 (t, 2H), 2.35 (q, 3H), 1.4 (t, 3H).

酢酸パラジウム(０.０６３ｇ、０.００３mol)、ＢＩＮＡＰ(０.２６３ｇ、０.０００３mol)、炭酸セシウム(１.３７ｇ、０.００４mol)をトルエンに溶解し、得られた混合物を３０分間、窒素で通気した。続いて５−オキソ−７−トリフルオロメタンスルホニルオキシ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エチルエステル(１ｇ、０.００３mol)および２−フルオロ−４−トリフルオロメチルアニリン(０.５４９ｇ、０.００３mol)を添加し、反応フラスコをさらに１５分間通気した。反応混合物を１１０℃で１.３０時間加熱した。反応混合物をセライトを通して濾過し、濾液を濃縮した。濃縮物をカラムクロマトグラフィー(メッシュサイズ６０−１２０のシリカゲル、溶離剤として７０％ＭｅＯＨのＣＨＣｌ_３溶液を使用)で精製して、０.４ｇ(３７％収率)の７−(２−フルオロ−４−トリフルオロメチル−フェニルアミノ)−５−オキソ−１,２,３,５−テトラ(tera)ヒドロ−インドリジン−８−カルボン酸エチルエステルを、望む生成物として得た。
¹H NMR (DMSO-D₆): 7.6 (t, 1H), 7.4 (t, 2H), 6.0 (s, 1H), 4.4 (q, 2H), 4.2 (t, 2H), 3.5 (t, 2H), 2.2 (q, 3H), 1.4 (t, 3H) Process 2
Synthesis of 7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetra (tera) hydro-indolizine-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 dissolved in nitrogen for 30 minutes. Aerated. Followed by 5-oxo-7-trifluoromethanesulfonyloxy-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester (1 g, 0.003 mol) and 2-fluoro-4-trifluoromethylaniline (0.549 g, 0.003 mol) was added and the reaction flask was vented for an additional 15 minutes. The reaction mixture was heated at 110 ° C. for 1.30 hours. The reaction mixture was filtered through celite and the filtrate was concentrated. The concentrate was purified by column chromatography (silica gel with mesh size 60-120, using 70% MeOH in CHCl ₃ as eluent) to give 0.4 g (37% yield) of 7- (2-fluoro- 4-Trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetra (tera) hydro-indolizine-8-carboxylic acid ethyl ester was obtained as the desired product.
¹ H NMR (DMSO-D ₆ ): 7.6 (t, 1H), 7.4 (t, 2H), 6.0 (s, 1H), 4.4 (q, 2H), 4.2 (t, 2H), 3.5 (t, 2H ), 2.2 (q, 3H), 1.4 (t, 3H)

Example 71
Steps 1 and 2 were performed according to the method described in Example 70.

ＬｉＯＨ(０.０７ｇ、０.００２mol)を、ＭｅＯＨ：ＴＨＦ(６mL)に溶解した撹拌している７−(２−フルオロ−４−トリフルオロメチル−フェニルアミノ)−５−オキソ−１,２,３,５−テトラ(tera)ヒドロ−インドリジン−８−カルボン酸エチルエステル(０.３０ｇ、０.０００８mol)の溶液に添加し、反応混合物をＲＴで４時間撹拌した。反応混合物を濃縮し、濃縮物を１０％ＨＣｌで酸性化して沈殿を得て、それを回収し、乾燥させて、０.２７０ｇ(９５.７４％収率)の７−(２−フルオロ−４−トリフルオロメチル−フェニルアミノ)−５−オキソ−１,２,３,５−テトラ(tera)ヒドロ−インドリジン−８−カルボン酸を、望む生成物として得た。
¹H NMR(DMSO-D₆, 300 MHz): 13.4 (s, 1H), 10.4 (s, 1H), 7.85-7.75 (m, 2H), 7.6 (d, 1H), 5.7 (s, 1H), 4.0 (t, 2H), 3.5 (t, 2H), 2.1 (t, 2H) Process 3
Synthesis of 7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetra (tera) hydro-indolizine-8-carboxylic acid

LiOH (0.07 g, 0.002 mol) dissolved in MeOH: THF (6 mL) is stirred with 7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2, To a solution of 3,5-tetra (tera) hydro-indolizine-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 was concentrated and the concentrate was acidified with 10% HCl to give a precipitate which was collected and dried to give 0.270 g (95.74% yield) of 7- (2-fluoro-4 -Trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetra (tera) hydro-indolizine-8-carboxylic acid was obtained as the desired product.
¹ H NMR (DMSO-D ₆ , 300 MHz): 13.4 (s, 1H), 10.4 (s, 1H), 7.85-7.75 (m, 2H), 7.6 (d, 1H), 5.7 (s, 1H), 4.0 (t, 2H), 3.5 (t, 2H), 2.1 (t, 2H)

Example 72
Steps 1-2 were performed according to the method described in Example 70, and Step 3 was performed according to the method described in Example 71.

ＥＤＣＩ(０.３２２ｇ、０.００２mol)、ＨＯＢｔ(０.２３ｇ、０.００２mol)および７−(２−フルオロ−４−トリフルオロメチル−フェニルアミノ)−５−オキソ−１,２,３,５−テトラ(tera)ヒドロ−インドリジン−８−カルボン酸(０.２ｇ、０.００１mol)を、不活性雰囲気下ＤＭＦに溶解し、反応混合物をＲＴで３０分間撹拌した。続いてシクロプロピルメチルヒドロキシルアミンヒドロクロライド(０.２１ｇ、０.００２mol)およびＴＥＡ(０.１７ｇ、０.００２mol)を添加し、反応混合物をＲＴで１６時間撹拌した。水を反応混合物に添加し、反応混合物を飽和ＮＨ_４Ｃｌでクエンチし、酢酸エチルで抽出した。有機層を飽和ビカーボネート溶液、塩水溶液で洗浄し、Ｎａ_２ＳＯ_４で乾燥させて沈殿を得て、それをエーテルで摩砕して、０.１ｇ(４１.８％収率)の７−(２−フルオロ−４−トリフルオロメチル−フェニルアミノ)−５−オキソ−１,２,３,５−テトラ(tera)ヒドロ−インドリジン−８−カルボン酸シクロプロピルメトキシアミドを純粋生成物として得た。
¹H NMR (DMSO-D₆, 300 MHz): 11.4 (s, 1H), 8.7 (s, 1H), 7.8 (d, 1H), 7.65-7.55 (m, 2H), 5.8 (s, 1H), 3.8 (t, 2H), 3.6 (d, 2H), 3.2 (t, 2H), 2.2 (t, 2H), 1.25-1.15 (m, 1H), 0.65-0.55 (m, 2H), 0.45-0.35 (m, 2H)。 Process 4
Synthesis of 7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetra (tera) hydro-indolizine-8-carboxylic acid cyclopropylmethoxyamide

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 -Tera hydro-indolizine-8-carboxylic acid (0.2 g, 0.001 mol) was dissolved in DMF under inert atmosphere and the reaction mixture was stirred at RT for 30 min. Subsequently cyclopropylmethylhydroxylamine hydrochloride (0.21 g, 0.002 mol) and TEA (0.17 g, 0.002 mol) were added and the reaction mixture was stirred at RT for 16 h. Water was added to the reaction mixture and 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 0.1 g (41.8% yield) of 7- (2-Fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetra (tera) hydro-indolizine-8-carboxylic acid cyclopropylmethoxyamide is obtained as pure product It was.
¹ H NMR (DMSO-D ₆ , 300 MHz): 11.4 (s, 1H), 8.7 (s, 1H), 7.8 (d, 1H), 7.65-7.55 (m, 2H), 5.8 (s, 1H), 3.8 (t, 2H), 3.6 (d, 2H), 3.2 (t, 2H), 2.2 (t, 2H), 1.25-1.15 (m, 1H), 0.65-0.55 (m, 2H), 0.45-0.35 ( m, 2H).

Scheme 14

Example 73
Step 1 was performed according to the method described in Example 70.

酢酸パラジウム(０.０６ｇ、０.００３mol)、ＢＩＮＡＰ(０.２６ｇ、０.０００２mol)、炭酸セシウム(１.３７ｇ、０.００４mol)をトルエンに溶解し、得られた混合物を３０分間窒素で通気した。続いて５−オキソ−７−トリフルオロメタンスルホニルオキシ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エチルエステル(１ｇ、０.００３mol)および２−フルオロ−４−メトキシアニリン(０.５４ｇ、０.００３mol)を添加し、反応フラスコをさらに１５分間再通気した。反応混合物を１１０℃で、１.３０時間加熱した。反応混合物をセライトを通して濾過し、濾液を濃縮した。濃縮物をカラムクロマトグラフィー(シリカゲル、溶離剤として７０％ＭｅＯＨのＣＨＣｌ_３溶液を使用)で精製して、０.２３０ｇ(２３.６％収率)の７−(２−フルオロ−４−メトキシ−フェニルアミノ)−５−オキソ−１,２,３,５−テトラ(tera)ヒドロ−インドリジン−８−カルボン酸エチルエステルを、望む生成物として得た。
¹H NMR (DMSO-D₆, 300 MHz): 9.2 (s, 1H), 7.2 (t, 1H), 6.85-6.75 (m, 2H), 5.5 (s, 1H), 4.4 (q, 2H), 4.2 (t, 2H), 3.8 (s, 3H), 3.5 (t, 2H), 2.2 (q, 2H), 1.4 (t, 3H)。 Process 2
Synthesis of 7- (2-fluoro-4-methoxy-phenylamino) -5-oxo-1,2,3,5-tetra (tera) hydro-indolizine-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 bubbled with nitrogen for 30 minutes. did. Subsequent 5-oxo-7-trifluoromethanesulfonyloxy-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester (1 g, 0.003 mol) and 2-fluoro-4-methoxyaniline (0 .54 g, 0.003 mol) was added and the reaction flask was re-vented for an additional 15 minutes. The reaction mixture was heated at 110 ° C. for 1.30 hours. 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 give 0.230 g (23.6% yield) of 7- (2-fluoro-4-methoxy- Phenylamino) -5-oxo-1,2,3,5-tetra (tera) hydro-indolizine-8-carboxylic acid ethyl ester was obtained as the desired product.
¹ H NMR (DMSO-D ₆ , 300 MHz): 9.2 (s, 1H), 7.2 (t, 1H), 6.85-6.75 (m, 2H), 5.5 (s, 1H), 4.4 (q, 2H), 4.2 (t, 2H), 3.8 (s, 3H), 3.5 (t, 2H), 2.2 (q, 2H), 1.4 (t, 3H).

ＬｉＯＨ(０.０５ｇ、０.００１mol)を、ＭｅＯＨ：ＴＨＦ(６mL)に溶解した撹拌している７−(２−フルオロ−４−メトキシ−フェニルアミノ)−５−オキソ−１,２,３,５−テトラ(tera)ヒドロ−インドリジン−８−カルボン酸エチルエステル(０.１９ｇ、０.００１mol)の溶液に添加し、得られた混合物をＲＴで４時間撹拌した。溶媒を留去し、粗生成物を１０％ＨＣｌで酸性化して沈殿を得て、それを回収し、乾燥させて、０.１３０ｇ(７６.０２３％収率)の７−(２−フルオロ−４−メトキシ−フェニルアミノ)−５−オキソ−１,２,３,５−テトラ(tera)ヒドロ−インドリジン−８−カルボン酸を得た。
¹H NMR (DMSO-D₆, 300 MHz): 13.45-13.35 (br s, 1H), 9.6 (s, 1H), 7.3 (t, 1H), 7.0 (d, 1H), 6.8 (d, 1H), 5.0 (s, 1H), 4.0 (t, 2H), 3.8 (s, 3H), 3.5 (t, 2H), 2.15-2.05 (m, 2H)。 Process 3
Synthesis of 7- (2-fluoro-4-methoxy-phenylamino) -5-oxo-1,2,3,5-tetra (tera) hydro-indolizine-8-carboxylic acid

LiOH (0.05 g, 0.001 mol) dissolved in MeOH: THF (6 mL) is stirred with 7- (2-fluoro-4-methoxy-phenylamino) -5-oxo-1,2,3, To a solution of 5-tetra (tera) hydro-indolizine-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 0.130 g (76.023% yield) of 7- (2-fluoro- 4-Methoxy-phenylamino) -5-oxo-1,2,3,5-tetra (tera) hydro-indolizine-8-carboxylic acid was obtained.
¹ H NMR (DMSO-D ₆ , 300 MHz): 13.45-13.35 (br s, 1H), 9.6 (s, 1H), 7.3 (t, 1H), 7.0 (d, 1H), 6.8 (d, 1H) , 5.0 (s, 1H), 4.0 (t, 2H), 3.8 (s, 3H), 3.5 (t, 2H), 2.15-2.05 (m, 2H).

ＥＤＣＩ(０.２２ｇ、０.００１mol)、ＨＯＢｔ(０.１５ｇ、０.００１mol)および７−(２−フルオロ−４−メトキシ−フェニルアミノ)−５−オキソ−１,２,３,５−テトラ(tera)ヒドロ−インドリジン−８−カルボン酸(０.１２ｇ、０.０００４mol)をＤＭＦに不活性雰囲気下溶解し、反応混合物をＲＴで３０分間撹拌した。続いてシクロプロピルメチルヒドロキシルアミンヒドロクロライド(０.１４０ｇ、０.００１mol)およびＴＥＡ(０.１１４ｇ、０.００１mol)を添加し、反応混合物をＲＴで一夜撹拌した。水を反応混合物に添加し、飽和ＮＨ_４Ｃｌを添加し、酢酸エチルで抽出した。有機層を飽和ビカーボネート溶液、塩水溶液で洗浄し、Ｎａ_２ＳＯ_４で乾燥させて沈殿を得て、それをエーテルで摩砕して、０.０９ｇ(６１.６％収率)の７−(２−フルオロ−４−メトキシ−フェニルアミノ)−５−オキソ−１,２,３,５−テトラ(tera)ヒドロ−インドリジン−８−カルボン酸シクロプロピルメトキシアミドを、望む生成物として得た。
¹H NMR (DMSO-D₆, 300 MHz): 11.4 (s, 1H), 7.9 (s, 1H), 7.2 (t, 1H), 6.9 (d, 1H), 6.8 (d, 1H), 5.0 (s, 1H), 3.9 (t, 2H), 3.8 (s, 3H), 3.7 (d, 2H), 3.2 (t, 2H), 2.05-2.0 (m, 2H), 1.05-1.0 (m, 1H), 0.65 (d, 2H), 0.2 (d, 2H)。 Process 4
Synthesis of 7- (2-fluoro-4-methoxy-phenylamino) -5-oxo-1,2,3,5-tetra (tera) hydro-indolizine-8-carboxylic acid cyclopropylmethoxyamide

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-tetra (tera) Hydro-indolizine-8-carboxylic acid (0.12 g, 0.0004 mol) was dissolved in DMF under inert atmosphere and the reaction mixture was stirred at RT for 30 min. Subsequently cyclopropylmethylhydroxylamine hydrochloride (0.140 g, 0.001 mol) and TEA (0.114 g, 0.001 mol) were added and the reaction mixture was stirred at RT overnight. Water was added to the reaction mixture, saturated NH ₄ Cl was added 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 0.09 g (61.6% yield) of 7- (2-Fluoro-4-methoxy-phenylamino) -5-oxo-1,2,3,5-tetra (tera) hydro-indolizine-8-carboxylic acid cyclopropylmethoxyamide was obtained as the desired product. .
¹ H NMR (DMSO-D ₆ , 300 MHz): 11.4 (s, 1H), 7.9 (s, 1H), 7.2 (t, 1H), 6.9 (d, 1H), 6.8 (d, 1H), 5.0 ( s, 1H), 3.9 (t, 2H), 3.8 (s, 3H), 3.7 (d, 2H), 3.2 (t, 2H), 2.05-2.0 (m, 2H), 1.05-1.0 (m, 1H) , 0.65 (d, 2H), 0.2 (d, 2H).

Example 74
Scheme 15

  Steps 1 and 2 were performed according to the method described in Example 27.

ＬＤＡ(５０mL)を、２−フルオロ−４−ブロモ−フェニルアミン(７ｇ、０.０３７mol)のＴＨＦ(５５０mL)溶液に−７８℃で添加し、得られた混合物を１時間撹拌した。続いて７−クロロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(５.５ｇ、０.０２５mol)の乾燥ＴＨＦ(２００mL)溶液を−７８℃で添加し、反応塊を室温で１６時間撹拌した。反応混合物を減圧下濃縮し、希ＨＣｌで中和した。ジエチルエーテルを添加し、１時間撹拌して沈殿を得て、それを回収して、５.２ｇ(５６％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸を、望む生成物として得た。 Process 3
Synthesis of 7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-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. Then a solution of 7-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (5.5 g, 0.025 mol) in dry THF (200 mL) was added at -78 ° C. The reaction mass was stirred at room temperature for 16 hours. 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 that was collected and recovered in 5.2 g (56% yield) of 7- (4-bromo-2-fluoro-phenylamino) -5-oxo. -1,2,3,5-Tetrahydro-indolizine-8-carboxylic acid was obtained as the desired product.

ＴＥＡ(１.５２mg、０.０１５mol)を７−(４−ブロモ−２−フルオロ−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(５ｇ、０.０１４mol)の乾燥ＤＭＦ(８mL)溶液に窒素雰囲気下添加し、反応混合物を３０分間撹拌した。ＤＰＰＡ(４.１４ｇ、０.０１５mol)を１５分間かけて、１０℃で撹拌しながら添加した。撹拌をさらに５時間、ＲＴで続けた。続いてトルエン(８０mL)を添加し、反応塊を９０℃で、４時間加熱した。反応塊を減圧下濃縮し、冷水を添加した。形成した沈殿を回収し、乾燥させて、３.４ｇ(７０％収率)の３−(４−ブロモ−２−フルオロ−フェニル)−１,６,７,８−テトラヒドロ−３Ｈ−１,３,５ａ−トリアザ−ａｓ−インダセン−２,５−ジオンを、望む生成物として得た。 Process 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 converted to 7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (5 g, To a solution of 0.014 mol) in dry DMF (8 mL) was added under nitrogen atmosphere and the reaction mixture was stirred for 30 min. DPPA (4.14 g, 0.015 mol) was added with stirring at 10 ° C. over 15 minutes. Stirring was continued for an additional 5 hours at RT. Toluene (80 mL) was then added and the reaction mass was heated at 90 ° C. for 4 hours. The reaction mass was concentrated under reduced pressure and cold water was added. The formed precipitate was collected and dried to give 3.4 g (70% yield) of 3- (4-bromo-2-fluoro-phenyl) -1,6,7,8-tetrahydro-3H-1,3. , 5a-triaza-as-indacene-2,5-dione was obtained as the desired product.

６０％ＮａＨ(７０mg、０.００３mol)を、撹拌している３−(４−ブロモ−２−フルオロ−フェニル)−１,６,７,８−テトラヒドロ−３Ｈ−１,３,５ａ−トリアザ−ａｓ−インダセン−２,５−ジオン(３００mg、０.００１mol)の乾燥ＤＭＦ(１０mL)溶液に０−５℃で窒素雰囲気下添加し、得られた混合物を１時間、ＲＴで撹拌した。メタンスルホニルクロライド(１５０mg、０.００１mol)の乾燥ＴＨＦ溶液を、５分間かけて、０℃で滴下し、１６時間、ＲＴで撹拌した。氷冷水を、反応フラスコに５分間撹拌しながら添加し、ｐＨを５に調節した。酢酸エチルで抽出し、Ｎａ_２ＳＯ_４で乾燥させ、減圧下濃縮して、１６０mg(４７％収率)の３−(４−ブロモ−２−フルオロ−フェニル)−１−メタンスルホニル−１,６,７,８−テトラヒドロ−３Ｈ−１,３,５ａ−トリアザ−ａｓ−インダセン−２,５−ジオンを、望む生成物として得た。
HPLC: 93.7%
¹H NMR (DMSO-D₆, 300 MHz): δ, 7.9-7.45 (m, 3H), 5.45 (s, 1H), 3.9 (t, 2H), 3.65 (s, 3H), 3.3 (t, 2H), 2.15-2.05 (m, 2H) Process 5
Synthesis of 3- (4-bromo-2-fluoro-phenyl) -1-methanesulfonyl-1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2,5-dione

60% NaH (70 mg, 0.003 mol) was stirred with 3- (4-bromo-2-fluoro-phenyl) -1,6,7,8-tetrahydro-3H-1,3,5a-triaza- To a solution of as-indacene-2,5-dione (300 mg, 0.001 mol) in dry DMF (10 mL) was added at 0-5 ° C. under a nitrogen atmosphere and the resulting mixture was stirred for 1 h at RT. Methanesulfonyl chloride (150 mg, 0.001 mol) in dry THF was added dropwise over 5 minutes at 0 ° C. and stirred for 16 hours at RT. Ice cold water was added to the reaction flask with stirring for 5 minutes to adjust the pH to 5. Extracted with ethyl acetate, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 160 mg (47% yield) of 3- (4-bromo-2-fluoro-phenyl) -1-methanesulfonyl-1,6. , 7,8-Tetrahydro-3H-1,3,5a-triaza-as-indacene-2,5-dione was obtained as the desired product.
HPLC: 93.7%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ, 7.9-7.45 (m, 3H), 5.45 (s, 1H), 3.9 (t, 2H), 3.65 (s, 3H), 3.3 (t, 2H ), 2.15-2.05 (m, 2H)

Example 75
Steps 1-2 were performed according to the method described in Example 27 and steps 3-4 were performed according to the method described in Example 74.

６０％ＮａＨ(２０mg)を、撹拌している３−(４−ブロモ−２−フルオロ−フェニル)−１,６,７,８−テトラヒドロ−３Ｈ−１,３,５ａ−トリアザ−ａｓ−インダセン−２,５−ジオン(２００mg、０.００１mol)の乾燥ＤＭＦ(５mL)溶液に０−５℃で窒素雰囲気下添加し、得られた混合物を１時間、ＲＴで撹拌した。シクロプロパンスルホニルクロライド(１５０mg、０.００２mol)の乾燥ＴＨＦ溶液を１０分間かけて、０℃で滴下し、撹拌を１６時間、ＲＴで続けた。反応混合物にＮａＨ(２０mg)を０℃で添加し、１５分間撹拌し、シクロプロパンスルホニルクロライド(１５０mg、０.００２mol)の乾燥ＤＭＦを添加し、撹拌をさらに５時間、ＲＴで続けた。粗生成物を次工程にさらに精製せずに使用した。 Process 5
Of 3- (4-bromo-2-fluoro-phenyl) -1-cyclopropanesulfonyl-1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2,5-dione Composition

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

１Ｎ 水性ＮａＯＨ(７mL)を、３−(４−ブロモ−２−フルオロ−フェニル)−１−シクロプロパンスルホニル−１,６,７,８−テトラヒドロ−３Ｈ−１,３,５ａ−トリアザ−ａｓ−インダセン−２,５−ジオンに添加し、得られた混合物を７５℃で、４時間加熱した。氷冷水を反応混合物に添加し、５％氷冷ＨＣｌで約３のｐＨに中和し、酢酸エチルおよび水に分配した。有機層をＮａ_２ＳＯ_４で乾燥させ、濃縮し、カラムクロマトグラフィー(シリカゲル、溶離剤として３％メタノールのＤＣＭ溶液を使用)で精製して、１７mg(７％収率)のシクロプロパンスルホン酸[７−(４−ブロモ−２−フルオロ−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−イル]−アミドを、望む生成物として得た。
LC-MS純度: 98.5%
HPLC: 97%
¹H NMR (DMSO-D₆, 300 MHz): δ 8.75 (s, 1H), 7.65-7.25 (m, 3H), 5.25 (s, 1H), 3.9 (t, 2H), 3.2 (t, 2H), 2.9-2.8 (m, 1H), 2.2-2.1 (m, 2H), 0.95-0.85 (m, 4H) Step 6
Synthesis of cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide

1N aqueous NaOH (7 mL) was added to 3- (4-bromo-2-fluoro-phenyl) -1-cyclopropanesulfonyl-1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as- Indacene-2,5-dione was added and the resulting mixture was heated at 75 ° C. for 4 hours. Ice cold water was added to the reaction mixture, neutralized with 5% ice cold HCl to a pH of about 3 and 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 give 17 mg (7% yield) of cyclopropanesulfonic acid [ 7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide was obtained as the desired product.
LC-MS purity: 98.5%
HPLC: 97%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 8.75 (s, 1H), 7.65-7.25 (m, 3H), 5.25 (s, 1H), 3.9 (t, 2H), 3.2 (t, 2H) , 2.9-2.8 (m, 1H), 2.2-2.1 (m, 2H), 0.95-0.85 (m, 4H)

Example 76
Steps 1-2 were performed according to the method described in Example 27 and steps 3-4 were performed according to the method described in Example 74.

６０％ＮａＨ(５０mg、０.００１mol)を、撹拌している３−(４−ブロモ−２−フルオロ−フェニル)−１,６,７,８−テトラヒドロ−３Ｈ−１,３,５ａ−トリアザ−ａｓ−インダセン−２,５−ジオン(３００mg、０.００１mol)の乾燥ＤＭＦ(６mL)溶液に０−５℃で窒素雰囲気下添加し、得られた混合物を１時間、ＲＴで撹拌した。４−フルオロ−ベンゼンスルホニルクロライド(２００mg、０.００１mol)の乾燥ＴＨＦ溶液を１０分間かけて添加し、撹拌を１６時間、ＲＴで続けた。粗生成物を次工程にさらに精製せずに使用した。 Process 5
3- (4-Bromo-2-fluoro-phenyl) -1- (4-fluoro-benzenesulfonyl) -1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2 Of 1,5-dione

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

１Ｎ ＮａＯＨ溶液(６mL)を３−(４−ブロモ−２−フルオロ−フェニル)−１−(４−フルオロ−ベンゼンスルホニル)−１,６,７,８−テトラヒドロ−３Ｈ−１,３,５ａ−トリアザ−ａｓ−インダセン−２,５−ジオンに添加し、得られた混合物を６０℃で、１時間加熱した。氷冷水を反応混合物に添加し、５％ＨＣｌで約４のｐＨに中和し、酢酸エチルおよび水に分配した。有機層をＮａＨＣＯ_３で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮し、カラムクロマトグラフィー(シリカゲル、溶離剤として２％メタノールのＤＣＭ溶液を使用)で精製して、２０mg(６％収率)のＮ−[７−(４−ブロモ−２−フルオロ−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−イル]−４−フルオロ−ベンゼンスルホンアミドを、望む生成物として得た。
LC-MS純度: 97.5%
HPLC: 96.274%
¹H NMR (DMSO-D₆, 300 MHz): δ 9.25 (s, 1H), 7.0-7.85 (m, 7H), 5.25 (s, 1H), 3.9 (t, 2H), 2.75 (t, 2H), 1.95-1.8 (m,1H) Step 6
Synthesis of N- [7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -4-fluoro-benzenesulfonamide

1N NaOH solution (6 mL) was added to 3- (4-bromo-2-fluoro-phenyl) -1- (4-fluoro-benzenesulfonyl) -1,6,7,8-tetrahydro-3H-1,3,5a- Triaza-as-indacene-2,5-dione was added and the resulting mixture was heated at 60 ° C. for 1 hour. Ice cold water was added to the reaction mixture, neutralized with 5% HCl to a pH of about 4 and 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 give 20 mg (6% yield) N- [7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -4-fluoro-benzenesulfonamide Obtained as the desired product.
LC-MS purity: 97.5%
HPLC: 96.274%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 9.25 (s, 1H), 7.0-7.85 (m, 7H), 5.25 (s, 1H), 3.9 (t, 2H), 2.75 (t, 2H) , 1.95-1.8 (m, 1H)

Example 77
Steps 1-2 were performed according to the method described in Example 27 and steps 3-4 were performed according to the method described in Example 74.

６０％ＮａＨ(６７mg、０.００３mol)を、撹拌している３−(４−ブロモ−２−フルオロ−フェニル)−４−フルオロ−１,６,７,８−テトラヒドロ−３Ｈ−１,３,５ａ−トリアザ−ａｓ−インダセン−２,５−ジオン(２.５mg、０.００１mol)の乾燥ＤＭＦ(１０mL)溶液に０℃で窒素雰囲気下添加した。ＢＯＣ無水物(２６０mg、０.００１mol)の乾燥ＴＨＦ溶液を５分間かけて０℃で添加し、得られた混合物を４時間、ＲＴで撹拌した。粗生成物をさらに精製せずに次工程に使用した。 Process 5
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 Synthesis of tert-butyl ester

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

１Ｎ 水性ＮａＯＨ(６mL)を３−(４−ブロモ−２−フルオロ−フェニル)−２,５−ジオキソ−２,３,５,６,７,８−ヘキサヒドロ−１,３,５ａ−トリアザ−ａｓ−インダセン−１−カルボン酸ｔｅｒｔ−ブチルエステルに添加し、得られた混合物を６５℃で、３時間加熱した。氷冷水を反応混合物に添加し、５％ＨＣｌでｐＨ約７に中和し、反応混合物を酢酸エチルおよび水に分配した。有機層をＮａ_２ＳＯ_４で乾燥させ、減圧下濃縮し、濃縮物をカラムクロマトグラフィー(中性アルミナ、溶離剤として３％メタノールのＤＣＭ溶液を使用)で精製して、１６５mg(４３.８％収率)の[７−(４−ブロモ−２−フルオロ−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−イル]−カルバミン酸ｔｅｒｔ−ブチルエステルを、望む生成物として得た。
HPLC: 94.2%
¹H NMR (DMSO-D₆, 300 MHz): δ 8.15 (s, 1H), 7.9-7.45 (m, 3H), 5.15 (s, 1H), 3.9 (t, 2H), 2.9 (t, 2H), 2.2-2.1 (m, 2H), 1.45 (s, 9H) Step 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 to 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 at 65 ° C for 3 hours. Ice cold water was added to the reaction mixture, neutralized with 5% HCl to pH˜7, and the reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure, the concentrate was purified by column chromatography (neutral alumina, using 3% methanol in DCM as eluent) to give 165 mg (43.8% Yield) of [7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -carbamic acid tert-butyl ester, Obtained as the desired product.
HPLC: 94.2%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 8.15 (s, 1H), 7.9-7.45 (m, 3H), 5.15 (s, 1H), 3.9 (t, 2H), 2.9 (t, 2H) , 2.2-2.1 (m, 2H), 1.45 (s, 9H)

Example 78
Steps 1-2 are performed according to the method described in Example 27, Steps 3-4 are performed according to the method described in Example 74, and Steps 5-6 are performed according to the method described in Example 77. went.

ＴＦＡ(１mL)を、撹拌している[７−(４−ブロモ−２−フルオロ−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−イル]−カルバミン酸ｔｅｒｔ−ブチルエステル(２００mg、０.０００５mol)の乾燥ＤＣＭ(５mL)溶液に５分間かけて、−１０℃で滴下し、得られた混合物を４時間、ＲＴで撹拌した。反応塊を減圧下濃縮した。水を添加し、ＮａＨＣＯ_３溶液で中和し、酢酸エチルで抽出し、Ｎａ_２ＳＯ_４で乾燥させて、１２０mg(７９％収率)の８−アミノ−７−(４−ブロモ−２−フルオロ−フェニルアミノ)−２,３−ジヒドロ−１Ｈ−インドリジン−５−オンを、望む生成物として得た。
LCMS純度: 88.3% Step 7
Synthesis of 8-amino-7- (4-bromo-2-fluoro-phenylamino) -2,3-dihydro-1H-indolizin-5-one

TFA (1 mL) was stirred with [7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -carbamic acid. To a solution of tert-butyl ester (200 mg, 0.0005 mol) in dry DCM (5 mL) was added dropwise over 5 minutes at −10 ° C. and the resulting mixture was stirred for 4 hours at RT. The reaction mass was concentrated under reduced pressure. Water was added, neutralized with NaHCO ₃ solution, extracted with ethyl acetate, dried over Na ₂ SO ₄ and 120 mg (79% yield) of 8-amino-7- (4-bromo-2-fluoro -Phenylamino) -2,3-dihydro-1H-indolizin-5-one was obtained as the desired product.
LCMS purity: 88.3%

ピリジンのＤＣＭ溶液(４mL)を、８−アミノ−７−(４−ブロモ−２−フルオロ−フェニルアミノ)−２,３−ジヒドロ−１Ｈ−インドリジン−５−オン(１１０mg、０.０００３mol)溶液に添加し、反応混合物を１０分間、窒素雰囲気下で撹拌した。続いてＤＭＡＰ(５mg、０.０００４mol)、反応塊を０−５℃に冷却し、シクロヘキシルスルホニルクロライド(８０mg、０.０００４mol)のＤＣＭ溶液を１０分間かけて滴下し、撹拌を１６時間、ＲＴで続けた。反応混合物を酢酸エチルおよび水に分配し、有機層を水、１Ｎ 希ＨＣｌで洗浄した。有機層をＮａ_２ＳＯ_４で乾燥させ、濃縮し、濃縮物をカラムクロマトグラフィー(シリカゲル、溶離剤として２％メタノールのＤＣＭ溶液を使用)で精製して、１０mg(８.５％収率)のシクロヘキサンスルホン酸[７−(４−ブロモ−２−フルオロ−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−イル]−アミドを、望む生成物として得た。
LC-MS純度: 96.8%, m/z=484, (M+1)
HPLC: 93.4%
¹H NMR (DMSO-D₆, 300 MHz): δ 7.8 (s, 1H), 7.65-7.25 (m, 3H), 5.95 (s, 1H), 4.1 (t, 2H), 3.2 (t, 2H), 3.15-3.05 (m, 1H), 2.25-2.15 (m, 1H), 2.2-2.1 (m, 2H), 1.85-1.75 (m, 2H), 1.65-1.6 (m, 4H), 1.3-1.25 (m, 2H) Process 8
Synthesis of cyclohexanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide

A solution of pyridine in DCM (4 mL) was added to a solution of 8-amino-7- (4-bromo-2-fluoro-phenylamino) -2,3-dihydro-1H-indolidin-5-one (110 mg, 0.0003 mol). And the reaction mixture was stirred for 10 minutes under a nitrogen atmosphere. Subsequently, DMAP (5 mg, 0.0004 mol), the reaction mass was cooled to 0-5 ° C., a solution of cyclohexylsulfonyl chloride (80 mg, 0.0004 mol) in DCM was added dropwise over 10 minutes and stirring was continued for 16 hours at RT. Continued. The reaction mixture was partitioned between ethyl acetate and water and the organic layer was washed with water, 1N dilute HCl. The organic layer was dried over Na ₂ SO ₄ and concentrated, and the concentrate was purified by column chromatography (silica gel, using 2% methanol in DCM as eluent) to yield 10 mg (8.5% yield). Cyclohexanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide was obtained as the desired product. .
LC-MS purity: 96.8%, m / z = 484, (M + 1)
HPLC: 93.4%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 7.8 (s, 1H), 7.65-7.25 (m, 3H), 5.95 (s, 1H), 4.1 (t, 2H), 3.2 (t, 2H) , 3.15-3.05 (m, 1H), 2.25-2.15 (m, 1H), 2.2-2.1 (m, 2H), 1.85-1.75 (m, 2H), 1.65-1.6 (m, 4H), 1.3-1.25 ( m, 2H)

Example 79
Steps 1-2 were performed according to the method described in Example 27 and steps 3-4 were performed according to the method described in Example 74.

６０％ＮａＨ(３１mg、０.００１mol)を、撹拌している３−(４−ブロモ−２−フルオロ−フェニル)−１,６,７,８−テトラヒドロ−３Ｈ−１,３,５ａ−トリアザ−ａｓ−インダセン−２,５−ジオン(２００mg、０.００１mol)の乾燥ＤＭＦ(４mL)溶液に０℃で添加し、得られた混合物を１時間、ＲＴで撹拌した。４−トリフルオロメチル−ベンゼンスルホニルクロライド(１８０mg、０.００１mol)の乾燥ＴＨＦ溶液を１０分間かけて、０℃で滴下した。撹拌を２日間、ＲＴで続け、粗生成物を得て、それをさらに精製せずに次工程に使用した。 Process 5
3- (4-Bromo-2-fluoro-phenyl) -1- (4-trifluoromethyl-benzenesulfonyl) -1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as-indacene Synthesis of -2,5-dione

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

１Ｎ 水性ＮａＯＨ(１５mL)を３−(４−ブロモ−２−フルオロ−フェニル)−１−(４−トリフルオロメチル−ベンゼンスルホニル)−１,６,７,８−テトラヒドロ−３Ｈ−１,３,５ａ−トリアザ−ａｓ−インダセン−２,５−ジオンに添加し、得られた混合物を６５℃で、２時間加熱した。希ＨＣｌ(ｐＨ＝４)を反応塊にＲＴで添加し、水性Ｎａ_２ＣＯ_３を使用してｐＨを７に調節し、反応塊を酢酸エチルで抽出した。有機層を塩水で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、減圧下濃縮し、濃縮物をカラムクロマトグラフィー(シリカゲル、１.５％メタノールのＤＣＭ溶液を使用)で精製して、１０２mg(３３％収率)のを、望む生成物として得た。
LC-MS純度: 98.9%, m/z=548, (M+2)
HPLC: 99.6%
¹H NMR (DMSO-D₆, 300 MHz): δ 9.4(s, 1H), 7.85-6.85 (m, 7H), 5.25 (s, 1H), 3.9 (t, 2H), 2.85 (t, 2H), 2.0-1.9 (m, 1H) Step 6
Of N- [7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -4-trifluoromethyl-benzenesulfonamide Composition

1N aqueous NaOH (15 mL) was added to 3- (4-bromo-2-fluoro-phenyl) -1- (4-trifluoromethyl-benzenesulfonyl) -1,6,7,8-tetrahydro-3H-1,3, 5a-Triaza-as-indacene-2,5-dione was added and the resulting mixture was heated at 65 ° C. for 2 hours. Dilute HCl (pH = 4) was added to the reaction mass at RT, the pH was adjusted to 7 using aqueous Na ₂ CO ₃ and the reaction mass 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) was obtained as the desired product.
LC-MS purity: 98.9%, m / z = 548, (M + 2)
HPLC: 99.6%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 9.4 (s, 1H), 7.85-6.85 (m, 7H), 5.25 (s, 1H), 3.9 (t, 2H), 2.85 (t, 2H) , 2.0-1.9 (m, 1H)

Example 80
Steps 1-2 are performed according to the method described in Example 27, Steps 3-4 are performed according to the method described in Example 74, and Steps 5-6 are performed according to the method described in Example 77. And Step 7 was performed according to the method described in Example 78.

Ｎ,Ｎ−ジメチルスルホニルクロライド(４０mg、０.０００３mol)を、８−アミノ−７−(４−ブロモ−２−フルオロ−フェニルアミノ)−２,３−ジヒドロ−１Ｈ−インドリジン−５−オン(８０mg、０.０００２mol)の乾燥ＴＨＦおよびＤＭＡＰ(３０mg、０.０００２mol)中の溶液に−３５℃で添加し、反応混合物をＲＴで２時間撹拌した。続いて乾燥ピリジン(１.５mL)を添加し、反応混合物を４０℃で、４時間加熱した。反応塊を減圧下濃縮し、濃縮物を分取ＨＰＬＣで精製して、６mg(９％収率)のＮ−[７−(４−ブロモ−２−フルオロ−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−イル]−Ｎ,Ｎ−ジメチルアミノスルホンアミドを、望む生成物として得た。
HPLC: 91.4%
¹H NMR (DMSO-D₆, 300 MHz): δ 7.15 (s, 1H), 7.85-7.25 (m, 3H), 5.9 (s, 1H), 4.2 (t, 2H), 3.29 (t, 2H), 2.9 (s, 6H), 2.25-2.15 (m, 2H) Process 8
Synthesis of N- [7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -N, N-dimethylaminosulfonamide

N, N-dimethylsulfonyl chloride (40 mg, 0.0003 mol) was added to 8-amino-7- (4-bromo-2-fluoro-phenylamino) -2,3-dihydro-1H-indolizin-5-one ( To a solution of 80 mg, 0.0002 mol) in dry THF and DMAP (30 mg, 0.0002 mol) was added at −35 ° C. and the reaction mixture was stirred at RT for 2 h. Subsequently dry pyridine (1.5 mL) was added and the reaction mixture was heated at 40 ° C. for 4 h. The reaction mass was concentrated under reduced pressure and the concentrate was purified by preparative HPLC to yield 6 mg (9% yield) of N- [7- (4-bromo-2-fluoro-phenylamino) -5-oxo-1 , 2,3,5-Tetrahydro-indolizin-8-yl] -N, N-dimethylaminosulfonamide was obtained as the desired product.
HPLC: 91.4%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 7.15 (s, 1H), 7.85-7.25 (m, 3H), 5.9 (s, 1H), 4.2 (t, 2H), 3.29 (t, 2H) , 2.9 (s, 6H), 2.25-2.15 (m, 2H)

Example 81
Scheme 16

マロニルクロライド(８.１０ｇ、０.０５７mol)を、(２,２−ジメチル−テトラヒドロ−[１,３]ジオキソロ[４,５−ｃ]ピロール−４−イリデン)−酢酸エチルエステル(J. Chem. Soc., Perkins Transactions 1: Organic and Bio-organic Chemistry, pgs 2371-2376, (1987))(１０.２ｇ、０.０４８mol)のＤＣＭ(３００mL)溶液に３０分間かけて滴下し、反応混合物をＲＴで３時間撹拌した。反応塊を５mLのＴＥＡでクエンチし、溶媒を濃縮した。濃縮物をカラムクロマトグラフィー(シリカゲル、溶離剤として３０−４５％酢酸エチルのヘキサン溶液を使用)で精製して、９.２５ｇ(６９％収率)の５−ヒドロキシ−２,２−ジメチル−７−オキソ−３ａ,７,８,８ａ−テトラヒドロ−１,３−ジオキサ−７ａ−アザ−シクロペンタ[ａ]インデン−４−カルボン酸エチルエステルを、望む生成物として得た。
¹H NMR (CDCl₃, 300 MHz): 11.25-11.15 (br s, 1H), 6.0 (s, 1H), 6.0-5.95 (m, 1H), 5.05-4.95 (m, 1H), 4.45-4.35 (m, 3H), 4.15-4.05 (m, 1H), 1.45-1.35 (m, 6H), 1.3 (s, 3H)。 Process 1
Synthesis of 5-hydroxy-2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylic acid ethyl ester

Malonyl chloride (8.10 g, 0.057 mol) was added to (2,2-dimethyl-tetrahydro- [1,3] dioxolo [4,5-c] pyrrol-4-ylidene) -acetic acid ethyl ester (J. Chem. Soc., Perkins Transactions 1: Organic and Bio-organic Chemistry, pgs 2371-2376, (1987)) (10.2 g, 0.048 mol) in DCM (300 mL) dropwise over 30 min. For 3 hours. The reaction mass was quenched with 5 mL 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 9.25 g (69% yield) of 5-hydroxy-2,2-dimethyl-7. -Oxo-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylic acid ethyl ester was obtained as the desired product.
¹ H NMR (CDCl ₃ , 300 MHz): 11.25-11.15 (br s, 1H), 6.0 (s, 1H), 6.0-5.95 (m, 1H), 5.05-4.95 (m, 1H), 4.45-4.35 ( m, 3H), 4.15-4.05 (m, 1H), 1.45-1.35 (m, 6H), 1.3 (s, 3H).

ＴＥＡ(４.９ｇ、０.０４９mol)を、５−ヒドロキシ−２,２−ジメチル−７−オキソ−３ａ,７,８,８ａ−テトラヒドロ−１,３−ジオキサ−７ａ−アザ−シクロペンタ[ａ]インデン−４−カルボン酸エチルエステル(９.２５ｇ、０.０３３mol)のＤＣＭ(２００mL)溶液に−７０℃で添加した。トリフル酸無水物(１２.０６ｇ、０.０４２７mol)のＤＣＭ(５００mL)溶液を１時間かけて滴下し、反応混合物をＲＴで１時間撹拌した。反応塊を酢酸エチルおよび水に分配した。有機層を塩水で洗浄し溶液および濃縮した。濃縮物をカラムクロマトグラフィー(シリカゲル、溶離剤としてを使用)で精製して、９ｇ(６４.３％収率)の２,２−ジメチル−７−オキソ−５−トリフルオロメタンスルホニルオキシ−３ａ,７,８,８ａ−テトラヒドロ−１,３−ジオキサ−７ａ−アザ−シクロペンタ[ａ]インデン−４−カルボン酸エチルエステルを、望む生成物として得た。
¹H NMR (CDCl₃, 300 MHz): 6.4 (s, 1H), 6.0 (d, 1H), 5.0 (t, 1H), 4.45-4.35 (m, 3H), 4.15-4.05 (m, 1H), 1.45-1.35 (m, 6H), 1.3 (s, 3H)。 Process 2
2,2-Dimethyl-7-oxo-5-trifluoromethanesulfonyloxy-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylic acid ethyl ester Composition

TEA (4.9 g, 0.049 mol) was added to 5-hydroxy-2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a]. Indene-4-carboxylic acid ethyl ester (9.25 g, 0.033 mol) was added to a solution of DCM (200 mL) at -70 ° C. A solution of triflic anhydride (12.06 g, 0.0427 mol) in DCM (500 mL) was added dropwise over 1 hour and the reaction mixture was stirred at RT for 1 hour. The reaction mass was partitioned between ethyl acetate and water. The organic layer was washed with brine, solution and concentrated. The concentrate was purified by column chromatography (silica gel, using eluent) to give 9 g (64.3% yield) of 2,2-dimethyl-7-oxo-5-trifluoromethanesulfonyloxy-3a, 7 , 8,8a-Tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylic acid ethyl ester was obtained as the desired product.
¹ H NMR (CDCl ₃ , 300 MHz): 6.4 (s, 1H), 6.0 (d, 1H), 5.0 (t, 1H), 4.45-4.35 (m, 3H), 4.15-4.05 (m, 1H), 1.45-1.35 (m, 6H), 1.3 (s, 3H).

酢酸パラジウム(０.４７ｇ、０.００２mol)、ＢＩＮＡＰ(１.９６ｇ、０.００３mol)、炭酸セシウム(１０.２６ｇ、０.０３２mol)をトルエン(２００mL)に溶解し、得られた混合物を３０分間窒素で通気した。続いて２,２−ジメチル−７−オキソ−５−トリフルオロメタンスルホニルオキシ−３ａ,７,８,８ａ−テトラヒドロ−１,３−ジオキサ−７ａ−アザ−シクロペンタ[ａ]インデン−４−カルボン酸エチルエステル(９ｇ、０.０２１mol)および２−フルオロ−４−ブロモアニリン(４.４ｇ、０.０２３mol)をさらに１５分間通気を続けながら添加した。反応混合物を９０℃で１.３０時間加熱した。反応混合物を冷却し、２００mLの酢酸エチルで希釈し、水、塩水溶液で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。濃縮物をカラムクロマトグラフィー(シリカゲル、溶離剤として１０−７０％酢酸エチルのヘキサン溶液を使用)で精製して、５ｇ(５１.５％収率)の５−(４−ブロモ−２−フルオロ−フェニルアミノ)−２,２−ジメチル−７−オキソ−３ａ,７,８,８ａ−テトラヒドロ−１,３−ジオキサ−７ａ−アザ−シクロペンタ[ａ]インデン−４−カルボン酸エチルエステルを、望む生成物として得た。
LCMS: m/z=467 (M+H)
¹H NMR (CDCl₃, 300 MHz): 9.3 (s, 1H), 7.45-7.35 (m, 1H), 7.35-7.25 (m, 2H), 6.0 (d, 1H), 5.8 (s, 1H), 5.0 (t, 1H), 4.45-4.35 (m, 2H), 4.15-4.05 (m, 1H), 1.45-1.35 (m, 6H), 1.3 (s, 3H)。 Process 3
5- (4-Bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a] indene Synthesis of -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 dissolved for 30 minutes. Aerated with nitrogen. Followed by ethyl 2,2-dimethyl-7-oxo-5-trifluoromethanesulfonyloxy-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylate The ester (9 g, 0.021 mol) and 2-fluoro-4-bromoaniline (4.4 g, 0.023 mol) were added for an additional 15 minutes with continued aeration. The reaction mixture was heated at 90 ° C. for 1.30 hours. The reaction mixture was cooled, diluted with 200 mL 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 g (51.5% yield) of 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 ethyl ester Obtained as a thing.
LCMS: m / z = 467 (M + H)
¹ H NMR (CDCl ₃ , 300 MHz): 9.3 (s, 1H), 7.45-7.35 (m, 1H), 7.35-7.25 (m, 2H), 6.0 (d, 1H), 5.8 (s, 1H), 5.0 (t, 1H), 4.45-4.35 (m, 2H), 4.15-4.05 (m, 1H), 1.45-1.35 (m, 6H), 1.3 (s, 3H).

ＬｉＯＨ(０.２２ｇ、０.００５mol)の水溶液を、ＭｅＯＨ：ＴＨＦ(１：４)に溶解した撹拌している５−(４−ブロモ−２−フルオロ−フェニルアミノ)−２,２−ジメチル−７−オキソ−３ａ,７,８,８ａ−テトラヒドロ−１,３−ジオキサ−７ａ−アザ−シクロペンタ[ａ]インデン−４−カルボン酸エチルエステル(１ｇ、０.００２mol)の溶液に添加し、得られた混合物をＲＴで２時間撹拌した。反応混合物を濃縮し、残留物を酢酸エチルおよび水に分配し、水性層を１０％クエン酸溶液(ｐＨ２.５)で酸性化した。形成した沈殿を回収し、減圧下乾燥させて、粗生成物を得て、それを分取ＨＰＬＣで精製して、５０mg(５８.５％収率)の５−(４−ブロモ−２−フルオロ−フェニルアミノ)−２,２−ジメチル−７−オキソ−３ａ,７,８,８ａ−テトラヒドロ−１,３−ジオキサ−７ａ−アザ−シクロペンタ[ａ]インデン−４−カルボン酸を、望む生成物として得た。
LCMS純度: 99.5%, m/z=439.0 (M-H)
HPLC: 99.3%
¹H NMR (DMSO-D₆, 300 MHz): 13.65-13.55 (br s, 1H), 9.55-9.45 (br s, 1H), 7.7 (dd, 1H), 7.55-7.45 (m, 2H), 6.0 (d, 1H), 5.4 (s, 1H), 4.9 (t, 1H), 4.05-3.95 (m, 2H), 1.4 (s, 3H), 1.2 (s, 3H)。 Process 4
5- (4-Bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a] indene Synthesis of -4-carboxylic acid

An aqueous solution of LiOH (0.22 g, 0.005 mol) dissolved in MeOH: THF (1: 4) is stirred with 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 ethyl ester (1 g, 0.002 mol) added to a solution The resulting mixture was stirred at RT for 2 hours. 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 formed precipitate was collected and dried under reduced pressure to give the crude product, which was purified by preparative HPLC to give 50 mg (58.5% yield) of 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, the desired product Got as.
LCMS purity: 99.5%, m / z = 439.0 (MH)
HPLC: 99.3%
¹ H NMR (DMSO-D ₆ , 300 MHz): 13.65-13.55 (br s, 1H), 9.55-9.45 (br s, 1H), 7.7 (dd, 1H), 7.55-7.45 (m, 2H), 6.0 (d, 1H), 5.4 (s, 1H), 4.9 (t, 1H), 4.05-3.95 (m, 2H), 1.4 (s, 3H), 1.2 (s, 3H).

Example 82
Steps 1 to 12 were performed according to the method described in Example 81.

ＥＤＣＩ(２６２.４mg、１.３６９mmol)、ＨＯＢｔ(１８４.６１mg、１.３６９mmol)およびＤＩＰＥＡ(３８７mg、２.７３６mmol)を撹拌している５−(４−ブロモ−２−フルオロ−フェニルアミノ)−２,２−ジメチル−７−オキソ−３ａ,７,８,８ａ−テトラヒドロ−１,３−ジオキサ−７ａ−アザ−シクロペンタ[ａ]インデン−４−カルボン酸(２００mg、０.４５６mmol)のＤＭＦ(５mL)およびＤＣＭ(５mL)中の溶液に添加した。続いてＯ−シクロプロピルメチル−ヒドロキシルアミン(１６８.３８mg、１.３６９mmol)を添加し、反応混合物を１６時間、ＲＴで撹拌した。反応混合物を水および酢酸エチルに分配した。有機層を飽和ＮａＨＣＯ_３、塩水溶液で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮して、１２０mg(５１.７％収率)の５−(４−ブロモ−２−フルオロ−フェニルアミノ)−２,２−ジメチル−７−オキソ−３ａ,７,８,８ａ−テトラヒドロ−１,３−ジオキサ−７ａ−アザ−シクロペンタ[ａ]インデン−４−カルボン酸シクロプロピルメトキシ−アミドを、望む生成物として得た。
LCMS純度: 82.9%, m/z=508.1 (M+H)。
HPLC: 79.5%
¹H NMR (DMSO-D₆, 300 MHz): 10.5 (s, 1H), 9.3 (s, 1H), 7.2-7.4 (m, 3H), 5.9 (s, 1H), 5.6 (d, 1H), 5.0 (t, 1H), 4.45-4.35 (m, 1H), 4.15-4.05 (m, 1H), 3.95-3.85 (m, 1H), 3.85-3.75 (m, 1H), 1.6 (s, 3H), 1.5 (s, 3H), 0.85-0.75 (m, 1H), 0.65-0.55 (m, 2H), 0.45-0.35 (m, 2H)。 Process 5
5- (4-Bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a] indene Synthesis of -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) are being stirred. 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 (200 mg, 0.456 mmol) in DMF ( To a solution in 5 mL) and DCM (5 mL). Subsequently O-cyclopropylmethyl-hydroxylamine (168.38 mg, 1.369 mmol) was added and the reaction mixture was stirred for 16 h at RT. 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 give 120 mg (51.7% yield) of 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 cyclopropylmethoxy-amide Got as.
LCMS purity: 82.9%, m / z = 508.1 (M + H).
HPLC: 79.5%
¹ H NMR (DMSO-D ₆ , 300 MHz): 10.5 (s, 1H), 9.3 (s, 1H), 7.2-7.4 (m, 3H), 5.9 (s, 1H), 5.6 (d, 1H), 5.0 (t, 1H), 4.45-4.35 (m, 1H), 4.15-4.05 (m, 1H), 3.95-3.85 (m, 1H), 3.85-3.75 (m, 1H), 1.6 (s, 3H), 1.5 (s, 3H), 0.85-0.75 (m, 1H), 0.65-0.55 (m, 2H), 0.45-0.35 (m, 2H).

濃ＨＣｌ(３mL)を、メタノール(３mL)に溶解した５−(４−ブロモ−２−フルオロ−フェニルアミノ)−２,２−ジメチル−７−オキソ−３ａ,７,８,８ａ−テトラヒドロ−１,３−ジオキサ−７ａ−アザ−シクロペンタ[ａ]インデン−４−カルボン酸シクロプロピルメトキシ−アミド(１２０mg)の溶液に添加し、得られた混合物をＲＴで３時間撹拌した。反応混合物を濃縮し、濃縮物を２回酢酸エチル(２×０.５mL)で摩砕した。残留物を乾燥させて、２０mg(１８.２％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−１,２−ジヒドロキシ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸シクロプロピルメトキシ−アミドを、望む生成物として得た。
LCMS純度: 95.3%, m/z=470 (M+H)。
HPLC: 94.1%
¹H NMR (DMSO-D₆, 300 MHz): 11.4 (s, 1H), 8.1 (s, 1H), 7.6 (dd, 1H), 7.45-7.35 (m, 2H), 5.4 (s, 1H), 5.1 (d, 1H), 4.35-4.25 (m, 1H), 3.95-3.85 (m, 1H), 3.8-3.7 (m, 3H), 1.25-1.15 (m, 1H), 0.6 (d, 2H), 0.4 (d, 2H) Step 6
Synthesis of 7- (4-bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide

Concentrated HCl (3 mL) was 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 cyclopropylmethoxy-amide (120 mg) was added and the resulting mixture was stirred at RT for 3 h. The reaction mixture was concentrated and the concentrate was triturated twice with ethyl acetate (2 × 0.5 mL). The residue was dried to give 20 mg (18.2% yield) of 7- (4-bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5- Tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide was obtained as the desired product.
LCMS purity: 95.3%, m / z = 470 (M + H).
HPLC: 94.1%
¹ H NMR (DMSO-D ₆ , 300 MHz): 11.4 (s, 1H), 8.1 (s, 1H), 7.6 (dd, 1H), 7.45-7.35 (m, 2H), 5.4 (s, 1H), 5.1 (d, 1H), 4.35-4.25 (m, 1H), 3.95-3.85 (m, 1H), 3.8-3.7 (m, 3H), 1.25-1.15 (m, 1H), 0.6 (d, 2H), 0.4 (d, 2H)

Example 83
Steps 1 to 12 were performed according to the method described in Example 81.

ＥＤＣＩ(２６２.４mg、１.３６９mmol)、ＨＯＢｔ(１８６.６mg、１.３６９mmol)、ＴＥＡ(２７９mg、２.７３６mmol)およびＯ−(２−ｔｅｒｔ−ブトキシ−エチル)−ヒドロキシルアミン(１８２mg、１.３６９mmol)を、撹拌している５−(４−ブロモ−２−フルオロ−フェニルアミノ)−２,２−ジメチル−７−オキソ−３ａ,７,８,８ａ−テトラヒドロ−１,３−ジオキサ−７ａ−アザ−シクロペンタ[ａ]インデン−４−カルボン酸(２００mg、０.４５６mmol)のＤＭＦ(５mL)およびＤＣＭ(５mL)中の溶液に添加した。反応混合物をＲＴで１６時間撹拌した。反応混合物を水および酢酸エチルに分配した。有機層を飽和ＮａＨＣＯ_３、塩水溶液で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。濃縮物をカラムクロマトグラフィー(シリカゲル、溶離剤として２％メタノールのＤＣＭ溶液を使用)で精製して、１００mg(３９.５％収率)の５−(４−ブロモ−２−フルオロ−フェニルアミノ)−２,２−ジメチル−７−オキソ−３ａ,７,８,８ａ−テトラヒドロ−１,３−ジオキサ−７ａ−アザ−シクロペンタ[ａ]インデン−４−カルボン酸(２−ヒドロキシ−エトキシ)−アミドを、望む生成物として得た。 Process 5
5- (4-Bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a] indene Synthesis of -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, 1.69 mmol) 369 mmol) is stirred with 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 (200 mg, 0.456 mmol) was added to a solution in DMF (5 mL) and DCM (5 mL). The reaction mixture was stirred at RT for 16 hours. 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, using 2% methanol in DCM as eluent) to give 100 mg (39.5% yield) of 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 (2-hydroxy-ethoxy) -amide Was obtained as the desired product.

濃ＨＣｌ(３mL)を、５−(４−ブロモ−２−フルオロ−フェニルアミノ)−２,２−ジメチル−７−オキソ−３ａ,７,８,８ａ−テトラヒドロ−１,３−ジオキサ−７ａ−アザ−シクロペンタ[ａ]インデン−４−カルボン酸(２−ヒドロキシ−エトキシ)−アミド(１００mg、０.１８mmol)のメタノール(３mL)溶液に添加し、反応混合物をＲＴで３時間撹拌した。反応混合物を濃縮し、濃縮物を酢酸エチルで摩砕した。回収した沈殿を分取ＨＰＬＣで精製して、５０mg(６１.３％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−１,２−ジヒドロキシ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２−ヒドロキシ−エトキシ)−アミドを、望む生成物として得た。
LCMS純度: 98.9%, m/z=458.0 (M+H)。
HPLC: 98.7%
¹H NMR (DMSO-D₆, 300 MHz): 11.4 (s, 1H), 8.2 (s, 1H), 7.7 (d, 1H), 7.45-7.35 (m, 2H), 5.8 (s, 1H), 5.4 (d, 1H), 5.3 (s, 1H), 5.1 (t, 1H), 4.8 (t, 1H), 4.3 (t, 1H), 4.0 (t, 2H), 3.7-3.9 (m, 2H), 3.65-3.55 (m, 2H)。 Step 6
7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)- Synthesis of amide

Concentrated HCl (3 mL) was added to 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 (2-hydroxy-ethoxy) -amide (100 mg, 0.18 mmol) in methanol (3 mL) was added 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 50 mg (61.3% yield) of 7- (4-bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2 , 3,5-Tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy) -amide was obtained as the desired product.
LCMS purity: 98.9%, m / z = 458.0 (M + H).
HPLC: 98.7%
¹ H NMR (DMSO-D ₆ , 300 MHz): 11.4 (s, 1H), 8.2 (s, 1H), 7.7 (d, 1H), 7.45-7.35 (m, 2H), 5.8 (s, 1H), 5.4 (d, 1H), 5.3 (s, 1H), 5.1 (t, 1H), 4.8 (t, 1H), 4.3 (t, 1H), 4.0 (t, 2H), 3.7-3.9 (m, 2H) , 3.65-3.55 (m, 2H).

Example 84
Steps 1 to 12 were performed according to the method described in Example 81.

ＥＤＣＩ(２６２.４mg、１.３６９mmol)、ＨＯＢｔ(６１mg、０.４５６mmol)、ＴＥＡ(２７９mg、２.７３６mmol)およびＯ−シクロブチルメチル−ヒドロキシルアミン(１３８mg、１.３６９mmol)を、撹拌している５−(４−ブロモ−２−フルオロ−フェニルアミノ)−２,２−ジメチル−７−オキソ−３ａ,７,８,８ａ−テトラヒドロ−１,３−ジオキサ−７ａ−アザ−シクロペンタ[ａ]インデン−４−カルボン酸(２００mg、０.４５６mmol)のＤＭＦ(５mL)およびＤＣＭ(５mL)中の溶液に添加した。反応混合物をＲＴで１６時間撹拌した。反応混合物を水および酢酸エチル(２×２５mL)に分配した。有機層を飽和ＮａＨＣＯ_３、塩水溶液で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。濃縮物をカラムクロマトグラフィー(シリカゲル、溶離剤として２％メタノールのＤＣＭ溶液を使用)で精製して、１４０mg(６１.４％収率)の５−(４−ブロモ−２−フルオロ−フェニルアミノ)−２,２−ジメチル−７−オキソ−３ａ,７,８,８ａ−テトラヒドロ−１,３−ジオキサ−７ａ−アザ−シクロペンタ[ａ]インデン−４−カルボン酸シクロブチルメトキシ−アミドを、望む生成物として得た。
LCMS: m/z=522.1 (M+H)。
¹H NMR (DMSO-D₆, 300 MHz): 10.4 (s, 1H), 9.2 (s, 1H), 7.2-7.4 (m, 3H), 5.8 (s, 1H), 5.6 (d, 1H), 5.1 (t, 1H), 4.4 (d, 1H), 3.95-4.05 (m, 3H), 2.85-2.75 (m, 1H), 2.15-2.05 (m, 2H), 1.95-1.85 (m, 4H), 1.5 (s, 6H) Process 5
5- (4-Bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a] indene Synthesis of -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) are being stirred. 5- (4-Bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a] indene To a solution of -4-carboxylic acid (200 mg, 0.456 mmol) in DMF (5 mL) and DCM (5 mL) was added. The reaction mixture was stirred at RT for 16 hours. The reaction mixture was partitioned between water and ethyl acetate (2 × 25 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, using 2% methanol in DCM as eluent) to give 140 mg (61.4% yield) of 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 cyclobutylmethoxy-amide Obtained as a thing.
LCMS: m / z = 522.1 (M + H).
¹ H NMR (DMSO-D ₆ , 300 MHz): 10.4 (s, 1H), 9.2 (s, 1H), 7.2-7.4 (m, 3H), 5.8 (s, 1H), 5.6 (d, 1H), 5.1 (t, 1H), 4.4 (d, 1H), 3.95-4.05 (m, 3H), 2.85-2.75 (m, 1H), 2.15-2.05 (m, 2H), 1.95-1.85 (m, 4H), 1.5 (s, 6H)

濃ＨＣｌ(３mL)を、メタノール(３mL)に溶解した５−(４−ブロモ−２−フルオロ−フェニルアミノ)−２,２−ジメチル−７−オキソ−３ａ,７,８,８ａ−テトラヒドロ−１,３−ジオキサ−７ａ−アザ−シクロペンタ[ａ]インデン−４−カルボン酸シクロブチルメトキシ−アミド(１３０mg、０.２４９mmol)の溶液に添加し、得られた混合物をＲＴで３時間撹拌した。反応混合物を濃縮し、濃縮物を酢酸エチルで摩砕した。形成した沈殿を回収し、分取ＨＰＬＣで精製して、３５mg(２９.１％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−１,２−ジヒドロキシ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸シクロブチルメトキシ−アミドを、望む生成物として得た。
¹H NMR (DMSO-D₆, 300 MHz): 11.4 (s, 1H), 8.1 (s, 1H), 7.7 (d, 1H), 7.45-7.35 (m, 2H), 5.3 (s, 1H), 5.1 (s, 1H), 4.35-4.25 (m, 1H), 3.85-3.75 (m, 6H), 3.8-3.7 (m, 3H), 2.65-2.55 (m, 1H), 2.05-1.95 (m, 2H), 1.85-1.75 (m, 4H)。 Step 6
Synthesis of 7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclobutylmethoxy-amide

Concentrated HCl (3 mL) was 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 cyclobutylmethoxy-amide (130 mg, 0.249 mmol) was added and the resulting mixture was stirred at RT for 3 h. The reaction mixture was concentrated and the concentrate was triturated with ethyl acetate. The formed precipitate was collected and purified by preparative HPLC to give 35 mg (29.1% yield) of 7- (4-bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo- 1,2,3,5-Tetrahydro-indolizine-8-carboxylic acid cyclobutylmethoxy-amide was obtained as the desired product.
¹ H NMR (DMSO-D ₆ , 300 MHz): 11.4 (s, 1H), 8.1 (s, 1H), 7.7 (d, 1H), 7.45-7.35 (m, 2H), 5.3 (s, 1H), 5.1 (s, 1H), 4.35-4.25 (m, 1H), 3.85-3.75 (m, 6H), 3.8-3.7 (m, 3H), 2.65-2.55 (m, 1H), 2.05-1.95 (m, 2H ), 1.85-1.75 (m, 4H).

Example 85
Steps 1 to 12 were performed according to the method described in Example 81.

ＥＤＣＩ(２６２.４mg、１.３６９mmol)、ＨＯＢｔ(１８６.６mg、１.３６９mmol)、ＴＥＡ(２７９mg、２.７３６mmol)およびＯ−(３−ｔｅｒｔ−ブトキシ−２−メチル−プロピル)−ヒドロキシルアミン(２２０mg、１.３６９mmol)を、撹拌している５−(４−ブロモ−２−フルオロ−フェニルアミノ)−２,２−ジメチル−７−オキソ−３ａ,７,８,８ａ−テトラヒドロ−１,３−ジオキサ−７ａ−アザ−シクロペンタ[ａ]インデン−４−カルボン酸(２００mg、０.４５６mmol)のＤＭＦ(５mL)およびＤＣＭ(５mL)中の溶液に添加した。反応混合物をＲＴで１６時間撹拌した。反応混合物を水および酢酸エチルに分配した。有機層を飽和ＮａＨＣＯ_３、塩水溶液で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。濃縮物をカラムクロマトグラフィー(シリカゲル、溶離剤として０−２％メタノールのＤＣＭ溶液を使用)で精製して、１００mg(３７.８％収率)の５−(４−ブロモ−２−フルオロ−フェニルアミノ)−２,２−ジメチル−７−オキソ−３ａ,７,８,８ａ−テトラヒドロ−１,３−ジオキサ−７ａ−アザ−シクロペンタ[ａ]インデン−４−カルボン酸(３−ｔｅｒｔ−ブトキシ−２−メチル−プロポキシ)−アミドを、望む生成物として得た。
LCMS純度: 76.9%, m/z=568.1 (M+H)
HPLC: 52.3% Process 5
5- (4-Bromo-2-fluoro-phenylamino) -2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydro-1,3-dioxa-7a-aza-cyclopenta [a] indene Synthesis of -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) is stirred with 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 (200 mg, 0.456 mmol) was added to a solution in DMF (5 mL) and DCM (5 mL). The reaction mixture was stirred at RT for 16 hours. 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 100 mg (37.8% yield) of 5- (4-bromo-2-fluoro-phenyl). Amino) -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 was obtained as the desired product.
LCMS purity: 76.9%, m / z = 568.1 (M + H)
HPLC: 52.3%

濃ＨＣｌ(３mL)を、メタノール(３mL)に溶解した５−(４−ブロモ−２−フルオロ−フェニルアミノ)−２,２−ジメチル−７−オキソ−３ａ,７,８,８ａ−テトラヒドロ−１,３−ジオキサ−７ａ−アザ−シクロペンタ[ａ]インデン−４−カルボン酸(３−ｔｅｒｔ−ブトキシ−２−メチル−プロポキシ)−アミド(１２０mg、０.２１mmol)の溶液に添加し、得られた混合物をＲＴで２時間撹拌した。反応混合物を濃縮し、濃縮物を酢酸エチルで摩砕して、沈殿を得た。分取ＨＰＬＣによる精製により、５０mg(４８.５％収率)の７−(４−ブロモ−２−フルオロ−フェニルアミノ)−１,２−ジヒドロキシ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(３−ヒドロキシ−２−メチル−プロポキシ)−アミドを、望む生成物として得た。
¹H NMR (DMSO-D₆, 300 MHz): 11.4 (s, 1H), 8.1 (d, 1H), 7.7 (dd, 1H), 7.45-7.35 (m, 2H), 5.85-5.75 (m, 1H), 5.4 (t, 1H), 5.3 (s, 1H), 5.15-5.05 (m, 1H), 4.7 (dt, 1H), 4.35-4.25 (m, 1H), 4.15-4.05 (m, 1H), 3.8 (dd, 1H), 3.7 (dd, 1H), 3.55-3.45 (m, 2H), 1.2 (d, 3H)。 Step 6
7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (3-hydroxy-2-methyl -Propoxy) -amide synthesis

Concentrated HCl (3 mL) was 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) was obtained. The mixture was stirred at RT for 2 hours. The reaction mixture was concentrated and the concentrate was triturated with ethyl acetate to give a precipitate. Purification by preparative HPLC gave 50 mg (48.5% yield) of 7- (4-bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5- Tetrahydro-indolizine-8-carboxylic acid (3-hydroxy-2-methyl-propoxy) -amide was obtained as the desired product.
¹ H NMR (DMSO-D ₆ , 300 MHz): 11.4 (s, 1H), 8.1 (d, 1H), 7.7 (dd, 1H), 7.45-7.35 (m, 2H), 5.85-5.75 (m, 1H ), 5.4 (t, 1H), 5.3 (s, 1H), 5.15-5.05 (m, 1H), 4.7 (dt, 1H), 4.35-4.25 (m, 1H), 4.15-4.05 (m, 1H), 3.8 (dd, 1H), 3.7 (dd, 1H), 3.55-3.45 (m, 2H), 1.2 (d, 3H).

Scheme 17
Steps 1-4 are the same as in Example 8

Example 86
Steps 1 to 4 were performed according to the method described in Example 8.

ＴＥＡ(１.３０mL、９.２５９mmol)およびＤＰＰＡ(２.０mL、９.２５９mmol)を、撹拌している６−フルオロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(４.０ｇ、９.２５９mmol)のＤＭＦ(３０mL)溶液に０℃で添加し、反応混合物を４時間、ＲＴで窒素雰囲気下撹拌した。反応混合物を６５℃で一夜加熱した。反応をＴＬＣ(１５％ＭｅＯＨのＤＣＭ溶液)でモニターした。得られた反応混合物を冷却し、水を添加して、沈殿の形成を促進し、それを回収し、減圧下乾燥させて、３.６５ｇの生成物を得た(９１％収率)。
LCMS純度: 98.96%, m/z=429.9 (M+1)
HPLC: 84.6%
¹H NMR (DMSO-D₆, 300 MHz): δ 11.3 (s, 1H), 7.9-7.25 (m, 3H), 4.0 (t, 2H), 3.1 (t, 2H), 2.3-2.2 (m, 2H) Process 5
Synthesis of 4-fluoro-3- (2-fluoro-4-iodo-phenyl) -1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2,5-dione

TEA (1.30 mL, 9.259 mmol) and DPPA (2.0 mL, 9.259 mmol) were stirred with 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo- 1,2,3,5-Tetrahydro-indolizine-8-carboxylic acid (4.0 g, 9.259 mmol) was added to a solution of DMF (30 mL) at 0 ° C., and the reaction mixture was 4 hours at RT under nitrogen atmosphere. Stir. The reaction mixture was heated at 65 ° C. overnight. The reaction was monitored by TLC (15% MeOH in DCM). The resulting reaction mixture was cooled and water was added to promote the formation of a precipitate that was collected and dried under reduced pressure to give 3.65 g of product (91% yield).
LCMS purity: 98.96%, m / z = 429.9 (M + 1)
HPLC: 84.6%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 11.3 (s, 1H), 7.9-7.25 (m, 3H), 4.0 (t, 2H), 3.1 (t, 2H), 2.3-2.2 (m, 2H)

６０％ＮａＨ(０.３７ｇ、９.３２４mol)を、撹拌している４−フルオロ−３−(２−フルオロ−４−ヨード−フェニル)−１,６,７,８−テトラヒドロ−３Ｈ−１,３,５ａ−トリアザ−ａｓ−インダセン−２,５−ジオン(２.０ｇ、４.６６２mmol)の乾燥ＤＭＦ(２０mL)溶液に、０℃で、窒素雰囲気下添加し、得られた混合物を２０分間、０℃で撹拌した。続いて１−アリル−シクロプロパンスルホニルクロライド(１.２６ｇ、６.９９３mol)を０℃で添加し、撹拌を１８時間、ＲＴで続けた。反応をＴＬＣ(１０％ＭｅＯＨのＤＣＭ溶液)でモニターした。反応混合物を水および酢酸エチルに分配した。有機層を水で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。シリカゲルカラムクロマトグラフィー(６０％酢酸エチルのヘキサン溶液)での精製により、１.２２ｇの生成物を得た(４６％収率)。
LCMS純度: 77.1%, m/z=573.9 (M+1)
¹H NMR (CDCl₃, 300 MHz): δ 7.62 (d, 2H), 7.15 (t, 1H), 5.7-5.6 (m, 1H), 5.1 (d, 2H), 4.4 (t, 2H), 3.5 (t, 2H), 2.7-2.6 (m, 2H), 2.3-2.2 (m, 2H), 1.9-1.8 (m, 1H), 1.8-1.7 (m, 1H), 1.2-1.1 (m, 2H) Step 6
1- (1-allyl-cyclopropanesulfonyl) -4-fluoro-3- (2-fluoro-4-iodo-phenyl) -1,6,7,8-tetrahydro-3H-1,3,5a-triaza- Synthesis of as-indacene-2,5-dione

60% NaH (0.37 g, 9.324 mol) was stirred into 4-fluoro-3- (2-fluoro-4-iodo-phenyl) -1,6,7,8-tetrahydro-3H-1, To a solution of 3,5a-triaza-as-indacene-2,5-dione (2.0 g, 4.662 mmol) in dry DMF (20 mL) was added at 0 ° C. under a nitrogen atmosphere and the resulting mixture was added for 20 minutes. And stirred at 0 ° C. Subsequently 1-allyl-cyclopropanesulfonyl chloride (1.26 g, 6.993 mol) was added at 0 ° C. and stirring was continued for 18 hours at RT. 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 SO ₄ and concentrated. Purification by silica gel column chromatography (60% ethyl acetate in hexane) gave 1.22 g of product (46% yield).
LCMS purity: 77.1%, m / z = 573.9 (M + 1)
¹ H NMR (CDCl ₃ , 300 MHz): δ 7.62 (d, 2H), 7.15 (t, 1H), 5.7-5.6 (m, 1H), 5.1 (d, 2H), 4.4 (t, 2H), 3.5 (t, 2H), 2.7-2.6 (m, 2H), 2.3-2.2 (m, 2H), 1.9-1.8 (m, 1H), 1.8-1.7 (m, 1H), 1.2-1.1 (m, 2H)

カリウムトリメチルシラノレート(０.２３ｇ、１.７７６mmol)を、１−(１−アリル−シクロプロパンスルホニル)−４−フルオロ−３−(２−フルオロ−４−ヨード−フェニル)−１,６,７,８−テトラヒドロ−３Ｈ−１,３,５ａ−トリアザ−ａｓ−インダセン−２,５−ジオン(０.５０ｇ、０.８８８mmol)のＴＨＦ(１０mL)溶液に添加した。反応混合物を６５℃で、３０分間還流した。反応をＴＬＣ(１０％ＭｅＯＨのＤＣＭ溶液)でモニターした。反応混合物を水および酢酸エチルに分配した。有機層をＮａ_２ＳＯ_４で乾燥させ、濃縮した。濃縮物をエーテルで洗浄して、４０５mgの生成物を得た(８３％収率)。
LCMS純度: 92.%, m/z=548 (M+1)
HPLC: 95.8%
¹H NMR (CDCl₃, 300 MHz): δ 7.4-7.3 (m, 2H), 6.7 (s, 1H), 6.6-6.5 (m, 1H), 5.8-56 (m, 1H), 5.2-5.1 (m, 2H), 4.2 (t, 2H), 3.3 (t, 2H), 2.7 (d, 2H), 2.3-2.1 (m, 2H), 1.3 (t, 2H), 0.8 (t, 2H) Step 7
1-allyl-cyclopropanesulfonic acid [6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl]- Synthesis of amide

Potassium trimethylsilanolate (0.23 g, 1.776 mmol) was added to 1- (1-allyl-cyclopropanesulfonyl) -4-fluoro-3- (2-fluoro-4-iodo-phenyl) -1,6,7. , 8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2,5-dione (0.50 g, 0.888 mmol) in THF (10 mL) was added. 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 SO ₄ and concentrated. The concentrate was washed with ether to give 405 mg of product (83% yield).
LCMS purity: 92.%, m / z = 548 (M + 1)
HPLC: 95.8%
¹ H NMR (CDCl ₃ , 300 MHz): δ 7.4-7.3 (m, 2H), 6.7 (s, 1H), 6.6-6.5 (m, 1H), 5.8-56 (m, 1H), 5.2-5.1 ( m, 2H), 4.2 (t, 2H), 3.3 (t, 2H), 2.7 (d, 2H), 2.3-2.1 (m, 2H), 1.3 (t, 2H), 0.8 (t, 2H)

Ｎ−メチル−モルホリン−Ｎ−オキシド(０.０７８ｇ、０.６７６mmol)およびＯｓＯ_４(０.０２ｇ、０.０６７mmol)を、撹拌している１−アリル−シクロプロパンスルホン酸[６−フルオロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−イル]−アミド(０.３７ｇ、０.６７６mmol)のＴＨＦ(１０mL)溶液に添加し、得られた混合物をＲＴで一夜撹拌した。反応をＴＬＣ(１０％ＭｅＯＨのＤＣＭ溶液)でモニターした。反応混合物を水および酢酸エチルに分配した。有機層を水、塩水溶液で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。シリカゲルカラムクロマトグラフィー(５％メタノールのクロロホルム溶液)での精製により、８６mgの生成物を得た(２２％収率)。
LCMS純度: 96.2%, m/z=582.1 (M+1)
HPLC: 98.7%
¹H NMR (DMSO-D₆, 300 MHz): δ 8.95-8.85 (br s, 1H), 7.9-7.8 (br s, 1H), 7.6 (d, 1H), 7.45 (d, 1H), 6.9-6.7 (m, 1H), 4.8-4.6 (m, 2H), 4.2-4.0 (m, 2H), 3.8-3.7 (m, 1H), 3.4-3.2 (m, 3H), 2.3 (d, 1H), 2.1 (t, 2H), 1.6-1.4 (m, 1H), 1.1-0.8 (m, 3H) Process 8
1- (2,3-dihydroxy-propyl) -cyclopropanesulfonic acid [6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro- Synthesis of indolizine-8-yl] -amide

N-methyl-morpholine-N-oxide (0.078 g, 0.676 mmol) and OsO ₄ (0.02 g, 0.067 mmol) were stirred with 1-allyl-cyclopropanesulfonic acid [6-fluoro-7. -(2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide (0.37 g, 0.676 mmol) in THF (10 mL ) Was added to the solution 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 SO ₄ and concentrated. Purification by silica gel column chromatography (5% methanol in chloroform) gave 86 mg of product (22% yield).
LCMS purity: 96.2%, m / z = 582.1 (M + 1)
HPLC: 98.7%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 8.95-8.85 (br s, 1H), 7.9-7.8 (br s, 1H), 7.6 (d, 1H), 7.45 (d, 1H), 6.9- 6.7 (m, 1H), 4.8-4.6 (m, 2H), 4.2-4.0 (m, 2H), 3.8-3.7 (m, 1H), 3.4-3.2 (m, 3H), 2.3 (d, 1H), 2.1 (t, 2H), 1.6-1.4 (m, 1H), 1.1-0.8 (m, 3H)

Example 87
Steps 1-3 were performed according to the method described in Example 14 and Step 4 was performed according to the method described in Example 15.

実施例８６の工程５と同じ反応条件を使用して、７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−メチル−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２.７５ｇ、７.２１７８４mmol)のＤＭＦ(２０mL)溶液をＴＥＡ(１.０mL、７.２１８mmol)およびＤＰＰＡ(１.５５mL、７.２１８mmol)と反応させて、２.２ｇの生成物を得た(８０％収率)。
¹H NMR (DMSO-D₆, 300 MHz): δ 11.0 (s, 1H), 7.8 (dd, 1H), 7.6 (m, 2H), 4.0 (t, 2H), 3.0 (t, 2H), 2.2 (t, 2H), 1.5 (s, 3H) Process 5
Synthesis of 3- (4-bromo-2-fluoro-phenyl) -4-methyl-1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2,5-dione

7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine using the same reaction conditions as in step 5 of Example 86 A solution of -8-carboxylic acid (2.75 g, 7.21784 mmol) in DMF (20 mL) was reacted with TEA (1.0 mL, 7.218 mmol) and DPPA (1.55 mL, 7.218 mmol) to give 2.2 g Product was obtained (80% yield).
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 11.0 (s, 1H), 7.8 (dd, 1H), 7.6 (m, 2H), 4.0 (t, 2H), 3.0 (t, 2H), 2.2 (t, 2H), 1.5 (s, 3H)

ＴＥＡ(０.１５mL、１.０６mmol)を、撹拌している３−(４−ブロモ−２−フルオロ−フェニル)−４−メチル−１,６,７,８−テトラヒドロ−３Ｈ−１,３,５ａ−トリアザ−ａｓ−インダセン−２,５−ジオン(０.２０ｇ、０.５３１mmol)のＤＣＭ(８mL)溶液に０℃で添加した。続いて１−アリル−シクロプロパンスルホニルクロライド(０.１９６ｇ、１.０６mmol)およびＤＭＡＰ(０.０１３ｇ、０.１０６mmol)を０℃で添加し、得られた混合物をＲＴで一夜撹拌した。反応をＴＬＣ(１０％ＭｅＯＨのＤＣＭ溶液)でモニターした。反応混合物を水およびＤＣＭに分配した。有機層を水、塩水溶液で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。シリカゲルカラムクロマトグラフィー(７０％酢酸エチルのヘキサン溶液)で精製して、７０mgの生成物を得た(２５％収率)。
¹H NMR (DMSO-D₆, 300 MHz): δ 7.5-7.3 (m, 3H), 5.9-5.6 (m, 1H), 5.1-4.9 (m, 3H), 4.2 (t, 2H), 3.5 (t, 2H), 2.7 (t, 2H), 2.3-2.1 (m, 2H), 2.1-2.0 (m, 2H), 1.9-1.8 (m, 1H), 1.8-1.7 (m, 2H), 1.2-1.1 (m, 4H) Step 6
1- (1-allyl-cyclopropanesulfonyl) -3- (4-bromo-2-fluoro-phenyl) -4-methyl-1,6,7,8-tetrahydro-3H-1,3,5a-triaza- Synthesis of as-indacene-2,5-dione

TEA (0.15 mL, 1.06 mmol) was stirred with 3- (4-bromo-2-fluoro-phenyl) -4-methyl-1,6,7,8-tetrahydro-3H-1,3, To a solution of 5a-triaza-as-indacene-2,5-dione (0.20 g, 0.531 mmol) in DCM (8 mL) was added at 0 ° C. Subsequently 1-allyl-cyclopropanesulfonyl chloride (0.196 g, 1.06 mmol) and DMAP (0.013 g, 0.106 mmol) were added 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 SO ₄ and concentrated. Purification by silica gel column chromatography (70% ethyl acetate in hexane) gave 70 mg of product (25% yield).
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 7.5-7.3 (m, 3H), 5.9-5.6 (m, 1H), 5.1-4.9 (m, 3H), 4.2 (t, 2H), 3.5 ( t, 2H), 2.7 (t, 2H), 2.3-2.1 (m, 2H), 2.1-2.0 (m, 2H), 1.9-1.8 (m, 1H), 1.8-1.7 (m, 2H), 1.2- 1.1 (m, 4H)

実施例８６の工程７と同じ反応条件を使用して、１−(１−アリル−シクロプロパンスルホニル)−３−(４−ブロモ−２−フルオロ−フェニル)−４−メチル−１,６,７,８−テトラヒドロ−３Ｈ−１,３,５ａ−トリアザ−ａｓ−インダセン−２,５−ジオン(０.０６５ｇ、０.１２４mmol)のＴＨＦ(４.０mL)溶液をカリウムトリメチルシラノレート(０.０３２ｇ、０.２４９mmol)と反応させて、４０mgの生成物を得た(５９％収率)。
LCMS純度: 87.3%, m/z=497.9 (M+)
¹H NMR (DMSO-D₆, 300 MHz): δ 8.9-8.8 (br s, 1H), 7.5 (d, 1H), 7.35 (s, 1H), 7.2 (d, 1H), 6.4 (t, 1H), 5.7-5.5 (m, 1H), 5.1-4.9 (m, 2H), 4.1 (t, 2H), 3.2 (t, 2H), 2.6 (d, 2H), 2.2-2.1 (m, 2H), 1.7 (s, 3H), 1.05 (t, 2H), 0.75 (t, 2H) Step 7
1-allyl-cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl]- Synthesis of amide

1- (1-allyl-cyclopropanesulfonyl) -3- (4-bromo-2-fluoro-phenyl) -4-methyl-1,6,7 using the same reaction conditions as in step 7 of Example 86. , 8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2,5-dione (0.065 g, 0.124 mmol) in THF (4.0 mL) was added potassium trimethylsilanolate (0.032 g). , 0.249 mmol) to give 40 mg of product (59% yield).
LCMS purity: 87.3%, m / z = 497.9 (M +)
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 8.9-8.8 (br s, 1H), 7.5 (d, 1H), 7.35 (s, 1H), 7.2 (d, 1H), 6.4 (t, 1H ), 5.7-5.5 (m, 1H), 5.1-4.9 (m, 2H), 4.1 (t, 2H), 3.2 (t, 2H), 2.6 (d, 2H), 2.2-2.1 (m, 2H), 1.7 (s, 3H), 1.05 (t, 2H), 0.75 (t, 2H)

実施例８６の工程８と同じ反応条件を使用して、１−アリル−シクロプロパンスルホン酸[７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−メチル−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−イル]−アミド(０.０２５ｇ、０.０５０mmol)のＴＨＦ(４.０mL)溶液をＮ−メチル−モルホリン−Ｎ−オキシド(０.００６ｇ、０.０５０mmol)、ＯｓＯ_４(０.００１ｇ、０.００５mmol)と反応させて、粗生成物を得た。シリカゲルカラムクロマトグラフィー(５％メタノールのＤＣＭ溶液)、分取ＨＰＬＣによる精製により、８mgの生成物を得た(２６％収率)。
LCMS純度: 96.32%, m/z=530 (M+)
HPLC: 93.5%
¹H NMR (CDCl₃-D₆, 300 MHz): δ 7.45-7.4 (br s, 1H), 7.21 (d, 1H), 7.15 (d, 1H), 7.1-7.0 (br s, 1H), 6.45 (t, 1H), 4.25 (t, 2H), 4.1-3.9 (m, 1H), 3.7-3.6 (m, 1H), 3.5-3.4 (m, 1H), 3.3 (t, 2H), 2.4-2.1 (m, 3H), 1.8-1.6 (m, 4H), 1.6-1.3 (m, 2H), 0.9 (t, 2H) Process 8
1- (2,3-dihydroxy-propyl) -cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro- Synthesis of indolizine-8-yl] -amide

Using the same reaction conditions as in step 8 of Example 86, 1-allyl-cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2 , 3,5-tetrahydro-indolizin-8-yl] -amide (0.025 g, 0.050 mmol) in THF (4.0 mL) was added N-methyl-morpholine-N-oxide (0.006 g, 0.005 g). 050 mmol), OsO ₄ (0.001 g, 0.005 mmol) to give the crude product. Purification by silica gel column chromatography (5% methanol in DCM), preparative HPLC gave 8 mg of product (26% yield).
LCMS purity: 96.32%, m / z = 530 (M +)
HPLC: 93.5%
¹ H NMR (CDCl ₃ -D ₆ , 300 MHz): δ 7.45-7.4 (br s, 1H), 7.21 (d, 1H), 7.15 (d, 1H), 7.1-7.0 (br s, 1H), 6.45 (t, 1H), 4.25 (t, 2H), 4.1-3.9 (m, 1H), 3.7-3.6 (m, 1H), 3.5-3.4 (m, 1H), 3.3 (t, 2H), 2.4-2.1 (m, 3H), 1.8-1.6 (m, 4H), 1.6-1.3 (m, 2H), 0.9 (t, 2H)

Example 88
Steps 1-3 were performed according to the method described in Example 8, Step 4 was performed according to the method described in Example 11, and Step 5 was performed according to the method described in Example 61.

実施例８６の工程６と同じ反応条件を使用して、３−(４−ブロモ−２−フルオロ−フェニル)−４−フルオロ−１,６,７,８−テトラヒドロ−３Ｈ−１,３,５ａ−トリアザ−ａｓ−インダセン−２,５−ジオン(１.０ｇ、２.６２４mmol)のＤＭＦ(１２mL)溶液をＮａＨ(０.２１ｇ、５.２４９mmol)および１−アリル−シクロプロパンスルホニルクロライド(０.７１ｇ、３.９３７mmol)を反応させて、粗生成物を得た。シリカゲルカラムクロマトグラフィー(５％メタノールのＤＣＭ溶液)での精製により、３００mgの生成物を得た(２１％収率)。
LCMS純度: 97.3%, m/z=526 (M+)
HPLC: 95.2%
¹H NMR (CDCl₃, 300 MHz): δ 7.5-7.4 (m, 2H), 7.35 (d, 1H), 5.8-5.6 (m, 1H), 5.1 (d, 2H), 4.25 (t, 2H), 3.45 (t, 2H), 2.8-2.6 (m, 2H), 2.3-2.1 (m, 2H), 2.0-1.7 (m, 2H), 1.3-1.1 (m, 2H) Step 6
1- (1-allyl-cyclopropanesulfonyl) -3- (4-bromo-2-fluoro-phenyl) -4-fluoro-1,6,7,8-tetrahydro-3H-1,3,5a-triaza- Synthesis of as-indacene-2,5-dione

Using the same reaction conditions as step 6 of example 86, 3- (4-bromo-2-fluoro-phenyl) -4-fluoro-1,6,7,8-tetrahydro-3H-1,3,5a -A solution of triaza-as-indacene-2,5-dione (1.0 g, 2.624 mmol) in DMF (12 mL) was added NaH (0.21 g, 5.249 mmol) and 1-allyl-cyclopropanesulfonyl chloride (0.20 mmol). 71 g, 3.937 mmol) were reacted to give the crude product. Purification by silica gel column chromatography (5% methanol in DCM) gave 300 mg of product (21% yield).
LCMS purity: 97.3%, m / z = 526 (M +)
HPLC: 95.2%
¹ H NMR (CDCl ₃ , 300 MHz): δ 7.5-7.4 (m, 2H), 7.35 (d, 1H), 5.8-5.6 (m, 1H), 5.1 (d, 2H), 4.25 (t, 2H) , 3.45 (t, 2H), 2.8-2.6 (m, 2H), 2.3-2.1 (m, 2H), 2.0-1.7 (m, 2H), 1.3-1.1 (m, 2H)

実施例８６の工程７と同じ反応条件を使用して、１−(１−アリル−シクロプロパンスルホニル)−３−(４−ブロモ−２−フルオロ−フェニル)−４−フルオロ−１,６,７,８−テトラヒドロ−３Ｈ−１,３,５ａ−トリアザ−ａｓ−インダセン−２,５−ジオン(０.２６ｇ、０.４９４mmol)のＴＨＦ(８mL)溶液をカリウムトリメチルシラノレート(０.１２ｇ、０.９８９mmol)と反応させて、１９５mgの生成物を得た(７９.２％収率)。
LCMS純度: 96.4%, m/z=500.0 (M+)
HPLC: 98.5%
¹H NMR (CDCl₃, 300 MHz): δ 7.25-7.1 (m, 2H), 6.8-6.1 (m, 1H), 6.65 (s, 1H), 6.4 (s, 1H), 5.8-5.6 (m, 1H), 5.2-5.1 (m, 2H), 4.2 (t, 2H), 3.3 (t, 2H), 2.7 (d, 2H), 2.3-2.1 (quin, 2H), 1.3 (t, 2H), 0.85 (t, 2H) Step 7
1-allyl-cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl]- Synthesis of amide

1- (1-Allyl-cyclopropanesulfonyl) -3- (4-bromo-2-fluoro-phenyl) -4-fluoro-1,6,7 using the same reaction conditions as in step 7 of Example 86. , 8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2,5-dione (0.26 g, 0.494 mmol) in THF (8 mL) was added potassium trimethylsilanolate (0.12 g, 0 (989 mmol) to give 195 mg of product (79.2% yield).
LCMS purity: 96.4%, m / z = 500.0 (M +)
HPLC: 98.5%
¹ H NMR (CDCl ₃ , 300 MHz): δ 7.25-7.1 (m, 2H), 6.8-6.1 (m, 1H), 6.65 (s, 1H), 6.4 (s, 1H), 5.8-5.6 (m, 1H), 5.2-5.1 (m, 2H), 4.2 (t, 2H), 3.3 (t, 2H), 2.7 (d, 2H), 2.3-2.1 (quin, 2H), 1.3 (t, 2H), 0.85 (t, 2H)

実施例８６の工程８と同じ反応条件を使用して、１−アリル−シクロプロパンスルホン酸[７−(４−ブロモ−２−フルオロ−フェニルアミノ)−６−フルオロ−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−イル]−アミド(０.１９ｇ、０.３８mmol)のＴＨＦ(４.０mL)溶液をＮ−メチル−モルホリン−Ｎ−オキシド(０.０４５ｇ、０.３８０mmol)、ＯｓＯ_４(０.０１ｇ、０.０３８mmol)と反応させて、粗生成物を得た。シリカゲルカラムクロマトグラフィー(７％メタノールのクロロホルム溶液)での精製により、６８mgの生成物を得た(３４％収率)。
LCMS純度: 96.8%, m/z=534.0 (M+)
HPLC: 99.7%
¹H NMR (DMSO-D₆, 300 MHz): δ 8.95-8.85 (br s, 1H), 7.9-7.8 (br s, 1H), 7.55 (d, 1H), 7.3 (d, 1H), 7.1-6.9 (m, 1H), 4.8-4.6 (m, 2H), 4.1 (t, 2H), 3.8-3.7 (br s, 1H), 3.3-3.1 (m, 4H), 2.3 (d, 1H), 2.1 (m, 2H), 1.6-1.5 (m, 1H), 1.2-0.8 (m, 4H) Process 8
1- (2,3-dihydroxy-propyl) -cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro- Synthesis of indolizine-8-yl] -amide

Using the same reaction conditions as in step 8 of Example 86, 1-allyl-cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2 , 3,5-tetrahydro-indolizin-8-yl] -amide (0.19 g, 0.38 mmol) in THF (4.0 mL) was added N-methyl-morpholine-N-oxide (0.045 g, 0.04 g). 380 mmol), OsO ₄ (0.01 g, 0.038 mmol) to give the crude product. Purification by silica gel column chromatography (7% methanol in chloroform) gave 68 mg of product (34% yield).
LCMS purity: 96.8%, m / z = 534.0 (M +)
HPLC: 99.7%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 8.95-8.85 (br s, 1H), 7.9-7.8 (br s, 1H), 7.55 (d, 1H), 7.3 (d, 1H), 7.1- 6.9 (m, 1H), 4.8-4.6 (m, 2H), 4.1 (t, 2H), 3.8-3.7 (br s, 1H), 3.3-3.1 (m, 4H), 2.3 (d, 1H), 2.1 (m, 2H), 1.6-1.5 (m, 1H), 1.2-0.8 (m, 4H)

Example 89
Steps 1 to 4 were performed according to the method described in Example 8.

ＥＤＣＩ(１.４５mg、０.００８mol)およびＨＯＢｔ(１.０３ｇ、０.００８mol)を、６−フルオロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(１.１ｇ、０.００３mol)のＤＭＦ(２０mL)溶液に添加した。反応混合物をＲＴで１時間撹拌した。続いてＯ−(２,２−ジメチル−[１,３]ジオキソラン−４−イルメチル)−ヒドロキシルアミン(１.１２ｇ、０.００８mol)およびＴＥＡ(０.７７ｇ、０.００８mol)を添加した。得られた混合物をＲＴで１８時間撹拌した。反応混合物を酢酸エチル(１００mL)および水(１５０mL)に分配した。有機層を飽和ＮａＨＣＯ_３溶液(５０mL)、ＮＨ_４Ｃｌ、塩水溶液で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、減圧下濃縮して、７８０mgの粗化合物を得て、それをさらに精製せずに次工程に使用した。 Process 5
6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2,2-dimethyl- [1, 3] Synthesis of dioxolan-4-ylmethoxy) -amide

EDCI (1.45 mg, 0.008 mol) and HOBt (1.03 g, 0.008 mol) were combined with 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2, 3,5-Tetrahydro-indolizine-8-carboxylic acid (1.1 g, 0.003 mol) was added to a solution of DMF (20 mL). The reaction mixture was stirred at RT for 1 hour. O- (2,2-dimethyl- [1,3] dioxolan-4-ylmethyl) -hydroxylamine (1.12 g, 0.008 mol) and TEA (0.77 g, 0.008 mol) were then added. The resulting mixture was stirred at RT for 18 hours. 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 without further purification. Used in the next step.

２Ｎ ＨＣｌ(５ml)を、６−フルオロ−７−(２−フルオロ−４−ヨード−フェニルアミノ)−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２、３−ジヒドロキシ−プロポキシ)−アミド(７８０mg、０.００１mol)のメタノール(２０ml)溶液に添加した。反応混合物をＲＴで１時間撹拌した。反応混合物を減圧下濃縮し、１Ｎ ＮａＯＨをｐＨが約８になるまで添加し、酢酸エチルで抽出した(２×１００ml)。有機層をＮａ_２ＳＯ_４で乾燥させ、減圧下濃縮して、２５０mgの粗生成物を得た。分取ＨＰＬＣでの精製により、１８mgの生成物を得た(２.４％収率)。
LC-MS純度: 96%, m/z=521.9, (M+)
¹H NMR (DMSO-D₆, 300 MHz): δ 11.5 (s, 1H), 8.06 (s, 1H), 7.58 (d,1H), 7.42 (d, 1H), 6.80 (t, 1H), 4.9-4.4 (m, 2H), 4.00 (t, 2H), 3.9-3.8 (m, 1H), 3.7-3.6 (m, 3H), 3.14-3.12 (m, 3H) 2.18-2.04 (m, 2H) Step 6
6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2,3-dihydroxy-propoxy)- Synthesis of amide

2N HCl (5 ml) was added to 6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2, 3-Dihydroxy-propoxy) -amide (780 mg, 0.001 mol) was added to a solution of methanol (20 ml). The reaction mixture was stirred at RT for 1 hour. The reaction mixture was concentrated under reduced pressure, 1N NaOH was added until the pH was about 8, and extracted with ethyl acetate (2 × 100 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 of product (2.4% yield).
LC-MS purity: 96%, m / z = 521.9, (M +)
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 11.5 (s, 1H), 8.06 (s, 1H), 7.58 (d, 1H), 7.42 (d, 1H), 6.80 (t, 1H), 4.9 -4.4 (m, 2H), 4.00 (t, 2H), 3.9-3.8 (m, 1H), 3.7-3.6 (m, 3H), 3.14-3.12 (m, 3H) 2.18-2.04 (m, 2H)

Example 90
Scheme 18

  Step 1 was performed according to the method described in Example 18.

オキシ塩化リン(５.８ｇ、０.０３８mol)を、７−ヒドロキシ−６−メチル−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エチルエステル(２ｇ、０.００８mol)のトルエン(７５mL)溶液にＲＴで添加した。反応混合物を２時間、１１０℃で撹拌した。反応をＴＬＣ(６０％酢酸エチルのヘキサン溶液)でモニターした。反応混合物を減圧下濃縮し、氷水(５０mL)および飽和Ｋ_２ＣＯ_３溶液(７５mL)(ｐＨ＝１０)を添加した。得られた反応混合物を酢酸エチル(３×５０mL)で抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥させ、減圧下濃縮して、１.６ｇの粗化合物を得た。ヘキサンを使用する再結晶による精製により、１.５４ｇの生成物を得た(％収率)。 Process 2
Synthesis of 7-chloro-6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester

Phosphorus oxychloride (5.8 g, 0.038 mol) was added to 7-hydroxy-6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester (2 g, 0.0. 008 mol) in toluene (75 mL) was added at RT. The reaction mixture was stirred at 110 ° C. for 2 hours. The reaction was monitored by TLC (60% ethyl acetate in hexane). The reaction mixture was concentrated under reduced pressure and 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 (3 × 50 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 using hexane gave 1.54 g of product (% yield).

１Ｎ ＬｉＯＨ溶液(２５mL)を、７−クロロ−６−メチル−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸エチルエステル(１.５ｇ、０.００６mol)の７５mlのＴＨＦ：ＭｅＯＨ(４：１)溶液に添加した。反応混合物をＲＴで１８時間撹拌した。反応をＴＬＣ(２０％メタノールのＤＣＭ溶液)でモニターした。反応混合物を減圧下濃縮し、１Ｎ ＨＣｌ(１００mL)をｐＨが約１になるまで添加した。沈殿を回収し、減圧下乾燥させて、１.１２ｇの生成物を得た(８４％収率)。
LC-MS純度: 98%, m/z=226 (M-)
¹H NMR (DMSO-D₆, 300 MHz): δ 13.2 (s, 1H), 4.00 (t, 2H), 3.28 (t, 2H), 2.2-2.02 (m, 5H) Process 3
Synthesis of 7-chloro-6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid

1N LiOH solution (25 mL) was added to 75 mL of 7-chloro-6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester (1.5 g, 0.006 mol). To a THF: MeOH (4: 1) solution. The reaction mixture was stirred at RT for 18 hours. The reaction was monitored by TLC (20% methanol in DCM). The reaction mixture was concentrated under reduced pressure and 1N HCl (100 mL) was added until the pH was about 1. The precipitate was collected and dried under reduced pressure to give 1.12 g of product (84% yield).
LC-MS purity: 98%, m / z = 226 (M-)
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 13.2 (s, 1H), 4.00 (t, 2H), 3.28 (t, 2H), 2.2-2.02 (m, 5H)

ＬＤＡ(１.８６ｇ、０.０１７mol)を、２−フルオロ−４−ヨード−フェニルアミン(２.９ｇ、０.０１２mol)の乾燥ＴＨＦ(２０mL)溶液に−７８℃で添加した。反応混合物を４５分間、−７８℃で撹拌した。続いて７−クロロ−６−メチル−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(１.１ｇ、０.００５mol)のＴＨＦ(９０mL)溶液を−７８℃で添加し、撹拌をさらに２０時間、ＲＴで続けた。反応をＴＬＣ(２０％メタノールのＤＣＭ溶液)でモニターした。反応混合物を減圧下濃縮し、２Ｎ ＨＣｌ溶液(５０mL)およびジエチルエーテル(５０mL)を添加した。反応混合物を１５分間撹拌した。沈殿を回収し、ジエチルエーテル(２×２０mL)で洗浄し、減圧下乾燥させて、８２０mgの生成物を得た(４１％収率)。
LC-MS純度: 94%, m/z=429 (M+)
¹H NMR (DMSO-D₆, 300 MHz): δ 13.30 (s, 1H), 9.36 (s, 1H), 7.60 (d, 1H), 7.38 (s, 1H), 6.40 (t, 1H), 4.04 (t, 2H), 3.48 (t, 2H), 2.18-2.02 (m, 2H), 1.64 (s, 3H) Process 4
Synthesis of 7- (2-fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-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. Subsequently, 7-chloro-6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (1.1 g, 0.005 mol) in THF (90 mL) was added at −78 ° C. And stirring was continued for an additional 20 hours at RT. The reaction was monitored by TLC (20% methanol in DCM). The reaction mixture was concentrated under reduced pressure and 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 (2 × 20 mL) and dried under reduced pressure to give 820 mg of product (41% yield).
LC-MS purity: 94%, m / z = 429 (M +)
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 13.30 (s, 1H), 9.36 (s, 1H), 7.60 (d, 1H), 7.38 (s, 1H), 6.40 (t, 1H), 4.04 (t, 2H), 3.48 (t, 2H), 2.18-2.02 (m, 2H), 1.64 (s, 3H)

ＥＤＣＩ(３３４mg、０.００２mol)およびＨＯＢｔ(２３６mg、０.００２mol)を、７−(２−フルオロ−４−ヨード−フェニルアミノ)−６−メチル−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２５０mg、０.００１mol)のＤＭＦ(１０mL)溶液に添加した。反応混合物をＲＴで１時間撹拌した。続いてＯ−シクロプロピルメチル−ヒドロキシルアミンヒドロクロライド(２１６mg、０.００２mol)およびＴＥＡ(１７６mg、０.００２mol)を添加した。得られた混合物をＲＴで２時間撹拌した。反応をＴＬＣ(１０％メタノールのＤＣＭ溶液)でモニターした。反応混合物を酢酸エチル(７５mL)および水(１２５mL)に分配した。有機層を飽和ＮＨ_４Ｃｌ(５０mL)、ＮａＨＣＯ_３、塩水溶液で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、減圧下濃縮して、２１０mgの粗化合物を得た。メタノール(２mL)およびジエチルエーテル(２０mL)を使用する再結晶により精製して、１４０mgの生成物を得た(４８.２％収率)。
LC-MS純度: 97%, m/z=498, (M+)
¹H NMR (DMSO-D₆, 300 MHz): δ 11.22 (s, 1H), 7.7 (s, 1H), 7.56 (d,1H), 7.32 (d, 1H), 6.40 (t, 1H), 4.02 (t, 2H), 3.48 (d, 2H), 3.2 (t, 2H), 2.18-2.04 (m, 2H), 1.68 (s, 3H), 1.04-.094 (m, 1H), 0.58-0.46 (m, 2H), 0.26-0.18 (m, 2H)。 Process 5
Synthesis of 7- (2-fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxyamide

EDCI (334 mg, 0.002 mol) and HOBt (236 mg, 0.002 mol) were combined with 7- (2-fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5- Tetrahydro-indolizine-8-carboxylic acid (250 mg, 0.001 mol) was added to a solution of DMF (10 mL). The reaction mixture was stirred at RT for 1 hour. Subsequently, O-cyclopropylmethyl-hydroxylamine hydrochloride (216 mg, 0.002 mol) and TEA (176 mg, 0.002 mol) were added. The resulting mixture was stirred at RT for 2 hours. 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 give 210 mg of crude compound. Purification by recrystallization using methanol (2 mL) and diethyl ether (20 mL) gave 140 mg of product (48.2% yield).
LC-MS purity: 97%, m / z = 498, (M +)
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 11.22 (s, 1H), 7.7 (s, 1H), 7.56 (d, 1H), 7.32 (d, 1H), 6.40 (t, 1H), 4.02 (t, 2H), 3.48 (d, 2H), 3.2 (t, 2H), 2.18-2.04 (m, 2H), 1.68 (s, 3H), 1.04-.094 (m, 1H), 0.58-0.46 ( m, 2H), 0.26-0.18 (m, 2H).

Example 91
Step 1 was performed according to the method described in Example 14 and Steps 2-4 were performed according to the method described in Example 90.

ＥＤＣＩ(３３４mg、０.００２mol)およびＨＯＢｔ(２３６mg、０.００２mol)を、７−(２−フルオロ−４−ヨード−フェニルアミノ)−６−メチル−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２５０mg、０.００１mol)のＤＭＦ(１０mL)溶液に添加した。反応混合物をＲＴで３０分間撹拌した。続いてＯ−(２−ｔｅｒｔ−ブトキシ−エチル)−ヒドロキシルアミン(２３３mg、０.００２mol)およびＴＥＡ(１７６mg、０.００２mol)を添加した。得られた混合物をＲＴで１６時間撹拌した。反応をＴＬＣ(１０％メタノールのＤＣＭ溶液)でモニターした。反応混合物を酢酸エチル(１００mL)および水(１００mL)に分配した。有機層を飽和ＮＨ_４Ｃｌ(５０mL)、ＮａＨＣＯ_３、塩水溶液で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、減圧下濃縮して、３００mgの粗化合物を得た。シリカゲルカラムクロマトグラフィー(２％メタノールのＤＣＭ溶液)での精製により、２２８mgの生成物を得た(７１％収率)。
LC-MS純度: 96%, m/z=544, (M+) Process 5
7- (2-Fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-tert-butoxy-ethoxy)- Synthesis of amide

EDCI (334 mg, 0.002 mol) and HOBt (236 mg, 0.002 mol) were combined with 7- (2-fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5- Tetrahydro-indolizine-8-carboxylic acid (250 mg, 0.001 mol) was added to a solution of DMF (10 mL). The reaction mixture was stirred at RT for 30 minutes. This was followed by the 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 hours. 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 silica gel column chromatography (2% methanol in DCM) gave 228 mg of product (71% yield).
LC-MS purity: 96%, m / z = 544, (M +)

トリフルオロ酢酸(２.５mL)を、７−(２−フルオロ−４−ヨード−フェニルアミノ)−６−メチル−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(２−ｔｅｒｔ−ブトキシ−エトキシ)−アミド(２２０mg、０.０００４mol)のＤＣＭ(２.５mL)溶液に０℃で添加した。反応混合物を２時間撹拌した。反応をＴＬＣ(１０％メタノールのＤＣＭ溶液)でモニターした。反応混合物を減圧下濃縮し、ＮａＨＣＯ_３をｐＨが約８になるまで添加し、酢酸エチルで抽出した。合わせた有機層を５％ＮａＨＣＯ_３溶液で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、減圧下濃縮した。濃縮物をジエチルエーテルおよび酢酸エチルで洗浄して、８９mgの生成物を得た(４５％収率)。
LC-MS純度: 93%, m/z=488, (M+)
¹H NMR (DMSO-D₆, 300 MHz): δ 11.24 (s, 1H), 7.68 (s, 1H), 7.54 (d,1H), 7.32 (d, 1H), 6.40 (t, 1H), 4.7 (s, 1H), 4.00 (t, 2H), 3.7 (t, 2H), 3.55-3.42 (m, 2H), 3.18 (t, 2H), 2.18-2.04 (m, 2H), 1.72 (s, 3H) Step 6
7- (2-Fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy) -amide Composition

Trifluoroacetic acid (2.5 mL) was added to 7- (2-fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid. To a solution of (2-tert-butoxy-ethoxy) -amide (220 mg, 0.0004 mol) in DCM (2.5 mL) 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, 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 of product (45% yield).
LC-MS purity: 93%, m / z = 488, (M +)
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 11.24 (s, 1H), 7.68 (s, 1H), 7.54 (d, 1H), 7.32 (d, 1H), 6.40 (t, 1H), 4.7 (s, 1H), 4.00 (t, 2H), 3.7 (t, 2H), 3.55-3.42 (m, 2H), 3.18 (t, 2H), 2.18-2.04 (m, 2H), 1.72 (s, 3H )

Example 92
Step 1 was performed according to the method described in Example 14 and Steps 2-4 were performed according to the method described in Example 90.

ＥＤＣＩ(１６７mg、０.００１mol)およびＨＯＢｔ(１１８mg、０.００１mol)を、７−(２−フルオロ−４−ヨード−フェニルアミノ)−６−メチル−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(１２５mg、０.０００３mol)のＤＭＦ(８mL)溶液に添加した。反応混合物をＲＴで１時間撹拌した。続いてＯ−シクロブチルメチル−ヒドロキシルアミン(８８mg、０.００１mol)およびＴＥＡ(８８mg、０.００１mol)を添加した。得られた混合物をＲＴで２時間撹拌した。反応をＴＬＣ(１０％メタノールのＤＣＭ溶液)でモニターした。反応混合物を酢酸エチル(５０mL)および水(７５mL)に分配した。有機層を飽和ＮＨ_４Ｃｌ(５０mL)、ＮａＨＣＯ_３、塩水溶液で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、減圧下濃縮して、１５０mgの粗化合物を得た。酢酸エチル(１０mL)およびジエチルエーテル(５０mL)を使用する再結晶により精製して、８５mgの生成物を得た(５７％収率)。
LC-MS純度: 94%, m/z=512, (M+)
¹H NMR (DMSO-D₆, 300 MHz): δ 11.2 (s, 1H), 7.68 (s, 1H), 7.58 (d,1H), 7.34 (d, 1H), 6.40 (t, 1H), 4.00 (t, 2H), 3.56 (d, 2H), 3.18 (t, 2H), 2.18-2.04 (m, 2H), 2.02-1.92 (m, 3H), 1.9-1.62 (m, 7H)。 Process 5
Synthesis of 7- (2-fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclobutylmethoxy-amide

EDCI (167 mg, 0.001 mol) and HOBt (118 mg, 0.001 mol) were combined with 7- (2-fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5- Tetrahydro-indolizine-8-carboxylic acid (125 mg, 0.0003 mol) was added to a solution of DMF (8 mL). The reaction mixture was stirred at RT for 1 hour. Subsequently O-cyclobutylmethyl-hydroxylamine (88 mg, 0.001 mol) and TEA (88 mg, 0.001 mol) were added. The resulting mixture was stirred at RT for 2 hours. 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 using ethyl acetate (10 mL) and diethyl ether (50 mL) gave 85 mg of product (57% yield).
LC-MS purity: 94%, m / z = 512, (M +)
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 11.2 (s, 1H), 7.68 (s, 1H), 7.58 (d, 1H), 7.34 (d, 1H), 6.40 (t, 1H), 4.00 (t, 2H), 3.56 (d, 2H), 3.18 (t, 2H), 2.18-2.04 (m, 2H), 2.02-1.92 (m, 3H), 1.9-1.62 (m, 7H).

Example 93
Steps and 3 were performed according to the method described in Example 14, and Step 4 was performed according to the method described in Example 15.

実施例８６の工程５と同じ反応条件を使用して、７−(２−フルオロ−４−ヨード−フェニルアミノ)−６−メチル−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−カルボン酸(３.１４ｇ、７.３４mmol)のＤＭＦ(３０mL)溶液をＴＥＡ(１.０３mL、７.３４mmol)およびＤＰＰＡ(１.５９mL、７.３４mmol)と反応させて、１.８５ｇの生成物を得た(５９％収率)。
LCMS純度: 97.0%, m/z=426.0 (M+)
¹H NMR (DMSO-D₆, 300 MHz): δ 11.1 (s, 1H), 7.9 (d, 1H), 7.7 (d, 1H), 7.4-7.1 (m, 2H), 3.9 (t, 2H), 3.1 (t, 2H), 2.4-2.2 (m, 2H), 1.45 (s, 3H) Process 5
Synthesis of 3- (2-fluoro-4-iodo-phenyl) -4-methyl-1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2,5-dione

7- (2-Fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine using the same reaction conditions as in step 5 of Example 86. A solution of -8-carboxylic acid (3.14 g, 7.34 mmol) in DMF (30 mL) was reacted with TEA (1.03 mL, 7.34 mmol) and DPPA (1.59 mL, 7.34 mmol) to give 1.85 g Product was obtained (59% yield).
LCMS purity: 97.0%, m / z = 426.0 (M +)
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 11.1 (s, 1H), 7.9 (d, 1H), 7.7 (d, 1H), 7.4-7.1 (m, 2H), 3.9 (t, 2H) , 3.1 (t, 2H), 2.4-2.2 (m, 2H), 1.45 (s, 3H)

実施例１０９の工程６(現行セット)と同じ反応条件を使用して、３−(２−フルオロ−４−ヨード−フェニル)−４−メチル−１,６,７,８−テトラヒドロ−３Ｈ−１,３,５ａ−トリアザ−ａｓ−インダセン−２,５−ジオン(１.８０ｇ、４.２４mmol)のＤＭＦ(２０mL)溶液をＮａＨ(０.３４ｇ、８.４７mmol)および１−アリル−シクロプロパンスルホニルクロライド(１.１４ｇ、６.３５mmol)と反応させて、粗生成物を得た。シリカゲルカラムクロマトグラフィー(５０％酢酸エチルのヘキサン溶液)による精製により、４９０mgの生成物を得た(２０％収率)。
LCMS純度: 83.9%, m/z=569.9 (M+)
¹H NMR (CDCl₃, 300 MHz): δ 7.7-7.6 (m, 2H), 7.15 (t, 1H), 5.7-5.6 (m, 1H), 5.1-4.9 (m, 2H), 4.2 (t, 2H), 3.5 (t, 2H), 2.7 (t, 2H), 2.3-2.1 (m, 3H), 1.9-1.8 (m, 1H), 1.8-1.6 (m, 1H), 1.3-1.11 (m, 2H) Step 6
1- (1-allyl-cyclopropanesulfonyl) -3- (2-fluoro-4-iodo-phenyl) -4-methyl-1,6,7,8-tetrahydro-3H-1,3,5a-triaza- Synthesis of as-indacene-2,5-dione

3- (2-Fluoro-4-iodo-phenyl) -4-methyl-1,6,7,8-tetrahydro-3H-1 using the same reaction conditions as in Example 6, step 6 (current set) , 3,5a-Triaza-as-indacene-2,5-dione (1.80 g, 4.24 mmol) in DMF (20 mL) was added NaH (0.34 g, 8.47 mmol) and 1-allyl-cyclopropanesulfonyl. Reaction with chloride (1.14 g, 6.35 mmol) gave the crude product. Purification by silica gel column chromatography (50% ethyl acetate in hexane) gave 490 mg of product (20% yield).
LCMS purity: 83.9%, m / z = 569.9 (M +)
¹ H NMR (CDCl ₃ , 300 MHz): δ 7.7-7.6 (m, 2H), 7.15 (t, 1H), 5.7-5.6 (m, 1H), 5.1-4.9 (m, 2H), 4.2 (t, 2H), 3.5 (t, 2H), 2.7 (t, 2H), 2.3-2.1 (m, 3H), 1.9-1.8 (m, 1H), 1.8-1.6 (m, 1H), 1.3-1.11 (m, 2H)

実施例１０９の工程７(現行セット)と同じ反応条件を使用して、１−(１−アリル−シクロプロパンスルホニル)−３−(２−フルオロ−４−ヨード−フェニル)−４−メチル−１,６,７,８−テトラヒドロ−３Ｈ−１,３,５ａ−トリアザ−ａｓ−インダセン−２,５−ジオン(０.４８ｇ、０.８４mmol)のＴＨＦ(１２mL)溶液をカリウムトリメチルシラノレート(０.２１ｇ、１.６９mmol)と反応させて、３１０mgの生成物を得た(６３％収率)。
LCMS純度: 85.2%, m/z=544.0 (M+)
HPLC: 86.7%
¹H NMR (DMSO-D₆, 300 MHz): δ 8.8 (s, 1H), 7.6 (d, 1H), 7.35 (d, 2H), 6.3 (t, 1H), 5.7-5.5 (m, 1H), 5.1 (d, 2H), 4.1 (t, 2H), 3.25 (t, 2H), 2.6 (d, 2H), 2.1 (quin, 2H), 1.7 (s, 3H), 1.1 (t, 2H), 0.75 (t, 2H) Step 7
1-allyl-cyclopropanesulfonic acid [7- (2-fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl]- Synthesis of amide

1- (1-allyl-cyclopropanesulfonyl) -3- (2-fluoro-4-iodo-phenyl) -4-methyl-1 using the same reaction conditions as in Example 109, step 7 (current set). , 6,7,8-Tetrahydro-3H-1,3,5a-triaza-as-indacene-2,5-dione (0.48 g, 0.84 mmol) in THF (12 mL) was added potassium trimethylsilanolate (0 Reaction with .21 g, 1.69 mmol) gave 310 mg of product (63% yield).
LCMS purity: 85.2%, m / z = 544.0 (M +)
HPLC: 86.7%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 8.8 (s, 1H), 7.6 (d, 1H), 7.35 (d, 2H), 6.3 (t, 1H), 5.7-5.5 (m, 1H) , 5.1 (d, 2H), 4.1 (t, 2H), 3.25 (t, 2H), 2.6 (d, 2H), 2.1 (quin, 2H), 1.7 (s, 3H), 1.1 (t, 2H), 0.75 (t, 2H)

実施例１０９の工程８(現行セット)と同じ反応条件を使用して、１−アリル−シクロプロパンスルホン酸[７−(２−フルオロ−４−ヨード−フェニルアミノ)−６−メチル−５−オキソ−１,２,３,５−テトラヒドロ−インドリジン−８−イル]−アミド(０.２５ｇ、０.４６mmol)のＴＨＦ(１０mL)溶液をＮ−メチル−モルホリン−Ｎ−オキシド(０.０５４ｇ、０.４６mmol)、ＯｓＯ_４(０.０１ｇ、０.０４６mmol)と反応させて、粗生成物を得た。シリカゲルカラムクロマトグラフィー(５％メタノールのＣＨＣｌ_３溶液)、分取ＨＰＬＣによる精製により、９５mgの生成物を得た(３６％収率)。
LCMS純度: 96.7%, m/z=577.8 (M+)
HPLC: 97.2%
¹H NMR (DMSO-D₆, 300 MHz): δ 8.75 (s, 1H), 7.6-7.3 (m, 3H), 6.3 (t, 1H), 4.6 (t, 2H), 4.1 (t, 2H), 3.6-3.5 (m, 1H), 3.3-3.2 (m, 4H), 2.1-2.0 (m, 3H), 1.75-1.6 (m, 5H), 1.3-1.0 (m, 4H) Process 8
1- (2,3-dihydroxy-propyl) -cyclopropanesulfonic acid [7- (2-fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro- Synthesis of indolizine-8-yl] -amide

Using the same reaction conditions as step 109 (current set) of Example 109, 1-allyl-cyclopropanesulfonic acid [7- (2-fluoro-4-iodo-phenylamino) -6-methyl-5-oxo -1,2,3,5-tetrahydro-indolizin-8-yl] -amide (0.25 g, 0.46 mmol) in THF (10 mL) was added N-methyl-morpholine-N-oxide (0.054 g, 0.46 mmol) and OsO ₄ (0.01 g, 0.046 mmol) to give the crude product. Purification by silica gel column chromatography (5% methanol in CHCl ₃ ), preparative HPLC gave 95 mg of product (36% yield).
LCMS purity: 96.7%, m / z = 577.8 (M +)
HPLC: 97.2%
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 8.75 (s, 1H), 7.6-7.3 (m, 3H), 6.3 (t, 1H), 4.6 (t, 2H), 4.1 (t, 2H) , 3.6-3.5 (m, 1H), 3.3-3.2 (m, 4H), 2.1-2.0 (m, 3H), 1.75-1.6 (m, 5H), 1.3-1.0 (m, 4H)

Scheme 19

Example 94
Steps 1-3 were performed according to the method described in Example 14, Step 4 was performed according to the method described in Example 15, and Step 5 was performed according to the method described in Example 87.

水素化ナトリウム(０.０４ｇｍ、０.００１mol)を、３−(４−ブロモ−２−フルオロ−フェニル)−４−メチル−１,６,７,８−テトラヒドロ−３Ｈ−１,３,５ａ−トリアザ−ａｓ−インダセン−２,５−ジオン(０.２gm、０.０００５mol)の乾燥ＤＭＦ(３ml)溶液に０℃で添加した。続いてシクロ(cycol)プロパンスルホニルクロライド(０.１１gm、０.０００８mol)を０℃で添加し、反応混合物をＲＴで一夜撹拌した。反応をＴＬＣ(５％ＭｅＯＨのＣＨＣｌ_３溶液)でモニターした。氷を添加し、希ＨＣｌで中和し、酢酸エチルで抽出し、濃縮して、０.２５ｇの粗生成物を得て、それをさらに精製せずに次工程に使用した。 Step 6
3- (4-bromo-2-fluoro-phenyl) -1-cyclopropanesulfonyl-4-methyl-1,6,7,8-tetrahydro-3H-1,3,5a-triaza-as-indacene-2, Synthesis of 5-dione

Sodium hydride (0.04 gm, 0.001 mol) was added to 3- (4-bromo-2-fluoro-phenyl) -4-methyl-1,6,7,8-tetrahydro-3H-1,3,5a- To a solution of triaza-as-indacene-2,5-dione (0.2 gm, 0.0005 mol) in dry DMF (3 ml) was added at 0 ° C. Cyclopropanepropanesulfonyl chloride (0.11 gm, 0.0008 mol) was then 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 concentrated to give 0.25 g of crude product that was used in the next step without further purification.

６mlの１Ｎ ＮａＯＨ溶液を３−(４−ブロモ−２−フルオロ−フェニル)−１−シクロプロパンスルホニル−４−メチル−１,６,７,８−テトラヒドロ−３Ｈ−１,３,５ａ−トリアザ−ａｓ−インダセン−２,５−ジオン(０.２５ｇ)のＤＭＦ溶液に添加し、混合物を６５℃で、１.３０時間加熱した。氷を添加し、希ＨＣｌで中和し、酢酸エチルで抽出し、濃縮し、シリカゲルカラムクロマトグラフィー(２％メタノールのＣＨＣｌ_３溶液)で精製して、０.０９０ｇの生成物を得た(３７.３４％収率)。
¹H NMR (DMSO-D₆, 300 MHz): δ 8.9 (s, 1H), 7.5 (d, 1H), 7.4 (s, 1H), 7.2 (d, 1H), 6.5 (t, 1H), 4.0 (t, 2H), 3.3 (t, 2H), 2.5 (m, 1H), 2.1 (q, 2H), 1.7 (s, 3H), 0.9 (m, 4H) Step 7
Synthesis of cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizin-8-yl] -amide

6 ml of 1N NaOH solution was added to 3- (4-bromo-2-fluoro-phenyl) -1-cyclopropanesulfonyl-4-methyl-1,6,7,8-tetrahydro-3H-1,3,5a-triaza- As-Indacene-2,5-dione (0.25 g) was added to the DMF solution and the mixture was heated at 65 ° C. for 1.30 hours. Ice was added, neutralized with dilute HCl, extracted with ethyl acetate, concentrated, and purified by silica gel column chromatography (2% methanol in CHCl ₃ ) to give 0.090 g of product (37 .34% yield).
¹ H NMR (DMSO-D ₆ , 300 MHz): δ 8.9 (s, 1H), 7.5 (d, 1H), 7.4 (s, 1H), 7.2 (d, 1H), 6.5 (t, 1H), 4.0 (t, 2H), 3.3 (t, 2H), 2.5 (m, 1H), 2.1 (q, 2H), 1.7 (s, 3H), 0.9 (m, 4H)

  The above example compounds were evaluated as inhibitors of the MAP kinase pathway in the BRAF-MEK-ERK enzyme cascade assay and cell viability assay and the results are summarized in Table 1. Other compounds described herein can be prepared using methods known to those skilled in the art and / or methods described herein.

  The examples described herein are only illustrative of the present invention and therefore should not be construed to limit the scope of the invention.

Claims (22)

Formula (I):

[Where,
X is C _1-3 alkylene, —N (R ⁶ ) —, —O—, or —S (O) _p —;
R ¹ is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein the ring is optionally substituted with one or more groups independently selected from List 1;
R ² is H, cyano, or a 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, diC _{1 -6} alkylamino, or R ³ is further monocyclic cycloalkyl or monocyclic heterocycloalkyl, wherein the ring is optionally substituted with one or more groups independently selected from List 1 May have been;
R ⁵ is H, halogen, C _1-3 alkyl, or C _1-3 haloalkyl;
Y is a group selected from -D-, -E-, -D-E-, 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 A group selected from (R ¹⁶ ) CO—, or —C (═NH) N (R ¹⁷ ) —;
E is a monocyclic arylene, heteroarylene, cycloalkylene or heterocycloalkylene, wherein the ring is optionally substituted with one or more groups independently selected from List 1;
R ⁷ is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, and when R ⁷ is other than H, optionally , 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 alkyl 1 to independently selected from amino, di-C _1-6 alkylamino, C _1-6 acylamino, C _1-6 acyl C _1-6 alkylamino, monocyclic cycloalkyl or monocyclic heterocycloalkyl good three optionally substituted by a group, wherein said ring is optionally 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 And optionally substituted by one or two groups independently selected from C _1-6 acylC _1-6 alkylamino;
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 alkylcarbonyl, carboxy, C _1-6 alkoxycarbonyl, amino, C _1-6 alkylamino, di-C _1-6 alkylamino, C _1-6 alkylaminocarbonyl, di-C _1-6 alkylaminocarbonyl C _1-6 alkylcarbonylamino, C _1-6 alkylcarbonyl (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 alkylsulfanyl, C 1-6} alkyl Ruhoniru, aminosulfonyl, is selected from C _1-6 alkylaminosulfonyl and di -C _1-6 alkylaminosulfonyl, wherein said each of the hydrocarbon groups, optionally substituted by one or more halogen, hydroxyl, C _1- Optionally substituted with ₆ alkoxy, amino, C _1-6 alkylamino, di-C _1-6 alkylamino or cyano;
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 diC _1-6 alkylamino Yes;
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 Is -6} alkyl;
m and n are independently 0, 1, 2, or 3; and m + n = 2 or 3.
p is 0, 1, or 2; where alkyl or alkylene means a straight, branched and / or cyclic hydrocarbon of 1 to 20 carbon atoms. Alkyl moieties having 1 to 5 carbons are termed “lower alkyl” and examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl;
Cycloalkyl or cycloalkylene is a 3-14 membered monocyclic or bicyclic carbocycle, wherein one of the monocycle or bicycle is saturated or partially unsaturated, optionally further —C (O) - it may include ring members, and the remaining ring in aromatic, may be either partially saturated or unsaturated, -C (= O), - N (R 20) q -, - O- and S (O ) containing 1 to 3 ring members selected from r wherein R ²⁰ is H or C _1-6 alkyl, q is 0-1 and r is 0-2. Often;
Aryl or arylene is a 6-14 membered monocyclic or bicyclic carbocycle, wherein one of the monocycle or bicycle is aromatic and the remaining ring is aromatic or saturated. It may be partially unsaturated, —C (O), —N (R ¹⁹ ) q—, —O— and S (O) r, wherein R ¹⁹ is H or C _1-6 alkyl, and q is 0-1 and r is 0-2) may comprise 1 to 3 ring members selected from;
A heteroaryl or heteroarylene is a 5-14 membered monocyclic or bicyclic ring, wherein one of the monocyclic or bicyclic rings is (a) 1-4 nitrogen atoms, (b) 1 oxygen. An atom or one sulfur atom or (c) an aromatic group containing one oxygen atom or one sulfur atom and one or two nitrogen atoms, the remaining rings being aromatic or saturated It may be partially unsaturated, -C (O), -N (R ²¹ ) q-, -O- and S (O) r, wherein R ²¹ is H or C _1-6 alkyl, q is 0-1 and r is 0-2) may contain 1 to 3 ring members; and heterocycloalkyl or heterocycloalkylene is a 3-14 membered monocyclic or dicyclic a ring, here, one of the monocyclic or ^{bicyclic, -N (R 22) -,} - O- and -S (O) _r - selected from A saturated or partially unsaturated group containing one or two ring members and optionally further containing —C (O) — ring members, the remaining rings being aromatic, saturated or partially -C (= O), -N (R ²³ ) q-, -O- and S (O) r where R ²² or R ²³ is H or C _1-6 alkyl , Q is 0-1, and r is 0-2). ]
And pharmaceutically acceptable salts thereof.   The compound according to claim 1, wherein X is -N (H)-. The compound according to claim 1 or 2, wherein R ¹ is phenyl substituted at the 2-position and 4-position. The compound according to any one of claims 1 to 3, wherein R ¹ is 4-bromo-2-fluorophenyl or 4-iodo-2-fluorophenyl. Y is D, and D is —C (O) —, —CO ₂ —, C (O) N (H) O—, —C (O) N (C _1-6 alkyl) O—, —C (O) N (H) - or -C (O) N (C _1-6 alkyl) - is a group selected from a compound according to any one of claims 1 to 4. 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 , where R ^7b is H, methyl, ethyl, cyclopropylmethyl, 2-methoxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, acetylaminomethyl, 2-dimethylaminoethyl, or cyclopentyl or 2-thiazolyl, or R ² is oxadiazolyl amino compound according to any one of claims 1 to 4. R ² is CONHOR ^{7a, wherein, R 7a} is cyclopropylmethyl or 2-hydroxyethyl, A compound according to claim 1 or 6.   5. A compound according to any of claims 1-4, wherein -E- is cycloalkyl, 5-membered heteroarylene or 5-membered heterocycloalkylene, which can be substituted or unsubstituted.   9. A compound according to any of claims 1 to 4 or 8, wherein E is cyclopentyl, thiazole or oxadiazole, which can be substituted or unsubstituted. The compound according to any one of claims 1 to 9, wherein R ³ and R ⁴ are H. R ⁵ is H, methyl, ethyl, chloro or fluoro, A compound according to any one of claims 1 to 10. R ⁵ is methyl, A compound according to any one of claims 1 to 8.   The compound according to any one of claims 1 to 12, wherein Z is O.   14. The compound according to any one of claims 1 to 13, wherein m and n are both 1, or one of m and n is 1 and the other is 2. Formula (Id):

[Where,
Rd ¹ is H, halogen, C _1-3 alkyl, or C _1-3 haloalkyl;
Rd ² is H, cyano, or a group -Y-Rd ^5,;
Rd ³ and Rd ⁴ are independently 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 alkylcarbonyl, carboxy, C _1-6 alkoxycarbonyl, amino, C _1-6 alkylamino, di-C _1-6 alkylamino, C _1-6 alkylaminocarbonyl, di-C _1-6 alkylaminocarbonyl, C _1-6 alkylcarbonylamino, C _1-6 alkylcarbonyl (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} alkylsulfanyl C _1-6 alkylsulfonyl, _{aminosulfonyl,} a _{C 1-6} alkylaminosulfonyl and di _{-C 1-6} alkyl aminosulfonyl, wherein each of the hydrocarbon groups, optionally substituted by one or more halogen, hydroxyl Optionally substituted with C _1-6 alkoxy, amino, C _1-6 alkylamino, di-C _1-6 alkylamino or cyano;
Y is a group selected from -D-, -E-, -D-E-, 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 is a monocyclic arylene, heteroarylene, cycloalkylene or heterocycloalkylene, wherein the ring is optionally substituted with one or more groups selected independently from List 1 as defined herein. Often;
Rd ⁵ is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein when Rd ⁵ is not H, Optionally 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- Independently selected from ₆ alkylamino, di-C _1-6 alkylamino, C _1-6 acylamino, C _1-6 acyl C _1-6 alkylamino, monocyclic cycloalkyl or monocyclic heterocycloalkyl It may be substituted with 1 to 3 groups, wherein the ring is optionally halogen, cyano, hydroxyl, C _1-6 alkoxy. _Shi, 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, Optionally substituted with one or two groups independently selected from C _1-6 acylamino and C _1-6 acylC _1-6 alkylamino;
Rd ⁶ and Rd ⁷ are independently 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 alkylcarbonyl, carboxy, C _1-6 alkoxycarbonyl, amino, C _1-6 alkylamino, di-C _1-6 alkylamino, C _1-6 alkylaminocarbonyl, di-C _1-6 alkylaminocarbonyl, C _1-6 alkylcarbonylamino, C _1-6 alkylcarbonyl (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} alkylsulfanyl C _1-6 alkylsulfonyl, _{aminosulfonyl,} a _{C 1-6} alkylaminosulfonyl and di _{-C 1-6} alkyl aminosulfonyl, wherein each of the hydrocarbon groups, optionally substituted by one or more halogen, hydroxyl Optionally substituted with C _1-6 alkoxy, amino, C _1-6 alkylamino, di-C _1-6 alkylamino or cyano;
j and g are independently 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 , and Rd ¹⁹ are independently H or C _1-6 alkyl (alky) Is;
Alkyl or alkylene means straight, branched and / or cyclic hydrocarbons of 1 to 20 carbon atoms. Alkyl moieties having 1 to 5 carbons are termed “lower alkyl” and examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl;
Cycloalkyl or cycloalkylene is a 3-14 membered monocyclic or bicyclic carbocycle, wherein one of the monocycle or bicycle is saturated or partially unsaturated, optionally further —C (O) - it may include ring members, and the remaining ring in aromatic, may be either partially saturated or unsaturated, -C (= O), - N (R 20) q -, - O- and S (O ) containing 1 to 3 ring members selected from r wherein R ²⁰ is H or C _1-6 alkyl, q is 0-1 and r is 0-2. Often;
Aryl or arylene is a 6-14 membered monocyclic or bicyclic carbocycle, wherein one of the monocycle or bicycle is aromatic and the remaining ring is aromatic or saturated. It may be partially unsaturated, —C (O), —N (R ¹⁹ ) q—, —O— and S (O) r, wherein R ¹⁹ is H or C _1-6 alkyl, and q is 0-1 and r is 0-2) may comprise 1 to 3 ring members selected from;
A heteroaryl or heteroarylene is a 5-14 membered monocyclic or bicyclic ring, wherein one of the monocyclic or bicyclic rings is (a) 1-4 nitrogen atoms, (b) 1 oxygen. An atom or one sulfur atom or (c) an aromatic group containing one oxygen atom or one sulfur atom and one or two nitrogen atoms, the remaining rings being aromatic or saturated It may be partially unsaturated, -C (O), -N (R ²¹ ) q-, -O- and S (O) r, wherein R ²¹ is H or C _1-6 alkyl, q is 0-1 and r is 0-2) may contain 1 to 3 ring members; and heterocycloalkyl or heterocycloalkylene is a 3-14 membered monocyclic or dicyclic a ring, here, one of the monocyclic or ^{bicyclic, -N (R 22) -,} - O- and -S (O) _r - selected from One or two ring members and optionally further —C (O) -ring members, which may be saturated or partially unsaturated groups, the remaining rings being aromatic, saturated or partially -C (= O), -N (R ²³ ) q-, -O- and S (O) r where R ²² or R ²³ is H or C _1-6 alkyl , Q is 0-1, and r is 0-2). ]
And salts thereof.   16. A compound according to any one of claims 1 to 15 for use in therapy.   A method of treating a disease, disorder or syndrome associated with MEK inhibition, comprising a compound according to any of claims 1-15 or a prodrug thereof or a compound of formula (I) or a prodrug thereof and Administering a pharmaceutically acceptable excipient to a subject in need thereof.   18. The method of claim 17, wherein the disease, disorder, or syndrome is hyperproliferation selected from the group consisting of cancer and inflammation in a subject that is an animal, including a human.   A compound of formula (I) substantially as described in the examples, a method of treating a disease, disorder or syndrome associated with MEK inhibition.   A pharmaceutical composition comprising a compound of formula (I) according to any of claims 1 to 15 and a pharmaceutically acceptable carrier or additive.   16. A pharmaceutical composition comprising a compound of formula (I) according to any of claims 1-15 in combination with a second active agent, and a pharmaceutically acceptable carrier or additive. A compound selected from:
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropyl-methoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid dimethylamide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylic acid methoxylamide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylic acid amide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylic acid ethoxyamide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylic acid (2-hydroxyethyl) amide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid methylamide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-ethyl-amide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carbaldehyde 6-fluoro-7- (2-fluoro-4-iodo -Phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid;
7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-vinyloxy-ethoxy) -amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethoxy-amide;
2- (4-Bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolidine-1-carboxylic acid ethyl ester;
2- (4-Bromo-2-fluoro-phenyl-amino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolidine-1-carboxylic acid;
2- (4-Bromo-2-fluoro-phenyl-amino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-1-carboxylic acid-cyclopropyl-methoxyamide;
2- (4-Bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolidine-1-carboxylic acid amide;
2- (4-Bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolidine-1-carboxylic acid- (2-vinyloxy-ethoxy) -amide;
2- (4-Bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolidine-1-carboxylic acid methoxyamide;
2- (4-Bromo-2-fluoro-phenylamino) -4-oxo-6,7,8,9-tetrahydro-4H-quinolidine-1-carboxylic acid ethoxyamide;
7- (4-Bromo-2-fluorophenylamino) -6-methyl-5-oxo-1,2,3,5-tetra (tetyra) hydro-indolizine-8-carboxylic acid (2-hydroxyethoxy) amide ;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (3-hydroxy-propyl) -amide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-methoxy-ethyl) -amide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-acetylamino-ethyl) -amide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-dimethylamino-ethyl) -amide;
6-fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy) -amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopentylamide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethylamide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (3-methoxy-propyl) -amide;
7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid;
7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid amide;
7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester;
7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy) -amide;
7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-amide;
7- (2-Fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2,3-dihydroxy-propoxy) -amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid;
7- (4-Bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-chloro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2,3-dihydroxy-propoxy)- An amide;
6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid;
6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-amide;
6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid amide;
6-chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethoxy-amide;
6-Chloro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2,3-dihydroxy-propoxy)- An amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid thiazol-2-ylamide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (3-hydroxy-propyl) -amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid dimethylamide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-methoxy-ethyl) -amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-acetylamino-ethyl) -amide ;
7- (4-Bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (pyridin-2-ylmethyl) -amide;
6-fluoro-7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid;
6-fluoro-7- (2-fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
6-fluoro-7- (2-fluoro-4-methylsulfanyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-8- [5- (2-hydroxy-ethylamino)-[1,3,4] oxadiazol-2-yl] -2 , 3-dihydro-1H-indolizin-5-one;
7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy) -amide;
7- (4-Bromo-2-methyl-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid;
7- (4-Bromo-2-methyl-phenylamino) -6-fluoro-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
7- (4-Bromo-2-methyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid;
7- (4-Bromo-2-methyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-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-India Lysine-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-India Lysine-5-one;
6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -8- (3-hydroxy-3-piperidin-2-yl-azetidine-1-carbonyl) -2,3-dihydro-1H-India Lysine-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-indolizine- 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-indolizine-8- Yl] -amide;
7- (4-Bromo-2-fluoro-phenylamino) -6-fluoro-8- (1-hydroxy-but-3-enyl) -2,3-dihydro-1H-indolizin-5-one;
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-one;
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-indolizine-8-carboxylic acid ethyl ester;
7- (2-Fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid;
7- (2-Fluoro-4-trifluoromethyl-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
7- (2-Fluoro-4-methoxy-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carbaldehyde oxime;
7- (4-Bromo-2-fluoro-phenylamino) -8- (3-hydroxy-3-pyridin-2-yl-azetidine-1-carbonyl) -2,3-dihydro-1H-indolizine-5 on;
7- (4-Bromo-2-fluoro-phenylamino) -8- (3-hydroxy-azetidine-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-benzenesulfonamide;
[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-dimethylaminosulfonamide;
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;
7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester;
7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)- An amide;
7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclobutylmethoxy-amide;
7- (4-Bromo-2-fluoro-phenylamino) -1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydro-indolizine-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- Indolizine-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- Indolizine-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- Indolizine-8-yl] -amide;
6-Fluoro-7- (2-fluoro-4-iodo-phenylamino) -5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2,3-dihydroxy-propoxy)- An amide;
7- (2-Fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxyamide;
7- (2-Fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy) -amide;
7- (2-Fluoro-4-iodo-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-indolizine-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- Indolizine-8-yl] -amide; and cyclopropanesulfonic acid [7- (4-bromo-2-fluoro-phenylamino) -6-methyl-5-oxo-1,2,3,5-tetrahydro-india Lysine-8-yl] -amide,
Or a pharmaceutically acceptable salt thereof.