HK1083098B

HK1083098B - Indole-3-carboxamides as glucokinase (gk) activators

Info

Publication number: HK1083098B
Application number: HK06104334.1A
Authority: HK
Inventors: 温迪‧莱亚‧科比特
Original assignee: 霍夫曼-拉罗奇有限公司
Priority date: 2002-10-03
Filing date: 2003-09-26
Publication date: 2008-02-22

Description

Indole-3-carboxamides as Glucokinase (GK) activators

[0001] Glucokinase (GK) is one of The four hexokinases found in mammals [ Colowick, S.P, The Enzymes, Vol.9 (edited by P.Boyer) Academic Press, New York, NY, pp.1-48, 1973 ]. Hexokinase catalyzes the first step in glucose metabolism, the conversion of glucose to glucose-6-phosphate. Glucokinase has a limited distribution in cells and is found predominantly in pancreatic beta-cells and hepatic parenchymal cells. In addition, GK is the rate-limiting enzyme for glucose metabolism in these two cell types and plays an important role in the systemic glucose homeostasis [ Chipkin, s.r., Kelly, k.l., and Ruderman, n.b. joslin's Diabetes (c.r.khan and g.c.wier, editors), Lea and Febiger, philiadelphia, PA, p.97-115, 1994 ]. The glucose concentration at which GK exhibits half-maximal activity is approximately 8 mM. The other three hexokinases are saturated at relatively low concentrations (< 1mM) of glucose. Thus, as blood glucose concentration increases from fasting state (5mM) to postprandial state with carbohydrate containing foods (. apprxeq.10-15 mM), glucose flux through the GK pathway also increases [ Printz, r.g., Magnuson, m.a., and Granner, d.k.ann.rev.nutrition, vol.13 (r.e.olson, d.m.bier, and d.b.mccormick editors ], Annual Review, inc., Palo Alto, CA, p.463-496, 1993 ]. These conclusions led a hypothesis ten years ago that GK functions as a glucose sensor in β -cells and hepatic parenchymal cells (Meglasson, m.d. and matchschinsky, f.m., amer.j. physiol.246, E1-E13, 1984). Recent studies in transgenic animals have demonstrated that GK does play a critical role in the global glucose homeostasis. Animals that do not express GK die from severe diabetes within days after birth, while animals that overexpress GK exhibit improved glucose tolerance (Grupe, A., Hultgren, B., Ryan, A. et al, Cell 83, 69-78, 1995; Ferrie, T., Riu, E., Bosch, F. et al, FASER J., 10, 1213-. Increased glucose exposure in beta cells leads to increased insulin secretion by GK, and increased glucose in hepatocytes leads to increased glycogen deposition by GK and possibly decreased glucose production.

[0002] The conclusion that type II adult diabetes (MODY-2) in young people is due to loss of function caused by mutations in the GK gene suggests that GK also functions as a glucose sensor in humans (Liang, Y., Kesavan, P., Wang, L., et al, biochem. J.309, 167-. Another evidence that supports the important role of GK in the regulation of human glucose metabolism is the identification of patients expressing GK mutants with increased enzymatic activity. These patients exhibit fasting hypoglycemia due to excessive plasma insulin levels (Glaser, b., Kesavan, p., Heyman, m. et al, new england j. med.338, 226-. No mutation in the GK gene is found in most type II diabetics, and compounds that activate GK and thereby increase the sensitivity of the GK sensor system remain useful in treating the hyperglycemic symptoms of all type II diabetics. Glucokinase activators will increase the flux of glucose metabolism in beta-cells and liver parenchymal cells, which will result in increased insulin secretion. These substances will play a role in the treatment of type II diabetes.

[0003] The present invention provides a compound of formula I:

wherein R is¹Is halogen, nitro, amino, cyano, methyl, trifluoromethyl, hydroxy, methoxy, trifluoromethoxy, methylthio, methylsulfinyl, or methylsulfonyl;

R²is lower alkyl having 2-5 carbon atoms or-CH₂-R⁴Wherein R is⁴Is cycloalkyl having 3 to 6 carbon atoms; and

R³is an unsubstituted or mono-substituted five-or six-membered heteroaromatic ring which is linked to the indicated amine group via a ring carbon atom, which five-or six-membered heteroaromatic ring contains 1 to 3 heteroatoms selected from sulfur, oxygen or nitrogen, one of which is the nitrogen adjacent to the attached ring carbon atom; the mono-substituted heteroaromatic ring is mono-substituted at a position on a ring carbon atom not adjacent to the linking carbon atom, and the substituent is selected from the group consisting of: methyl, trifluoromethyl, chlorine, bromine, nitro, cyano,

-(CH_z)_n-OR⁵；

and- (CH)₂)_n-NHR⁵；

Wherein n is 0 or 1;

R⁵is hydrogen or lower alkyl.

[0004] It has been found that the compounds of formula I activate glucokinase in vitro. Glucokinase activators are used to increase insulin secretion in the treatment of type II diabetes.

[0005] The invention also relates to pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable carrier and/or adjuvant. In addition, the invention relates to the use of these compounds as therapeutically active substances and to their use for the preparation of medicaments for the treatment or prophylaxis of type II diabetes. The invention also relates to a preparation method of the compound shown in the formula I. Furthermore, the present invention relates to a method for the prevention or treatment of type II diabetes, which method comprises administering a compound of formula I to a human being or animal.

[0006] More specifically, the present invention provides a compound which is an amide according to formula I:

-(CH₂)_n-OR⁵；

and- (CH)₂)_n-NHR⁵；

Wherein n is 0 or 1;

R⁵is hydrogen or lower alkyl.

[0007] The term "lower alkyl" as used in the context of the present application includes straight or branched chain alkyl groups having 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl and the like. Preferred lower alkyl groups are lower alkyl groups having 2 to 5 carbon atoms, such as propyl and isopropyl.

[0008] As used herein, "perfluoro-lower alkyl" refers to any lower alkyl group wherein all of the hydrogens of the lower alkyl group are replaced or replaced with fluorine. Among the preferred perfluoro lower alkyl groups are trifluoromethyl, pentafluoroethyl, heptafluoropropyl, and the like.

[0009] "cycloalkyl" as used herein means a saturated hydrocarbon ring having 3 to 10 carbon atoms. Preferred cycloalkyl groups have 3 to 6 carbon atoms. A preferred cycloalkyl group is cyclobutyl.

[010] As used herein, "halogen" and "halo" refer to all four halogens, i.e., fluorine, chlorine, bromine, and iodine, unless otherwise indicated. The preferred halogen is chlorine.

[011] The term "aryl" as used herein denotes aromatic mononuclear aromatic hydrocarbon radicals, such as phenyl and tolyl, which may be unsubstituted or substituted in one or more positions by halogen, nitro, lower alkyl, or lower alkoxy. The term "aryl" also denotes polynuclear aryl radicals, such as, for example, naphthyl, anthryl, phenanthryl, which may be unsubstituted or substituted in one or more positions by halogen, nitro, lower alkyl or lower alkoxy. Preferred aryl groups are substituted and unsubstituted mononuclear aryl groups, in particular phenyl and tolyl. The term "aralkyl" denotes an alkyl group, preferably a lower alkyl group, wherein one hydrogen atom may be replaced by an aryl group. Examples of aralkyl groups are benzyl, 2-phenylethyl, 3-phenylpropyl, 4-chlorobenzyl, 4-methoxybenzyl and the like.

[012] The term "lower alkoxy" as used herein includes straight or branched chain alkoxy groups having 1 to 7 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, preferably methoxy and ethoxy.

[013] The term "lower alkanoic acid" as used herein means a lower alkanoic acid containing 2 to 7 carbon atoms, such as propionic acid, acetic acid, and the like. The term "lower alkanoyl" refers to monovalent alkanoyl groups having 2 to 7 carbon atoms, such as propionyl, acetyl, and the like. The term "aromatic acids" refers to arylalkanoic acids wherein the aryl group is as defined above and the alkane (alkanoic) contains 1 to 6 carbon atoms. The term "aroyl" refers to aromatic acids (aroic acids) wherein the aryl group is as defined above, wherein the hydroxyl group in the-COOH moiety is removed. Among them, benzoyl is preferred as the aroyl group.

[014] "lower alkylthio" as used herein means a lower alkyl group as described above attached to a thio group, which is attached to the rest of the molecule, for example methylthio. "lower alkylsulfinyl" as used herein means lower alkyl as described above attached to a sulfinyl group (sulfoxide) which is attached to the rest of the molecule, for example methylsulfinyl. "lower alkylsulfonyl" as used herein means that a lower alkyl group, as described above, is attached to a sulfonyl group, which is attached to the rest of the molecule, e.g., methanesulfonyl.

[015] During the synthesis reaction, various functional groups such as free carboxylic acid or hydroxyl groups may be protected by conventional hydrolyzable ester or ether protecting groups. The term "hydrolyzable ester or ether protecting group" as used herein refers to any ester or ether conventionally used to protect carboxylic acids or alcohols, which can be hydrolyzed to yield a hydroxyl or carboxyl group, respectively. Examples of ester groups useful for this purpose are those where the acyl moiety is derived from a lower alkane, aryl lower alkane, or lower alkane dicarboxylic acid. Among the activated acids that may be used to form these groups are acid anhydrides, acid halides, preferably acid chlorides or acid bromides derived from aryl or lower alkanoic acids. Examples of anhydrides are anhydrides derived from monocarboxylic acids, such as acetic anhydride, benzoic anhydride, and lower alkanedicarboxylic anhydrides, such as succinic anhydride, and chloroformates, such as trichloromethyl chloroformate and ethyl chloroformate being preferred. Suitable ether protecting groups for alcohols may be, for example, tetrahydropyranyl ethers, such as 4-methoxy-5, 6-dihydroxy-2H-pyranyl ether. Other suitable ethers are aroylmethyl ethers, such as benzyl, benzhydryl or trityl ethers or α -lower alkoxy lower alkyl ethers, for example, methoxymethyl or allyl ethers or alkyl silyl ethers, such as trimethylsilyl ether.

[016] The term "amino protecting group" refers to any conventional amino protecting group that can be cleaved to yield a free amino group. Preferred protecting groups are conventional amino protecting groups used in peptide synthesis. Particularly preferred are those amino protecting groups that are cleavable under moderately acidic conditions at pH 2-3. Particularly preferred amino protecting groups include tert-butyl carbamate (BOC), benzyl Carbamate (CBZ), and 9-fluorenyl (flurorenyl) methyl carbamate (FMOC).

[017]By R³The heteroaromatic ring as defined may be an unsubstituted or monosubstituted five-or six-membered aromatic heterocyclic ring having from 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur and which is attached to the amine of the amide group indicated via a ring carbon atom. The heteroaromatic ring contains the first nitrogen heteroatom adjacent to the attached ring carbon atom, and the other heteroatom, if present, can be sulfur, oxygen, or nitrogen. These heteroaromatic rings include, for example, pyridazinyl, isoxazolyl, isothiazolyl, and pyrazolyl. Among them, preferred heteroaromatic rings are pyridyl, pyrazinyl, thiazolyl, and particularly preferred are pyridyl and thiazolyl. These form R³The heteroaromatic ring of (a) is attached to the amide group through a ring carbon atom to form the amide of formula I. The carbon atoms of the rings attached by amide bonds to form the heteroaromatic ring of the compounds of formula I are not substituted by any substituent.

[018]R³Is an unsubstituted or mono-substituted five-or six-membered, preferably five-membered, heteroaromatic ring, the preferred ring containing a nitrogen heteroatom adjacent to the attached ring carbon atom and a second heteroatom adjacent to the attached ring carbon atom or adjacent to the first heteroatom. Preferred five-membered heteroaromatic rings contain 2 or 3 heteroatoms, of which thiazolyl, imidazolyl, oxazolyl and thiadiazolyl are particularly preferred. Most preferred are five-membered hetero compoundsThe aromatic ring is thiazolyl. When the heteroaromatic ring is a six-membered heteroaromatic ring, the ring is attached to the indicated amine group through a ring carbon atom, and one nitrogen heteroatom is adjacent to the attached ring carbon atom. Preferred six-membered heteroaromatic rings include, for example, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl, with pyridyl being particularly preferred.

[019] The term "pharmaceutically acceptable salt" as used herein includes any salt with an inorganic or organic pharmaceutically acceptable acid, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like. The term "pharmaceutically acceptable salt" also includes any pharmaceutically acceptable base salt, such as amine salts, trialkylamine salts, and the like. These salts can be readily formed by one of ordinary skill in the art using standard techniques.

[020]In one embodiment, the invention relates to compounds of formula I wherein R¹Is halogen, nitro, methyl, trifluoromethyl, hydroxy, methoxy, methylthio, or methylsulfonyl. Substituent R¹Preferred halogens in (1) are fluorine, chlorine and bromine. Preferred R¹Is halogen such as chlorine.

[021]In another embodiment, the invention relates to compounds of formula I wherein R²Lower alkyl having 2 to 5 carbon atoms, such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl and isopentyl. In another embodiment, R²is-CH₂-R⁴Wherein R is⁴Cycloalkyl groups having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, with cyclobutyl being preferred.

[022]In another embodiment, the invention relates to compounds of formula I wherein R³Is an unsubstituted or mono-substituted five-or six-membered heteroaromatic ring which is linked to the indicated amine group via a ring carbon atom and which contains 1, 2 or 3 heteroatoms selected from sulfur or nitrogen, one of which is the nitrogen adjacent to the attached ring carbon atom. Preferred unsubstituted or mono-substituted five-or six-membered heteroaromatic rings R³Is thiazolyl, thiadiazolylPyridyl, pyrazinyl, pyridazinyl, isoxazolyl, isothiazolyl, and pyrazolyl, with pyridyl and thiazolyl being particularly preferred.

[023]Mono-substituted five-or six-membered heteroaromatic ring R³Preferably substituted at a position of a ring carbon atom not adjacent to said linking carbon atom, and the substituent is selected from the group consisting of: methyl, trifluoromethyl, chloro, bromo, or

。

[024]In a preferred embodiment, R³Is a mono-substituted heteroaromatic ring selected from thiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, isoxazolyl, isothiazolyl, or pyrazolyl, with pyridyl and thiazolyl being particularly preferred. The mono-substituted heteroaryl ring is substituted with the following groups: methyl, trifluoromethyl, chloro, bromo, or

。

[025]In another preferred embodiment, a five-or six-membered heteroaromatic ring R³Is unsubstituted.

[026]In another preferred embodiment, the invention relates to compounds of formula I, wherein R⁵Is lower alkyl, preferably having 1 or 2 carbon atoms, such as for example ethyl.

[027] In a preferred embodiment, n is 1.

[028] Preferred compounds according to the invention are selected from the following group:

1-isopropyl-6-methyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

1-isopropyl-6-trifluoromethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

1-isopropyl-6-nitro-1H-indole-3-carboxylic acid thiazol-2-ylamide;

6-hydroxy-1-isopropyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

1-isopropyl-6-methoxy-1H-indole-3-carboxylic acid thiazol-2-ylamide;

1-isopropyl-6-methylthioalkyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

1-isopropyl-6-methanesulfonyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

6-fluoro-1-isopropyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

6-bromo-1-isopropyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

6-chloro-1-isopropyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

6-chloro-1-ethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

6-chloro-1-propyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

1-butyl-6-chloro-1H-indole-3-carboxylic acid thiazol-2-ylamide;

6-chloro-1-isobutyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

6-chloro-1-pentyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

6-chloro-1- (3-methyl-butyl) -1H-indole-3-carboxylic acid thiazol-2-ylamide;

6-chloro-1-cyclopropylmethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

6-chloro-1-cyclobutylmethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

6-chloro-1-cyclopentylmethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

6-chloro-1-cyclohexylmethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

6-chloro-1-isopropyl-1H-indole-3-carboxylic acid [1, 3, 4] thiadiazol-2-ylamide;

6-chloro-1-isopropyl-1H-indole-3-carboxylic acid pyridin-2-ylamide;

6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-methyl-thiazol-2-yl) -amide;

6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (4-methyl-thiazol-2-yl) -amide;

6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-chloro-thiazol-2-yl) -amide;

6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-bromo-thiazol-2-yl) -amide;

{2- [ (6-chloro-1-isopropyl-1H-indole-3-carbonyl) -amino ] -thiazol-4-yl } -acetic acid ethyl ester;

6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-methyl-pyridin-2-yl) -amide;

6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-trifluoromethyl-pyridin-2-yl) -amide;

6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-chloro-pyridin-2-yl) -amide;

6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-bromo-pyridin-2-yl) -amide; and pharmaceutically acceptable salts thereof.

[029] Further preferred compounds according to the invention are selected from the following group:

1-isopropyl-6-methyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

1-isopropyl-6-trifluoromethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

1-isopropyl-6-nitro-1H-indole-3-carboxylic acid thiazol-2-ylamide;

6-hydroxy-1-isopropyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

1-isopropyl-6-methoxy-1H-indole-3-carboxylic acid thiazol-2-ylamide;

1-isopropyl-6-methylthioalkyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

1-isopropyl-6-methanesulfonyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

6-fluoro-1-isopropyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

6-bromo-1-isopropyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

6-chloro-1-isopropyl-1H-indole-3-carboxylic acid thiazol-2-ylamide; and pharmaceutically acceptable salts thereof.

[030] Further preferred compounds according to the invention are selected from the following group:

6-chloro-1-ethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

6-chloro-1-propyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

1-butyl-6-chloro-1H-indole-3-carboxylic acid thiazol-2-ylamide;

6-chloro-1-isobutyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

6-chloro-1-pentyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

6-chloro-1- (3-methyl-butyl) -1H-indole-3-carboxylic acid thiazol-2-ylamide; and pharmaceutically acceptable salts thereof.

[031] Further preferred compounds according to the invention are selected from the following group:

6-chloro-1-cyclopropylmethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

6-chloro-1-cyclobutylmethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

6-chloro-1-cyclopentylmethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide;

6-chloro-1-cyclohexylmethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide; and pharmaceutically acceptable salts thereof.

[032] Further preferred compounds according to the invention are selected from the following group:

6-chloro-1-isopropyl-1H-indole-3-carboxylic acid pyridin-2-ylamide; and pharmaceutically acceptable salts thereof.

[033] Further preferred compounds according to the invention are selected from the following group:

6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-bromo-thiazol-2-yl) -amide;

{2- [ (6-chloro-1-isopropyl-1H-indole-3-carbonyl) -amino ] -thiazol-4-yl } -acetic acid ethyl ester; and pharmaceutically acceptable salts thereof.

[034] Further preferred compounds according to the invention are selected from the following group:

[035] The compounds of formula I can be prepared according to the following reaction scheme:

reaction scheme

Wherein R, R¹And R³As mentioned above, X is halogen, preferably iodine or bromine.

[036] In the first step of the scheme, the indole compounds of the formula II are converted into the corresponding 3-trifluoroacetyl indole compounds of the formula III by treatment with trifluoroacetic anhydride in a polar, water-miscible solvent such as tetrahydrofuran or N, N-dimethylformamide (J.chem.Soc.1954, 1651-1653; org.Prep.Proc.int.1970, 2, 297-303).

[037] The 3-trifluoroacetyl indole compound of formula III can be reacted with an alkyl halide of formula IV to produce an N-alkylated compound of formula V. The reaction may be carried out by any conventional means of N-alkylation of indoles. Preferred conditions for the N-alkylation of 3-trifluoroacetylindole of the compound of formula III include deprotection of the indole-NH with excess potassium carbonate in N, N-dimethylformamide followed by treatment with the desired alkyl halide and subsequent heating of the reaction mixture at elevated temperature, preferably 60-75 ℃.

[038] The N-alkylated 3-trifluoroacetyl indole compound of formula V is then converted to an N-alkylated indole-3-carboxylic acid compound of formula VI. The compound of formula V is susceptible to haloform cleavage using 20% aqueous sodium hydroxide at reflux to provide the desired indole-3-carboxylic acid compound of formula VI (J.chem.Soc.1954, 1651-.

[039] The compound of formula VI is then condensed with the compound of formula VII via conventional peptide coupling to yield the desired compound of formula I. In carrying out the reaction, the conversion may be carried out by any conventional method of condensing a primary amine with a carboxylic acid.

[040]Indoles of formula II are commercially available wherein R¹Is chloro [ 6-chloroindole]Fluoro [ 6-fluoroindole]Bromo [ 6-bromoindole]Nitro [ 6-nitroindole]Amino [ 6-aminoindoles]Cyano [ 6-cyanoindole]Methyl [ 6-methylindole]Trifluoromethyl [6- (trifluoromethyl) indole]Hydroxy [ 6-hydroxyindole]Methoxy [ 6-methoxyindole ]]And benzyloxy [ 6-benzyloxyindole]。

[041]Indoles of formula II wherein R¹Are trifluoromethoxy, methylthio, and iodo, and can be prepared by one skilled in the art by applying the synthetic transformations reported in the following chemical literature: (a)6- (trifluoromethoxy) indole, J.Med.chem.1998, 41(10), 1598-; (b)6- (methylthio) indole, PCT International application (1998), WO 9804553A 1; and (c) 6-iodoindole, Heterocycles 1987, 26(11), 2817-2822.

[042]Before carrying out the reaction scheme, wherein R¹The indoles of formula II which are amino and hydroxy must be protected. The amino and hydroxyl groups may be protected using any conventional acid removable group. Removal of the protecting groups from the amine and hydroxy group after coupling of the compound of formula VI with the amine of formula VII affords the desired compound of formula I

[043]Once in which R is obtained¹Compounds of formula I which are methylthio groups, which can be converted into the corresponding compounds in which R is¹A compound of formula I which is methylsulfinyl. This conversion can be carried out using any conventional method for converting a methylthio substituent to a methylsulfinyl substituent (sulfoxide). On the other hand, if desired, in which R is prepared¹Compounds of formula I which are mesyl, wherein R¹Compounds of formula I which are methylthio groups may also be used as starting materials. This conversion can be carried out using any conventional method for converting a methylthio substituent to a methylsulfonyl substituent.

[044]The aminoheteroaromatic compounds of formula VII may be obtained commercially, or are known in the chemical literature, or may be prepared by one skilled in the art by modification using standard synthetic transformations reported in the chemical literature. For the production of compounds of formula I, hereinPreparation of the desired R³The synthetic transformation of substituents can be carried out before or after the transformation of the compound of the formula VII into the compound of the formula I.

[045]For example, it can be derived from the corresponding carboxylic acid- (CH)₂)_nCOOR⁵(n-0 and R⁵Hydrogen) to an aminoheteroaromatic compound of formula VII in which one substituent is- (CH)₂)_nCOOR⁵And wherein n is 0 or 1, and R⁵Is hydrogen or lower alkyl. Lower carboxylic acids can be converted to their higher homologues using any conventional carbon homologation (homologation) method (see, e.g., Skeean, R.W; Goel, o.p. synthesis, 1990, 628), which in turn can be converted to the corresponding lower alkyl esters by applying conventional esterification methods. The amino heteroaromatic compounds of formula VII, wherein one substituent is- (CH), can be prepared in turn by means of the carboxylic acids mentioned above₂)_nC(＝O)NHR⁵And wherein n is 0 or 1, and R⁵Is hydrogen or lower alkyl. The conversion can be carried out using any conventional method for converting carboxylic acids to the corresponding amides. In turn, the lower alkyl amide may be converted to the corresponding amine of formula VII, wherein one substituent is- (CH), by any conventional amide reduction method₂)_nNHR⁵Wherein n is 1. Aminoheteroaromatic compounds of formula VII, wherein one of the desired substituents is- (CH), can be prepared from the corresponding lower alkyl esters described above₂)_nOR⁵Wherein n is 1. The lower alkyl ester can be converted to the corresponding alcohol using any conventional ester reduction method.

[046] The above amines and alcohols must be selectively protected before the condensation step is carried out. Any conventional acid-removable group may be used to protect the amino and alcohol groups. After the coupling step, the protecting groups are removed from the amine and alcohol to produce the desired compound of formula I.

[047] If it is desired to prepare aminoheteroaromatic compounds of the formula VII in which one substituent is cyano or compounds of the formula I in which one substituent on the five-or six-membered heteroaromatic ring is cyano, the corresponding halogen, in particular bromine, can be used as starting material. The conversion may be carried out using any conventional method for converting a halogen to a cyanide.

[048] All compounds of formula I, including the compounds listed in the examples, activate glucokinase in vitro by the method of biologically active example a. In this method, they increase the flux (flux) of glucose metabolism, causing an increase in insulin secretion. Thus, the compounds of formula I are glucokinase activators useful for increasing insulin secretion.

[049] The compounds of formula I above may be used as medicaments for the treatment of type II diabetes, depending on their ability to activate glucokinase. Thus, as mentioned above, medicaments containing a compound of formula I are also an object of the present invention, and likewise a process for the preparation of such medicaments, which comprises bringing one or more compounds of formula I and, if desired, one or more other therapeutically valuable substances into a galenical administration form, for example by combining a compound of formula I with pharmaceutically acceptable carriers and/or adjuvants.

[050] The pharmaceutical compositions can be administered orally, for example in the form of tablets, coated tablets, dragees, hard or soft gelatine capsules, solutions, emulsions or suspensions. Administration can also be effected rectally, e.g., using suppositories; topical or transdermal administration, for example using ointments, creams, gels or solutions; or parenterally, e.g., intravenously, intramuscularly, subcutaneously, intrathecally, or transdermally, using injectable solutions. Also, administration may be sublingual or as an aerosol, e.g., spray. For the preparation of tablets, coated tablets, dragees, hard gelatin capsules, the compounds of the present invention may be mixed with pharmaceutically inert, organic or inorganic excipients. Examples of suitable excipients for tablets, coated tablets, dragees, hard gelatine capsules include lactose, maize starch or derivatives thereof, talc or stearic acid or salts thereof. Suitable excipients for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid or liquid polyols and the like; however, depending on the nature of the active ingredient, there may be cases where the soft gelatin capsule does not require any excipients at all. For the preparation of solutions and syrups, excipients which may be used include, for example, water, polyols, sugars, invert sugar and glucose. For the preparation of injectable solutions, excipients which may be used include, for example, water, alcohols, polyols, glycerol, and vegetable oils. For the preparation of suppositories and for topical or transdermal administration, excipients which may be used include, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols. The pharmaceutical compositions may also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They may also contain other therapeutically valuable active agents. It is a prerequisite that all adjuvants used in the preparation of the formulation are non-toxic.

[051] Preferred dosage forms for use are intravenous, intramuscular or oral administration, most preferably oral administration. The effective dosage for administering a compound of formula (I) will depend on the nature of the particular active ingredient, the age and requirements of the patient and the mode of administration. In general, dosages of about 1-100mg/kg body weight/day are contemplated.

[052] The invention includes the following examples.

Example 11-isopropyl-6-methyl-1H-indole-3-carboxylic acid thiazol-2-ylamide

[053]A solution of 6-methyl-1H-indole (1.0g, 7.62mmol) in tetrahydrofuran (10mL) cooled to 0 deg.C was treated with trifluoroacetic anhydride (1.62mL, 11.43 mmol). The reaction was stirred at 0 ℃ for 1 hour. At this point, the resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 2, 2, 2-trifluoro-1- (6-methyl-1H-indol-3-yl) -ethanone (146mg, 8%) as a white solid: mp 216-; EI-HRMS m/e calculation value C₁₁H₈F₃NO(M⁺)227.0558, found 227.0554.

[054]A solution of 2, 2, 2-trifluoro-1- (6-methyl-1H-indol-3-yl) -ethanone (1.5g, 6.60mmol) in N, N-dimethylformamide (15mL) at 25 ℃ was treated with potassium carbonate (2.28g, 16.51 mmol). The resulting mixture was stirred at 25 ℃ for 15 minutes and then treated with 2-iodopropane (0.99mL, 9.90 mmol). The reaction was heated at 65 ℃ for 3 hours. At this point, the reaction was cooled to 25 ℃ and partitioned between water (100mL) and ethyl acetate (100 mL). The organic layer was then washed with 1N aqueous hydrochloric acid (1X 50mL) and saturated aqueous sodium chloride (1X 50mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH40M, Silica, 4/1 hexane/ethyl acetate) afforded 2, 2, 2-trifluoro-1- (1-isopropyl-6-methyl-1H-indol-3-yl) -ethanone (1.61g, 90.6%) as a pink solid: mp 65-68 ℃; EI-HRMS m/e calculation value C₁₄H₁₄F₃NO(M⁺)269.1027, found 269.1037.

[055]A solution of 2, 2, 2-trifluoro-1- (1-isopropyl-6-methyl-1H-indol-3-yl) -ethanone (1.50g, 5.57mmol) in 20% aqueous sodium hydroxide (20mL) was heated to 110 ℃ for 18H. At this point, the reaction was cooled to 25 ℃, partitioned between water (150mL) and ethyl acetate (150mL), and then treated with 1N aqueous hydrochloric acid (50 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (1X 50mL), water (1X 50mL) and saturated aqueous sodium chloride (1X 50 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated under vacuum to give 1-isopropyl-6-methyl-1H-indole-3-carboxylic acid (1.19g, 98%) as a yellow solid: mp 185-186 ℃; EI-HRMSm/e calculated value C₁₃H₁₅NO₂(M⁺)217.1103, found 217.1110.

[056]A solution of triphenylphosphine (628mg, 2.39mmo1) in dichloromethane (5mL) cooled to 0 ℃ was treated with N-bromosuccinimide (425mg, 2.39 mmol). The reaction was stirred at 0 ℃ for 15 min and then treated with 1-isopropyl-6-methyl-1H-indole-3-carboxylic acid (400mg, 1.84 mmol). The reaction was stirred at 0 ℃ for 15 minutes and then warmed to 25 ℃ at which temperatureStirred for 30 minutes. The reaction was then treated with 2-aminothiazole (424mg, 4.23mmol) and stirred at 25 ℃ for 16 h. At this time, the mixture was partitioned between water (75mL) and ethyl acetate (75mL) and treated with 1N aqueous hydrochloric acid (40 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (1 × 40mL) and saturated aqueous sodium chloride (1 × 40mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH40M, Silica, 1/1 hexane/ethyl acetate) gave 1-isopropyl-6-methyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (229mg, 41.5%) as a tan solid: mp 215-217 ℃; EI-HRMS m/e calculation value C₁₆H₁₇N₃OS(M⁺)363.0041, found 363.0034.

Example 21-isopropyl-6-trifluoromethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide

[057]A solution of 6-trifluoromethyl-1H-indole (2.0g, 10.80mmol) in tetrahydrofuran (10mL) cooled to 0 deg.C was treated with trifluoroacetic anhydride (2.29mL, 16.20 mmol). The reaction was stirred at 0 ℃ for 1 hour and then allowed to warm to 25 ℃ and stirred for 16 hours. At this time, the reaction was poured into water (150mL) and stirred at 25 ℃ for 5 minutes. The resulting precipitate was collected by filtration, washed with water (200mL), and dried under vacuum to give 2, 2, 2-trifluoro-1- (6-trifluoromethyl-1H-indol-3-yl) -ethanone (2.95g, 97%) as a white solid: mp 250-251 ℃; EI-HRMS m/e calculation value C₁₁H₅F₆NO(M⁺)281.0275, found 281.0266.

[058]A solution of 2, 2, 2-trifluoro-1- (6-trifluoromethyl-1H-indol-3-yl) -ethanone (1.0g, 3.56mmol) in N, N-dimethylformamide (10mL) at 25 ℃ was treated with potassium carbonate (1.22g, 8.89 mmol). The resulting mixture was stirred at 25 ℃ for 15 minutes and then treated with 2-iodopropane (0.53mL, 5.34 mmol). The reaction was heated at 65 ℃ for 4 hours. At this point, the reaction was cooled to 25 ℃ and quenched in water (75mL) and EtOHPartition between ethyl acetate (75 mL). The organic layer was then washed with 1N aqueous hydrochloric acid (1X 25mL), water (1X 50mL) and saturated aqueous sodium chloride (1X 50 mL). Drying over magnesium sulfate, filtration, and concentration of the organic layer under vacuum gave 2, 2, 2-trifluoro-1- (1-isopropyl-6-trifluoromethyl-1H-indol-3-yl) -ethanone (850mg, 74%) as a light orange solid: mp92-93 ℃; EI-HRMS m/e calculation value C₁₄H₁₁F₆NO(M⁺)323.0745, found 323.0739.

[059]A solution of 2, 2, 2-trifluoro-1- (1-isopropyl-6-trifluoromethyl-1H-indol-3-yl) -ethanone (800mg, 2.48mmol) in 20% aqueous sodium hydroxide (12mL) was heated to 110 ℃ for 3H. At this point, the reaction was cooled to 25 ℃, partitioned between water (100mL) and ethyl acetate (100mL), and then treated with 1N aqueous hydrochloric acid (50 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated under vacuum to give 1-isopropyl-6-trifluoromethyl-1H-indole-3-carboxylic acid (704mg, 99%) as a yellow solid: mp177-178 ℃; EI-HRS m/e calculation value C₁₃H₁₂F₃NO₂(M⁺)271.0820, found 271.0807.

[060]A solution of triphenylphosphine (377mg, 1.44mmol) in dichloromethane (4mL) cooled to 0 deg.C was treated with N-bromosuccinimide (256mg, 1.44 mmol). The reaction was stirred at 0 ℃ for 15 minutes. At this point, 1-isopropyl-6-trifluoromethyl-1H-indole-3-carboxylic acid (300mg, 1.11mmol) was treated. The reaction was stirred at 0 ℃ for 5 minutes, then warmed to 25 ℃ and stirred at this temperature for 30 minutes. The reaction was then treated with 2-aminothiazole (255mg, 2.54mmol) and stirred at 25 ℃ for 24 h. At this time, the mixture was partitioned between water (50mL) and ethyl acetate (50mL) and treated with 1N aqueous hydrochloric acid (25 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (1 × 25mL) and saturated aqueous sodium chloride (1 × 25mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH40S, Silica, diethyl ether) afforded 1-isopropyl-6-trifluoromethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (43mg, 11%) as a pale pink solid: mp 246-247 deg.C; EI-HRMS m/e calculation value C₁₆H₁₄F₃N₃OS(M⁺)353.0810, found 353.0801.

Example 31-isopropyl-6-nitro-1H-indole-3-carboxylic acid thiazol-2-ylamide

[061]A solution of 6-nitro-1H-indole (1.0g, 6.17mmol) cooled to 0 ℃ in tetrahydrofuran (5mL) was treated with trifluoroacetic anhydride (1.31mL, 9.25 mmol). The reaction was stirred at 0 ℃ for 1 hour and then allowed to warm to 25 ℃ and stirred for 16 hours. At this time, the reaction mixture was poured into water (100ml) and stirred at 25 ℃ for 5 minutes. The resulting precipitate was collected by filtration, washed with water (100mL), and dried under vacuum. The solid was redissolved in tetrahydrofuran (8mL) at 25 ℃ and the resulting solution was treated with trifluoroacetic anhydride (1mL, 7.08mmol) and stirred at 25 ℃ for 1 hour. The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 2, 2, 2-trifluoro-1- (6-nitro-1H-indol-3-yl) -ethanone (646mg, 40%) as a yellow solid: mp263-265 ℃; EI-HRMS m/e calculation value C₁₀H₅F₃N₂O₃(M⁺)258.0252, found 258.0253.

[062]A solution of 2, 2, 2-trifluoro-1- (6-trifluoromethyl-1H-indol-3-yl) -ethanone (1.0g, 3.87mmol) in N, N-dimethylformamide (10mL) at 25 ℃ was treated with potassium carbonate (1.34g, 9.68 mmol). The resulting mixture was stirred at 25 ℃ for 10 minutes and then treated with 2-iodopropane (0.58mL, 5.81 mmol). The reaction was heated at 65 ℃ for 3 hours. At this point, the reaction was cooled to 25 ℃ and partitioned between water (50mL) and ethyl acetate (50 mL). The mixture was then treated with 1N aqueous hydrochloric acid (25 mL). The organic layer was washed with water (1 × 50mL) and saturated aqueous sodium chloride (1 × 50mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give 2, 2, 2-trifluoro-1- (1-isopropyl-6-nitro-1H-indol-3-yl) -ethanone (581mg, 98%) as a yellow solid: mp 143-145 ℃; EI-HRMS m/e calculation value C₁₄H₁₄F₃NO(M⁺)269.1027, found 269.1037.

[063]A solution of 2, 2, 2-trifluoro-1- (1-isopropyl-6-nitro-1H-indol-3-yl) -ethanone (525mg, 1.75mmol) in 20% aqueous sodium hydroxide (10mL) was heated to 110 ℃ for 2H. At this point, the reaction was cooled to 25 ℃, partitioned between water (75mL) and ethyl acetate (75mL), and then treated with 1N aqueous hydrochloric acid (25 mL). The organic layer was washed with water (1 × 50mL) and saturated aqueous sodium chloride (1 × 50mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give 1-isopropyl-6-nitro-1H-indole-3-carboxylic acid (436mg, 99%) as a yellow solid: mp 242-243 ℃; EI-HRMS m/e calculation value C₁₂H₁₂N₂O₄(M⁺)248.0797, found 248.0796.

[064]A solution of 1-isopropyl-6-nitro-1H-indole-3-carboxylic acid (200mg, 0.81mmol) in dichloromethane (4mL) and N, N-diisopropylethylamine (0.32mL, 1.85mmol) at 25 ℃ was treated with benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluoro-phosphate (463mg, 1.05 mmol). The reaction was stirred at 25 ℃ for 20 minutes. At this point, the reaction was treated with 2-aminothiazole (186mg, 1.85mmol) and stirred at 25 ℃ for 24 hours. At this time, the reaction mixture was partitioned between water (50mL) and ethyl acetate (50mL) and treated with 1N aqueous hydrochloric acid (25 mL). The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting solid was dissolved in a hot solution of hexane/ethyl acetate 1/1 and then filtered. The filtrate was cooled in a refrigerator for 1 hour. At this time, the resulting solid was collected by filtration. The filtrate was concentrated in vacuo. Biotage chromatography (FLASH40S, Silica, 1/1 hexane/ethyl acetate) gave 1-isopropyl-6-nitro-1H-indole-3-carboxylic acid thiazol-2-ylamide (13mg, 4.9%) as a yellow solid: mp 236-239 ℃; EI-HRMS m/e calculation value C₁₅H₁₄N₄O₃S(M⁺)330.0786, found 330.0792.

Example 46-hydroxy-1-isopropyl-1H-indole-3-carboxylic acid thiazol-2-ylamide

[065]A solution of 6-methoxy-1H-indole (927mg, 6.30mmol) in tetrahydrofuran (5mL) cooled to 0 deg.C was treated with trifluoroacetic anhydride (1.33mL, 9.45mmol) before tetrahydrofuran (3mL) was added. The reaction was stirred at 0 ℃ for 30 minutes. At this time, the reaction mixture was poured into water (75 mL). The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 2, 2, 2-trifluoro-1- (6-methoxy-1H-indol-3-yl) -ethanone (1.56g, 94.5%) as a yellow solid: mp 206-208 ℃; EI-HRMS m/e calculation value C₁₁H₈F₃NO₂(M⁺)243.0507, found 243.0515.

[066]A solution of 2, 2, 2-trifluoro-1- (6-methoxy-1H-indol-3-yl) -ethanone (1.0g, 4.11mmol) in N, N-dimethylformamide (10mL) at 25 ℃ was treated with potassium carbonate (1.42mg, 10.28 mmol). The resulting mixture was stirred at 25 ℃ for 30 minutes and then treated with 2-iodopropane (0.62mL, 6.17 mmol). The reaction was heated at 65 ℃ for 20 hours. At this point, the reaction was cooled to 25 ℃ and partitioned between water (50mL) and ethyl acetate (50 mL). The mixture was then treated with 1N aqueous hydrochloric acid (25mL), shaken and separated. The organic layer was washed with water (1 × 50mL) and saturated aqueous sodium chloride (1 × 50mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH40M, Silica, 3/1 hexane/ethyl acetate) afforded 2, 2, 2-trifluoro-1- (1-isopropyl-6-methoxy-1H-indol-3-yl) -ethanone (99mg, 85%) as a yellow solid: mp 58-60 ℃; EI-HRMS m/e calculation value C₁₄H₁₄F₃NO₂(M⁺)285.0977, found 285.0974.

[067]A solution of 2, 2, 2-trifluoro-1- (1-isopropyl-6-methoxy-1H-indol-3-yl) -ethanone (950mg, 3.33mmol) in 20% aqueous sodium hydroxide (12mL) was heated to 105 ℃ for 18H. At this point, the reaction was cooled to 25 ℃, partitioned between water (50mL) and ethyl acetate (50mL), then taken up with 1N saltAqueous acid (35 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting solid was collected by filtration, washed with petroleum ether and dried in vacuo to give 1-isopropyl-6-methoxy-1H-indole-3-carboxylic acid (553mg, 71%) as orange needle crystals: mp 162-163 ℃; EI-HRMS m/e calculation value C₁₃H₁₅NO₃(M⁺)233.1052, found 233.1056.

[068]A solution of triphenylphosphine (219mg, 0.84mmol) in dichloromethane (3mL) cooled to 0 deg.C was treated with N-bromosuccinimide (149mg, 0.84 mmol). The reaction was stirred at 0 ℃ for 15 minutes. At this point, the reaction was treated with 1-isopropyl-6-methoxy-1H-indole-3-carboxylic acid (150mg, 0.64 mmol). The reaction was stirred at 0 ℃ for 5 minutes, then warmed to 25 ℃ and stirred at this temperature for 30 minutes. The reaction was then treated with 2-aminothiazole (148mg, 1.48mmol) and stirred at 25 ℃ for 24 h. At this time, the mixture was partitioned between water (50mL) and ethyl acetate (50mL) and treated with 1N aqueous hydrochloric acid (25 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (1 × 25mL) and saturated aqueous sodium chloride (1 × 25mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH40S, Silica, 1/1 hexane/ethyl acetate) gave 1-isopropyl-6-methoxy-1H-indole-3-carboxylic acid thiazol-2-ylamide (101mg, 50%) as a brown solid: mp 182 and 185 ℃; EI-HRMS m/e calculation value C₁₆H₁₇N₃O₂S(M⁺)315.1041, found 315.1039.

[069]A solution of 1.0M boron tribromide in dichloromethane (2.70mL, 2.70mmol) at 25 ℃ was treated with a solution of 1-isopropyl-6-methoxy-1H-indole-3-carboxylic acid thiazol-2-ylamide (85mg, 0.27mmol) in dichloromethane (2.7 mL). The reaction was stirred at 25 ℃ for 1 hour. At this point, the reaction was cooled to 0 ℃ and then treated with 20% aqueous ammonium hydroxide (3 mL). The reaction mixture was stirred at 0 ℃ for 15 minutes. At this time, the resulting precipitate was collected by filtration to give (6-hydroxy-1-isopropyl-1H-indole-3-carboxylic acid thiazol-2-ylamide) (31.9mg, 39%) as a yellow solid at mp 239 ℃; EI-HRMS calculated as m/e C₁₅H₁₅N₃O₂S(M⁺)315.1041, found 315.1039.

Example 51-isopropyl-6-methoxy-1H-indole-3-carboxylic acid thiazol-2-ylamide

[070]A solution of 6-methoxy-1H-indole (927mg, 6.30mmol) in tetrahydrofuran (5mL) cooled to 0 deg.C was treated with trifluoroacetic anhydride (1.33mL, 9.45mmol) before tetrahydrofuran (3mL) was added. The reaction was stirred at 0 ℃ for 30 minutes. At this time, the reaction mixture was poured into water (75 mL). The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 2, 2, 2-trifluoro-1- (6-methoxy-1H-indol-3-yl) -ethanone (1.56g, 94.5%) as a yellow solid: mp 206-208 ℃; EI-HRMS m/e calculation value C₁₁H₈F₃NO₂(M⁺)243.0507, found 243.0515.

[071]A solution of 2, 2, 2-trifluoro-1- (6-methoxy-1H-indol-3-yl) -ethanone (1.0g, 4.11mmol) in N, N-dimethylformamide (10mL) at 25 ℃ was treated with potassium carbonate (1.42mg, 10.28 mmol). The resulting mixture was stirred at 25 ℃ for 30 minutes and then treated with 2-iodopropane (0.62mL, 6.17 mmol). The reaction was heated at 65 ℃ for 20 hours. At this point, the reaction was cooled to 25 ℃ and partitioned between water (50mL) and ethyl acetate (50 mL). The mixture was then treated with 1N aqueous hydrochloric acid (25mL), shaken and separated. The organic layer was washed with water (1 × 50mL) and saturated aqueous sodium chloride (1 × 50mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH40M, Silica, 3/1 hexane/ethyl acetate) afforded 2, 2, 2-trifluoro-1- (1-isopropyl-6-methoxy-1H-indol-3-yl) -ethanone (99mg, 85%) as a yellow solid: mp 58-60 ℃; EI-HRMS m/e calculation value C₁₄H₁₄F₃NO₂(M⁺)285.0977, found 285.0974.

[072]A solution of 2, 2, 2-trifluoro-1- (1-isopropyl-6-methoxy-1H-indol-3-yl) -ethanone (950mg, 3.33mmol) in 20% aqueous sodium hydroxide (12mL) was heated to 105 ℃ for 18H. At this point, the reaction was cooled to 25 ℃, partitioned between water (50mL) and ethyl acetate (50mL), and then treated with 1N aqueous hydrochloric acid (35 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting solid was collected by filtration, washed with petroleum ether and dried in vacuo to give 1-isopropyl-6-methoxy-1H-indole-3-carboxylic acid (553mg, 71%) as orange needle crystals: mp 162-163 ℃; EI-HRMS m/e calculation value C₁₃H₁₅NO₃(M⁺)233.1052, found 233.1056.

[073]A solution of triphenylphosphine (219mg, 0.84mmol) in dichloromethane (3mL) cooled to 0 deg.C was treated with N-bromosuccinimide (149mg, 0.84 mmol). The reaction was stirred at 0 ℃ for 15 minutes. At this point, the reaction was treated with 1-isopropyl-6-methoxy-1H-indole-3-carboxylic acid (150mg, 0.64 mmol). The reaction was stirred at 0 ℃ for 5 minutes, then warmed to 25 ℃ and stirred at this temperature for 30 minutes. The reaction was then treated with 2-aminothiazole (148mg, 1.48mmol) and stirred at 25 ℃ for 24 h. At this time, the mixture was partitioned between water (50mL) and ethyl acetate (50mL) and treated with 1N aqueous hydrochloric acid (25 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (1 × 25mL) and saturated aqueous sodium chloride (1 × 25mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH40S, Silica, 1/1 hexane/ethyl acetate) gave 1-isopropyl-6-methoxy-1H-indole-3-carboxylic acid thiazol-2-ylamide (101mg, 50%) as a brown solid: mp 182 and 185 ℃; EI-HRMS m/e calculation value C₁₆H₁₇N₃O₂S(M⁺)315.1041, found 315.1039.

Example 61-isopropyl-6-methylthioalkyl-1H-indole-3-carboxylic acid thiazol-2-ylamide

[074]A mixture of potassium hydride in mineral oil (35 wt.%, 3.04g, 26.52mmol) was cooled to 0 ℃ in tetrahydrofuran (53mL) and then treated with a solution of 6-bromo-1H-indole (5.20g, 26.52mmol) in tetrahydrofuran (53 mL). The reaction was stirred at 0 ℃ for 30 minutes. At this point, the reaction was cooled to-78 ℃ and treated with a solution of 1.7M t-butyllithium in pentane (31.2mL, 53.04 mmol). The reaction mixture was stirred at-78 ℃ for 20 minutes. At this point, a solution of dimethyldisulfide (4.78mL, 53.04mmol) in tetrahydrofuran (15mL) was added to the reaction. The reaction was then warmed to 25 ℃ and stirred at this temperature for 18 hours. The reaction was then quenched by the addition of saturated aqueous ammonium chloride (300mL) and extracted with ethyl acetate (1X 500 mL). The organic layer was washed with saturated aqueous sodium chloride (1 × 300mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 9/1 hexanes/ethyl acetate) afforded 6-methionyl-1H-indole (2.3g, 53%) as an off-white solid, mp 88-90 ℃; EI-HRMS m/e calculation value C₉H₉NS(M⁺)163.0456, found 163.0457.

[075]A solution of 6-methionyl-1H-indole (1.30g, 7.96mmol) in tetrahydrofuran (5mL) cooled to 0 deg.C was treated with trifluoroacetic anhydride (1.69mL, 11.94mmol) before tetrahydrofuran (5mL) was added. The reaction was stirred at 0 ℃ for 30 minutes and then warmed to 25 ℃. At this time, the reaction mixture was poured into water (50mL) and stirred at 25 ℃ for 30 minutes. The resulting precipitate was collected by filtration and dried under vacuum. The resulting solid was suspended in tetrahydrofuran (5mL) due to the presence of about 10% unreacted 6-methionyl-1H-indole and treated again with trifluoroacetic anhydride (1.12mL, 7.96 mmol). The reaction mixture was stirred at 25 ℃ for 2 days. At this point, the resulting solid was collected by filtration, washed with petroleum ether, and dried under vacuum to give 2, 2, 2-trifluoro-1- (6-methylthioalkyl-1H-indol-3-yl) -ethanone (1.03g, 50%) as a yellow solid: mp 237-; EI-HRMS m/e calculation value C₁₁H₈F₃NOS(M⁺)259.0279, found 259.0270.

[076]The reaction solution of 2,a solution of 2-trifluoro-1- (6-methylthioalkyl-1H-indol-3-yl) -ethanone (200mg, 0.77mmol) in N, N-dimethylformamide (2mL) at 25 ℃ was treated with potassium carbonate (160mg, 1.16 mmol). The resulting mixture was stirred at 25 ℃ for 15 minutes and then treated with 2-iodopropane (0.11mL, 1.16 mmol). The reaction was stirred at 25 ℃ for 18 hours and then heated to 60 ℃ for 2 hours. At this point, the reaction was cooled to 25 ℃ and partitioned between water (50mL) and ethyl acetate (50 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate (1X 50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40S, Silica, 3/1 hexane/ethyl acetate) gave 2, 2, 2-trifluoro-1- (1-isopropyl-6-methylthioalkyl-1H-indol-3-yl) -ethanone (216mg, 93%) as an off-white solid: mp 67-69 ℃; EI-HRMS m/e calculation value C₁₄H₁₄F₃NOS(M⁺)301.0748, found 301.0740.

[077]A solution of 2, 2, 2-trifluoro-1- (1-isopropyl-6-methylthioalkyl-1H-indol-3-yl) -ethanone (200mg, 0.77mmol) in tetrahydrofuran (1mL) at 25 ℃ was treated with 20% aqueous sodium hydroxide (2 mL). The mixture was heated to 100 ℃ for 24 hours. At this point, the reaction was cooled to 25 ℃, partitioned between water (40mL) and ethyl acetate (40mL), and the solution was then treated with 1N aqueous hydrochloric acid. The layers were shaken and separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40S, Silica, 2/1 hexane/ethyl acetate) gave 1-isopropyl-6-methylthioalkyl-1H-indole-3-carboxylic acid (126mg, 77%) as a white solid: mp 132-; EI-HRMS m/e calculation value C₁₃H₁₅NO₂S(M⁺)249.0823, found 249.0819.

[078]A solution of 1-isopropyl-6-methylthioalkyl-1H-indole-3-carboxylic acid (275mg, 1.10mmol) and benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (585mg, 1.32mmol) in dichloromethane (5mL) at 25 ℃ was treated with N, N-diisopropylethylamine (0.44mL, 2.54 mmol). The reaction was stirred at 25 ℃ for 30 minutes. At this point, the reaction was treated with 2-aminothiazole (254mg, 2.54mmol) and stirred at 25 ℃ for 18 h. At this time, the process of the present invention,the reaction was partitioned between water (40mL) and ethyl acetate (40mL) and treated with 1N aqueous hydrochloric acid (25 mL). Shaken and the layers separated. The organic layer was washed with saturated aqueous sodium bicarbonate (1X 25mL), water (1X 25mL) and saturated aqueous sodium chloride (1X 25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40S, Silica, 1/1 hexane/ethyl acetate) gave 1-isopropyl-6-methylthioalkyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (155mg, 42%) as a light yellow solid: mp 172-176 ℃; (ES)⁺Calculation of HRMS m/e C₁₆H₁₇N₃OS₂(M+Na)⁺354.0705, found 354.0709.

Example 71-isopropyl-6-methanesulfonyl-1H-indole-3-carboxylic acid thiazol-2-ylamide

[079]A mixture of potassium hydride in mineral oil (35 wt.%, 3.04g, 26.52mmol) was cooled to 0 ℃ in tetrahydrofuran (53mL) and then treated with a solution of 6-bromo-1H-indole (5.20g, 26.52mmol) in tetrahydrofuran (53 mL). The reaction was stirred at 0 ℃ for 30 minutes. At this point, the reaction was cooled to-78 ℃ and treated with a solution of 1.7M t-butyllithium in pentane (31.2mL, 53.04 mmol). The reaction mixture was stirred at-78 ℃ for 20 minutes. At this point, a solution of dimethyldisulfide (4.78mL, 53.04mmol) in tetrahydrofuran (15mL) was added to the reaction. The reaction was then warmed to 25 ℃ and stirred at this temperature for 18 hours. The reaction was then quenched by the addition of saturated ammonium chloride solution (300mL) and extracted with ethyl acetate (1X 500 mL). The organic layer was washed with saturated aqueous sodium chloride (1 × 300mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-mesh 400, 9: 1 hexane/ethyl acetate) afforded 6-methionyl-1H-indole (2.3g, 53%) as an off-white solid, mp 88-90 ℃; EI-HRMS m/e calculation value C₉H₉NS(M⁺)163.0456, found 163.0457.

[080]A solution of 6-methionyl-1H-indole (1.30g, 7.96mmol) in tetrahydrofuran (5mL) cooled to 0 deg.C was treated with trifluoroacetic anhydride (1.69mL, 11.94mmol) before tetrahydrofuran (5mL) was added. The reaction was stirred at 0 ℃ for 30 minutes and then warmed to 25 ℃. At this time, the reaction mixture was poured into water (50mL) and stirred at 25 ℃ for 30 minutes. The resulting precipitate was collected by filtration and dried under vacuum. The resulting solid was suspended in tetrahydrofuran (5mL) due to the presence of about 10% unreacted 6-methionyl-1H-indole and treated again with trifluoroacetic anhydride (1.12mL, 7.96 mmol). The reaction mixture was stirred at 25 ℃ for 2 days. At this point, the resulting solid was collected by filtration, washed with petroleum ether, and dried under vacuum to give 2, 2, 2-trifluoro-1- (6-methylthioalkyl-1H-indol-3-yl) -ethanone (1.03g, 50%) as a yellow solid: mp 237-; EI-HRMS m/e calculation value C₁₁H₈F₃NOS(M⁺)259.0279, found 259.0270.

[081]A solution of 2, 2, 2-trifluoro-1- (6-methylthioalkyl-1H-indol-3-yl) -ethanone (200mg, 0.77mmol) in N, N-dimethylformamide (2mL) at 25 ℃ was treated with potassium carbonate (160mg, 1.16 mmol). The reaction was stirred at 25 ℃ for 15 minutes and then treated with 2-iodopropane (0.11mL, 1.16 mmol). The reaction was stirred at 25 ℃ for 18 hours and then heated to 60 ℃ for 2 hours. At this point, the reaction was cooled to 25 ℃ and partitioned between water (50mL) and ethyl acetate (50 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate (1X 50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40S, Silica, 3/1 hexane/ethyl acetate) gave 2, 2, 2-trifluoro-1- (1-isopropyl-6-methylthioalkyl-1H-indol-3-yl) -ethanone (216mg, 93%) as an off-white solid: mp 67-69 ℃; (ES)⁺Calculation of HRMSm/e C₁₄H₁₄F₃NOS(M⁺)301.0748, found 301.0740.

[082]A solution of 2, 2, 2-trifluoro-1- (1-isopropyl-6-methylthioalkyl-1H-indol-3-yl) -ethanone (200mg, 0.77mmol) in tetrahydrofuran (1mL) at 25 ℃ was treated with 20% aqueous sodium hydroxide (2 mL). Mixing the mixtureHeated to 100 ℃ for 24 hours. At this point, the reaction was cooled to 25 ℃, partitioned between water (40mL) and ethyl acetate (40mL), and the solution was then treated with 1N aqueous hydrochloric acid. The layers were shaken and separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40S, Silica, 2/1 hexane/ethyl acetate) gave 1-isopropyl-6-methylthioalkyl-1H-indole-3-carboxylic acid (126mg, 77%) as a white solid: mp 132-; EI-HRMS m/e calculation value C₁₃H₁₅NO₂S(M⁺)249.0823, found 249.0819.

[083]A solution of 1-isopropyl-6-methylthioalkyl-1H-indole-3-carboxylic acid (275mg, 1.10mmol) and benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (585mg, 1.32mmol) in dichloromethane (5mL) at 25 ℃ was treated with N, N-diisopropylethylamine (0.44mL, 2.54 mmol). The reaction was stirred at 25 ℃ for 30 minutes. At this point, the reaction was treated with 2-aminothiazole (254mg, 2.54mmol) and stirred at 25 ℃ for 18 h. At this time, the reaction was partitioned between water (40mL) and ethyl acetate (40mL) and treated with 1N aqueous hydrochloric acid (25 mL). Shaken and the layers separated. The organic layer was washed with saturated aqueous sodium bicarbonate (1X 25mL), water (1X 25mL) and saturated aqueous sodium chloride (1X 25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40S, Silica, 1/1 hexane/ethyl acetate) gave 1-isopropyl-6-methylthioalkyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (155mg, 42%) as a light yellow solid: mp 172-176 ℃; (ES)⁺Calculation of HRMS m/e C₁₆H₁₇N₃OS₂(M+Na)⁺354.0705, found 354.0709.

[084]A solution of 1-isopropyl-6-methylthioalkyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (55mg, 0.17mmol) in tetrahydrofuran (0.5mL) at 25 ℃ was treated with formic acid (0.03 mL). The reaction was cooled to 0 ℃ and then treated with 30% aqueous hydrogen peroxide (94mg, 0.83 mmol). The reaction was stirred at 0 ℃ for 15 minutes, then warmed to 25 ℃ and stirred at this temperature for 2 hours. At this point, the reaction was again cooled to 0 ℃ and quenched by addition of saturated aqueous sodium sulfite solution, thenThen extracted with ethyl acetate (1X 50 mL). The organic layer was washed with water (1 × 50mL) and saturated aqueous sodium chloride (1 × 50mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was treated with 3/1 ethyl acetate/hexane. The resulting precipitate was collected by filtration and dried under vacuum to give 1-isopropyl-6-methanesulfonyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (33mg, 55%) as a white solid: mp247-249 ℃; (ES)⁺Calculation of HRMS m/e C₁₆H₁₇N₃O₃S₂(M+H)⁺364.0784, found 364.0788.

Example 86-fluoro-1-isopropyl-1H-indole-3-carboxylic acid thiazol-2-ylamide

[085]A solution of 6-fluoro-1H-indole (1.0g, 7.40mmol) in tetrahydrofuran (5mL) cooled to 0 deg.C was treated with trifluoroacetic anhydride (1.57mL, 11.10 mmol). The reaction was stirred at 0 ℃ for 1 hour, then warmed to 25 ℃ and stirred for 2 hours. At this point, the resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 2, 2, 2-trifluoro-1- (6-fluoro-1H-indol-3-yl) -ethanone (330mg, 19.3%) as a white solid: mp 234-; EI-HRMS m/e calculation value C₁₀H₅F₄NO(M⁺)231.0307, found 231.0307.

[086]A solution of 2, 2, 2-trifluoro-1- (6-fluoro-1H-indol-3-yl) -ethanone (1.63g, 7.05mmol) in N, N-dimethylformamide (15mL) at 25 ℃ was treated with potassium carbonate (2.44g, 17.63 mmol). The resulting mixture was stirred at 25 ℃ for 15 minutes. At this point, the reaction was treated with 2-iodopropane (1.06mL, 10.58 mmol). The reaction was heated at 65 ℃ for 18 hours. At this point, the reaction was cooled to 25 ℃ and partitioned between water (100mL) and ethyl acetate (100 mL). The organic layer was washed with 1N aqueous hydrochloric acid (1X 25mL) and saturated aqueous sodium chloride (1X 100mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH40M, Silica, 2)Hexane/ethyl acetate) to give 2, 2, 2-trifluoro-1- (6-fluoro-1-isopropyl-1H-indol-3-yl) -ethanone (1.74g, 90%) as a yellow solid: mp 67-69 ℃; EI-HRMS m/e calculation value C₁₃H₁₁F₄NO(M⁺)273.0776, found 273.0780.

[087]A solution of 2, 2, 2-trifluoro-1- (6-fluoro-1-isopropyl-1H-indol-3-yl) -ethanone (1.65g, 6.04mmol) in 20% aqueous sodium hydroxide (25mL) was heated at 110 ℃ for 18H. At this point, the reaction was cooled to 25 ℃, partitioned between water (50mL) and ethyl acetate (50mL), and then treated with 1N aqueous hydrochloric acid (50 mL). The organic layer was washed with saturated aqueous sodium chloride (1 × 100mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give 6-fluoro-1-isopropyl-1H-indole-3-carboxylic acid (1.29g, 96%) as a yellow solid: mp 177-180 ℃; EI-HRMS m/e calculation value C₁₂H₁₂FNO₂(M⁺)221.0852, found 221.0850.

[088]A solution of triphenylphosphine (771mg, 2.94mmol) in dichloromethane (7mL) cooled to 0 deg.C was treated with N-bromosuccinimide (523mg, 2.94 mmol). The reaction was stirred at 0 ℃ for 15 minutes. At this point, the reaction was treated with 6-fluoro-1-isopropyl-1H-indole-3-carboxylic acid (500mg, 2.26 mmol). The reaction was stirred at 0 ℃ for 15 minutes, then warmed to 25 ℃ and stirred at this temperature for 15 minutes. The reaction was then treated with 2-aminothiazole (521mg, 5.20mmol) and stirred at 25 ℃ for 18 h. At this time, the mixture was partitioned between water (75mL) and ethyl acetate (75mL) and treated with 1N aqueous hydrochloric acid (50 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (1X 50mL), water (1X 50mL) and saturated aqueous sodium chloride (1X 50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40M, Silica, 1/1 hexane/ethyl acetate) afforded 6-fluoro-1-isopropyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (160mg, 23%) as a pink solid: mp 203-; EI-HRMS m/e calculation value C₁₅H₁₄FN₃OS(M⁺)303.0842, found 303.0844.

Example 96-bromo-1-isopropyl-1H-indole-3-carboxylic acid thiazol-2-ylamide

[089]A solution of 6-bromo-1H-indole (2.0g, 10.20mmol) in tetrahydrofuran (10mL) cooled to 0 deg.C was treated with trifluoroacetic anhydride (2.16mL, 15.30 mmol). The reaction was stirred at 0 ℃ for 1 hour, then warmed to 25 ℃ and stirred for 2 hours. At this point, the resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 2, 2, 2-trifluoro-1- (6-bromo-1H-indol-3-yl) -ethanone (1.79g, 60%) as a white solid: mp 258-260 ℃; EI-HRMS m/e calculation value C₁₀H₅BrF₃NO(M⁺)290.9511, found 290.9511.

[090]A solution of 2, 2, 2-trifluoro-1- (6-bromo-1H-indol-3-yl) -ethanone (3.0g, 10.27mmol) in N, N-dimethylformamide (20mL) at 25 ℃ was treated with potassium carbonate (3.54g, 25.68 mmol). The resulting mixture was stirred at 25 ℃ for 15 minutes, then the reaction was treated with 2-iodopropane (1.54mL, 15.41 mmol). The reaction was heated at 65 ℃ for 18 hours. At this point, the reaction was cooled to 25 ℃ and partitioned between water (100mL) and ethyl acetate (100 mL). The organic layer was washed with 1N aqueous hydrochloric acid (1X 25mL) and saturated aqueous sodium chloride (1X 100mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH40M, Silica, 2/1 hexane/ethyl acetate) afforded 2, 2, 2-trifluoro-1- (6-bromo-1-isopropyl-1H-indol-3-yl) -ethanone (3.38g, 99%) as a pink solid: mp 77-79 ℃; EI-HRMS m/e calculation value C₁₃H₁₁BrF₃NO(M⁺)332.9976, found 332.9975.

[091]A solution of 2, 2, 2-trifluoro-1- (6-bromo-1-isopropyl-1H-indol-3-yl) -ethanone (3.30g, 9.88mmol) in 20% aqueous sodium hydroxide (35mL) was heated at 110 ℃ for 18H. At this point, the reaction was cooled to 25 ℃, partitioned between water (100mL) and ethyl acetate (100mL), and then treated with 1N aqueous hydrochloric acid (60 mL). By saturated chlorinationThe organic layer was washed with aqueous sodium solution (1 × 100mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give 6-bromo-1-isopropyl-1H-indole-3-carboxylic acid (2.63g, 94%) as a yellow solid: mp 207-; EI-HRMS m/e calculation value C₁₂H₁₂BrNO₂(M⁺)281.0051, found 281.0047.

[092]A solution of triphenylphosphine (2.42mg, 9.22mmol) in dichloromethane (25mL) cooled to 0 deg.C was treated with N-bromosuccinimide (1.64mg, 9.22 mmol). The reaction was stirred at 0 ℃ for 15 minutes. At this point, the reaction was treated with 6-bromo-1-isopropyl-1H-indole-3-carboxylic acid (2.0g, 7.09 mmol). The reaction was stirred at 0 ℃ for 15 minutes, then warmed to 25 ℃ and stirred at this temperature for 15 minutes. The reaction was then treated with 2-aminothiazole (1.63g, 16.31mmol) and stirred at 25 ℃ for 18 h. At this time, the mixture was partitioned between water (150mL) and ethyl acetate (150mL) and treated with 1N aqueous hydrochloric acid (100 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (1X 100mL), water (1X 100mL) and saturated aqueous sodium chloride (1X 100 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40M, Silica, 1/1 hexane/ethyl acetate) gave 6-bromo-1-isopropyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (300mg, 11.6%) as a white solid: mp 205-; EI-HRMS m/e calculation value C₁₅H₁₄BrN₃OS(M⁺)363.0041, found 363.0034.

Example 106-chloro-1-isopropyl-1H-indole-3-carboxylic acid thiazol-2-ylamide

[093]A solution of 6-chloro-1H-indole (1.0g, 6.60mmol) in tetrahydrofuran cooled to 0 ℃ was treated with trifluoroacetic anhydride. The reaction was stirred at 0 ℃ for 30 minutes, then warmed to 25 ℃ and stirred at this temperature for 1 hour. At this time, the reaction was poured into water (75 mL). The resulting precipitate was collected by filtration, washed with water, and evaporated under vacuumDrying afforded 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (1.52g, 93%) as an off-white solid: mp 256-258 ℃; EI-HRMS m/e calculation value C₁₀H₁₅ClF₃NO(M⁺)247.0012, found 247.0006.

[094]A solution of 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone in N, N-dimethylformamide (5mL) was treated with potassium carbonate (698mg, 5.05 mmol). The reaction was stirred at 25 ℃ for 15 minutes and then treated with 2-iodopropane (0.30mL, 3.03 mmol). The reaction was heated at 65 ℃ for 20 hours. At this point, the reaction was cooled to 25 ℃, quenched with water (5mL), and then partitioned between water (50mL) and ethyl acetate (50 mL). The mixture was treated with saturated aqueous sodium chloride (1X 25mL), shaken, and separated. The organic layer was then dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40M, Silica, 3/1 hexane/ethyl acetate) afforded 1- (6-chloro-1-isopropyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (483mg, 83%) as a pale pink solid: mp 94-96 ℃; EI-HRMS m/e calculation value C₁₃H₁₁ClF₃NO(M⁺)289.0481, found 289.0482.

[095]A solution of 1- (6-chloro-1-isopropyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (475mg, 1.64mmol) in 20% aqueous sodium hydroxide was heated at 110 ℃ for 18H. At this point, the reaction was cooled to 25 ℃ and treated with 1N aqueous hydrochloric acid. The solution was extracted with ethyl acetate (1X 50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (385mg, 99%) as a yellow solid: mp 206-208 ℃; EI-HRMS m/e calculation value C₁₂H₁₂ClNO₂(M⁺)237.0056, found 237.0554.

[096]A solution of triphenylphosphine (179mg, 0.68mmol) in dichloromethane (3mL) cooled to 0 deg.C was treated with N-bromosuccinimide (122mg, 0.68 mmol). The solution was stirred at 0 ℃ for 15 minutes. At this point, the reaction was treated with 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (125mg, 0.53 mmol). The solution was stirred at 0 ℃ for 5 minAfter this time, the temperature was raised to 25 ℃ and stirred at this temperature for 30 minutes. The reaction was then treated with 2-aminothiazole (121mg, 1.21mmol) and stirred at 25 ℃ for 3 days. At this time, the reaction was partitioned between water (30mL) and ethyl acetate (30 mL). The organic layer was separated and then washed with 1N aqueous hydrochloric acid (1X 20mL), saturated aqueous sodium bicarbonate (1X 20mL), water (1X 20mL) and saturated aqueous sodium chloride (1X 20 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40S, Silica, 1/1 hexane/ethyl acetate) afforded 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (62mg, 37%) as a pink solid: mp 202-204 ℃; EI-HRMS m/e calculation value C₁₇H₁₆ClN₃OS(M⁺)319.0546, found 319.0547.

Example 116-chloro-1-ethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide

[097]A solution of 6-chloro-1H-indole (1.0g, 6.60mmol) in tetrahydrofuran cooled to 0 ℃ was treated with trifluoroacetic anhydride. The reaction was stirred at 0 ℃ for 30 minutes, then warmed to 25 ℃ and stirred at this temperature for 1 hour. At this time, the reaction was poured into water (75 mL). The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (1.52g, 93%) as an off-white solid: mp 256-258 ℃; EI-HRMS m/e calculation value C₁₀H₁₅ClF₃NO(M⁺)247.0012, found 247.0006.

[098]A mixture of 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (300mg, 1.21mmol), potassium carbonate (419mg, 3.03mmol) and ethyl iodide (0.14mL, 1.82mmol) in N, N-dimethylformamide (4mL) in a sealed reaction vessel was heated at 60 ℃ for 16H. At this point, the reaction was cooled to 25 ℃ and partitioned between water (30mL) and ethyl acetate (30 mL). The mixture was treated with 1N aqueous hydrochloric acid (6mL)The mixture was shaken and isolated. The organic layer was concentrated under vacuum to give a yellow solid. The resulting solid was then treated with 20% aqueous sodium hydroxide (7mL) and heated at 115 ℃ for 24 hours. At this point, the reaction was cooled to 25 ℃ and partitioned between water (75mL) and ethyl acetate (75 mL). The solution was treated with 1N aqueous hydrochloric acid (25mL), shaken, and separated. The organic layer was washed with saturated aqueous sodium chloride (1 × 50mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give 6-chloro-1-ethyl-1H-indole-3-carboxylic acid (250mg, 92%) as a light yellow solid: mp 225-; EI-HRMS m/e calculation value C₁₁H₁₀ClNO₂(M⁺)223.0400, found 223.0400.

[099]A solution of 6-chloro-1-ethyl-1H-indole-3-carboxylic acid (240mg, 1.07mmol) in dichloromethane (3mL) was cooled to 0 deg.C and then treated with N, N-dimethylformamide (1 drop) and oxalyl chloride (0.14mL, 1.61 mmol). The reaction was stirred at 0 ℃ for 15 minutes, then warmed to 25 ℃ and stirred at this temperature for 1 hour. At this time, the reaction was concentrated under vacuum. The residue was dissolved in methylene chloride (1mL), and the mixture was added to a solution of 2-aminothiazole (214mg, 2.14mmol) and triethylamine (0.30mL, 2.14mmol) in N, N-dimethylformamide (2 mL). The mixture was stirred at 25 ℃ for 16 hours. At this time, the reaction was partitioned between water (40mL) and ethyl acetate (40 mL). The mixture was then treated with 1N aqueous hydrochloric acid (15mL), and the organic layer was washed with saturated aqueous sodium bicarbonate (1X 30mL), water (1X 30mL), and saturated aqueous sodium chloride (1X 30 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated under vacuum. Recrystallization from ethyl acetate gave 6-chloro-1-ethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (27mg, 8%) as a light yellow solid: mp 234-; EI-HRMS m/e calculation value C₁₄H₁₂ClN₃OS(M⁺)305.0390, found 305.0383.

Example 126-chloro-1-propyl-1H-indole-3-carboxylic acid thiazol-2-ylamide

[0100]A solution of 6-chloro-1H-indole (1.0g, 6.60mmol) in tetrahydrofuran cooled to 0 ℃ was treated with trifluoroacetic anhydride. The reaction was stirred at 0 ℃ for 30 minutes, then warmed to 25 ℃ and stirred at this temperature for 1 hour. At this time, the reaction was poured into water (75 mL). The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (1.52g, 93%) as an off-white solid: mp 256-258 ℃; EI-HRMS m/e calculation value C₁₀H₁₅ClF₃NO(M⁺)247.0012, found 247.0006.

[0101] A mixture of 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (200mg, 0.81mmol) and potassium carbonate (214mg, 2.02mmol) in N, N-dimethylformamide (4mL) was stirred at 25 ℃ for 30 min. At this point, the reaction was treated with 1-iodopropane (0.12mL, 1.21mmol) and heated at 60 ℃ for 5 hours. The reaction mixture was cooled to 25 ℃ and then concentrated under vacuum. The residue was diluted with ethyl acetate (50mL), and washed with saturated aqueous sodium bicarbonate (1X 50mL), water (2X 50mL), and saturated aqueous sodium chloride (1X 50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 1- (6-chloro-1-propyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (277.1mg) as an orange solid, which was used without further purification or identification.

[0102]A mixture of 1- (6-chloro-1-propyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (277.1mg, 0.81mmol) in 20% aqueous sodium hydroxide (2.7mL) was heated at reflux for 17H. At this point, the reaction was cooled to 25 ℃, partitioned between water (75mL) and ethyl acetate (75mL), and extracted with diethyl ether (1 × 50 mL). The aqueous layer was acidified to pH 1 with concentrated hydrochloric acid and then extracted with ethyl acetate (1 × 75 mL). The combined organic layers were washed with water (1 × 50mL) and saturated aqueous sodium chloride (1 × 50mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give 6-chloro-1-propyl-1H-indole-3-carboxylic acid (141.4mg, 74%) as a cream solid: mp179-180 ℃; EI-HCalculated RMS m/e C₁₂H₁₂ClNO₂(M⁺)237.0556, found 237.0558.

[0103]A solution of triphenylphosphine (172mg, 0.66mmol) in dichloromethane (2mL) cooled to 0 deg.C was treated with N-bromosuccinimide (117mg, 0.66 mmol). The reaction was stirred at 0 ℃ for 10 minutes. At this point, the reaction was treated with 6-chloro-1-propyl-1H-indole-3-carboxylic acid (120mg, 0.50 mmol). The reaction was stirred at 0 ℃ for 10 minutes, then warmed to 25 ℃ and stirred at this temperature for 30 minutes. The reaction was then treated with 2-aminothiazole (126mg, 1.26mmol) and stirred at 25 ℃ for 3 days. At this point, the reaction was partitioned between water (50mL) and ethyl acetate (50 mL). The mixture was treated with 10% aqueous hydrochloric acid (15mL), shaken, and separated. The organic layer was washed with saturated aqueous sodium bicarbonate (1X 25mL), water (1X 25mL) and saturated aqueous sodium chloride (1X 25 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40S, Silica, 1/1 hexane/ethyl acetate) afforded a pale pink solid, which was slurried with 3/1 ethyl acetate/hexane solution. The solid was collected by filtration to give 6-chloro-1-propyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (47mg, 29%) as a white solid: mp 175-176 ℃; EI-HRMS m/e calculation value C₁₅H₁₄ClN₃O(M⁺)319.0546, found 319.0540.

Example 131-butyl-6-chloro-1H-indole-3-carboxylic acid thiazol-2-ylamide

[0104]A solution of 6-chloro-1H-indole (1.0g, 6.60mmol) in tetrahydrofuran cooled to 0 ℃ was treated with trifluoroacetic anhydride. The solution was stirred at 0 ℃ for 30 minutes, then warmed to 25 ℃ and stirred at this temperature for 1 hour. At this time, the reaction was poured into water (75 mL). The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (1.52g, 93%),it was an off-white solid: mp 256-258 ℃; EI-HRMS m/e calculation value C₁₀H₁₅ClF₃NO(M⁺)247.0012, found 247.0006.

[0105] A mixture of 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (200mg, 0.81mmol) and potassium carbonate (214mg, 2.02mmol) in N, N-dimethylformamide (2.0mL) was stirred at 25 ℃ for 30 min. At this point, the reaction was treated with 1-iodobutane (0.14mL, 1.21mmol) and heated at 60 ℃ for 5 hours. At this point, the reaction mixture was cooled to 25 ℃ and concentrated under vacuum. The residue was diluted with ethyl acetate (50mL), and washed with saturated aqueous sodium bicarbonate (1X 50mL), water (2X 50mL), and saturated aqueous sodium chloride (1X 50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 1- (1-butyl-6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (283.7mg) as an orange oil, which was used without further purification or identification.

[0106]A mixture of 1- (1-butyl-6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (283.7mg, 0.81mmol) in 20% aqueous sodium hydroxide (2.7mL) was heated at reflux for 17H. At this point, the reaction was cooled to 25 ℃ and diluted with water (75 mL). The mixture was extracted with diethyl ether (1X 50 mL). The aqueous layer was acidified to pH 1 with concentrated hydrochloric acid and then extracted with ethyl acetate (1 × 75 mL). The combined organic layers were washed with water (1 × 50mL) and saturated aqueous sodium chloride (1 × 50mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give 1-butyl-6-chloro-1H-indole-3-carboxylic acid (141.4mg, 69.6%) as a light orange solid: mp 149-151 deg.C; EI-HRMS m/e calculation value C₁₃H₁₄ClNO₂(M⁺)251.0713, found 251.0721.

[0107]A solution of triphenylphosphine (176mg, 0.67mmol) in dichloromethane (2mL) cooled to 0 deg.C was treated with N-bromosuccinimide (119mg, 0.67 mmol). The reaction was stirred at 0 ℃ for 10 minutes. At this point, the reaction was treated with 1-butyl-6-chloro-1H-indole-3-carboxylic acid (130mg, 0.52 mmol). The reaction was stirred at 0 ℃ for 10 minutes, then warmed to 25 ℃ and stirred at this temperature for 30 minutes. Then useThe reaction was treated with 2-aminothiazole (129mg, 1.29mmol), and stirred at 25 ℃ for 3 days. At this point, the reaction was partitioned between water (50mL) and ethyl acetate (50 mL). The mixture was treated with 10% aqueous hydrochloric acid (15mL), shaken, and separated. The organic layer was washed with saturated aqueous sodium bicarbonate (1X 25mL), water (1X 25mL) and saturated aqueous sodium chloride (1X 25 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40S, Silica, 1/1 hexane/ethyl acetate) afforded a pale pink solid, which was slurried with 3/1 ethyl acetate/hexane solution. The solid was collected by filtration to give 1-butyl-6-chloro-1H-indole-3-carboxylic acid thiazol-2-ylamide (45mg, 26%) as a white solid: mp 168-169 deg.C; EI-HRMS m/e calculation value C₁₆H₁₆ClN₃OS(M⁺)333.0702, found 333.0699.

Example 146-chloro-1-isobutyl-1H-indole-3-carboxylic acid thiazol-2-ylamide

[0108]A solution of 6-chloro-1H-indole (1.0g, 6.60mmol) in tetrahydrofuran cooled to 0 ℃ was treated with trifluoroacetic anhydride. The reaction was stirred at 0 ℃ for 30 minutes, then warmed to 25 ℃ and stirred at this temperature for 1 hour. At this time, the reaction was poured into water (75 mL). The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (1.52g, 93%) as an off-white solid: mp 256-258 ℃; EI-HRMS m/e calculation value C₁₀H₁₅ClF₃NO(M⁺)247.0012, found 247.0006.

[0109] A mixture of 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (200mg, 0.81mmol) and potassium carbonate (214mg, 2.02mmol) in N, N-dimethylformamide (2mL) was stirred at 25 ℃ for 30 min. At this point, the reaction was treated with 1-bromo-2-methylpropane (0.13mL, 1.21mmol) and heated at 60 ℃ for 5 hours. At this point, the reaction mixture was cooled to 25 ℃ and concentrated under vacuum. The residue was diluted with ethyl acetate (50mL), and washed with saturated aqueous sodium bicarbonate (1X 50mL), water (2X 50mL), and saturated aqueous sodium chloride (1X 50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 1- (6-chloro-1-isobutyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (282.7mg) as a dark yellow solid, which was used without further purification or identification.

[0110]A mixture of 1- (6-chloro-1-isobutyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (282.7mg, 0.81mmol) in 20% aqueous sodium hydroxide (2.7mL) was heated at reflux for 17H. At this point, the reaction was cooled to 25 ℃ and diluted with water (75 mL). The mixture was extracted with diethyl ether (1X 50 mL). The aqueous layer was acidified to pH 1 with concentrated hydrochloric acid and then extracted with ethyl acetate (1 × 75 mL). The combined organic layers were washed with water (1 × 50mL) and saturated aqueous sodium chloride (1 × 50mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give 6-chloro-1-isobutyl-1H-indole-3-carboxylic acid (161.4mg, 79%) as a cream solid: mp 205-; EI-HRMSm/e calculated value C₁₃H₁₄ClNO₂(M⁺)251.0713, found 251.0713.

[0111]A solution of triphenylphosphine (196mg, 0.75mmol) in dichloromethane (2mL) cooled to 0 deg.C was treated with N-bromosuccinimide (133mg, 0.75 mmol). The reaction was stirred at 0 ℃ for 10 minutes. At this point, the reaction was treated with 6-chloro-1-isobutyl-1H-indole-3-carboxylic acid (145mg, 0.58 mmol). The reaction was stirred at 0 ℃ for 10 minutes, then warmed to 25 ℃ and stirred at this temperature for 30 minutes. The reaction was then treated with 2-aminothiazole (144mg, 1.44mmol) and stirred at 25 ℃ for 3 days. At this point, the reaction was partitioned between water (50mL) and ethyl acetate (50 mL). The mixture was treated with 10% aqueous hydrochloric acid (15mL), shaken, and separated. The organic layer was washed with saturated aqueous sodium bicarbonate (1X 25mL), water (1X 25mL) and saturated aqueous sodium chloride (1X 25 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40S, Silica, 1/1 hexane/ethyl acetate) afforded a pink solid, which was purified with 3/1 ethyl acetate/hexaneThe alkane solution (3.0mL) was slurried. The solid was collected by filtration to give 6-chloro-1-isobutyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (57mg, 29%) as a pale pink solid: mp200-202 ℃; EI-HRMS m/e calculation value C₁₆H₁₆ClN₃OS(M⁺)333.0702, found 333.0707.

Example 156-chloro-1-pentyl-1H-indole-3-carboxylic acid thiazol-2-ylamide

[0112]A solution of 6-chloro-1H-indole (1.0g, 6.60mmol) in tetrahydrofuran cooled to 0 ℃ was treated with trifluoroacetic anhydride. The solution was stirred at 0 ℃ for 30 minutes, then warmed to 25 ℃ and stirred at this temperature for 1 hour. At this time, the reaction was poured into water (75 mL). The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (1.52g, 93%) as an off-white solid: mp 256-258 ℃; EI-HRMS m/e calculation value C₁₀H₁₅ClF₃NO(M⁺)247.0012, found 247.0006.

[0113]A mixture of 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (300mg, 1.21mmol), potassium carbonate (419mg, 3.03mmol) and 1-bromopentane (0.23mL, 1.82mmol) in N, N-dimethylformamide (4mL) in a sealed reaction vessel was heated at 60 ℃ for 16H. At this point, the reaction was cooled to 25 ℃ and partitioned between water (30mL) and ethyl acetate (30 mL). The mixture was treated with 1N aqueous hydrochloric acid (6mL), shaken, and separated. The organic layer was concentrated under vacuum to give a yellow solid. The resulting solid was then treated with 20% aqueous sodium hydroxide (7mL) and heated at 115 ℃ for 24 hours. At this point, the reaction was cooled to 25 ℃ and partitioned between water (75mL) and ethyl acetate (75 mL). The solution was treated with 1N aqueous hydrochloric acid (25mL), shaken, and separated. The organic layer was washed with saturated aqueous sodium chloride (1X 50mL), dried over magnesium sulfate, filtered, and washed with brineConcentration in vacuo afforded 6-chloro-1-pentyl-1H-indole-3-carboxylic acid (315mg, 98%) as a yellow solid: mp 152-; EI-HRMS m/e calculation value C₁₄H₁₆ClNO₂(M⁺)265.0870, found 265.0865.

[0114]A solution of triphenylphosphine (355mg, 1.35mmol) in dichloromethane (3mL) cooled to 0 deg.C was treated with N-bromosuccinimide (240mg, 1.35 mmol). The reaction was stirred at 0 ℃ for 15 minutes. At this point, the reaction was treated with 6-chloro-1-pentyl-1H-indole-3-carboxylic acid (300mg, 1.13 mmol). The reaction was stirred at 0 ℃ for 10 minutes, then warmed to 25 ℃ and stirred at this temperature for 1 hour. The reaction was then treated with 2-aminothiazole (283 mg, 2.83 mmol) and stirred at 25 ℃ for 3 days. At this point, the reaction was partitioned between water (50mL) and ethyl acetate (50 mL). The mixture was treated with 10% aqueous hydrochloric acid (15mL), shaken, and separated. The organic layer was washed with saturated aqueous sodium bicarbonate (1X 30mL), water (1X 30mL) and saturated aqueous sodium chloride (1X 30 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40S, Silica, 2/1 hexane/ethyl acetate) afforded 6-chloro-1-pentyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (101mg, 25%) as a pink solid: mp 139-141 ℃; EI-HRMS m/e calculation value C₁₇H₁₈ClN₃OS(M⁺)347.0859, found 347.0859.

Example 166-chloro-1- (3-methyl-butyl) -1H-indole-3-carboxylic acid thiazol-2-ylamide

[0112]A solution of 6-chloro-1H-indole (1.0g, 6.60mmol) in tetrahydrofuran cooled to 0 ℃ was treated with trifluoroacetic anhydride. The reaction was stirred at 0 ℃ for 30 minutes, then warmed to 25 ℃ and stirred at this temperature for 1 hour. At this time, the reaction was poured into water (75 mL). The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 1- (6-chloro-1H-indol-3-yl) -2, 2-trifluoro-ethanone (1.52g, 93%) as an off-white solid: mp 256-258 ℃; EI-HRMS m/e calculation value C₁₀H₁₅ClF₃NO(M⁺)247.0012, found 247.0006.

[0116] A mixture of 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (200mg, 0.81mmol) and potassium carbonate (214mg, 2.02mmol) in N, N-dimethylformamide (2mL) was stirred at 25 ℃ for 30 min. At this point, the reaction was treated with 1-bromo-3-methylbutane (0.15mL, 1.21mmol) and heated at 60 ℃ for 5 hours. At this point, the reaction mixture was cooled to 25 ℃ and concentrated under vacuum. The residue was diluted with ethyl acetate (50mL), and washed with saturated aqueous sodium bicarbonate (1X 50mL), water (2X 50mL), and saturated aqueous sodium chloride (1X 50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 1- [ 6-chloro-1- (3-methyl-butyl) -1H-indol-3-yl ] -2, 2, 2-trifluoro-ethanone (284.9mg) as a dark yellow solid, which was used without further purification or identification.

[0117]1- [ 6-chloro-1- (3-methyl-butyl) -1H-indol-3-yl]A mixture of-2, 2, 2-trifluoro-ethanone (284.9mg, 0.81mmol) in 20% aqueous sodium hydroxide (2.7mL) was heated at reflux for 17 h. At this point, the reaction was cooled to 25 ℃ and diluted with water (75 mL). The mixture was extracted with diethyl ether (1X 50 mL). The aqueous layer was acidified to pH 1 with concentrated hydrochloric acid and then extracted with ethyl acetate (1 × 75 mL). The combined organic layers were washed with water (1 × 50mL) and saturated aqueous sodium chloride (1 × 50mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give 6-chloro-1- (3-methyl-butyl) -1H-indole-3-carboxylic acid (149.3mg, 69.5%) as a light orange solid: mp 53-55 ℃; EI-HRMS m/e calculation value C₁₄H₁₆ClNO₂(M⁺)265.0870, found 265.0860.

[0118]A solution of triphenylphosphine (180mg, 0.69mmol) in dichloromethane (2mL) cooled to 0 deg.C was treated with N-bromosuccinimide (122mg, 0.69 mmol). The reaction was stirred at 0 ℃ for 10 minutes. At this point, the reaction was treated with 6-chloro-1- (3-methyl-butyl) -1H-indole-3-carboxylic acid (140mg, 0.53 mmol). The reaction is carried out at 0 DEG CStirred for 10 minutes, then warmed to 25 ℃ and stirred at this temperature for 30 minutes. The reaction was then treated with 2-aminothiazole (132mg, 1.32mmol) and stirred at 25 ℃ for 3 days. At this point, the reaction was partitioned between water (50mL) and ethyl acetate (50 mL). The mixture was treated with 10% aqueous hydrochloric acid (15mL), shaken, and separated. The organic layer was washed with saturated aqueous sodium bicarbonate (1X 25mL), water (1X 25mL) and saturated aqueous sodium chloride (1X 25 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40S, Silica, 1/1 hexane/ethyl acetate) afforded a pink solid, which was slurried with 3/1 ethyl acetate/hexane solution (3 mL). The solid was collected by filtration to give 6-chloro-1- (3-methyl-butyl) -1H-indole-3-carboxylic acid thiazol-2-ylamide (58mg, 31%) as a white solid: mp179-180 ℃; EI-HRMS m/e calculation value C₁₇H₁₈ClN₃OS(M⁺)347.0859, found 347.0864.

Example 176-chloro-1-cyclopropylmethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide

[0119]A solution of 6-chloro-1H-indole (1.0g, 6.60mmol) in tetrahydrofuran cooled to 0 ℃ was treated with trifluoroacetic anhydride. The reaction was stirred at 0 ℃ for 30 minutes, then warmed to 25 ℃ and stirred at this temperature for 1 hour. At this time, the reaction was poured into water (75 mL). The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (1.52g, 93%) as an off-white solid: mp 256-258 ℃; EI-HRMS m/e calculation value C₁₀H₁₅ClF₃NO(M⁺)247.0012, found 247.0006.

[0120]1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (300mg, 1.21mmol), potassium carbonate (419mg, 3.03mmol) and (bromomethyl) -cyclopropane (0.18mL, 1.82mmol) in a sealed reaction vessel were added to N, N-dimethylformamideThe mixture in (4mL) was heated at 60 ℃ for 16 h. At this point, the reaction was cooled to 25 ℃ and partitioned between water (30mL) and ethyl acetate (30 mL). The mixture was treated with 1N aqueous hydrochloric acid (5mL), shaken, and separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum to give a yellow oil. The resulting oil was treated with 20% aqueous sodium hydroxide (7mL) and heated at 110 ℃ for 2 days. At this point, the reaction was cooled to 25 ℃ and partitioned between water (75mL) and ethyl acetate (75 mL). The solution was treated with 1N aqueous hydrochloric acid (30mL), shaken, and separated. The organic layer was washed with saturated aqueous sodium chloride (1 × 50mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give 6-chloro-1-cyclopropylmethyl-1H-indole-3-carboxylic acid (287mg, 95%) as a pale yellow solid: mp 219-220 ℃; EI-HRMS m/e calculation value C₁₃H₁₂ClNO₂(M⁺)249.0556, found 249.0558.

[0121]A solution of triphenylphosphine (315mg, 1.20mmol) in dichloromethane (3mL) cooled to 0 deg.C was treated with N-bromosuccinimide (214mg, 1.20 mmol). The reaction was stirred at 0 ℃ for 20 minutes. At this point, the reaction was treated with 6-chloro-1-cyclopropylmethyl-1H-indole-3-carboxylic acid (250mg, 1.00 mmol). The reaction was stirred at 0 ℃ for 15 minutes, then warmed to 25 ℃ and stirred at this temperature for 45 minutes. The reaction was then treated with 2-aminothiazole (250mg, 2.50mmol) and stirred at 25 ℃ for 24 h. At this point, the reaction was partitioned between water (50mL) and ethyl acetate (50 mL). The mixture was treated with 10% aqueous hydrochloric acid (10mL), shaken, and separated. The organic layer was washed with saturated aqueous sodium bicarbonate (1 × 50mL), water (1 × 50mL), and saturated aqueous sodium chloride (1 × 50mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH40S, Silica, 1/1 hexane/ethyl acetate) gave a yellow solid. The solid was dissolved in ethyl acetate (25mL) and washed with 1N aqueous sodium hydroxide (1X 25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 6-chloro-1-cyclopropylmethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (25mg, 8%) as a yellow solid: mp 185-187 deg.C; EI-HRMS m/e calculation value C₁₆H₁₄ClN₃OS(M⁺) 331.0542, found 331.0542.

Example 186-chloro-1-cyclobutylmethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide

[0122]A solution of 6-chloro-1H-indole (1.0g, 6.60mmol) in tetrahydrofuran cooled to 0 ℃ was treated with trifluoroacetic anhydride. The reaction was stirred at 0 ℃ for 30 minutes, then warmed to 25 ℃ and stirred at this temperature for 1 hour. At this time, the reaction was poured into water (75 mL). The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (1.52g, 93%) as an off-white solid: mp 256-258 ℃; EI-HRMS m/e calculation value C₁₀H₁₅ClF₃NO(M⁺)247.0012, found 247.0006.

[0123]A mixture of 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (300mg, 1.21mmol), potassium carbonate (419mg, 3.03mmol) and (bromomethyl) -cyclobutane (0.21mL, 1.82mmol) in N, N-dimethylformamide (4mL) in a sealed reaction vessel was heated at 60 ℃ for 16H. At this point, the reaction was cooled to 25 ℃ and partitioned between water (30mL) and ethyl acetate (30 mL). The mixture was treated with 1N aqueous hydrochloric acid (6mL), shaken, and separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum to give a yellow oil. The resulting oil was treated with 20% aqueous sodium hydroxide (7mL) and heated at 115 ℃ for 24 hours. At this point, the reaction was cooled to 25 ℃ and partitioned between water (75mL) and ethyl acetate (75 mL). The solution was treated with 1N aqueous hydrochloric acid (30mL), shaken, and separated. The organic layer was washed with saturated aqueous sodium chloride (1 × 50mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give 6-chloro-1-cyclobutylmethyl-1H-indole-3-carboxylic acid (318mg, 99%) as a yellow solid: mp 191-193 ℃; EI-HRMS m/e calculation value C₁₄H₁₄ClNO₂(M⁺)263.0713, found 263.0715.

[0124]A solution of triphenylphosphine (358mg, 1.37mmol) in dichloromethane (3mL) cooled to 0 deg.C was treated with N-bromosuccinimide (243mg, 1.37 mmol). The reaction was stirred at 0 ℃ for 15 minutes. At this point, the reaction was treated with 6-chloro-1-cyclobutylmethyl-1H-indole-3-carboxylic acid (300mg, 1.14 mmol). The reaction was stirred at 0 ℃ for 10 minutes, then warmed to 25 ℃ and stirred at this temperature for 1 hour. The reaction was then treated with 2-aminothiazole (285mg, 2.85mmol) and stirred at 25 ℃ for 18 h. At this point, the reaction was partitioned between water (50mL) and ethyl acetate (50 mL). The mixture was treated with 10% aqueous hydrochloric acid (15mL), shaken, and separated. The organic layer was washed with saturated aqueous sodium bicarbonate (1 × 30mL), water (1 × 30mL), and saturated aqueous sodium chloride (1 × 30mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH40S, Silica, 1/1 hexane/ethyl acetate) gave a yellow solid. The solid was dissolved in ethyl acetate (25mL) and washed with 1N aqueous sodium hydroxide (1X 25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 6-chloro-1-cyclobutylmethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (85mg, 21%) as a yellow solid: mp 169-173 ℃; EI-HRMS m/e calculation value C₁₇H₁₆ClN₃OS(M⁺)345.0703, found 345.0700.

Example 196-chloro-1-cyclopentylmethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide

[0125]A solution of 6-chloro-1H-indole (1.0g, 6.60mmol) in tetrahydrofuran cooled to 0 ℃ was treated with trifluoroacetic anhydride. The solution was stirred at 0 ℃ for 30 minutes, then warmed to 25 ℃ and stirred at this temperature for 1 hour. At this time, the reaction was poured into water (75 mL). The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 1- (6-chloro-1H-indol-3-yl) -2,2-trifluoro-ethanone (1.52g, 93%) as an off-white solid: mp 256-258 ℃; EI-HRMS m/e calculation value C₁₀H₁₅ClF₃NO(M⁺)247.0012, found 247.0006.

[0126]A solution of triphenylphosphine (28.80g, 109.8mmol) and imidazole (14.9g, 219.6mmol) in dichloromethane (160mL) was cooled to 0 deg.C and then treated slowly with iodine (27.87g, 109.8 mmol). The reaction mixture was then treated dropwise with a solution of cyclopentylmethanol (10.00g, 99.8mmol) in dichloromethane (10 mL). The resulting reaction mixture was warmed to 25 ℃ and stirred at this temperature for 4 hours. The reaction mixture was diluted with water (50mL) and further extracted with dichloromethane (3X 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo at 25 ℃. The resulting solid was washed with pentane (4X 50mL) and filtered through a plug of silica gel. The filtrate was concentrated under vacuum at 25 ℃ to give iodomethylcyclopentane (18.48g, 88%) as a colorless clear liquid: EI-HRMS m/e calculation value C₆H₁₁I(M⁺)209.9906, found 209.9911.

[0127]A mixture of 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (300mg, 1.21mmol), potassium carbonate (419mg, 3.03mmol) and iodomethylcyclopentane (383mg, 1.82mmol) in N, N-dimethylformamide (4mL) in a sealed reaction vessel was heated at 60 ℃ for 6 hours. At this point, the reaction was cooled to 25 ℃ and partitioned between water (50mL) and ethyl acetate (50 mL). The mixture was treated with 1N aqueous hydrochloric acid (15mL), shaken, and separated. Concentration under vacuum gave an orange oil. The resulting oil was treated with 20% aqueous sodium hydroxide (7mL) and heated at 110 ℃ for 40 hours. At this point, the reaction was cooled to 25 ℃ and partitioned between water (50mL) and ethyl acetate (50 mL). The solution was treated with 1N aqueous hydrochloric acid (20mL), shaken, and separated. The organic layer was washed with saturated aqueous sodium chloride (1 × 50mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give 6-chloro-1-cyclopentylmethyl-1H-indole-3-carboxylic acid (331mg, 98%) as a yellow orange solid: mp 181-184 ℃; EI-HRMS m/e calculation value C₁₅H₁₆ClNO₂(M⁺)277.0870, found 277.0873.

[0128]A solution of triphenylphosphine (300mg, 1.08mmol) in dichloromethane (3mL) cooled to 0 deg.C was treated with N-bromosuccinimide (231mg, 1.30 mmol). The reaction was stirred at 0 ℃ for 15 minutes. At this point, the reaction was treated with 6-chloro-1-cyclopentylmethyl-1H-indole-3-carboxylic acid (300mg, 1.08 mmol). The reaction was stirred at 0 ℃ for 15 minutes, then warmed to 25 ℃ and stirred at this temperature for 30 minutes. The reaction was then treated with 2-aminothiazole (270mg, 2.70mmol) and stirred at 25 ℃ for 20 h. At this time, the reaction was partitioned between water (30mL) and ethyl acetate (30 mL). The mixture was treated with 10% aqueous hydrochloric acid (10mL), shaken, and separated. The organic layer was washed with saturated aqueous sodium chloride (1 × 30mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH40S, Silica, 1/1 hexane/ethyl acetate) gave a pink foam. The foam was recrystallized from 3/1 hexane/ethyl acetate to give 6-chloro-1-cyclopentylmethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (87mg, 22%) as a pink solid: mp 117-119 deg.C; EI-HRMS m/e calculation value C₁₈H₁₈ClN₃OS(M⁺)359.0859, found 359.0854.

Example 206-chloro-1-cyclohexylmethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide

[0129]A solution of 6-chloro-1H-indole (1.0g, 6.60mmol) in tetrahydrofuran cooled to 0 ℃ was treated with trifluoroacetic anhydride. The reaction was stirred at 0 ℃ for 30 minutes, then warmed to 25 ℃ and stirred at this temperature for 1 hour. At this time, the reaction was poured into water (75 mL). The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (1.52g, 93%) as an off-white solid: mp 256-258 ℃; EI-HRMS m/e calculation value C₁₀H₁₅ClF₃NO(M⁺)247.0012, found 247.0006.

[0130]A mixture of 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (300mg, 1.21mmol), potassium carbonate (419mg, 3.03mmol) and bromomethylcyclohexane (0.25mL, 1.82mmol) in N, N-dimethylformamide (4mL) in a sealed reaction vessel was heated at 60 ℃ for 6 hours. At this point, the reaction was cooled to 25 ℃ and partitioned between water (50mL) and ethyl acetate (50 mL). The mixture was treated with 1N aqueous hydrochloric acid (15mL), shaken, and separated. Concentration under vacuum gave an orange oil. The resulting oil was treated with 20% aqueous sodium hydroxide (7mL) and heated at 110 ℃ for 40 hours. At this point, the reaction was cooled to 25 ℃ and partitioned between water (50mL) and ethyl acetate (50 mL). The solution was treated with 1N aqueous hydrochloric acid (20mL), shaken, and separated. The organic layer was washed with saturated aqueous sodium chloride (1 × 50mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a yellow solid. The resulting solid was slurried in 3/1 ethyl acetate/hexane solution for 5 minutes. The solid was collected by filtration to give 6-chloro-1-cyclohexylmethyl-1H-indole-3-carboxylic acid (247mg, 70%) as a pale yellow solid: mp 170-172 ℃; EI-HRMS m/e calculation value C₁₆H₁₈ClNO₂(M⁺)291.1026, found 291.1026.

[0131]A solution of triphenylphosphine (240mg, 0.82mmol) in dichloromethane (3mL) cooled to 0 deg.C was treated with N-bromosuccinimide (176mg, 0.99 mmol). The reaction was stirred at 0 ℃ for 15 minutes. At this point, the reaction was treated with 6-chloro-1-cyclohexylmethyl-1H-indole-3-carboxylic acid (240mg, 0.82 mmol). The reaction was stirred at 0 ℃ for 5 minutes, then warmed to 25 ℃ and stirred at this temperature for 30 minutes. The reaction was then treated with 2-aminothiazole (206mg, 2.06mmol) and stirred at 25 ℃ for 20 h. At this time, the reaction was partitioned between water (30mL) and ethyl acetate (30 mL). The mixture was treated with 10% aqueous hydrochloric acid (10mL), shaken, and separated. The organic layer was washed with saturated aqueous sodium chloride (1 × 30mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH40S, Silica, 1/1 hexane/ethyl acetate) gave a pink foam. Will be provided withThe foam was recrystallized from 3/1 hexane/ethyl acetate to give 6-chloro-1-cyclohexylmethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (48mg, 16%) as a pale pink solid: mp 181-183 ℃; EI-HRMS m/e calculation value C₁₉H₂₀ClN₃OS(M⁺)373.1016, found 373.1024.

Example 216-chloro-1-isopropyl-1H-indole-3-carboxylic acid [1, 3, 4] thiadiazol-2-ylamide

[0132]A solution of 6-chloro-1H-indole (1.0g, 6.60mmol) in tetrahydrofuran cooled to 0 ℃ was treated with trifluoroacetic anhydride. The reaction was stirred at 0 ℃ for 30 minutes, then warmed to 25 ℃ and stirred at this temperature for 1 hour. At this time, the reaction was poured into water (75 mL). The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (1.52g, 93%) as an off-white solid: mp 256-258 ℃; EI-HRMS m/e calculation value C₁₀H₁₅ClF₃NO(M⁺)247.0012, found 247.0006.

[0133]A solution of 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone in N, N-dimethylformamide (5mL) was treated with potassium carbonate (698mg, 5.05 mmol). The reaction was stirred at 25 ℃ for 15 minutes and then treated with 2-iodopropane (0.30mL, 3.03 mmol). The mixture was heated at 65 ℃ for 20 hours. At this point, the reaction was cooled to 25 ℃, quenched with water (5mL), and then partitioned between water (50mL) and ethyl acetate (50 mL). The mixture was treated with saturated aqueous sodium chloride (1X 25mL), shaken, and separated. The organic layer was then dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40M, Silica, 3/1 hexane/ethyl acetate) afforded 1- (6-chloro-1-isopropyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (483mg, 83%) as a pale pink solid: mp 94-96 ℃; EI-HRMS m/e calculation value C₁₃H₁₁ClF₃NO(M⁺)289.0481, found 289.0482.

[0134]A mixture of 1- (6-chloro-1-isopropyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (475mg, 1.64mmol) in 20% aqueous sodium hydroxide was heated at 110 ℃ for 18H. At this point, the reaction was cooled to 25 ℃ and treated with 1N aqueous hydrochloric acid. The solution was extracted with ethyl acetate (1X 50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (385mg, 99%) as a yellow solid: mp 206-208 ℃; EI-HRMS m/e calculation value C₁₂H₁₂ClNO₂(M⁺)237.0056, found 237.0554.

[0135]A solution of 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (150mg, 0.63mmol) in toluene (3mL) at 25 deg.C was treated with oxalyl chloride (0.09mL, 1.10 mmol). The reaction was stirred at 25 ℃ for 2 hours and then treated with N, N-dimethylformamide (1 drop). The reaction was then stirred at 25 ℃ for 1 hour. At this time, the reaction was concentrated under vacuum. The residue was dissolved in toluene (2mL) and washed with [1, 3, 4]]Thiadiazole-2-ylamine (128mg, 1.26mmol) in N, N-dimethylformamide (1 mL). The mixture was stirred at 25 ℃ for 3 hours. At this time, the reaction was partitioned between water (30mL) and ethyl acetate (30 mL). The mixture was treated with 1N aqueous hydrochloric acid (10mL), shaken, and separated. The organic layer was washed with saturated aqueous sodium chloride (1 × 30mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH40S, Silica, 1/1 hexane/ethyl acetate) gave a white solid. The solid was dissolved in 1/1 hexane/7 ethyl acetate solution and washed with saturated aqueous sodium bicarbonate (1X 10mL) and saturated aqueous sodium chloride (1X 10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid [1, 3, 4%]Thiadiazol-2-ylamide (12mg, 6%) as a white solid: mp274-275 deg.C; (ES)⁺Calculation of HRMS m/e C₁₄H₁₃ClN₄OS(M+H)⁺321.0572, found 321.0575.

Example 226-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-methyl-thiazol-2-yl) -amide

[0136]A solution of 6-chloro-1H-indole (1.0g, 6.60mmol) in tetrahydrofuran cooled to 0 ℃ was treated with trifluoroacetic anhydride. The reaction was stirred at 0 ℃ for 30 minutes, then warmed to 25 ℃ and stirred at this temperature for 1 hour. At this time, the reaction was poured into water (75 mL). The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (1.52g, 93%) as an off-white solid: mp 256-258 ℃; EI-HRMS m/e calculation value C₁₀H₁₅ClF₃NO(M⁺)247.0012, found 247.0006.

[0137]A solution of 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone in N, N-dimethylformamide (5mL) was treated with potassium carbonate (698mg, 5.05 mmol). The reaction was stirred at 25 ℃ for 15 minutes and then treated with 2-iodopropane (0.30mL, 3.03 mmol). The mixture was heated at 65 ℃ for 20 hours. At this point, the reaction was cooled to 25 ℃, quenched with water (5mL), and then partitioned between water (50mL) and ethyl acetate (50 mL). The mixture was treated with saturated aqueous sodium chloride (1X 25mL), shaken, and separated. The organic layer was then dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40M, Silica, 3/1 hexane/ethyl acetate) afforded 1- (6-chloro-1-isopropyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (483mg, 83%) as a pale pink solid: mp 94-96 ℃; EI-HRMS m/e calculation value C₁₃H₁₁ClF₃NO(M⁺)289.0481, found 289.0482.

[0138]A mixture of 1- (6-chloro-1-isopropyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (475mg, 1.64mmol) in 20% aqueous sodium hydroxide was heated at 110 ℃ for 18H. At this point, the reaction was cooled to 25 ℃ and treated with 1N aqueous hydrochloric acid. The solution was extracted with ethyl acetate (1X 50 mL). Tong (Chinese character of 'tong')The organic layer was dried over magnesium persulfate, filtered, and concentrated in vacuo to give 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (385mg, 99%) as a yellow solid: mp 206-208 ℃; EI-HRMS m/e calculation value C₁₂H₁₂ClNO₂(M⁺)237.0056, found 237.0554.

[0139]A solution of triphenylphosphine (251mg, 0.82mmol) in dichloromethane (3mL) cooled to 0 deg.C was treated with N-bromosuccinimide (146mg, 0.82 mmol). The solution was stirred at 0 ℃ for 5 minutes. At this point, the reaction was treated with 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (150mg, 0.63 mmol). The solution was stirred at 0 ℃ for 5 minutes, then warmed to 25 ℃ and stirred at this temperature for 30 minutes. The reaction was then treated with 5-methyl-thiazol-2-ylamine (166mg, 1.45mmol) and stirred at 25 ℃ for 2 days. At this time, the reaction was diluted with water (25mL) and ethyl acetate (25 mL). The mixture was treated with 1N aqueous hydrochloric acid (5 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (1X 10mL) and saturated aqueous sodium chloride (1X 10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40S, Silica, 1/1 hexane/ethyl acetate) afforded 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-methyl-thiazol-2-yl) -amide (120mg, 57%) as a pink solid: mp 216-219 ℃; (ES)⁺Calculation of HRMS m/e C₁₆H₁₆ClN₃OS(M⁺)333.0703, found 333.0708.

Example 236-chloro-1-isopropyl-1H-indole-3-carboxylic acid (4-methyl-thiazol-2-yl) -amide

[0140]A solution of 6-chloro-1H-indole (1.0g, 6.60mmol) in tetrahydrofuran cooled to 0 ℃ was treated with trifluoroacetic anhydride. The solution was stirred at 0 ℃ for 30 minutes, then warmed to 25 ℃ and stirred at this temperature for 1 hour. At this time, the reaction was poured into water (75 mL). The resulting precipitate was collected by filtration, washed with water and concentrated inDrying under vacuum gave 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (1.52g, 93%) as an off-white solid: mp 256-258 ℃; EI-HRMS m/e calculation value C₁₀H₁₅ClF₃NO(M⁺)247.0012, found 247.0006.

[0141]A solution of 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone in N, N-dimethylformamide (5mL) was treated with potassium carbonate (698mg, 5.05 mmol). The reaction was stirred at 25 ℃ for 15 minutes and then treated with 2-iodopropane (0.30mL, 3.03 mmol). The reaction was heated at 65 ℃ for 20 hours. At this point, the reaction was cooled to 25 ℃, quenched with water (5mL), and then partitioned between water (50mL) and ethyl acetate (50 mL). The mixture was treated with saturated aqueous sodium chloride (1X 25mL), shaken, and separated. The organic layer was then dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40M, Silica, 3/1 hexane/ethyl acetate) afforded 1- (6-chloro-1-isopropyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (483mg, 83%) as a pale pink solid: mp 94-96 ℃; EI-HRMS m/e calculation value C₁₃H₁₁ClF₃NO(M⁺)289.0481, found 289.0482.

[0142]A mixture of 1- (6-chloro-1-isopropyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (475mg, 1.64mmol) in 20% aqueous sodium hydroxide was heated at 110 ℃ for 18H. At this point, the reaction was cooled to 25 ℃ and treated with 1N aqueous hydrochloric acid. The solution was extracted with ethyl acetate (1X 50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (385mg, 99%) as a yellow solid: mp 206-208 ℃; EI-HRMS m/e calculation value C₁₂H₁₂ClNO₂(M⁺)237.0056, found 237.0554.

[0143]A solution of triphenylphosphine (251mg, 0.82mmol) in dichloromethane (3mL) cooled to 0 deg.C was treated with N-bromosuccinimide (146mg, 0.82 mmol). The solution was stirred at 0 ℃ for 5 minutes. At this point, the reaction was treated with 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (150mg, 0.63mmo 1). The solution was brought to 0 deg.CStirred for 5 minutes, then warmed to 25 ℃ and stirred at this temperature for 30 minutes. The reaction was then treated with 4-methyl-thiazol-2-ylamine (166mg, 1.45mmo1) and stirred at 25 ℃ for 2 days. At this time, the reaction was diluted with water (25mL) and ethyl acetate (25mL) and treated with 1N aqueous hydrochloric acid (10 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (1X 20mL) and saturated aqueous sodium chloride (1X 20 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40S, Silica, 1/1 hexane/ethyl acetate) gave 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (4-methyl-thiazol-2-yl) -amide (50mg, 24%) as a yellow solid: mp 201-; (ES)⁺Calculation of HRMS m/e C₁₆H₁₆ClN₃OS(M⁺)333.0703, found 333.0704.

Example 246-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-chloro-thiazol-2-yl) -amide

[0144]A solution of 6-chloro-1H-indole (1.0g, 6.60mmo1) in tetrahydrofuran cooled to 0 ℃ was treated with trifluoroacetic anhydride. The reaction was stirred at 0 ℃ for 30 minutes, then warmed to 25 ℃ and stirred at this temperature for 1 hour. At this time, the reaction was poured into water (75 mL). The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (1.52g, 93%) as an off-white solid: mp 256-258 ℃; EI-HRMS m/e calculation value C₁₀H₁₅ClF₃NO(M⁺)247.0012, found 247.0006.

[0145]A solution of 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone in N, N-dimethylformamide (5mL) was treated with potassium carbonate (698mg, 5.05mmo 1). The reaction was stirred at 25 ℃ for 15 minutes and then treated with 2-iodopropane (0.30mL, 3.03mmo 1). The reaction was heated at 65 ℃ for 20 hours. At this point, the reaction was cooled to 25 ℃, quenched with water (5mL), and then quenchedPartitioned between water (50mL) and ethyl acetate (50 mL). The mixture was treated with saturated aqueous sodium chloride (1X 25mL), shaken, and separated. The organic layer was then dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40M, Silica, 3/1 hexane/ethyl acetate) afforded 1- (6-chloro-1-isopropyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (483mg, 83%) as a pale pink solid: mp 94-96 ℃; EI-HRMS m/e calculation value C₁₃H₁₁ClF₃NO(M⁺)289.0481, found 289.0482.

[0146]A mixture of 1- (6-chloro-1-isopropyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (475mg, 1.64mmol) in 20% aqueous sodium hydroxide was heated at 110 ℃ for 18H. At this point, the reaction was cooled to 25 ℃ and treated with 1N aqueous hydrochloric acid. The solution was extracted with ethyl acetate (1X 50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (385mg, 99%) as a yellow solid: mp 206-208 ℃; EI-HRMS m/e calculation value C₁₂H₁₂ClNO₂(M⁺)237.0056, found 237.0554.

[0147]A solution of triphenylphosphine (251mg, 0.82mmol) in dichloromethane (4mL) cooled to 0 deg.C was treated with N-bromosuccinimide (146mg, 0.82 mmol). The solution was stirred at 0 ℃ for 15 minutes. At this point, the reaction was treated with 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (150mg, 0.63 mmol). The solution was stirred at 0 ℃ for 15 minutes, then warmed to 25 ℃ and stirred at this temperature for 30 minutes. The reaction was then treated with 5-chloro-thiazol-2-ylamine (248mg, 1.45mmol) and stirred at 25 ℃ for 30 min. The reaction was then treated with N, N-diisopropylethylamine (0.22mL, 1.26mmol) and stirred at 25 ℃ for 2 days. At this time, the reaction was diluted with water (30mL) and ethyl acetate (30 mL). The mixture was treated with 1N aqueous hydrochloric acid (10 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (1X 25mL) and saturated aqueous sodium chloride (1X 25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40S, Silica, 1/1 hexane/ethyl acetate) afforded 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-chloro-thiazol-2-yl) -amide (30mg, 13%) as a pink solid: mp 252 and 253 ℃; (ES)⁺Calculation of HRMS m/e C₁₅H₁₃Cl₂N₃OS(M+H)⁺354.0229, found 354.0233.

Example 256-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-bromo-thiazol-2-yl) -amide

[0148]A solution of 6-chloro-1H-indole (1.0g, 6.60mmol) in tetrahydrofuran cooled to 0 ℃ was treated with trifluoroacetic anhydride. The reaction was stirred at 0 ℃ for 30 minutes, then warmed to 25 ℃ and stirred at this temperature for 1 hour. At this time, the reaction was poured into water (75 mL). The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (1.52g, 93%) as an off-white solid: mp 256-258 ℃; EI-HRMS m/e calculation value C₁₀H₁₅ClF₃NO(M⁺)247.0012, found 247.0006.

[0149]A solution of 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone in N, N-dimethylformamide (5mL) was treated with potassium carbonate (698mg, 5.05 mmol). The reaction was stirred at 25 ℃ for 15 minutes and then treated with 2-iodopropane (0.30mL, 3.03 mmol). The reaction was heated at 65 ℃ for 20 hours. At this point, the reaction was cooled to 25 ℃, quenched with water (5mL), and then partitioned between water (50mL) and ethyl acetate (50 mL). The mixture was treated with saturated aqueous sodium chloride (1X 25mL), shaken, and separated. The organic layer was then dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40M, Silica, 3/1 hexane/ethyl acetate) gave 1- (6-chloro-1-isopropyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (483mg, 83%) as a pale pink solid: mp 94-96 ℃; EI-HRMS m/e calculation value C₁₃H₁₁ClF₃NO(M⁺)289.0481, found 289.0482.

[0150]A mixture of 1- (6-chloro-1-isopropyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (475mg, 1.64mmol) in 20% aqueous sodium hydroxide was heated at 110 ℃ for 18H. At this point, the reaction was cooled to 25 ℃ and treated with 1N aqueous hydrochloric acid. The solution was extracted with ethyl acetate (1X 50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (385mg, 99%) as a yellow solid: mp 206-208 ℃; EI-HRMS m/e calculation value C₁₂H₁₂ClNO₂(M⁺)237.0056, found 237.0554.

[0151]A solution of triphenylphosphine (251mg, 0.82mmol) in dichloromethane (4mL) cooled to 0 deg.C was treated with N-bromosuccinimide (146mg, 0.82 mmol). The solution was stirred at 0 ℃ for 15 minutes. At this point, the reaction was treated with 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (150mg, 0.63 mmol). The solution was stirred at 0 ℃ for 15 minutes, then warmed to 25 ℃ and stirred at this temperature for 30 minutes. The reaction was then treated with 5-bromo-thiazol-2-ylamine (377mg, 1.45mmol) and stirred at 25 ℃ for 30 min. The reaction was then treated with N, N-diisopropylethylamine (0.22mL, 1.26mmol) and stirred at 25 ℃ for 2 days. At this time, the reaction was diluted with water (30mL) and ethyl acetate (30 mL). The mixture was treated with 1N aqueous hydrochloric acid (10 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (1X 25mL) and saturated aqueous sodium chloride (1X 25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40S, Silica, 1/1 hexane/ethyl acetate) gave 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-bromo-thiazol-2-yl) -amide (33mg, 13%) as a yellow solid: mp 240-242 ℃; (ES)⁺Calculation of HRMSm/e C₁₅H₁₃BrClN₃OS(M+H)⁺397.9724, found 397.9730.

Example 26 {2- [ (6-chloro-1-isopropyl-1H-indole-3-carbonyl) -amino ] -thiazol-4-yl } -acetic acid ethyl ester

[0152]A solution of 6-chloro-1H-indole (1.0g, 6.60mmol) in tetrahydrofuran cooled to 0 ℃ was treated with trifluoroacetic anhydride. The reaction was stirred at 0 ℃ for 30 minutes, then warmed to 25 ℃ and stirred at this temperature for 1 hour. At this time, the reaction was poured into water (75 mL). The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (1.52g, 93%) as an off-white solid: mp 256-258 ℃; EI-HRMS m/e calculation value C₁₀H₁₅ClF₃NO(M⁺)247.0012, found 247.0006.

[0153]A solution of 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone in N, N-dimethylformamide (5mL) was treated with potassium carbonate (698mg, 5.05 mmol). The reaction was stirred at 25 ℃ for 15 minutes and then treated with 2-iodopropane (0.30mL, 3.03 mmol). The reaction was heated at 65 ℃ for 20 hours. At this point, the reaction was cooled to 25 ℃, quenched with water (5mL), and then partitioned between water (50mL) and ethyl acetate (50 mL). The mixture was treated with saturated aqueous sodium chloride (1X 25mL), shaken, and separated. The organic layer was then dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40M, Silica, 3/1 hexane/ethyl acetate) afforded 1- (6-chloro-1-isopropyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (483mg, 83%) as a pale pink solid: mp 94-96 ℃; EI-HRMS m/e calculation value C₁₃H₁₁ClF₃NO(M⁺)289.0481, found 289.0482.

[0154]A mixture of 1- (6-chloro-1-isopropyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (475mg, 1.64mmol) in 20% aqueous sodium hydroxide was heated at 110 ℃ for 18H. At this point, the reaction was cooled to 25 ℃ and treated with 1N aqueous hydrochloric acid. The solution was extracted with ethyl acetate (1X 50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (385mg, 99%) as a yellow solid: mp 206-208 ℃; EI-HRMS m/e calculationValue C₁₂H₁₂ClNO₂(M⁺)237.0056, found 237.0554.

[0155]A solution of triphenylphosphine (182mg, 0.69mmol) in dichloromethane (3mL) cooled to 0 deg.C was treated with N-bromosuccinimide (124mg, 0.69 mmol). The solution was stirred at 0 ℃ for 15 minutes. At this point, the reaction was treated with 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (150mg, 0.63 mmol). The solution was stirred at 0 ℃ for 5 minutes, then warmed to 25 ℃ and stirred at this temperature for 30 minutes. The reaction was then treated with (2-amino-thiazol-4-yl) -acetic acid ethyl ester (294mg, 1.58mmol) and stirred at 25 ℃ for 16 h. At this time, the reaction was diluted with water (50mL) and ethyl acetate (50 mL). The mixture was treated with 1N aqueous hydrochloric acid (10 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (1X 25mL) and saturated aqueous sodium chloride (1X 25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40S, Silica, 3/1 Hexane/EtOAc) afforded {2- [ (6-chloro-1-isopropyl-1H-indole-3-carbonyl) -amino group]-thiazol-4-yl } -acetic acid ethyl ester (62mg, 24%) as orange foam: mp 65-75 deg.C (ES)⁺Calculation of HRMS m/e C₁₉H₂₀ClN₃O₃S(M+H)⁺406.0987, found 406.0986.

Example 276-chloro-1-isopropyl-1H-indole-3-carboxylic acid pyridin-2-ylamide

[0156]A solution of 6-chloro-1H-indole (1.0g, 6.60mmol) in tetrahydrofuran cooled to 0 ℃ was treated with trifluoroacetic anhydride. The solution was stirred at 0 ℃ for 30 minutes, then warmed to 25 ℃ and stirred at this temperature for 1 hour. At this time, the reaction was poured into water (75 mL). The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (1.52g, 93%) as an off-white solid: mp 256-258 ℃; EI-HRMS m/e calculation value C₁₀H₁₅ClF₃NO(M⁺)247.0012, found 247.0006.

[0157]A solution of 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone in N, N-dimethylformamide (5mL) was treated with potassium carbonate (698mg, 5.05 mmol). The reaction was stirred at 25 ℃ for 15 minutes and then treated with 2-iodopropane (0.30mL, 3.03 mmol). The reaction was heated at 65 ℃ for 20 hours. At this point, the reaction was cooled to 25 ℃, quenched with water (5mL), and then partitioned between water (50mL) and ethyl acetate (50 mL). The mixture was treated with saturated aqueous sodium chloride (1X 25mL), shaken, and separated. The organic layer was then dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40M, Silica, 3/1 hexane/ethyl acetate) afforded 1- (6-chloro-1-isopropyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (483mg, 83%) as a pale pink solid: mp 94-96 ℃; EI-HRMS m/e calculation value C₁₃H₁₁ClF₃NO(M⁺)289.0481, found 289.0482.

[0158]A mixture of 1- (6-chloro-1-isopropyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (475mg, 1.64mmol) in 20% aqueous sodium hydroxide was heated at 110 ℃ for 18H. At this point, the reaction was cooled to 25 ℃ and treated with 1N aqueous hydrochloric acid. The solution was extracted with ethyl acetate (1X 50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (385mg, 99%) as a yellow solid: mp 206-208 ℃; EI-HRMS m/e calculation value C₁₂H₁₂ClNO₂(M⁺)237.0056, found 237.0554.

[0159]A solution of triphenylphosphine (251mg, 0.82mmol) in dichloromethane (3mL) cooled to 0 deg.C was treated with N-bromosuccinimide (146mg, 0.82 mmol). The solution was stirred at 0 ℃ for 15 minutes. At this point, the reaction was treated with 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (150mg, 0.63 mmol). The solution was stirred at 0 ℃ for 15 minutes, then warmed to 25 ℃ and stirred at this temperature for 30 minutes. Then the reaction was treated with 2-amino-4, 5-dimethylthiazole hydrochloride (239mg, 1.45mmol),and stirred at 25 ℃ for 30 minutes. The reaction was then treated with N, N-diisopropylethylamine (0.22mL, 1.26mmol) and stirred at 25 ℃ for 2 days. At this time, the reaction was diluted with water (30mL) and ethyl acetate (30 mL). The mixture was treated with 1N aqueous hydrochloric acid (10 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (1X 25mL) and saturated aqueous sodium chloride (1X 25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40S, Silica, 1/1 hexane/ethyl acetate) gave 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid pyridin-2-ylamide (483mg, 83%) as a yellow solid: mp 149-150 ℃; (ES)⁺Calculation of HRMS m/e C₁₇H₁₆ClN₃O(M+Na)⁺336.0874, found 336.0876.

Example 286-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-methyl-pyridin-2-yl) -amide

[0160]A solution of 6-chloro-1H-indole (1.0g, 6.60mmol) in tetrahydrofuran cooled to 0 ℃ was treated with trifluoroacetic anhydride. The reaction was stirred at 0 ℃ for 30 minutes, then warmed to 25 ℃ and stirred at this temperature for 1 hour. At this time, the reaction was poured into water (75 mL). The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (1.52g, 93%) as an off-white solid: mp 256-258 ℃; EI-HRMS m/e calculation value C₁₀H₁₅ClF₃NO(M⁺)247.0012, found 247.0006.

[0161]A solution of 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone in N, N-dimethylformamide (5mL) was treated with potassium carbonate (698mg, 5.05 mmol). The reaction was stirred at 25 ℃ for 15 minutes and then treated with 2-iodopropane (0.30mL, 3.03 mmol). The reaction was heated at 65 ℃ for 20 hours. At this point, the reaction was cooled to 25 ℃, quenched with water (5mL), then taken up between water (50mL) and ethyl acetate (50mL)And (4) distributing. The mixture was treated with saturated aqueous sodium chloride (1X 25mL), shaken, and separated. The organic layer was then dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40M, Silica, 3/1 hexane/ethyl acetate) afforded 1- (6-chloro-1-isopropyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (483mg, 83%) as a pale pink solid: mp 94-96 ℃; EI-HRMS m/e calculation value C₁₃H₁₁ClF₃NO(M⁺)289.0481, found 289.0482.

[0162]A mixture of 1- (6-chloro-1-isopropyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (475mg, 1.64mmol) in 20% aqueous sodium hydroxide was heated at 110 ℃ for 18H. At this point, the reaction was cooled to 25 ℃ and treated with 1N aqueous hydrochloric acid. The solution was extracted with ethyl acetate (1X 50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (385mg, 99%) as a yellow solid: mp 206-208 ℃; EI-HRMS m/e calculation value C₁₂H₁₂ClNO₂(M⁺)237.0056, found 237.0554.

[0163]A solution of triphenylphosphine (243mg, 0.92mmol) in dichloromethane (3mL) cooled to 0 deg.C was treated with N-bromosuccinimide (165mg, 0.92 mmol). The solution was stirred at 0 ℃ for 15 minutes. At this point, the reaction was treated with 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (200mg, 0.84 mmol). The solution was stirred at 0 ℃ for 15 minutes, then warmed to 25 ℃ and stirred at this temperature for 30 minutes. The reaction was then treated with 2-amino-5-methylpyridine (227mg, 2.10mmol) and stirred at 25 ℃ for 18 h. At this time, the reaction was diluted with water (50mL) and ethyl acetate (50 mL). The mixture was treated with saturated aqueous sodium bicarbonate (15 mL). The organic layer was separated and washed with saturated aqueous sodium chloride (1 × 25mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH40S, Silica, 3/1 hexane/ethyl acetate) gave 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-methyl-pyridin-2-yl) -amide (53mg, 19%) as a light yellow solid: mp 132-; EI-HRMS m/e calculation value C₁₈H₁₈ClN₃O(M⁺)327.1138, found 327.1135.

Example 296-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-trifluoromethyl-pyridin-2-yl) -amide

[0164]A solution of 6-chloro-1H-indole (1.0g, 6.60mmol) in tetrahydrofuran cooled to 0 ℃ was treated with trifluoroacetic anhydride. The solution was stirred at 0 ℃ for 30 minutes, then warmed to 25 ℃ and stirred at this temperature for 1 hour. At this time, the reaction was poured into water (75 mL). The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (1.52g, 93%) as an off-white solid: mp 256-258 ℃; calculation of E-HRMS m/E C₁₀H₁₅ClF₃NO(M⁺)247.0012, found 247.0006.

[0165]A solution of 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone in N, N-dimethylformamide (5mL) was treated with potassium carbonate (698mg, 5.05 mmol). The reaction was stirred at 25 ℃ for 15 minutes and then treated with 2-iodopropane (0.30mL, 3.03 mmol). The reaction was heated at 65 ℃ for 20 hours. At this point, the reaction was cooled to 25 ℃, quenched with water (5mL), and then partitioned between water (50mL) and ethyl acetate (50 mL). The mixture was treated with saturated aqueous sodium chloride (1X 25mL), shaken, and separated. The organic layer was then dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40M, Silica, 3/1 hexane/ethyl acetate) afforded 1- (6-chloro-1-isopropyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (483mg, 83%) as a pale pink solid: mp 94-96 ℃; EI-HRMS m/e calculation value C₁₃H₁₁ClF₃NO(M⁺)289.0481, found 289.0482.

[0166]A mixture of 1- (6-chloro-1-isopropyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (475mg, 1.64mmol) in 20% aqueous sodium hydroxide solutionHeating at 110 ℃ for 18 hours. At this point, the reaction was cooled to 25 ℃ and treated with 1N aqueous hydrochloric acid. The solution was extracted with ethyl acetate (1X 50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (385mg, 99%) as a yellow solid: mp 206-208 ℃; EI-HRMS m/e calculation value C₁₂H₁₂ClNO₂(M⁺)237.0056, found 237.0554.

[0167]A solution of triphenylphosphine (243mg, 0.92mmol) in dichloromethane (3mL) cooled to 0 deg.C was treated with N-bromosuccinimide (165mg, 0.92 mmol). The solution was stirred at 0 ℃ for 15 minutes. At this point, the reaction was treated with 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (200mg, 0.84 mmol). The solution was stirred at 0 ℃ for 15 minutes, then warmed to 25 ℃ and stirred at this temperature for 30 minutes. The reaction was then treated with 2-amino-5- (trifluoromethyl) pyridine (340mg, 2.10mmol) and stirred at 25 ℃ for 18 h. At this time, the reaction was diluted with water (50mL) and ethyl acetate (50 mL). The mixture was treated with saturated aqueous sodium bicarbonate (15 mL). The organic layer was separated and washed with saturated aqueous sodium chloride (1 × 25mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH40S, Silica, 3/1 hexane/ethyl acetate) gave 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-trifluoromethyl-pyridin-2-yl) -amide (53mg, 19%) as a light yellow solid: mp 179-181 ℃; EI-HRMS m/e calculation value C₁₈H₁₅ClF₃N₃O(M⁺)381.0856, found 381.0851.

Example 306-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-chloro-pyridin-2-yl) -amide

[0168]A solution of 6-chloro-1H-indole (1.0g, 6.60mmol) in tetrahydrofuran cooled to 0 ℃ was treated with trifluoroacetic anhydride. The reaction was stirred at 0 ℃ for 30 minutes and then warmed to 25 ℃ at which temperatureStirred for 1 hour. At this time, the reaction was poured into water (75 mL). The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (1.52g, 93%) as an off-white solid: mp 256-258 ℃; EI-HRMS m/e calculation value C₁₀H₁₅ClF₃NO(M⁺)247.0012, found 247.0006.

[0169]A solution of 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone in N, N-dimethylformamide (5mL) was treated with potassium carbonate (698mg, 5.05 mmol). The reaction was stirred at 25 ℃ for 15 minutes and then treated with 2-iodopropane (0.30mL, 3.03 mmol). The reaction was heated at 65 ℃ for 20 hours. At this point, the reaction was cooled to 25 ℃, quenched with water (5mL), and then partitioned between water (50mL) and ethyl acetate (50 mL). The mixture was treated with saturated aqueous sodium chloride (1X 25mL), shaken, and separated. The organic layer was then dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40M, Silica, 3/1 hexane/ethyl acetate) afforded 1- (6-chloro-1-isopropyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (483mg, 83%) as a pale pink solid: mp 94-96 ℃; EI-HRMS m/e calculation value C₁₃H₁₁ClF₃NO(M⁺)289.0481, found 289.0482.

[0170]A mixture of 1- (6-chloro-1-isopropyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (475mg, 1.64mmol) in 20% aqueous sodium hydroxide was heated at 110 ℃ for 18H. At this point, the reaction was cooled to 25 ℃ and treated with 1N aqueous hydrochloric acid. The solution was extracted with ethyl acetate (1X 50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (385mg, 99%) as a yellow solid: mp 206-208 ℃; EI-HRMS m/e calculation value C₁₂H₁₂ClNO₂(M⁺)237.0056, found 237.0554.

[0171]A solution of triphenylphosphine (243mg, 0.92mmol) in dichloromethane (3mL) cooled to 0 deg.C was treated with N-bromosuccinimide (165mg, 0.92 mmol). The solution was stirred at 0 deg.CFor 15 minutes. At this point, the reaction was treated with 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (200mg, 0.84 mmol). The solution was stirred at 0 ℃ for 15 minutes, then warmed to 25 ℃ and stirred at this temperature for 30 minutes. The reaction was then treated with 2-amino-5-chloropyridine (270mg, 2.10mmol) and stirred at 25 ℃ for 40 h. At this time, the reaction was diluted with water (25mL) and ethyl acetate (25 mL). The mixture was treated with saturated aqueous sodium bicarbonate (10 mL). The organic layer was separated and washed with saturated aqueous sodium chloride (1 × 25mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH40S, Silica, 5/1 hexane/ethyl acetate) gave 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-chloro-pyridin-2-yl) -amide (84mg, 29%) as a light yellow solid: mp 131-; EI-HRMS m/e calculation value C₁₇H₁₅Cl₂N₃O(M⁺)347.0592, found 347.0594.

Example 316-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-bromo-pyridin-2-yl) -amide

[ 0172A solution of 6-chloro-1H-indole (1.0g, 6.60mmol) in tetrahydrofuran cooled to 0 ℃ was treated with trifluoroacetic anhydride. The reaction was stirred at 0 ℃ for 30 minutes, then warmed to 25 ℃ and stirred at this temperature for 1 hour. At this time, the reaction was poured into water (75 mL). The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (1.52g, 93%) as an off-white solid: mp 256-258 ℃; EI-HRMS m/e calculation value C₁₀H₁₅ClF₃NO(M⁺)247.0012, found 247.0006.

[0173]A solution of 1- (6-chloro-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone in N, N-dimethylformamide (5mL) was treated with potassium carbonate (698mg, 5.05 mmol). The reaction was stirred at 25 ℃ for 15 minutes and then treated with 2-iodopropane (0.30mL, 3.03 mmol). The reaction is carried out at 65 DEG CThe mixture was heated for 20 hours. At this point, the reaction was cooled to 25 ℃, quenched with water (5mL), and then partitioned between water (50mL) and ethyl acetate (50 mL). The mixture was treated with saturated aqueous sodium chloride (1X 25mL), shaken, and separated. The organic layer was then dried over magnesium sulfate, filtered, and concentrated under vacuum. Biotage chromatography (FLASH40M, Silica, 3/1 hexane/ethyl acetate) afforded 1- (6-chloro-1-isopropyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (483mg, 83%) as a pale pink solid: mp 94-96 ℃; EI-HRMS m/e calculation value C₁₃H₁₁ClF₃NO(M⁺)289.0481, found 289.0482.

[0173]A mixture of 1- (6-chloro-1-isopropyl-1H-indol-3-yl) -2, 2, 2-trifluoro-ethanone (475mg, 1.64mmol) in 20% aqueous sodium hydroxide was heated at 110 ℃ for 18H. At this point, the reaction was cooled to 25 ℃ and treated with 1N aqueous hydrochloric acid. The solution was extracted with ethyl acetate (1X 50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (385mg, 99%) as a yellow solid: mp 206-208 ℃; EI-HRMS m/e calculation value C₁₂H₁₂ClNO₂(M⁺)237.0056, found 237.0554.

[0175]A solution of triphenylphosphine (243mg, 0.92mmol) in dichloromethane (3mL) cooled to 0 deg.C was treated with N-bromosuccinimide (165mg, 0.92 mmol). The solution was stirred at 0 ℃ for 15 minutes. At this point, the reaction was treated with 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (200mg, 0.84 mmol). The solution was stirred at 0 ℃ for 15 minutes, then warmed to 25 ℃ and stirred at this temperature for 30 minutes. The reaction was then treated with 2-amino-5-bromopyridine (363mg, 2.10mmol) and stirred at 25 ℃ for 10 days. At this time, the reaction was diluted with water (50mL) and ethyl acetate (50 mL). The mixture was treated with saturated aqueous sodium bicarbonate (25 mL). The organic layer was separated and washed with saturated aqueous sodium chloride (1 × 25mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH40M, Silica, 3/1 hexane/ethyl acetate) afforded 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-bromo-pyridin-2-yl) -amide (100mg, 30%) It is an off-white foam: mp 57-64 ℃; EI-HRMS m/e calculation value C₁₇H₁₅BrClN₃O(M⁺)391.0087, found 391.0092.

Examples of biological activity:

biological activity example a: in vitro glucokinase Activity

[0176] Glucokinase assay protocol: glucokinase (GK) was analyzed by coupling the production of glucose-6-phosphate with the production of NADH by glucose-6-phosphate dehydrogenase (G6PDH, 0.75-1 kunits/mg; Boehringer Mannheim, Indianapolis, IN) from Leuconostoc mesenteroides as a coupling enzyme (scheme 2).

Reaction scheme 2

[0177] Recombinant human liver GK1 was expressed in E.coli as glutathione S-transferase fusion protein (GST-GK) [ Liang et al, 1995] and chromatographed on a glutathione Sepharose 4B affinity column using the method provided by the manufacturer (Amersham Pharmacia Biotech, Piscataway, N.J.). Previous studies have demonstrated that the nature of the enzymes of native GK and GST-GK are essentially identical (Liang et al, 1995; Neet et al, 1990).

[0178]Assays were performed in 96-well flat-bottomed tissue culture plates from Costar (Cambridge, MA) at 25 ℃ in a final culture volume of 120. mu.l. The culture mixture contains: 25mM Hepes buffer (pH, 7.1), 25mM KCl, 5mM D-glucose, 1mM ATP, 1.8mM NAD, 2mM MgCl₂1 μ M sorbitol-6-phosphate, 1mM dithiothreitol, test drug or 10% DMSO, 1.8 units/ml G6PDH, and GK (see below). All organic reagents were > 98% pure, except D-glucose and Hepes from Sigma Chemical Co, St Louis, MO, others from Boehringer Mannheim. Test compounds were dissolved in DMSO and then added in a volume of12 μ l of the GST-GK free incubation mixture to a final DMSO concentration of 10%. The mixture was pre-incubated in a temperature-controlled bath of a SPECTRAmax 250 microplate spectrophotometer (Molecular devices corporation, Sunnyvale, Calif.) for 10 minutes, the temperature was equilibrated, and 20. mu.l GST-GK was added to initiate the reaction.

[0179]After addition of the enzyme, the increase in Optical Density (OD) at 340nm was monitored over a 10-minute incubation period as a measure of GK activity. Sufficient GST-GK was added to allow the OD of wells containing 10% DMSO without test compound to be in a 10 minute incubation period₃₄₀Increasing from 0.08 to 0.1 units. Preliminary experiments indicate that the GK response is linear over this period, even in the presence of an activator that produces a 5-fold increase in GK activity. GK activity in control wells was compared to wells containing the test GK activator. The concentration of activator that increases GK activity by 50% was calculated and expressed as SC1.5, the activator stimulation concentration required to activate GK enzyme by 50%. All compounds described in the examples have an SC of less than or equal to 100. mu.M_1.5。

Reference to bioactive example a:

liang, y., Kesavan, p., Wang, l., nisswender, k., Tanizawa, y., Permut, m.a., Magnuson, m., and matchinsty, f.m.variable effects of raw-on-diabetes-of-yourh (mody) -associated glucose enzyme activity of the substrate interactions and stability of the enzyme, biochemistry.j.309: 167-173, 1995.

Neet, k., Keenan, r.p., and Tippett, p.s.observer of a kinetic slope transition in monomeric glucose oxidase.biochemistry 29; 770-777, 1990.

Galenic example A

Tablets containing the following ingredients may be prepared according to conventional methods:

component (A)	mg/tablet
component (A)	mg/tablet	A compound of formula I	10.0-100.0
Lactose	125.0	A compound of formula I	10.0-100.0
Lactose	125.0	Corn starch	75.0
Talc	4.0	Corn starch	75.0
Talc	4.0	Magnesium stearate	1.0

Galenic example B

Capsules containing the following ingredients can be prepared according to conventional methods:

component (A)	Mg/capsule
component (A)	Mg/capsule	A compound of formula I	25.0
Lactose	150.0	A compound of formula I	25.0
Lactose	150.0	Corn starch	20.0
Talc	5.0	Corn starch	20.0

Claims

1. A compound of formula I:

R²is lower alkyl having 2-5 carbon atoms or-CH₂-R⁴WhereinR⁴Is cycloalkyl having 3 to 6 carbon atoms; and

-(CH₂)_n-OR⁵，

and- (CH)₂)_n-NHR⁵，

Wherein n is 0 or 1;

R⁵is hydrogen or lower alkyl.

2. A compound according to claim 1, wherein R is¹Is halogen, nitro, methyl, trifluoromethyl, hydroxy, methoxy, methylthio, or methylsulfonyl.

3. A compound according to claim 2 wherein halogen is fluorine, chlorine or bromine.

4. A compound according to claim 1, wherein R is¹Is chlorine.

5. A compound according to claim 1, wherein R is²Is a lower alkyl group.

6. A compound according to claim 5, wherein R is²Is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl andand (3) isoamyl.

7. A compound according to claim 1, wherein R is²is-CH₂-R⁴Wherein R is⁴Is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

8. A compound according to claim 7, wherein R is⁴Is a cyclobutyl group.

9. A compound according to claim 1, wherein R is³Is an unsubstituted or mono-substituted five-or six-membered heteroaromatic ring which is linked to the indicated amine group via a ring carbon atom, which five-or six-membered heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from sulfur or nitrogen, wherein one heteroatom is nitrogen adjacent to the attached ring carbon atom and the substituents are selected from the group consisting of: methyl, trifluoromethyl, chloro, bromo, or

10. A compound according to claim 9, wherein the unsubstituted or mono-substituted five-or six-membered heteroaromatic ring R³Is thiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, isoxazolyl, isothiazolyl, or pyrazolyl.

11. A compound according to claim 10, wherein the unsubstituted or mono-substituted five-or six-membered heteroaromatic ring R³Is pyridyl or thiazolyl.

12. Compounds according to any of claims 9 to 11, wherein the five-or six-membered heteroaromatic ring R³Is monosubstituted at a position on a ring carbon atom not adjacent to the linking carbon atom, and the substituent is selected from the group consisting of: methyl, trifluoromethyl, chloro, bromo, or

13. A compound according to claim 12, wherein R⁵Is a lower alkyl group.

14. A compound according to claim 12 wherein n is 1.

15. Compounds according to any of claims 9 to 11, wherein the five-or six-membered heteroaromatic ring R³Is unsubstituted.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 and a pharmaceutically acceptable carrier and/or adjuvant.

17. A process for the preparation of a pharmaceutical composition according to claim 16, which comprises bringing a compound of formula I according to any one of claims 1 to 15 into association with a pharmaceutically acceptable carrier and/or adjuvant.

18. The use of a compound according to any one of claims 1 to 15 for the preparation of a medicament for the treatment or prophylaxis of type II diabetes.

19. A process for the preparation of a compound according to claim 1, which process comprises

a) Reacting a compound of formula VI

Wherein R is¹And R²As defined in claim 1;

coupling with compounds of the formula VII

R³-NH₂ VII

Wherein R is³As defined in claim 1;

b) oxidation of R in the¹Compounds of formula I to R as methylthio groups¹A compound of formula I which is methylsulfinyl;

c) oxidation of R in the¹Compounds of formula I to R as methylthio groups¹A compound of formula I which is methanesulfonyl;

or

d) In which R is¹Deprotection of a compound of formula I which is a protected amino group or a protected hydroxy group to obtain a compound of formula I wherein R is¹A compound of formula I which is amino or hydroxy.