AU2012227171A1 - Process for preparing 2,3-disubstituted indoles - Google Patents

Abstract

C:NRPonb\CC\REC\459836R_ I DOC. 1/09/2012 Disclosed are processes for making 2,3-disubstituted indole compounds such as compounds of general formula I comprised of the steps of a) reacting a bromoindole compound (i) with a dialkoxyl CI. 5 borane in the presence of a ligand, a palladium catalyst and a base to make a compound of general formula (ii); or alternatively reacting compound (i) with a trialkyl magnesiate reagent, followed by treatment with a borate; b) reacting the product of step a with a R2-Hal where R2-Hal is defined herein.

Description

Australian Patents Act 1990 - Regulation 3.2A ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Invention Title "Process for preparing 2,3-disubstituted indoles" The following statement is a full description of this invention, including the best method of performing it known to me/us: C-\NRPortbl\DCC\REC\4617209 I.DOC - 18/9/12 C.\NRPonblDCC\REC\4598368_L DOC-18/9W2012 PROCESS FOR PREPARING 2,3-DISUBSTITUTED INDOLES RELATED APPLICATIONS This application claims benefit to US Provisional application No. 60/652,072 filed February 11, 2005 the contents of which are incorporated herein. This application is a divisional of Australian Patent Application No. 2006213769, the entire content of which is incorporated herein by reference. BACKGROUND OF THE INVENTION 1. TECHNICAL FIELD The invention relates to a process for the preparation 2, 3 disubstituted indoles useful as pharmaceutical agents and particularly pharmaceutical agents for the treatment of hepatitis C viral (HCV) infections. 2. BACKGROUND INFORMATION Substituted indoles are useful as pharmaceutical agents. Examples of substituted indoles used as pharmaceutical agents thereof include the anti-inflammatory agents indomethacin and tropesin, the antihistamine mebhydroline, and the vasodilator vinpocetine. Other examples of indole compounds used as pharmaceutical agents are indole compounds such as disclosed in US patent application No. 10/198,384 filed July, 7, 2002 and U.S. provisional application 60/546,213, filed February 20, 2004. One of the key aspects in the synthesis of disubstituted indoles is the coupling of the substituents at the 2, 3 positions of the indole and a number of general methods have been used to perform the coupling. One method was exemplified by employing a dipyridyl zinc intermediate and a palladium catalyst as shown in US provisional patent application No. 60/551,107 filed March 8, 2004. This process is referred to herein as Process A.

C :NRPonbPDCC\REC\4598368_ .DOC-IM)9/2)12 -2 Br_/ 2 -N N CO 2 R Pd(OAc) 2 , Ph 3 P N CO 2 R NMP-THF, 90 *C PROCESS A Another approach employs the use of Pd-catalyzed indolization of 2-bromo- or chloro anilines with internal alkynes and is described in US provisional patent application No. 60/553,596, filed March 16, 2004. This process is referred herein as Process B 1) Pd(OAc) 2 (3%), Dtbpf (6%) H 0 K 2 CO3 (2.5eq) -N

H

2 N+ NMP (5 Vol) 130 C O N 2) DMC (5 eq) /N OMe N K 2 CO0 (1.2 eq), 130 *C 0 PROCESS B Although Processes A and B can be used in the preparation 2, 3 disubstituted indoles both processes have some limitations. When the product contains the moiety of arylbromide as in the case shown below, Process A can potentially result in the formation of polymerization product from the competing side reaction of the desired product with the nucleophile i.e. the zinc reagent. Br -N N-N /N Br I \ N N CO 2 R N N CO 2 R / Pd(OAc) 2 , Ph 3 P f NMP-THF, 90 *C Similarly, when the substitutents of the internal alkynes contain the moiety of vinyl bromide, vinyliodide, arylbromide and aryliodide that would compete with 2-halogen anilines for oxidative insertion to the palladium catalyst, Process B can have poor efficiency.

C:\NRPorb\DCC\R \459836_1 DOC-IA)9/2012 -3 + 2 N - OR - Br_ C / H2OR Br N N CO 2 R N N O Br Synthetic routes for preparation of arylboronic esters 1-3 via palladium-catalyzed borylation were developed by Miyaura and Murata, by reaction of bis(pinacolato)diboron 1-1 with aryl halides [Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508], or from dialkoxyhydroborane 1-2 with aryl halides or triflates [Murata, M.; Oyama, T.; Watanabe, S., Masuda, Y. J. Org. Chem. 2000, 65, 164]. However, optimal reaction conditions are often varied significantly, depending upon the structures of the substrates. 0 1 or O' 'O cat. Pd 0,B IB 0'6,0 X = I,Br,OTf 1-1 1-2 1-3 Therefore, design of new process for making 2, 3 disubstituted indoles is needed in the art. BRIEF SUMMARY OF THE INVENTION The present invention provides a process for making 2, 3 disubstituted indoles of general formula (I):

R

3 R27 N R said method comprised of the steps of C \NRPorhl\DCC\REC459836.1 .DOC-1I/9/2012 -4 a) reacting a bromoindole compound (i): R3 Br / x N R1 (i) with a dialkoxyl CI.

5 borane in the presence of a ligand, a palladium catalyst and a base to make a compound of general formula (ii); R3 0B x 0 N R1 (ii) or alternatively reacting compound (i) with a trialkyl magnesiate reagent, followed by treatment with a borate to make a compound of general formula (ii) above; b) reacting the product of step a with: R 2-Hal to provide the desired product of general formula I: wherein: R', R 2 and R 3 , X and Hal are defined herein.

CNRPonbl\DCC\REC45%916X I DOC-19/2012 -5 The invention also relates to a process for making compounds of general formula III: R3 O R 9

R

10 4 N

R

2 H R 5 H N N1~ RI R7 R6 III Wherein R'-R 0 are defined herein. The invention also provides compounds which are active as pharmaceutical agents such as HCV inhibitors and useful as intermediates in the synthesis of HCV inhibitors in making intermediates of said compounds. DETAILED DESCRIPTION OF THE INVENTION Definitions and Terms Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to. In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, (Ci.

8 )alkyl means an alkyl group or radical having I to 8 carbon atoms and (C 3

.

7 )cycloalkyl means a cycloalkyl group having from 3 to 7 carbon atoms in the ring. In general, for groups comprising two or more subgroups, the last named group is the radical attachment point, for example, "cycloalkylalkyl" means a monovalent radical of the formula cycloalkyl-alkyl- and phenylalkyl means a monovalent radical of the formula phenyl-alkyl-. Unless otherwise specified below, conventional definitions of terms control and conventional stable atom valences are presumed and achieved in all formulas and groups.

CANRPonbI\DCC\REC459X36Hl .DOC-18/09/2012 -6 The term "alkyl" as used herein, either alone or in combination with another substituent, means acyclic, straight or branched chain alkyl substituents containing the specified number of carbon atoms. The term "alkoxy" as used herein, either alone or in combination with another substituent, means an alkyl group as defined above linked as a substituent through an oxygen atom: alkyl-O-. In general, all tautomeric forms and isomeric forms and mixtures, whether individual geometric isomers or optical isomers or racemic or non-racemic mixtures of isomers, of a chemical structure or compound are intended, unless the specific stereochemistry or isomeric form is specifically indicated in the compound name or structure. The term "pharmaceutically acceptable salt" as used herein includes those derived from pharmaceutically acceptable bases. Examples of suitable bases include choline, ethanolamine and ethylenediamine. Na*, K*, and Ca+* salts are also contemplated to be within the scope of the invention (also see Pharmaceutical Salts, Birge, S.M. et al., J. Pharm. Sci., (1977), 66, 1-19, incorporated herein by reference). The term "pharmaceutically acceptable ester" as used herein, either alone or in combination with another substituent, means esters of the compound of formula I in which any of the carboxyl functions of the molecule, but preferably the carboxy terminus, is replaced by an alkoxycarbonyl function: 0 ORc in which the Re moiety of the ester is selected from alkyl (e.g. methyl, ethyl, n-propyl, t butyl, n-butyl); alkoxyalkyl (e.g. methoxymethyl); alkoxyacyl (e.g. acetoxymethyl); aralkyl (e.g. benzyl); aryloxyalkyl (e.g. phenoxymethyl); aryl (e.g. phenyl), optionally substituted with halogen, C1A alkyl or Ci4 alkoxy. Other suitable prodrug esters are found in Design of Prodrugs, Bundgaard, H. Ed. Elsevier (1985) incorporated herewith by reference. Such pharmaceutically acceptable esters are usually hydrolyzed in vivo when C:\NRPonblCCREC459369l .DOC-IMK /2012 -7 injected in a mammal and transformed into the acid form of the compound of formula I. With regard to the esters described above, unless otherwise specified, any alkyl moiety present advantageously contains 1 to 16 carbon atoms, particularly I to 6 carbon atoms. Any aryl moiety present in such esters advantageously comprises a phenyl group. In particular the esters may be a CI 1 6 alkyl ester, an unsubstituted benzyl ester or a benzyl ester substituted with at least one halogen, C 1

.

6 alkyl, C 1

.

6 alkoxy, nitro or trifluoromethyl. The following chemicals may be referred to by these abbreviations: TABLE I Abbreviation Chemical Name NMP 1 -methyl-2-pyrrolidinone DMC N,N'-dimethyl acetamide PH3P Triphenyl phosphine Net 3 or Et 3 N or TEA Triethyl amine TFP Isopropyl alcohol IPA Dimethylaminopyridine DMAP N,N-Dimethylformamide DMF 0-(Benzotriazol- 1 -yl)-N,N,N',N' tetramethyluronium tetrafluoroborate MTBE Methyl tert-butyl ether SEH Sodium 2-ethylhexanoate GENERAL SYNTHETIC METHODS In the synthetic schemes below, unless specified otherwise, all the substituent groups in the chemical formulas shall have the same meanings as in general Formula (I). The reactants used in the synthetic schemes described below may be obtained either as described herein, or if not described herein, are themselves either commercially available or may be prepared from commercially available materials by methods known in the art. Certain starting materials, for example, may be obtained by methods described in U.S. patent application number 60/546,213 filed February 20, 2004. Optimum reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific C:\NRPonblDCC\REC4598368-1 DOC.IN/9/2012 -8 procedures are provided in the Synthetic Examples section. Typically, reaction progress may be monitored by High Pressure Liquid Chromatography (HPLC), if desired, and intermediates and products may be purified by chromatography on silica gel and/or by recrystallization. I. Preparation of Bromoindoles The following scheme shows a general method for preparing bromoindole starting materials for the inventive process. Stage 1a Stage 1b Stage 2 0 / 2 3R R

R

3 MeCO 3 , K 2 CO, C72-X _______ / ~10% Pd/C, 3 atm H 2 Base,H 2 N NMP, 130 *C glycerol, 100 *C H 3 80% H 4 Stage 3 RR3 3 Br 2 Br X NCNxCH 3 CN, -6 *C N / 5 6 Condensation of an indole derivative (1) can be performed with a cycloalkylanone (2) compound such as cyclopropanone or cyclohexanone in the presence of an aqueous base. Suitable bases include aqueous sodium hydroxide can be used to prepare the 3 cycloalkenyl compound R 3 ' (3), which can then be subjected to hydrogenation in the presence of a catalytic amount of palladium on carbon to afford the corresponding cycloalkyl indole derivative (4). In the event that the X substituent has an active species then protection of the active specifies may be necessary. For instance if X is a carboxylic acid group then methylation of the carboxylic acid group may be performed. Methylation of the Nitrogen on the indole ring can also be performed at this step. Bromination of the indole derivative with bromine in acetonitrile is then performed to furnish the 2-bromo-3 cycloalkyl indole product (6).

C\NRPortbrDCOREC\459368_l.DOC-18/9/A2012 -9 II. General procedure for making 2, 3 disubstituted indoles from bromoindoles

R

3

R

3 Pd(OAc) 2 Br / -X Method A B-XAqueous baseR -X I N" Ror R1 R2-Hal Method B 2 3 R2-H1= Method A Method B N H i, i-Pr(n-Bu) 2 MgLi, THF MeO \ I CI H t Et 3 NN Oii, -PrO)-

CF

3 I Pd(OAc) 2 , TFP N THF or DME, 70-80 'C N N\ F I Br Br A bromoindole derivative compound (1) can be converted into a dialkylboronate indole derivate compound (2) by using either Method A which employs a dialkoxylborane in the presence of a ligand such as TFP, a palladium catalyst and a base. The preferred reaction conditions are as follows 1.2 equivalent of pinacolborane, 1.5 equivalent of Et3N, catalytic amount of Pd(OAc)2 (3 mol%) and tri(2-furyl)phosphine (12 mol%) in solvent such as DME, or THF. The reaction is performed at between 70 - 80 'C. Alternatively, Method B can be used to obtain product (2). Method B includes reacting a trialkylmagnesiate reagent followed by treatment with a borate. The range of acceptable conditions for this reaction are: treatment of bromoindole I with trialkylmagnesiate, such as iso-PrHex2MgLi (between 0.5 equivalent and 0.7 equivalent) at a temperature between 20 'C and 0 'C, followed by subsequent addition of a borate such as 2-isopropoxy 4,4,5,5,-tetramethyl-1,3,2-dioxaborolane at 0 'C. The indole derivative (2) can then be reacted with an iodo or bromo heterocyclic compound of general formula R2-Hal to provide the desired produce of general formula 1.

C:NRPonbl\DCC\REC459836Hl DOC-I8/09/2012 - 10 Ligands - Ligand that can be used in the inventive process include tri(2-furyl)phosphine, allowing the Suzuki style coupling reaction to be carried out under mild conditions. The use of tri(2-furyl)phosphine also allows simple aqueous inorganic salts, such as K 2

CO

3 or

K

3

PO

4 to be used. In addition, tri(2-furyl)phosphine can catalyze the first step process (borylation) as well, therefore, allowing the combination of the two-step sequence in one pot reaction. Magnesiate - another aspect of the inventive process relates to the use of the Br-metal exchange of the 2-bromoindole using a magnesiate. Examples of magnesiates that can be used include G 1

.

3 MgLi wherein G is any C 1

.

6 alkyl group. The preferred magnesiate is i-Pr(n-Hex)2MgLi or i-Pr(n-Bu)2MgLi etc. The use of the magnesiate in Method B can allow for the 2-indole anion to be readily generated at above -20 'C in the presence of a carboxylate functionality at the X position. Bases -another aspect of the inventive process relates to the use of aqueous bases. Bases that can be used with the method of the invention include K 2

CO

3 and K 2

PO

4 . One pot reaction - In certain embodiments the inventive process can be performed as a "one-pot" process for preparation of 2, 3-disubstituted indoles from 2-bromoindole intermediates via the palladium-catalyzed borylation and Suzuki coupling reactions. This process provides a way to make a variety of 2, 3-disubstituted indoles without using the costly palladium catalyst two times. Tri(2-furyl)phosphine can be used as the common ligand for the two steps of the process, (i.e. the borylation and the Suzuki coupling reactions) and is the preferred ligand for the inventive process. Preparation of compounds of general formula III Indole derivatives according to general formula Ill such as those described in U.S. provisional application 60/546,213 and particularly those of Table I of the application can be synthesized according to this invention and preferably using the following the general procedure outlined in Scheme 1 below.

C \NRPonbrDCC\REC459X368_ LDOC.Ix/9/2012 - 11 Scheme 1 R' R R'4 R' O R N R' CO,H R1 0 N R R R'K RI N NR NH,N N:]# N /! R I R R' R' R Compounds of general formula III, wherein R', R 2 , R 3 , R 4 , R', R , R 7 , R', R 9 and R' are defined as herein before, are preferably prepared by coupling carboxylic acids of general formula ' with amines of general formula II, as illustrated in Scheme 1 above, using carboxyl-activating reagents well known by those skilled in the art. Such reagents include, but are not limited to, TBTU, HATU, BOP, BrOP, EDAC, DCC, isobutyl chloroformate and the like. Alternatively, carboxylic acids of general formula 1' may be converted to the corresponding acid chlorides using standard reagents, then coupled with amine derivatives of the general formula II. In the cases where either R 5 or R 6 contain an ester-protected carboxylic acid moiety, a saponification reaction is carried out (using protocols well known by those skilled in the art) to obtain the final inhibitor product as the free carboxylic acid. Intermediate carboxylic acids of general formula I' may be prepared by procedures described in WO 03/010141, or by procedures described in the examples below. Intermediate amines of formula II may be prepared according to the general procedures outlined in Schemes 2 and 3 below. Scheme 2

R"

0 R 1) R R C R4 HRN R H 3 N+ R N R 5 CI- 0 R1 HN

H

2 N N R R R 2) AcOH, heat R R IV ' III' Scheme I may be prepared from the corresponding diamine precursors of general formula IV' by coupling with the appropriate ct,a-disubstituted amino acid chloride hydrochlorides.

C:NRPonbl\DCC\REC\459K36X_1 DOC.I )9/2012 - 12 Preparation of the appropriate a,a-disubstituted amino acid chloride hydrochlorides from the corresponding a,a-disubstituted amino acids may be carried out as described in WO 03/007945 or WO 03/010141, or by using the procedure, or an adaptation thereof, described by E. S. Uffelman et al. (Org. Lett. 1999, 1, 1157). The amide intermediate formed in the coupling reaction is then cyclized to provide amine intermediates of general formula II. Scheme 3 1) R R OH R BocNH

R

2 Rl Fl R 0 N R 5 coupling reagent HN R 6 H 2 N N R Ra R 2) AcOH, heat R a R 7 IV 3) Boc deprotection III Alternatively, amine intermediates of general formula II in Scheme I may be prepared from the corresponding diamine precursors of general formula IV by coupling with the appropriate Boc-protected a,a-disubstituted amino acid as illustrated in Scheme 3, using coupling reagents well known to one skilled in the art, such as TBTU, HATU, BOP, BrOP, EDAC, DCC, isobutyl chloroformate and the like. Appropriate Boc-protected a,a disubstituted amino acids may be prepared from the free a,a-disubstituted amino acids, using standard conditions well known to one skilled in the art, such as reaction with Boc 2 0 in the presence of a tertiary amine such as triethylamine, and the like. The amide intermediate formed in the coupling reaction is then cyclized by heating in the presence of an acid such as acetic acid, or hydrochloric acid. Deprotection of the Boc group to provide the amine intermediate of general formula 11 in Scheme 1 is carried out using standard reagents well known to one skilled in the art. Such reagents include, but are not limited to, trifluoroacetic acid, a solution of HCI in dioxane and the like. Preparation of the diamine precursors of general formula IV in Schemes 2 and 3 is preferably carried out by applying the procedures as outlined in the examples, including any adaptation of these procedures, and/or applying additional synthetic steps known to the C :NRPonblDCC\REO459836_.L)OC.-18/09/21'12 - 13 person skilled in the art. 6I Amine intermediates of general formula II in Scheme 1 wherein one of R and R6 is CH=C(R 5 )-COOR, wherein R 50 is selected from (CI.

6 )alkyl and halogen and wherein R is, for example, methyl or ethyl, may be prepared from the corresponding amine intermediates of general formula Ill, or suitably protected derivatives thereof, wherein one of R 5 and R 6 is -COOR, wherein R is, for example, methyl or ethyl, by applying the procedures of Scheme 4 below. While Scheme 4 specfically illustrates the preparation of amine intermediates of general formula II wherein R 5 is -CH=C(R" 0 )-COOR, it is understood by the person skilled in the art that when R6 is -COOR, the illustrated procedures, or adaptations thereof, will result in a product wherein R is -CH=C(R 0) COOR. Also, it is understood by the person skilled in the art that the procedures of Scheme 4, or adaptations thereof, may also be used when converting a diamine precursor of general formula IV' in Schemes 2 and 3 above, or a suitably protected derivative thereof, or a suitable intermediate in its preparation, wherein one of R 5 and R 6 is -COOR, to a diamine precursor of general formula IV', or a suitably protected derivative thereof, or a suitable intermediate in its preparation wherein one of R 5 and R 6 is -CH=C(R 50 )-COOR, wherein R 5 0 and R defined as hereinbefore.

C:\NRPortblDCC\REC\459MX_1 DOC-lM)/W2012 - 14 Scheme 4 R 4 R4

R

9 R N COOR reduction R OH N H N R PG ,NH N R PG R RR R Ilia' 1li1b' O 1) Roxidation 1) ROOC P__ \ OR R ROR R 9R* N COOR R9 R N R strong base R O

H

2 N N R R NH N 2) deprotection PG R' R R R IIld' Illc' A suitably protected amine intermediate of general formula Illa' in Scheme 4 above may be converted to an alcohol intermediate of general formula IIb' by treatment with a suitable reducing agent such as DIBAL-H and the like. Suitable protecting groups (PG) include, but are not limited to, carbamate protecting groups, such as Boc (tert butyloxycarbonyl) and the like. Preparation of protected amine intermediates of general formula lla from amine intermediates of general formula II in Scheme I above may be carried out by standard procedures well-known to one skilled in the art. The alcohol intermediate Illb' may be converted to the aldehyde intermediate Illc', using standard oxidizing agents well-known to one skilled in the art, such as 1,1,1-tris(acetyloxy 1,1-dihydro-1,2-benziodoxol-3-(IH)-one (also known as Dess-Martin periodinane) and the like. The aldehyde intermediate Ilc' may be converted to an amine intermediate of general formula Ild' using a standard Horner-Emmons procedure, or related procedures such as Wittig procedures or the like, well known to a person skilled in the art, followed by deprotection of the PG group using well-known standard procedures. In the case where the PG group is Boc, such procedures include, but are not limited to, treatment with acidic C:\NRPonb\CC\REC I9836_1 DOC-18/09/2012 - 15 conditions such as trifluoroacetic acid, HCl dissolved in dioxane and the like. Pharmaceutically acceptable salts of compound disclosed herein could include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfuric, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfuric and benzenesulfonic acids. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(CI-C 4 alkyl) 4 + salts. Embodiments of the invention A first embodiment of the invention provides a process for making 2, 3 disubstituted indoles of general formula (I):

R

3 R2 I N R said method comprised of the steps of a) reacting a bromoindole compound (i): R3 Br X N Ri (i) C:\NRPortbl\DCC\RECW598168_ DOC-IM)9/21112 - 16 with a dialkoxyl CI- 5 borane in the presence of a ligand, a palladium catalyst and a base to make a compound of general formula ii; R3 0B X o N R1 (ii) or alternatively reacting compound (i) with a trialkyl magnesiate reagent, followed by treatment with a borate to make a compound of general formula ii above; b) reacting the product of step a with: R2-Hal to provide a compound of general formula I; wherein: R' is H or (CI- 6 )alkyl;

R

2 is Het or aryl having 5 or 6 members and Het or aryl being optionally substituted with R21 wherein R21 is one, two or three substituents selected from -OH, -CN, -N(I N2)R", halogen, (C 1

.

6 )alkyl, (CI.

6 )alkoxy, (CI.

6 )alkylthio, Het and -CO-N(R 2)RNI; wherein said alkyl, alkoxy and alkylthio are each optionally substituted with one, two or three halogen atoms;

R

3 is (C 5

-

6 )cycloalkyl, optionally substituted with from one to four halogen atoms; C:\NRPonbl\DCC\REC.5916_ LDOC.I8/)9/2012 - 17 0 X is: H, C 1

-

6 alkyl, C 1

-

6 alkoxy; L Hal is Br or I L is H or a group further comprised of general formula iii:

R

9 R 1 0 NN R R R7 R iii wherein

R

4 and R 7 are each independently selected from H, (C 1

-

6 )alkyl, (CI- 6 )alkoxy,

(CI-

6 )alkylthio, -NH 2 , -NH(C I- 6 )alkyl, -N((CI.

6 )alkyl) 2 and halogen; One of R" and R 6 is selected from COOH, -CO-N(RN 2 )RNI, Het' and (C 2

.

6 )alkenyl, wherein Het', (C 2

-

6 )alkenyl and RN' or any heterocycle formed between 1 N2 and RNI iS optionally substituted with R 50 ; wherein R 50 is one, two or three substituents selected from (CI- 6 )alkyl, -COOH, NZ NI, C-( N2 NI -N(R 2)RN, -CO-N(RN)R , and halogen; and the other of R 5 and R 6 is selected from H, (CI- 6 )alkyl, (CI- 6 )alkoxy, (CI- 6 )alkylthio, and N(R N2)RNI;

R

8 is (CI- 6 )alkyl, (C 3

-

7 )cycloalkyl or (C 3

.

7 )cycloalkyl-(Ci.

6 )alkyl-; wherein said alkyl, cycloalkyl and cycloalkyl-alkyl are optionally substituted with one, two or three substituents selected from halogen, (CI.

6 )alkoxy and (Ci. 6 )alkylthio;

R

9 and R' 0 are each independently selected from (CI- 6 )alkyl; or R 9 and R' 0 are covalently C.\NRPonb\DCC\REC\4598%X_.DOC-1 KO/2012 - 18 bonded together to form (C 3

.

7 )cycloalkyl, (C 5

.

7 )cycloalkenyl or a 4-, 5- or 6 membered heterocycle having from I to 3 heteroatoms selected from 0, N, and S; wherein said cycloalkyl, cycloalkenyl or heterocycle is optionally substituted with

(C

1 4)alkyl; R NI is selected from H, (C I- 6 )alkyl, (C 3

.

7 )cycloalkyl, (C 3

-

7 )cycloalkyl-(C- 6 )alkyl-,

-CO-(CI.

6 )alkyl, -CO-0-(CI.

6 )alkyl and Het ; wherein all of said alkyl and cycloalkyl is optionally substituted with one, two or three substituents selected from halogen, (C 1

.

6 )alkoxy and (CI.

6 )alkylthio; and RN2 is H or (C 1

-

6 )alkyl, or RN2 and R may be covalently bonded together to form a 4-, 5-, 6- or 7-membered saturated or unsaturated N-containing heterocycle or a 8-, 9-, 10- or I1 -membered N containing heterobicycle, each having additionally from 1 to 3 heteroatoms selected from 0, N, and S; wherein the heterocycle or heterobicycle formed by RN 2 and R NI is optionally substituted with one, two or three substituents selected from halogen, (C 1

-

6 )alkyl, (Ci.

6 )alkoxy and (C I.

6 )alkylthio; wherein Het is defined as a 4-, 5-, 6- or 7-membered heterocycle having I to 4 heteroatoms selected from 0, N and S, which may be saturated, unsaturated or aromatic, or a 8-, 9-, 10- or 1 1-membered heterobicycle having 1 to 5 heteroatoms wherever possible, selected from 0, N and S, which may be saturated, unsaturated or aromatic; or a pharmaceutically acceptable salt thereof A second embodiment of the invention provides a method for making 2, 3 disubstituted indoles of general formula (1) wherein R' is H or (CI- 6 )alkyl; R2 is Het; or aryl having 5 or 6 members and Het or aryl being optionally substituted with C:\NRPonbl\DCCRE0459M3681 DOC. IM19/2112 - 19 R21 21 N2 N I wherein R is one, two or three substituents selected from -OH, -CN, -N(RN )R halogen, (CI- 6 )alkyl, (Ci- 6 )alkoxy, (CI- 6 )alkylthio, Het and -CO-N(R N2)RNI; wherein said alkyl, alkoxy and alkylthio are each optionally substituted with one, two or three halogen atoms; R3 is cyclopentyl; 0 X is: H, CI.

6 alkyl, CI_ 6 alkoxy, L Hal is I or Br; L is H or a group further comprised of general formula iii:

R

9 Rio NH/ RN R

RR

6 R 7 R' iii wherein

R

4 and R 7 are each independently selected from H, (Ci.

6 )alkyl, (Ci.

6 )alkoxy,

(CI.

6 )alkylthio, -NH 2 , -NH(C I 6 )alkyl, -N((CI- 6 )alkyl) 2 and halogen; One of R 5 and R 6 is selected from COOH, -CO-N(RN 2 )RNI, Het' and (C 2

-

6 )alkenyl, wherein Het', (C 2

.

6 )alkenyl and RNI or any heterocycle formed between RN2 and RN' is optionally substituted with R5 0 ; wherein R 50 is one, two or three substituents selected from (CI.

6 )alkyl, -COOH, -N(R N2)R N, -CO-N(R N)R N, and halogen; and the other of R 5 and R 6 is selected from H, (CI.

6 )alkyl, (Ci- 6 )alkoxy, (Ci.

6 )alkylthio, and N(R N2)R N1 C:\RPonb\DCC\REC\459K168_IDOC-I /9/2012 -20

R

8 is (Ci.6)alkyl, (C 3

.

7 )cycloalkyl or (C 3

.

7 )cycloalkyl-(Ci.

6 )alkyl-; wherein said alkyl, cycloalkyl and cycloalkyl-alkyl are optionally substituted with one, two or three substituents selected from halogen, (CI.

6 )alkoxy and (C 1 . 6 )alkylthio;

R

9 and R' 0 are each independently selected from (CI.

6 )alkyl; or R 9 and R' 0 are covalently bonded together to form (C 3

.

7 )cycloalkyl, (C 5

.

7 )cycloalkenyl or a 4-, 5- or 6 membered heterocycle having from I to 3 heteroatoms selected from 0, N, and S; wherein said cycloalkyl, cycloalkenyl or heterocycle is optionally substituted with (CI4)alkyl; R"' is selected from H, (C 1

-

6 )alkyl, (C 3

-

7 )cyCloalkyl, (C 3

-

7 )cycloalkyl-(C- 6 )alkyl-,

-CO-(C

1

.

6 )alkyl, -CO-0-(CI.

6 )alkyl and Het'; wherein all of said alkyl and cycloalkyl is optionally substituted with one, two or three substituents selected from halogen, (Ci- 6 )alkoxy and (CI- 6 )alkylthio; and RN2 is H or (Ci- 6 )alkyl, or N2

RN

2 and R may be covalently bonded together to form a 4-, 5-, 6- or 7-membered saturated or unsaturated N-containing heterocycle or a 8-, 9-, 10- or I I-membered N containing heterobicycle, each having additionally from 1 to 3 heteroatoms selected from 0, N, and S; wherein the heterocycle or heterobicycle formed by RN 2 and RNI is optionally substituted with one, two or three substituents selected from halogen, (C 1 6 )alkyl, (Ci- 6 )alkoxy and (CI.

6 )alkylthio; wherein Het is defined as a 4-, 5-, 6- or 7-membered heterocycle having 1 to 4 heteroatoms selected from 0, N and S, which may be saturated, unsaturated or aromatic, or a 8-, 9-, 10- or I 1-membered heterobicycle having I to 5 heteroatoms wherever possible, selected from 0, N and S, which may be saturated, unsaturated or aromatic.

C:\NRPonbrDCCREC\4598168_ .DOC-IMN9/21112 -21 A third embodiment of the invention provides a method for making 2, 3 disubstituted indoles of general formula (1) wherein R' is H or (C 1

.

6 )alkyl; -BF clBrCF, R2 is selected from ND/ F (NN

R

3 is (C 5

-

6 )cycloalkyl, optionally substituted with from one to four halogen atoms; 0 X is: H, CI.

6 alkyl, Ci.

6 alkoxy, L Hal is Br or I; L is H or a group further comprised of general formula iii:

R

9 R 10 NH N N R R 8

R

7 R iii wherein

R

4 and R 7 are each independently selected from Hl, (CI- 6 )alkyl, (C 1

.

6 )alkoxy, (Ci- 6 )alkylthio, -NH 2 , -N H(CI- 6 )alkyl, -N((CI.

6 )alkyl) 2 and halogen; One of R and R 6 is selected from COOH, -CO-N(R N2)RN , Het' and (C 2

-

6 )alkenyl, wherein Het', (C 2

-

6 )alkenyl and RNI or any heterocycle formed between RN2 and R N is optionally substituted with R5 0

;

C:\NRPonb\DCC\REC\45936_I. DOC-IK09/2012 -22 wherein R 50 is one, two or three substituents selected from (Ci.

6 )alkyl, -COOI, -N(RN2 NI, -CO-N(R )RNI, and halogen; and the other of R 5 and R 6 is selected from H, (CI- 6 )alkyl, (CI- 6 )alkoxy, (CI.

6 )alkylthio, and N(R )RNI;

R

8 is (CI-6)alkyl, (C 3

.

7 )cycloalkyl or (C 3

.

7 )cycloalkyl-(CI- 6 )alkyl-; wherein said alkyl, cycloalkyl and cycloalkyl-alkyl are optionally substituted with one, two or three substituents selected from halogen, (Ci.

6 )alkoxy and (C 1 . 6 )alkylthio;

R

9 and R' 0 are each independently selected from (Ci.

6 )alkyl; or R 9 and R' are covalently bonded together to form (C 3

.

7 )cycloalkyl, (C 5

.

7 )cycloalkenyl or a 4-, 5- or 6 membered heterocycle having from I to 3 heteroatoms selected from 0, N, and S; wherein said cycloalkyl, cycloalkenyl or heterocycle is optionally substituted with

(C

1 4)alkyl; RN1 is selected from H, (CI- 6 )alkyl, (C 3

.

7 )cycloalkyl, (C 3

.

7 )cycloalkyl-(CI- 6 )alkyl-,

-CO-(CI-

6 )alkyl, -CO-O-(CI- 6 )alkyl and Het'; wherein all of said alkyl and cycloalkyl is optionally substituted with one, two or three substituents selected from halogen, (CI.

6 )alkoxy and (CI_ 6 )alkylthio; and RN2 is H or (Ci- 6 )alkyl, or RN2 and RNI may be covalently bonded together to form a 4-, 5-, 6- or 7-membered saturated or unsaturated N-containing heterocycle or a 8-, 9-, 10- or I I-membered N containing heterobicycle, each having additionally from 1 to 3 heteroatoms selected from 0, N, and S; wherein the heterocycle or heterobicycle formed by RN 2 and RNI is optionally substituted with one, two or three substituents selected from halogen, (CI.

6 )alkyl,

(CI-

6 )alkoxy and (CI.

6 )alkylthio; wherein Het is defined as a 4-, 5-, 6- or 7-membered heterocycle having 1 to 4 heteroatoms selected from 0, N and S, which may be saturated, unsaturated or aromatic, or CkNRPonbl\DCCREC\459X368 I DOC-18A9/20I12 - 23 a 8-, 9-, 10- or 1 1-membered heterobicycle having I to 5 heteroatoms wherever possible, selected from 0, N and S, which may be saturated, unsaturated or aromatic; or a pharmaceutically acceptable salt thereof Another embodiment of the invention provides a method of claim I wherein R' is H or (CI.

6 )alkyl;

R

2 is Het; or aryl having 5 or 6 members and Het or aryl being optionally substituted with R21 wherein R is one, two or three substituents selected from -OH, -CN, -N(R N2)RNI halogen, (CI- 6 )alkyl, (CI- 6 )alkoxy, (Ci- 6 )alkylthio, Het and -CO-N(R N2)RN ; wherein said alkyl, alkoxy and alkylthio are each optionally substituted with one, two or three halogen atoms; R3 is cyclopentyl; X is carboxymethyl; Hal is Br or I; L is H or a group further comprised of general formula iii:

R

9 R 10 NH N R R7 R iii wherein

R

4 and R 7 are each independently selected from H, (Ci.6)alkyl, (CI- 6 )alkoxy, C:\NRPortbl\DCC\REC459368_ DOC-1M1/9/2012 - 24 (CI- 6 )alkylthio, -NH 2 , -N H(CI- 6 )alkyl, -N((CI- 6 )alkyl) 2 and halogen; One of R 5 and R 6 is selected from COOH, -CO-N(R 2)RN, Het' and (C 2

-

6 )alkenyl, wherein Heti, (C 2

.

6 )alkenyl and R or any heterocycle formed between RN2 and R I 1s optionally substituted with R 5. wherein R; 0 is one, two or three substituents selected from (CI- 6 )alkyl, -COOH, -N(R )R N, -CO-N(R N2)R N, and halogen; and the other of R 5 and R 6 is selected from H, (CI.o)alkyl, (CI.

6 )alkoxy, (C,.

6 )alkylthio, and N(R N2)RNI;

R

8 is (CI-6)alkyl, (C 3

.

7 )cycloalkyl or (C 3

.

7 )cycloalkyl-(CI.

6 )alkyl-; wherein said alkyl, cycloalkyl and cycloalkyl-alkyl are optionally substituted with one, two or three substituents selected from halogen, (C 1

.

6 )alkoxy and (C 1 . 6 )alkylthio; R' and R' 0 are each independently selected from (C 1

.

6 )alkyl; or R) and R' are covalently bonded together to form (C 3

.

7 )cycloalkyl, (C 5 .7)cycloalkenyl or a 4-, 5- or 6 membered heterocycle having from I to 3 heteroatoms selected from 0, N, and S; wherein said cycloalkyl, cycloalkenyl or heterocycle is optionally substituted with (C 1A)alkyl; R N is selected from H, (CI- 6 )alkyl, (C 3

.

7 )cycloalkyl, (C 3

.

7 )cycloalkyl-(Ci.

6 )alkyl-,

-CO-(CI-

6 )alkyl, -CO-O-(C 1

.

6 )alkyl and Het'; wherein all of said alkyl and cycloalkyl is optionally substituted with one, two or three substituents selected from halogen, (CI.

6 )alkoxy and (CI.

6 )alkylthio; and RN2 is H4 or (CI.

6 )alkyl, or

RN

2 and RNI may be covalently bonded together to form a 4-, 5-, 6- or 7-membered saturated or unsaturated N-containing heterocycle or a 8-, 9-, 10- or 1 I-membered N containing heterobicycle, each having additionally from I to 3 heteroatoms selected from 0, N, and S; wherein the heterocycle or heterobicycle formed by R and RNI is optionally C NRPortbl\DCC\REC\459368_ .DOC. 1/9/920l2 -25 substituted with one, two or three substituents selected from halogen, (CI- 6 )alkyl, (Ci- 6 )alkoxy and (CI- 6 )alkylthio; wherein Het is defined as a 4-, 5-, 6- or 7-membered heterocycle having 1 to 4 heteroatoms selected from 0, N and S, which may be saturated, unsaturated or aromatic, or a 8-, 9-, 10- or 1 1-membered heterobicycle having 1 to 5 heteroatoms wherever possible, selected from 0, N and S, which may be saturated, unsaturated or aromatic. Another embodiment of the invention provides a method for making the compounds of general formula III: R3 0 R 9

R

10 4 N

R

2 H N R N R8/N 1 R7 R6 RI R R III said method comprised of the steps of: a) reacting a bromoindole compound (iv): R3 0 R 9

R

1 0 4 N R Br , H N /\ R 5 N / R 8 RI R 7

R

6 (iv) with a dialkoxyl borane in the presence of a ligand and a palladium catalyst and a base to obtain compound of general formula (v); C:\RPonbDCC\RECt459836K_ .DOC.IA/9/2012 -26 R3 0 R R1 R4 O N N O N R 8 1 R7 '6 RI

R

7 (v) b) reacting the product of step a with: R2-Hal to provide the desired product of general formula III wherein: R1 is H or (CI- 6 )alkyl;

R

2 is Het; or aryl having 5 or 6 members and Het or aryl being optionally substituted with

R

21 21 N2 NI wherein R is one, two or three substituents selected from -OH, -CN, -N(R )R, halogen, (CI- 6 )alkyl, (CI.

6 )alkoxy, (Ci- 6 )alkylthio, Het and -CO-N(R N2)RN wherein said alkyl, alkoxy and alkylthio are each optionally substituted with one, two or three halogen atoms;

R

3 is (C 5

.

6 )cycloalkyl, optionally substituted with from one to four halogen atoms; 0 X is: H, CI -C6 alkyl, C1 C6 alkoxy, L Hal is Br or 1; L is H or a group further comprised of general formula iii: C:NRPortbDCC\REC\459836_ I DOC-18M/2012 -27 R R 10 NHR N R5 R8/ R R 7 R iii wherein

R

4 and R 7 are each independently selected from Hl, (CI- 6 )alkyl, (CI- 6 )alkoxy,

(CI-

6 )alkylthio, -NH 2 , -NH(CI- 6 )alkyl, -N((CI- 6 )alkyl) 2 and halogen; One of R and R6 is selected from COOH, -CO-N(R N2)RNI, Het' and (C 2

-

6 )alkenyl, wherein Het', (C 2

-

6 )alkenyl and RN1 or any heterocycle formed between RN2 and RN' is optionally substituted with R 50 ; wherein R 50 is one, two or three substituents selected from (CI- 6 )alkyl, -COOH,

-N(RN

2 )RNI, -CO-N(RN 2 )RN', and halogen; and the other of R 5 and R 6 is selected from H, (C 1

.

6 )alkyl, (CI- 6 )alkoxy, (CI.

6 )alkylthio, and N(R N2)RN;

R

8 is (CI.)alkyl, (C 3

.

7 )cycloalkyl or (C 3

.

7 )cycloalkyl-(Ci.

6 )alkyl-; wherein said alkyl, cycloalkyl and cycloalkyl-alkyl are optionally substituted with one, two or three substituents selected from halogen, (CI.

6 )alkoxy and (Ci. 6 )alkylthio;

R

9 and R' 0 are each independently selected from (CI.

6 )alkyl; or R 9 and R' 0 are covalently bonded together to form (C 3

.

7 )cycloalkyl, (C 5

.

7 )cycloalkenyl or a 4-, 5- or 6 membered heterocycle having from 1 to 3 heteroatoms selected from 0, N, and S; wherein said cycloalkyl, cycloalkenyl or heterocycle is optionally substituted with (C,4)alkyl; RNI is selected from H, (CI- 6 )alkyl, (C 3

.

7 )cycloalkyl, (C 3

.

7 )cycloalkyl-(CI- 6 )alkyl-,

-CO-(CI.

6 )alkyl, -CO-O-(Ci.

6 )alkyl and Het'; C :RPonblDCCREC\459X6X_1 DOC.I9/2O12 - 28 wherein all of said alkyl and cycloalkyl is optionally substituted with one, two or three substituents selected from halogen, (CI.

6 )alkoxy and (CI.

6 )alkylthio; and RN2 is H or (CI- 6 )alkyl, or

RN

2 and R may be covalently bonded together to form a 4-, 5-, 6- or 7-membered saturated or unsaturated N-containing heterocycle or a 8-, 9-, 10- or I1 -membered N containing heterobicycle, each having additionally from I to 3 heteroatoms selected from 0, N, and S; wherein the heterocycle or heterobicycle formed by RN 2 and RNI is optionally substituted with one, two or three substituents selected from halogen, (CI- 6 )alkyl,

(CI-

6 )alkoxy and (Ci- 6 )alkylthio; wherein Het is defined as a 4-, 5-, 6- or 7-membered heterocycle having I to 4 heteroatoms selected from 0, N and S, which may be saturated, unsaturated or aromatic, or a 8-, 9-, 10- or 1 -membered heterobicycle having 1 to 5 heteroatoms wherever possible, selected from 0, N and S, which may be saturated, unsaturated or aromatic. Another embodiment of the invention provides a palladium-catalyzed borylation process wherein the dialkoxylborane is 4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Another embodiment of the invention provides a method for making compounds of general formula I wherein the borate used in the Br-Mg exchange process is isopropoxy 4,4,5,5,5-tetramethyl- 1,3,2-dioxaborolane. Another embodiment of the invention provides a method for making a compound of general formula I wherein step (a) is comprised of the step of reacting a bromoindole compound of formula (vi): C\NRPonbl\DCCREC\459K36A_ DOC-18/09/202 -29 RO N Br O Me R = H, Alkyl, aryl, Na, Li, K, Mg (vi) with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane to provide (vii) 0 RO BO o Me R = H, Alkyl, aryl, Na, Li, K, Mg (vii) b) reacting the product of step a with: 1I- ) -Br I CI N or N to provide: Me x/N N N OR X = CI, Br R = H, Alkyl, aryl, Na, Li, K, Mg (viii) c) performing a hydrolysis with NaOH to provide (ix): C:WRPonbhDCC\RECU59x36XI DOC.IA9/2012 - 30 Me XYN O N OH X = CI, Br (ix). In another embodiment of the invention the ligand is chosen from tri(2-furyl)phosphine and 2-(dicyclohexylphosphino) biphenyl for conversion of vi into vii by the Pd-catalyzed borylation process, and tri(2-furyl)phosphine for conversion of vii into viii by the Pd catalyzed Suzuki coupling reaction. In another embodiment of the invention the palladium catalyst is chosen from Pd(OAc) 2 , PdC 2 , PdBr 2 , Pd 2 (dba) 3 , Pd 2 (dba) 3 .CHCl 3 , [Pd(ally)Cl] 2 , Pd(CH 3

CN)

2

C

2 , Pd(PhCN) 2 Cl 2 , Pd/C and encapsulated Pd. In another embodiment of the invention the solvent is DME, or THF and the base is triethylamine for the Pd-catalyzed borylation process that converts vi into vii. The solvent is DME, THF, or 2-propanol for the Suzuki coupling process and the base is potassium phosphate, or potassium carbonate. In another embodiment of the invention the reagent for the bromo-magnesium exachange is trialkylmagnesiate is G 1

.

3 MgLi wherein G is any C 1

.

6 alkyl group and preferably GI-3 MgLi chosen from i-Pr(n-Hex) 2 MgLi or i-Pr(n-Bu) 2 MgLi, n-Bu 3 MgLi. All references cited herein, including the journal articles or abstracts published or corresponding U.S. or foreign applications, issued or U.S. or foreign patents, or any other references, are entirely incorporated by reference herein, including any tables, figures and texts presented in the cited references.

C.NRPonb\DCCREC\459368_1 DOC-18/9/2012 -31 SYNTHETIC EXAMPLES The compounds shown in Table I were made according to the following examples. Example AR Number 1N ND 2 c S 3N F 4 N CI 5 Br O 6 7 ~C

F

3 8 (N 9 N 10 N, 11 C OMe C \NRPonblDCC\,REC\4598368_1 DOC- 1)9/2012 -32 TABLE 2 Example 1: One pot Borylation/Suzuki Coupling Process H-B, , 1 - Br Br Et 3 N I 4 Br DME. 70 *C j O-c O DME,70 *C 0 aq. K3PO4, 80 *C ON N 1 Pd(OAc) 2 3 0 3 5 2 To a solution of the 2-bromoindole (1) (13.45 g, 40.0 mmol) in dry DME (100 mL) was added Et 3 N (13.4 mL, 96.0 mmol), Tri-(2-furyl)phosphine (2) (1.11 g, 4.8 mmol, 0.12 eq) and Pd(OAc) 2 (269.4 mg, 1.2 mmol, 0.03 eq). The mixture was degasssed with N 2 and pinacolborane (14.12 mL, 94.40 mmol, 2.36 eq) was added dropwise to the mixture at r.t.. The resulting mixture was heated to 70 *C and stirred at the same temperature for 16 hrs upon when the reaction was completed. The reaction mixture so obtained was directly used for the next coupling reaction. To the reaction mixture of the pinacolate boronate (3) (20.0 mmol in 71.4 mL of DME), obtained from the borylation as described above, was charged sequentially with 120 (l1 mL, 15% of DME volume), K 3 P04-H 2 0 (25.0 g, 108.56 mmol, 5.4 eq.) and. 4 (6.5 g, 22.82 mmol, 1.1 eq.). The reaction mixture was warmed to 80 'C and stirred at the same temperature for about 7 hrs upon when the reaction was completed as monitored by -IPLC. The reaction mixture was cooled to r.t. and quenched with 100 mL of 10% NaCl aq. solution. The mixture was then extracted with EtOAc (2 X 120 mL), and the combined organic layers were dried over Na 2

SO

4 and rotovapored. The crude solid was slurred in 20 mL of cold acetone and then filtered off. The solid was washed further with 2 portions of cold acetone (2 X 10 ml) to afford 6.23 g of the product 5 as yellowish solid (75% yield, 97.9 A% purity). 'H NMR (300 HMz, CDCl 3 ) 8.94 (2H, s), 8.15 (1 H, s), 7.81-7.75 (2H, m), 3.96 (31H, s), 3.90 (31H, s), 3.73 (1 H, m), 2.20-1.95 (611, m), 1.74-1.71 (2H, m); C -WRPonbl\DCCR EC459836N.DOC.Ix/09/2112 - 33 "C NMR (100 HMz, CDC1 3 ) 8 168.1, 158.8, 157.7, 138.2, 135.6, 129.2, 124.6, 123.4, 121.0, 119.8, 118.2, 112.6, 52.0, 36.8, 33.3, 31.9, 26.7. Example 2: MeO MeO Pd(OAc) 2 s 0 N B\:TFP 0 N

K

2 0CO 3 Me H 2 0, DME Me A flask was charged with pinacol borobate (383.0 mg, 1.0 mmol), 2-iodothiophene (231.0 mg, 1.1 mmol), Pd(OAc) 2 (11.2 mg, 0.05 mmol), TFP (46.4 mg, 0.2 mmol), K 2

CO

3 (690.0 mg, 5 mmol), water (3 mL) and DME (2 mL). After 3 vacuum/argon cycles, the resulting mixture was heated to 80 C. 30 min later, HPLC revealed that all boronate disappeared. The area ratio of C-H, coupling product and dimer was about 3.2: 92.7: 4.1 on HPLC. After the reaction mixture was cooled down to room temperature, EtOAc (5 mL) was added. The aqueous layer was separated and extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na 2

SO

4 , and concentrated in vacuo. The crude product was purified via silica gel chromatography to afford the indole (0.31 g, 91%). H NMR (300 HMz, CDCl 3 ) 8 8.10 (11H, s), 7.78 (1 H, d, J= 6.3 Hz), 7.71 (1 H, d, J= 6.3 Hz), 7.49 (1 H, d, J= 3.9 Hz), 7.18-7.10 (1 H, m), 7.09 (1 H, d, J= 0.9 Hz), 3.94 (3H, s), 3.64 (3H, s), 3.21 (1 H, m), 2.01-1.88 (61H, m), 1.68-1.65 (2H, m); "C NMR (100 HMz, CDCl 3 ) 8 168.2, 137.2, 133.1, 132.0, 129.8, 129.2, 127.9, 127.3, 123.4, 120.0, 119.9, 119.8, 112.1, 52.0, 37.5, 33.5, 30.8, 26.5.

C:\NRPonbl\DCC\RECW598368_1 DOC-I&8/9/2012 - 34 Example 3: F I MeO MeO 0 TFP O B O Pd(OAc) 2 \I 0K 2 C0 3 0 N

OH

2 0 DME e F A flask was charged with pinacol borobate (383.0 mg, 1.0 mmol), 1-fluoro-4-iodobenzene (244.2 mg, 1.1 mmol), Pd(OAc) 2 (11.2 mg, 0.05 mmol), TFP (46.4 mg, 0.2 mmol), K 2 CO3 (690.0 mg, 5 mmol), water (3 mL) and DME (2 mL). After 3 vacuum/argon cycles, the resulting mixture was heated to 80 *C. 90 min later, HPLC revealed that all boronate disappeared. The area ratio of C-H, coupling product and dimer was about 10.7: 87.3: 2.0 on HPLC. After the reaction mixture was cooled down to room temperature, EtOAc (5 mL) was added. The aqueous layer was separated and extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na 2

SO

4 , and concentrated in vacuo. The crude product was purified via silica gel chromatography to afford the indole (0.28 g, 80%). 'H NMR (300 HMz, CDCl 3 ) 6 8.11 (1H. s), 7.80 (1 H, d, J = 6.3 Hz), 7.70 (11-1, d, J= 6.3Hz) 7.34-7.31 (2H, m), 7.20-7.14 (2H, m), 3.98 (3H, s), 3.55 (3H, s), 3.02 (I1H, m), 2.02-1.89 (6H, m), 1.26 (2H, bs); 1 3 C NMR (100 HMz, CDCl 3 ) 8 168.3, 139.9, 137.0, 132.5, 132.5, 129.6, 123.0, 112.0, 119.7, 117.4, 115.7, 115.5, 112.0, 51.9, 37.4, 33.5, 30.8, 26.4. Example 4: MeD MeO B,0Pd(OAC)2 N 0 N BTFP 0

IK

2

CO

3 I_ / c me H 2 0, DME me A flask was charged with pinacol borobate (383.0 mg, 1.0 mmol), 2-chloro-5-iodopyridine (263.4 mg, 1.1 mmol), Pd(OAc) 2 (11.2 mg, 0.05 mmol), TFP (46.4 mg, 0.2 mmol), K 2 CO3 (690.0 mg, 5 mmol), water (3 mL) and DME (2 mL). After 3 vacuum/argon cycles, the CNRPonbl\DCCREC\459X36_ DOC-IM19/2012 - 35 resulting mixture was heated to 80 C. 30 min later, HPLC revealed that all boronate disappeared. The area ratio of C-H, coupling product and dimer was about 8.0: 90.2: 1.8 on HPLC. After the reaction mixture was cooled down to room temperature, EtOAc (5 mL) was added. The aqueous layer was separated and extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na 2

SO

4 , and concentrated in vacuo. The crude product was purified via silica gel chromatography to afford the indole (0.32 g, 86%). 'H NMR (300 HMz, CDCl 3 ) 8 8.45 (1 H, d, J= 1.8 Hz), 8.12 (1 H, s), 7.80 (1 H, d,1 = 6.3 Hz), 7.74-7.68 (2H, m), 7.50 (I H, d, J = 6.3 Hz), 3.96 (3H, s),3.62 (3H, s), 2.98 (1 H, m), 2.05-1.89 (6H, m), 1.69-1.66 (2H, m); "C NMR (100 HMz, CDCI 3 ) 8 168.1, 151.6, 151.0, 140.5, 137.5, 135.5, 129.2, 126.8, 124.2, 123.7, 120.2, 120.0, 119.1, 112.1, 52.0, 37.3, 33.5, 31.0, 26.4. Example 5: MeO , MeO B Oc Pd(OAC)2 0 N B\TFP N SO K 2

CO

3 Me H 2 0. DME Me A flask was charged with pinacol borobate (383.0 mg, 1.0 mmol), bromobenzene (172.7 mg, 116 piL, 1.1 mmol), Pd(OAc) 2 (11.2 mg, 0.05 mmol), TFP (46.4 mg, 0.2 mmol), K 2

CO

3 (690.0 mg, 5 mmol), water (3 mL) and DME (2 mL). After 3 vacuum/argon cycles, the resulting mixture was heated to 80 C. 120 min later, HPLC revealed that all boronate disappeared. The area ratio of C-H, coupling product and dimer was about 13.2: 80.0: 6.8 on HPLC. After the reaction mixture was cooled down to room temperature, EtOAc (5 mL) was added. The aqueous layer was separated and extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na 2

SO

4 , and concentrated in vacuo. The crude product was purified via silica gel chromatography to afford the indole (0.25 g, 76%).

C-\RPonb\DCCRECJ59836_ LDOC. I 0/2012 - 36 'H NMR (300 HMz, CDCI 3 ) 8 8.11 (1 H, s), 7.79 (l H, d, J= 6.3 Hz), 7.72 (1 H, d, J= 6.3 Hz), 7.52-7.37 (5H, m), 3.95 (3H, s), 3.60 (3H, s), 3.07 (1 H, m), 2.04-1.88 (6H, m), 1.66 1.63 (2H, m); 1 3 C NMR (100 HMz, CDCl 3 ) 8 168.3, 141.1, 137.0, 131.9, 130.7, 129.6, 128.4, 122.8. 119.8, 119.6, 117.2, 112.0, 51.9, 37.3, 33.4, 30.9, 26.4. Example 6: MeO , MeO B 0 APd(OAc) 2 0 N B%:TFP OC) N 0 0 K 2 CO3 , Me H 2 0. DME Me A flask was charged with pinacol borobate (383.0 mg, 1.0 mmol), iodobenzene (204.0 mg, 1.1 mmol), Pd(OAc) 2 (11.2 mg, 0.05 mmol), TFP (46.4 mg, 0.2 mmol), K 2 CO3 (690.0 mg, 5 mmol), water (3 mL) and DME (2 mL). After 3 vacuum/argon cycles, the resulting mixture was heated to 80 C. 60 min later, HPLC revealed that all boronate disappeared. The area ratio of C-H, coupling product and dimer was about 3.6: 95.5: 0.9 on HPLC. After the reaction mixture was cooled down to room temperature, EtOAc (5 mL) was added. The aqueous layer was separated and extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na 2

SO

4 , and concentrated in vacuo. The crude product was purified via silica gel chromatography to afford the indole (0.30 g, 9 1%). 'H NMR (300 HMz, CDCl 3 ) 6 8.11 (11H, s), 7.79 (IlH, d, J= 6.3 Hz), 7.72 (111, d,, = 6.3 Hz), 7.52-7.37 (51-1, m), 3.95 (3H, s), 3.60 (3H, s), 3.07 (1 H, m), 2.04-1.88 (61H, m), 1.66 1.63 (2H, m); 3 C NMR (100 HMz, CDCl 3 ) 6 168.3, 141.1, 137.0, 131.9, 130.7, 129.6, 128.4, 122.8. 119.8, 119.6, 117.2, 112.0, 51.9, 37.3, 33.4, 30.9, 26.4.

C:\NRPorb\DCCREC\4S9A36I_ DOC-IR)1 2012 -37 Example 7: 0 MeO - - MeO ~' ~B 0 Pd(OAc) 2 \" 0 N % TFP 0 N 0 1 0 KC0 3 I ~ me H 2 0. DME Me A flask was charged with pinacol borobate (383.0 mg, 1.0 mmol), 4-iodoacetophenone (270.7 mg, 1.1 mmol), Pd(OAc) 2 (11.2 mg, 0.05 mmol), TFP (46.4 mg, 0.2 mmol), K 2 CO3 (690.0 mg, 5 mmol), water (3 mL) and DME (2 mL). After 3 vacuum/argon cycles, the resulting mixture was heated to 80 C. 30 min later, HPLC revealed that all boronate disappeared. The area ratio of C-H, coupling product and dimer was about 9.1: 90.3: 1.6 on HPLC. After the reaction mixture was cooled down to room temperature, EtOAc (5 mL) was added. The aqueous layer was separated and extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na 2

SO

4 , and concentrated in vacuo. The crude product was purified via silica gel chromatography to afford the indole (0.31 g, 83%). 'H NMR (300 HMz, CDCl 3 ) 5 8.12-8.05 (3H, m), 7.80 (1 H, d, J= 6.6 Hz), 7.72 (1 H, d, J = 6.3 Hz), 7.50 (2H, d, J= 6.0 Hz), 3.96 (31H, s), 3.62 (3H, s), 3.05 (I1H, m), 2.68 (3H, s), 2.04-1.90 (6H, m), 1.67-1.64 (2H, m); 1 3 C NMR (100 HMz, CDCl 3 ) 6 197.6, 168.2, 139.6, 137.4, 136.8, 136.6, 130.9, 129.5, 129.0, 128.4, 127.5, 123.3, 120.0, 119.9, 118.0, 112.1, 52.0, 37.3, 33.4, 31.1, 26.7, 26.4. Example 8: I CF 3 MeO -, MeO B O Pd(OAc) 2 O N TFP 0 N I 0K 2 C0 3 ICF me H 2 0, DME Me F 3 A flask was charged with pinacol borobate (383.0 mg, 1.0 mmol), 4-iodobenzotrifluoride (299.2 mg, 1.1 mmol), Pd(OAc) 2 (11.2 mg, 0.05 mmol), TFP (46.4 mg, 0.2 mmol), K 2 CO3 (690.0 mg, 5 mmol), water (3 mL) and DME (2 mL). After 3 vacuum/argon cycles, the C \NRPonbl\DCC\REC\598368_1 DOC- 18A)9/20l2 -38 resulting mixture was heated to 80 'C. 30 min later, HPLC revealed that all boronate disappeared. The area ratio of C-H, coupling product and dimer was about 7.5: 89.9: 2.6 on HPLC. After the reaction mixture was cooled down to room temperature, EtOAc (5 mL) was added. The aqueous layer was separated and extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na 2

SO

4 , and concentrated in vacuo. The crude product was purified via silica gel chromatography to afford the indole (0.33 g. 83%). 'H NMR (300 HMz, CDCl 3 ) 8 8.13 (1 H, s), 7.83-7.73 (4H, m), 7.50 (2H, J= 6.0 Hz), 3.92 (3H, s), 3.59 (3H, s), 3.03 (1 H, m), 2.03-1.90 (6H, in), 1.65 (2H, bs); "C NMR (100 HMz, CDCl 3 ) 6 168.1, 139.2, 137.4, 135.6, 131.1, 129.4, 125.5, 125.4, 123.4, 120.1, 119.9, 118.1, 112.2, 51.9, 37.3, 33.5, 31.0, 26.4, 25.2. Example 9: N MeO -N - e \ /Me O N O Pd(OAc) 2 N 0 N TFP I 0 K 2 CO O N Me

H

2 0. DME Me N A flask was charged with pinacol borobate (383.0 mg, 1.0 mmol), iodopyrazole (226.6 mg, 1.1 mmol), Pd(OAc) 2 (11.2 mg, 0.05 mmol), TFP (46.4 mg, 0.2 mmol), K 2

CO

3 (690.0 mg, 5 mmol), water (3 mL) and DME (2 mL). After 3 vacuum/argon cycles, the resulting mixture was heated to 80 C. 45 min later, HPLC revealed that all boronate disappeared. The area ratio of C-H, coupling product and dimer was about 3.3: 85.3: 11.4 on HPLC. After the reaction mixture was cooled down to room temperature, EtOAc (5 mL) was added. The aqueous layer was separated and extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na 2

SO

4 , and concentrated in vacuo. The crude product was purified via silica gel chromatography to afford the indole (0.27 g, 81%).

C:RPonbDCCORE04598368_LDOC.8IW/21 12 -39 'H NMR (300 HMz, CDCl 3 ) 8 8.77 (2H, bs), 8.60 (1 H, s), 8.16 (1 H, s), 7.82-7.76 (2H, m), 3.96 (3H, s), 3.78 (3H, s), 3.20 (1 H, m), 2.08-1.92 (6H, m), 1.72-1.69 (2H, m); "C NMR (100 HMz, CDCl 3 ) 8 168.0, 147.4, 146.6, 144.4, 143.2, 138.0, 135.3, 129.0, 124.2, 120.5, 120.3, 120.0, 112.4, 52.0, 37.3, 33.6, 31.3, 26.5. Example 10: MeO N_ _ MeO B/0 Pd(OAc) 2 N 0 N TFP 0N Or0 K 2

CO

3 Me H 2 0, DME Me A flask was charged with pinacol borobate (383.0 mg, 1.0 mmol), 2-iodopyridine (226.6 mg, 1.1 mmol), Pd(OAc) 2 (11.2 mg, 0.05 mmol), TFP (46.4 mg, 0.2 mmol), K 2

CO

3 (690.0 mg, 5 mmol), water (3 mL) and DME (2 mL). After 3 vacuum/argon cycles, the resulting mixture was heated to 80 C. 60 min later, HPLC revealed that all boronate disappeared. The area ratio of C-H, coupling product and dimer was about 23.5: 74.2: 2.3 on HIPLC. After the reaction mixture was cooled down to room temperature, EtOAc (5 mL) was added. The aqueous layer was separated and extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na 2

SO

4 , and concentrated in vacuo. The crude product was purified via silica gel chromatography to afford the indole (0.23 g, 68%). 'H NMR (300 HMz, CDCl 3 ) 8 8.81 (1H, d, J= 0.6 Hz), 8.14 (1 H-, s), 7.83-7.75 (3H, m), 7.46 (1 H, d, J= 5.4 Hz), 7.35 (1 H, m), 3.95 (3H, s), 3.74 (3 H, s), 2.04 (1 H, m), 2.04-1.91 (6H, m), 1.69-1.66 (2H, m); 3 C NMR (100 HMz, CDCl 3 ) 6 168.3, 151.4, 150.0, 139.1, 137.5, 136.3, 129.4, 126.2, 123.4, 122.6, 120.1, 119.7, 118.6, 112.2, 51.9, 37.3, 33.4, 31.1, 26.5.

C:\NRP nb\DCC\REC\F45916_ 1 DOC-1m9(20 12 - 40 Example 11: - ~ MeO /I MeO -, MeO B 0 ~Pd(OAc) 2 0 NTFP 0 N O 0k K 2

CO

3 OMe me 0H 2 0, DME me A flask was charged with pinacol borobate (766.0 mg, 2.0 mmol), 2-iodoanisole (514.9 mg, 2.2 mmol), Pd(OAc) 2 (22.4 mg, 0.1 mmol), TFP (92.9 mg, 0.4 mmol), K 2

CO

3 (1380 mg, 10 mmol), water (6 mL) and DME (4 mL). After 3 vacuum/argon cycles, the resulting mixture was heated to 80 C. 30 min later, HPLC revealed that all boronate disappeared. The area ratio of C-H, coupling product and dimer was about 4.6: 94.5: 0.9 on HPLC. After the reaction mixture was cooled down to room temperature, EtOAc (5 mL) was added. The aqueous layer was separated and extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na 2

SO

4 , and concentrated in vacuo. The crude product was purified via silica gel chromatography to afford the indole (0.64 g, 88%). 'H NMR (300 HMz, CDCl 3 ) 8 8.11 (1H, s), 7.80 (IH, d, J= 6.3 Hz), 7.71 (11H, d, J = 6.3 Hz), 7.21 (2H, d, J= 6.6 Hz), 7.00 (2H, d, J= 6.3Hz), 3.92 (31-1, s), 3.83 (3H, s), 3.56 (3H, s), 3.07 (1 H, m), 2.02-1.87 (6H, m), 1.65-1.62 (2H, m); 3 C NMR (100 HMz, CDCl 3 ) 5 168.4, 159.8, 141.1, 136.9, 131.9, 129.7, 124.0, 122.6, 119.8, 119.5, 117.0, 114.0, 112.0, 55.3, 51.9, 37.5, 33.4, 30.8, 26.4. Example 12: Preparation of a bromoindole In one embodiment, the present invention is directed to the following general multi-step synthetic method for preparing the intermediate compounds of general formula I, as set forth in Scheme I below, as well as the individual steps and intermediates set forth therein: C:WRPrtblDCC\REC4598368_LDOC.-)M9/2012 -41 Stage la Stage Ib Stage 2 H C 10% Pd/C, 3 atm H 2 Me 2

CO

3 , K 2

CO

3 H0 2 C HN NaOH, H 2 0 HO 2 C 13 I N NaoH, H0 H02C THF, 65 "C HO 2 C N NMP, 130 *C glycerol, 100 *C H 80% H 90% Stage 3 Br 2 MeN2C CH 3 CN, -6 *C MeO 2 C N 90% Condensation of the indole carboxylic acid with cyclopentanone in the presence of aqueous sodium hydroxide gave the 3-cyclopenteneyl indole carboxylic acid, which was subjected to hydrogenation in the presence of catalytic amount of palladium on carbon to afford the corresponding cyclopentyl carboxylic acid in 80% overall yield. Double methylation of the carboxylic acid and the nitrogen with methyl carbonate in NMP at 130 0 C provided the N-methyl indole carboxylate methyl ester in 90% yield. Bromination of the indole carboxylate with bromine in acetonitrile furnished the 2-bromo-3-cyclopentyl indole carboxylate in 90% yield. Example 13: Preparation of boronate 3 via Pd catalyzed borylation 0 H-B 'N EtN Br E - / N Pd(OAc) 2 N O O THF, 70 *C O 1 23

PCY

2 2 An oven dried three-neck IL round bottom flask fitted with condenser, temperature control, and dropping funnel was charged with bromide (50g, 148.7 mmol), dry THIF (500ml), Et 3 N (49.6 ml, 357 mmol), 2-dicyclohexylphosphinobiphenyl (2.08g, 6 mmol) C:\NRPorl\DCC\EC45981(8_ .DOC-IM/9/2012 - 42 and Pd(OAc) 2 (0.33g, 1.5 mmol). Pinacolborane (32.4 ml, 223 mmol) was added to the dropping funnel and the system was evacuated for 5-10 min and backfilled with N 2 . Then pinacolborane was added dropwise to the reaction mixture and when addition was completed (ca. 30-45 min.) the mixture was heated to 60 C until reaction was completed (HPLC monitoring). The residue was filtered off and washed with THF (100 ml) and the filtrate was evaporated to dryness. The crude product was slurried in MeOH (200 ml) for ca 15 min and then filtered off. The cake was washed with a further portion of MeOH (100 ml) and then air dried to constant weight (53.74 g, 94%, 97 A%). Example 14: Preparation of Boronate 3 via Br-Mg Exchange Using Magnesiate Reagents MeO 1. i-PrHeX 2 MgLi MeO \/ \ 2. o\ 0 N Br 0-B' 0 N ' Me 0 M e 0 To a solution of i-PrMgCl (9.75 mL, 19.5 mmol, 2M in THF) in 22.5 mL of THF was added n-HexLi (16.96 mL, 39 mmol, 2.3M in hexane) at 0 C. The resulting mixture was stirred for 10 min. The concentration of i-Pr(n-Hex) 2 MgLi solution is 0.4 M in TIF. To another flask was charged a solution of the indole bromide (33.6 g, 0.1 mol) in THF (30 mL). After the solution was cooled down to -15 C, i-Pr(n-Hex) 2 MgLi was added dropwise while maintaining the internal temperature at around -15 0 C. The reaction completed in about 15 min after the addition. Neat 2-isopropoxy-4,4,5,5,-tetramehthyl-1,3,2-dioxoborolane (40.8 mL, 0.2 mol) was added to the above solution at -15 0 C. The mixture was allowed to warm up to room temperature. After stirring 30 min at room temperature, the reaction mixture was diluted with EtOAc and aqueous NH 4 CI solution. The organic layer was separated and washed with water. Removal of the solvent gave an oily product. The oil was diluted with MeOH (about 30 mL). The solution was stirred at room temperature for a little while to form solid C\NRPortbl\CCREC4596X I DOC-I/A)2012 - 43 precipitation. The solid was collected, dried under vacuum and used for Suzuki coupling directly. 'H NMR (300 HMz, CDCi 3 ) 8 8.07 (1 H, s), 7.73 (1 H, d, J= 6.6 Hz), 7.68 (1 H, d, J= 6.3 Hz), 3.99 (3H, s), 3.96 (3H, s), 3.88 (1H, m), 2.02-1.94 (6H, m), 1.78-1.75 (2H, m), 1.37 (12H, s); 13 C NMR (100 HMz, CDCI 3 ) 8 166.1, 137.6, 130.4, 127.2, 122.0, 118.5, 116.7, 110.2, 81.4, 49.7, 35.1, 31.8, 30.2, 24.6, 22.6. Bromoindoles having moieties other than cyclopentyl group at the 2' position can be made using the same general procedure described above. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims (2)

1. A method for making 2, 3 disubstituted indoles of general formula (I): R 3 R2 K 1 N I I R wherein: R' is H or (CI. 6 )alkyl; R 2 is Het; or aryl having 5 or 6 members and Het or aryl being optionally substituted with R21 wherein R21 is one, two or three substituents selected from -OH, -CN, -N(RN 2 )RN, halogen, (CI- 6 )alkyl, (CI. 6 )alkoxy, (CI. 6 )alkylthio, Het and -CO-N(RN 2 )I N1. wherein said alkyl, alkoxy and alkylthio are each optionally substituted with one, two or three halogen atoms; R 3 is (Cs- 6 )cycloalkyl, optionally substituted with from one to four halogen atoms; 0 X is: H, C 1 . 6 alkyl, C 1 - 6 alkoxy; L L is H or a group further comprised of general formula iii: R 9 R 1 0 NH N N R5 R8/ iii wherein R 4 and R 7 are each independently selected from H, (CI- 6 )alkyl, (Ci- 6 )alkoxy, C:\NRPorb\DCCRECM459836RB_ DOC-18/19/2012 -45 (Ci- 6 )alkylthio, -NH 2 , -NH(CI. 6 )alkyl, -N((Cj. 6 )alkyl) 2 and halogen; One of R 5 and R 6 is selected from COOH, -CO-N(R N2)R N, Het' and (C 2 - 6 )alkenyl, wherein HetI, (C 2 - 6 )alkenyl and R or any heterocycle formed between RN2 and RN is

50. optionally substituted with R 5 . wherein R 5 0 is one, two or three substituents selected from (CI- 6 )alkyl, -COOH, -N(R N2)R ', -CO-N(R N2)R N, and halogen; and the other of R and R is selected from H, (CI- 6 )alkyl, (CI- 6 )alkoxy, (Ci. 6 )alkylthio, and N(R N2)R NI R 8 is (CI-6)alkyl, (C 3 . 7 )cycloalkyl or (C 3 .7)cycloalkyl-(Ci. 6 )alkyl-; wherein said alkyl, cycloalkyl and cycloalkyl-alkyl are optionally substituted with one, two or three substituents selected from halogen, (CI. 6 )alkoxy and (C 6 )alkylthio; R 9 and R' 0 are each independently selected from (Ci. 6 )alkyl; or R 9 and R' 0 are covalently bonded together to form (C 3 . 7 )cycloalkyl, (C 5 . 7 )cycloalkenyl or a 4-, 5- or 6 membered heterocycle having from 1 to 3 heteroatoms selected from 0, N, and S; wherein said cycloalkyl, cycloalkenyl or heterocycle is optionally substituted with (C. 4 )alkyl; RNI is selected from H, (CI. 6 )alkyl, (C 3 . 7 )cycloalkyl, (C 3 . 7 )cycloalkyl-(Ci- 6 )alkyl-, -CO-(CI. 6 )alkyl, -CO-O-(CI. 6 )alkyl and Het'; wherein all of said alkyl and cycloalkyl is optionally substituted with one, two or three substituents selected from halogen, (C . 6 )alkoxy and (C 1 - 6 )alkylthio; and RN2 is H or (CI- 6 )alkyl, or RN 2 and R may be covalently bonded together to form a 4-, 5-, 6- or 7-membered saturated or unsaturated N-containing heterocycle or a 8-, 9-, 10- or I -membered N containing heterobicycle, each having additionally from I to 3 heteroatoms selected from 0, N, and S; wherein the heterocycle or heterobicycle formed by RN 2 and RNI is optionally C:\NRPonbI\DCC\RECJ59936_I DOC-18/)9/2012 - 46 substituted with one, two or three substituents selected from halogen, (CI- 6 )alkyl, (CI. 6 )alkoxy and (CI. 6 )alkylthio; wherein Het is defined as a 4-, 5-, 6- or 7-membered heterocycle having I to 4 heteroatoms selected from 0, N and S, which may be saturated, unsaturated or aromatic, or a 8-, 9-, 10- or 1 1-membered heterobicycle having I to 5 heteroatoms wherever possible, selected from 0, N and S, which may be saturated, unsaturated or aromatic; or a pharmaceutically acceptable salt thereof which comprises forming a compound of Formula (ii) R3 0 B _X Br / X N R1 (i) wherein R', R 3 and X are as defined above, a) either by reaction thereof with a dialkoxyl CI- 5 borane in the presence of a ligand, a palladium catalyst and a base, or by reaction thereof with a trialkyl magnesiate reagent, followed by treatment with a borate; and b) reacting the product of step a thus formed with: R 2 -Hal, C:\NRPonbPDCC\REC\459368_1 DOC-MJ9/l(I2 - 47 wherein R 2 is as defined above and Hal is Br or I, to provide a compound of general formula I or a pharmaceutically acceptable salt thereof. 2. The method of claim I wherein R' is H or (Ci- 6 )alkyl; R 2 is Het; or aryl having 5 or 6 members and Het or aryl being optionally substituted with R 21NI wherein R 2 ' is one, two or three substituents selected from -OH, -CN, -N(RN2 )RNI halogen, (CI- 6 )alkyl, (CI- 6 )alkoxy, (C 1 . 6 )alkylthio, Het and -CO-N(R N2)R '; wherein said alkyl, alkoxy and alkylthio are each optionally substituted with one, two or three halogen atoms; R3 is cyclopentyl; 0 X is: H, CI- 6 alkyl, CI- 6 alkoxy, L L is H or a group further comprised of general formula iii: R 9 R' 0 NHR N R R 8 R 7 R' iii wherein R 4 and R 7 are each independently selected from H, (Ci- 6 )alkyl, (Ci- 6 )alkoxy, (CI. 6 )alkylthio, -NH 2 , -NH(CI- 6 )alkyl, -N((CI- 6 )alkyl) 2 and halogen; 5 6 N2 NI I One of R and R is selected from COOH, -CO-N(R )R , Het' and (C 2 - 6 )alkenyl, C\NRPonbl\DCC\REC\459368_1 DOC.I/9/2012 - 48 wherein Het, (C 2 - 6 )alkenyl and RNI or any heterocycle formed between RN2 and R NI is optionally substituted with R 50 ; wherein R 50 is one, two or three substituents selected from (CI- 6 )alkyl, -COOH, -N(R N2)R NI, -CO-N(R N2)R N, and halogen; and the other of R 5 and R 6 is selected from H, (CI- 6 )alkyl, (CI. 6 )alkoxy, (CI. 6 )alkylthio, and N(R N2)RNI. R 8 is (Ci- 6 )alkyl, (C 3 . 7 )cycloalkyl or (C 3 .7)cycloalkyl-(C i 6 )alkyl-; wherein said alkyl, cycloalkyl and cycloalkyl-alkyl are optionally substituted with one, two or three substituents selected from halogen, (Ci. 6 )alkoxy and (Ci. 6 )alkylthio; R 9 and R' 0 are each independently selected from (C 1 . 6 )alkyl; or R 9 and R' are covalently bonded together to form (C 3 . 7 )cycloalkyl, (C 5 . 7 )cycloalkenyl or a 4-, 5- or 6 membered heterocycle having from 1 to 3 heteroatoms selected from 0, N, and S; wherein said cycloalkyl, cycloalkenyl or heterocycle is optionally substituted with (C 1 .4)alkyl; RNI is selected from H, (CI. 6 )alkyl, (C 3 . 7 )cycloalkyl, (C 3 . 7 )cycloalkyl-(CI. 6 )alkyl-, -CO-(Ci. 6 )alkyl, -CO-0-(CI. 6 )alkyl and Het'; wherein all of said alkyl and cycloalkyl is optionally substituted with one, two or three substituents selected from halogen, (Ci- 6 )alkoxy and (Ci. 6 )alkylthio; and RN2 is H or (C 1 - 6 )alkyl, or RN2 and RNI may be covalently bonded together to form a 4-, 5-, 6- or 7-membered saturated or unsaturated N-containing heterocycle or a 8-, 9-, 10- or I I -membered N containing heterobicycle, each having additionally from I to 3 heteroatoms selected from 0, N, and S; wherein the heterocycle or heterobicycle formed by RN2 and RN1 is optionally substituted with one, two or three substituents selected from halogen, (Ci- 6 )alkyl, (CI- 6 )alkoxy and (Ci- 6 )alkylthio; C:NRPorbl\DCC\REC459936H I DOC- I-9/2012 - 49 wherein Het is defined as a 4-, 5-, 6- or 7-membered heterocycle having I to 4 heteroatoms selected from 0, N and S, which may be saturated, unsaturated or aromatic, or a 8-, 9-, 10- or 1 1-membered heterobicycle having I to 5 heteroatoms wherever possible, selected from 0, N and S, which may be saturated, unsaturated or aromatic. 3. The method of claim I or claim 2 wherein R' is H or (Ci-6)alkyl; 2~B -O-l rCF, R 2is chosen from (ND 3 F9135 NN R 3 is (C 5 -6)cycloalkyl, optionally substituted with from one to four halogen atoms; 0 X is: H, C 1 - 6 alkyl, Ci- 6 alkoxy, L L is H or a group further comprised of general formula iii: R N 9 RR NH R N R5 R 8 R 7 R' iii wherein R 4 and R 7 are each independently selected from H, (Ci. 6 )alkyl, (Ci- 6 )alkoxy, (CI- 6 )alkylthio, -NH 2 , -NH(CI- 6 )alkyl, -N((Ci- 6 )alkyl) 2 and halogen; One of R 5 and R 6 is selected from COOH, -CO-N(RN2)R NI, Het' and (C 2 . 6 )alkenyl, wherein Het, (C 2 - 6 )alkenyl and R or any heterocycle formed between RN2 and R is optionally substituted with R 50 ; wherein R 50 is one, two or three substituents selected from (CI- 6 )alkyl, -COOH, C:\NRPonbl\DCC\REC459X368_ I DOC.IM)912012 - 50 -N(RN2)RN, -CO-N(R N)RNI, and halogen; and the other of R 5 and R 6 is selected from H, (CI- 6 )alkyl, (C. 6 )alkoxy, (Ci- 6 )alkylthio, and N(R N2)RNI; R 8 is (CI-6)alkyl, (C 3 . 7 )cycloalkyl or (C 3 . 7 )cycloalkyl-(Ci. 6 )alkyl-; wherein said alkyl, cycloalkyl and cycloalkyl-alkyl are optionally substituted with one, two or three substituents selected from halogen, (CI. 6 )alkoxy and (C 1 . 6 )alkylthio; R 9 and R' 0 are each independently selected from (CI- 6 )alkyl; or R 9 and R' 0 are covalently bonded together to form (C 3 . 7 )cycloalkyl, (C 5 . 7 )cycloalkenyl or a 4-, 5- or 6 membered heterocycle having from 1 to 3 heteroatoms selected from 0, N, and S; wherein said cycloalkyl, cycloalkenyl or heterocycle is optionally substituted with (CI4)alkyl; R N is selected from H, (CI- 6 )alkyl, (C 3 . 7 )cycloalkyl, (C3. 7 )cycloalkyl-(Ci. 6 )alkyl-, -CO-(CI- 6 )alkyl, -CO-O-(CI- 6 )alkyl and Het'; wherein all of said alkyl and cycloalkyl is optionally substituted with one, two or three substituents selected from halogen, (CI- 6 )alkoxy and (CI. 6 )alkylthio; and RN 2 is H or (CI- 6 )alkyl, or RN2 and RNI may be covalently bonded together to form a 4-, 5-, 6- or 7-membered saturated or unsaturated N-containing heterocycle or a 8-, 9-, 10- or I1 -membered N containing heterobicycle, each having additionally from 1 to 3 heteroatoms selected from 0, N, and S; wherein the heterocycle or heterobicycle formed by RN2 and R is optionally substituted with one, two or three substituents selected from halogen, (Ci- 6 )alkyl, (C 1 . 6 )alkoxy and (CI. 6 )alkylthio; wherein Het is defined as a 4-, 5-, 6- or 7-membered heterocycle having I to 4 heteroatoms selected from 0, N and S, which may be saturated, unsaturated or aromatic, or a 8-, 9-, 10- or I 1-membered heterobicycle having I to 5 heteroatoms wherever possible, selected from 0, N and S, which may be saturated, unsaturated or aromatic; CNRPorbl\DCC\REC\4598368 LDOCl )9I/20 12 -51 or a pharmaceutically acceptable salt thereof. 4. The method of any one of claims I to 3 wherein R' is H or (CI.)alkyl; R 2 is Het; or aryl having 5 or 6 members and Het or aryl being optionally substituted with R 21 21 N2 NI wherein R is one, two or three substituents selected from -OI, -CN, -N(RN )RN halogen, (Ci. 6 )alkyl, (Ci. 6 )alkoxy, (CI. 6 )alkylthio, Het and -CO-N(RN 2 )RN I; wherein said alkyl, alkoxy and alkylthio are each optionally substituted with one, two or three halogen atoms; R 3 is cyclopentyl; X is carboxymethyl; L is H or a group further comprised of general formula iii: 9' R 10 NH N R N R R8/ 6 R7 R iii wherein R 4 and R 7 are each independently selected from H, (CI- 6 )alkyl, (CI- 6 )alkoxy, (C . 6 )alkylthio, -NH 2 , -NH(CI. 6 )alkyl, -N((Ci. 6 )alkyl) 2 and halogen; One of R 5 and R 6 is selected from COOH, -CO-N(RN 2 )RNI, Het' and (C 2 - 6 )alkenyl, wherein Het, (C 2 - 6 )alkenyl and RNI or any heterocycle formed between R and R ' is optionally substituted with R 50 ; wherein R 50 is one, two or three substituents selected from (CI. 6 )alkyl, -COOH, -N(R N)R NI, -CO-N(R N)R , and halogen; and the other of R 5 and R 6 is selected from H, (CI- 6 )alkyl, (CI- 6 )alkoxy, (CI- 6 )alkylthio, and N(RN 2 )RNI; C WRPotb\DCC\REC\459836_ 1.DOC.IA)9/2012 -52 R 8 is (CI- 6 )alkyl, (C 3 . 7 )cycloalkyl or (C 3 . 7 )cycloalkyl-(Ci- 6 )alkyl-; wherein said alkyl, cycloalkyl and cycloalkyl-alkyl are optionally substituted with one, two or three substituents selected from halogen, (CI- 6 )alkoxy and (C. 6 )alkylthio; R 9 and R' 0 are each independently selected from (CI_ 6 )alkyl; or R 9 and R' 0 are covalently bonded together to form (C 3 . 7 )cycloalkyl, (C 5 . 7 )cycloalkenyl or a 4-, 5- or 6 membered heterocycle having from I to 3 heteroatoms selected from 0, N, and S; wherein said cycloalkyl, cycloalkenyl or heterocycle is optionally substituted with (C.4)alkyl; RN is selected from H, (C 1 - 6 )alkyl, (C 3 - 7 )cycloalkyl, (C3- 7 )cycloalkyl-(Cj- 6 )alkyl-, -CO-(Ci- 6 )alkyl, -CO-0-(CI- 6 )alkyl and Het'; wherein all of said alkyl and cycloalkyl is optionally substituted with one, two or three substituents selected from halogen, (CI. 6 )alkoxy and (CI. 6 )alkylthio; and RN2 is H or (CI. 6 )alkyl, or RN2 and RNI may be covalently bonded together to form a 4-, 5-, 6- or 7-membered saturated or unsaturated N-containing heterocycle or a 8-, 9-, 10- or 11 -membered N containing heterobicycle, each having additionally from I to 3 heteroatoms selected from 0, N, and S; wherein the heterocycle or heterobicycle formed by RN 2 and RN1 is optionally substituted with one, two or three substituents selected from halogen, (Ci. 6 )alkyl, (C 1 . 6 )alkoxy and (CI- 6 )alkylthio; wherein Het is defined as a 4-, 5-, 6- or 7-membered heterocycle having 1 to 4 heteroatoms selected from 0, N and S, which may be saturated, unsaturated or aromatic, or a 8-, 9-, 10- or I I-membered heterobicycle having 1 to 5 heteroatoms wherever possible, selected from 0, N and S, which may be saturated, unsaturated or aromatic. 5. The method of claim I for making the compounds of general formula III: C:\NRPonbl\DCCREC4598368 I.DOC. IM9/2012 -53 R3 0 R 9 R 1 0 4 N R 2 H R 5 N R/N R1 R 7 R III wherein: R' is H or (CI 6 )alkyl; R 2 is Het; or aryl having 5 or 6 members and Het or aryl being optionally substituted with R21 wherein R21 is one, two or three substituents selected from -OH, -CN, -N(RN2)RN', IN2 N halogen, (CI- 6 )alkyl, (CI. 6 )alkoxy, (CI. 6 )alkylthio, Het and -CO-N(R )RNI wherein said alkyl, alkoxy and alkylthio are each optionally substituted with one, two or three halogen atoms; R 3 is (C 5 - 6 )cycloalkyl, optionally substituted with from one to four halogen atoms; 0 X is: H, CI-C6 alkyl, CI-C6 alkoxy, L L is H or a group further comprised of general formula iii: R 9 R 1 0 NH /\ R N R 5 R 8 R 7 R iii wherein R 4 and R 7 are each independently selected from H, (CI.)alkyl, (Ci. 6 )alkoxy, (CI- 6 )alkylthio, -NH 2 , -NH(C I- 6 )alkyl, -N((CI-6)alkyl) 2 and halogen; C\N4RPonblDCC\REC\459836X_ LDOC-18M)912012 -54 One of R 5 and R 6 is selected from COOH, -CO-N(R 2)RN, Het' and (C 2 - 6 )alkenyl, wherein Het, (C 2 - 6 )alkenyl and RNI or any heterocycle formed between RN2 and RN' is optionally substituted with R 5 0 ; wherein R 50 is one, two or three substituents selected from (Ci. 6 )alkyl, -COOH, -N(RN2)RNI, -CO-N(R N2)R N, and halogen; and the other of R 5 and R 6 is selected from H, (CI- 6 )alkyl, (CI. 6 )alkoxy, (CI. 6 )alkylthio, and N(RN 2 )RNI; R 8 is (CI- 6 )alkyl, (C 3 . 7 )cycloalkyl or (C 3 . 7 )cycloalkyl-(Ci- 6 )alkyl-; wherein said alkyl, cycloalkyl and cycloalkyl-alkyl are optionally substituted with one, two or three substituents selected from halogen, (Ci. 6 )alkoxy and (CI- 6 )alkylthio; R9 and R' 0 are each independently selected from (CI- 6 )alkyl; or R 9 and R' are covalently bonded together to form (C 3 . 7 )cycloalkyl, (C 5 7 )cycloalkenyl or a 4-, 5- or 6 membered heterocycle having from 1 to 3 heteroatoms selected from 0, N, and S; wherein said cycloalkyl, cycloalkenyl or heterocycle is optionally substituted with (C.4)alkyl; RN Is selected from H, (Ci- 6 )alkyl, (C 3 .7)cycloalkyl, (C 3 . 7 )cycloalkyl-(Ci- 6 )alkyl-, -CO-(C 1 - 6 )alkyl, -CO-O-(Ci. 6 )alkyl and Het'; wherein all of said alkyl and cycloalkyl is optionally substituted with one, two or three substituents selected from halogen, (C1. 6 )alkoxy and (CI- 6 )alkylthio; and RN2 is H or (Cl- 6 )alkyl, or RN 2 and R may be covalently bonded together to form a 4-, 5-, 6- or 7-membered saturated or unsaturated N-containing heterocycle or a 8-, 9-, 10- or 11-membered N containing heterobicycle, each having additionally from I to 3 heteroatoms selected from 0, N, and S; wherein the heterocycle or heterobicycle formed by RN2 and R Nis optionally C:\NRPo nb\DCC\REC\4598 36R 1 DOC-IM19/212 - 55 substituted with one, two or three substituents selected from halogen, (C 1 - 6 )alkyl, (Ci. 6 )alkoxy and (CI. 6 )alkylthio; wherein Het is defined as a 4-, 5-, 6- or 7-membered heterocycle having 1 to 4 heteroatoms selected from 0, N and S, which may be saturated, unsaturated or aromatic, or a 8-, 9-, 10- or 1 1-membered heterobicycle having I to 5 heteroatoms wherever possible, selected from 0, N and S, which may be saturated, unsaturated or aromatic; or a pharmaceutically acceptable salt thereof, said method comprised of the steps of: a) reacting a bromoindole compound (iv): R3 0 R 9 R 1 0 4 NN R N Br H N /\ R 5 N R 8N RI R7 R (iv) with a dialkoxyl borane in the presence of a ligand and a palladium catalyst and a base to obtain compound of general formula (v); R3 0 R 9 R 1 0 N R O N N 86 RI R7 R (v) and b) reacting the product of step a with: R 2 -Hal wherein Hal is Br or I; C-\NRPonbI\DCC\REC5983681 .DOC- IWA9/2012 - 56 to provide the desired product of general formula III. 6. The method of any one of claims I to 5 wherein, in a palladium-catalyzed borylation, said dialkoxylborane is 4,4,5,5-tetramethyl-1,3,2-dioxaborolane. 7. The method of any one of claims 1 to 5 wherein, in a bromine-magnesion exchange process, said borate is isopropoxy-4,4,5,5,5-tetramethyl-1,3,2-dioxaborolane. 8. The method of claim 1 for making a compound of general formula I wherein step (a) is comprised of the step of reacting a bromoindole compound of formula (vi): RO NB o Me R = H, Alkyl, aryl, Na, Li, K, Mg (vi) with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane to provide (vii) R| B o Me R = H, Alkyl, aryl, Na, Li, K, Mg (vii) b) reacting the product of step a with: N N I / -Br 1-C \>I -- or - C to provide: C:\NRPortbl\DCC\REC\459836_ I DOC. I A9/2012 - 57 Me x/N O N OR X = CI, Br R = H, Alkyl, aryl, Na, Li, K, Mg (viii) c) performing a hydrolysis with NaOH to provide (ix): Me X /N N N OH X = CI, Br (ix). 9. The method of any one of claims I to 8 wherein the ligand is selected from tri(2 furyl)phosphine and 2-(dicyclohexylphosphino) biphenyl. 10. The method of any one of claims 1 to 8 wherein the ligand is tri(2-furyl)phosphine, and reaction b) is carried out on the product of step a) in a "one-pot" process. 11. The method of any one of claims I to 10 wherein the palladium catalyst is chosen from, Pd(OAc) 2 , PdCl 2 , PdBr 2 , Pd 2 (dba) 3 , Pd 2 (dba) 3 .C-C1 3 , [Pd(ally)Cl]2, Pd(CH 3 CN) 2 C 2 , Pd(PhCN) 2 Cl 2 , Pd/C and encapsulated Pd. 12. The method of any one of claims I to II wherein reaction with the dialkenyl C 1 . 5 borane is carried out in a solvent which is DME or THF, and the base is triethylamine. 13. The method of any one of claims 1 to 11 wherein reaction with the dialkoxyl C 1 . 5 borane is carried out in a solvent which is DME, THF, or 2-propanol and the base is potassium phosphate, or potassium carbonate when reaction b) is to follow step a) in a "one-pot" process. C:\NRPonblDCCREC4598368 I.DOC.18092012 - 58 14. The method of any one of claims I to 5, 7 and 8 wherein the reagent for a bromo magnesium exchange is a trialkylmagnesiate GI. 3 MgLi wherein G is a CI- 6 alkyl group. 15. A method as claimed in claim 14 wherein GI.3 MgLi is selected from i-Pr(n Fex) 2 MgLi or i-Pr(n-Bu) 2 MgLi, n-Bu 3 MgLi. 16. A method as claimed in claim 1 substantially as hereinbefore described. 17. A 2,3 disubstituted indole of general formula (I) according to claim I produced according to the method of any one of claims I to 16.