EP1204644A1

EP1204644A1 - Synthesis of substituted amidines

Info

Publication number: EP1204644A1
Application number: EP00941119A
Authority: EP
Inventors: Daniele Choueiry; Daniel Lionel Giraud; Theo Schotten
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 1999-06-18
Filing date: 2000-06-19
Publication date: 2002-05-15
Also published as: GB9914253D0; WO2000078725A1; GB2351082A; AU5587200A

Abstract

The present invention provides a process for preparing amidines starting from carboxylic acid derivatives, in which the carboxylic acid containing moiety is attached to a sp3-, or sp?2- or sp1¿-hybridized carbon atom. The sp2-hybridized carbon atom, to which the carboxylic acid containing moiety is attached to may be part of an aromatic or heteroaromatic or olefinic system.

Description

Synthesis of Substituted Amidines

The present invention relates to a novel process for the preparation of substituted amidine compounds.

There are several synthetic methods which can be used to prepare certain cyclic amidines by cyclisation of acyclic precursors which are known from the literature. However, the methods which are known in the literature have disadvantages which might make a particular process commercially undesired or the process is only applicable to a narrow range of functionalities. Some of the disadvantages observed in the known processes include, harsh reaction conditions, ( e.g. high temperatures, extreme pH values), potentially hazardous reagents (e.g. phosphoryl chloride, trialkyl aluminium, hydrogen sulphide, carbon disulphide, or iodomethane), low yields, tedious work-up, or precursors, which are not easily accessible. Consequently, only a rather limited number of functionalities in a molecule is tolerated using the known methods and thus narrowing the scope of the methods available in the literature. The invention claimed herein, provides a generally applicable synthetic process which is not known through the scientific literature.

For example, to point out some of the methods which are available to prepare 2-substituted 4,5-dihydroirnidazoles (imidazolines) see, J.Med.Chem. 1990, 33, 2501- 8 (uses (CH₂NH₂)₂); J.Chem.Soc. 1947, 497(uses (CH₂NH₂)₂ and TsOH/200-220°C); J.Am.Chem.Soc. 1953, 75, 2986-8(uses (CH₂NH₂)₂ and 200-220°C); J.Med.Chem. 1987, 30, 1482-9 (uses A1(CH₃)₃ and (CH₂NH₂)₂); Tetrahedron Lett. 1990, 31, 1771- 74(uses (CH₂NH₂)₂); J.Org.Chem.1987, 52, 1017-21 (La(OSO₂CF₃)₃ and (CH₂NH₂)₂); Zh.Prikl.Khim. 1970, 43, 1641 (CA:73:77138r) (uses (CH₂NH₂)₂ and strongly acidic cation exchanger); Arch.Pharm. 1986, 319, 830-34 (uses (CH NH₂)₂); J.Heterocycl.Chem. 1990, 27, 803-5 (uses (CH₂NH₂)₂); Tetrahedron Lett. 1995, 51, 6315-36 (uses two step process with 1) H₂S and Mel then 2)(CH₂NH₂)₂).

The process provided by this invention provides a method for making useful amidine compounds. For example, certain imidazoline-type compounds and analogues thereof, can be useful in the treatment of diabetes, diabetic complications, metabolic disorders, or related diseases where impaired glucose disposal is present. These compounds can also be useful for the treatment of cardiovascular disease where above normal glucose levels are present or initial insulin resistance has occurred. The compounds which can be prepared using the process of this invention can be used for a broad range of pharmaceutical indications as well as for other utilities such as in the area of photographic developers and pesticides. The process of this invention can fulfil a long felt need for a more efficient and broadly applicable process to prepare amidines.

The present invention provides a process for preparing amidines starting from carboxylic acid derivatives, in which the carboxylic acid containing moiety is attached to a sp³-, or sp²- or sp¹ -hybridized carbon atom. The sp²-hypridized carbon atom, to which the carboxylic acid containing moiety is attached to may be part of an aromatic or heteroaromatic or olefinic system. The present invention provides a process for preparing a compound of Formula π,

comprising contacting a compound of the Formula I:

with a silylating agent or for preparing a compound of Formula II' :

comprising contacting a compound of the Formula F :

with a silylating reagent

wherein

R is independently selected from the group consisting of hydrogen, optionally substituted C_MS alkyl, optionally substituted C₃.₁₀ cycloalkyl, optionally substituted

C₃-ιo cycloalkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl;

R is hydrogen or optionally substituted Cι-₁₈ alkyl, optionally substituted C₃-₁₀ cycloalkyl, optionally substituted C₃-₁₀ cycloalkenyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;

X is selected from the group consisting of a bond and a linker element -X^X^X³-; and when X and Y are each -X'-X²-X³- and each of X¹, X², and X³ are (CR¹²R¹³)_Z or

(CR¹²R¹³)_Z< then X and Y optionally together combine and along with the nitrogen and carbon to which they are each respectively attached optionally form a fused C₄-₁₈ heterocyclic ring;

X¹ is attached to the amidine forming moiety and is independently selected from the group consisting of

-(CR¹²R¹³)_Z, -(CR¹² =CR¹³)_Z", and -(C≡Qz-.

X² andX³- are each independently selected from the group consisting of - (CR¹²R¹³)_Z>,

-(CR¹² =CR¹³)_Z-, -(C=C)_Z ■», -O-, -NR¹¹-, -CONR¹¹-, -NR^πCO-, -S-, -SO-, -SO₂-, - NR^πSO₂- , and -SO₂NR^π, provided that, if one of X² and X³ is a selected from the group consisting of -O-, -NR¹¹-, -S-, -SO-, and -SO₂-, then the other remaining X²or X³ is selected from the group consisting of -(CR¹²R¹³)_Z-, -(CR¹² =CR¹³)_Z-, -(C=C)_Z-; z is independently 1 to 18; z'is independently 0 to 18; z" and z'" are each independently 0 to 3;

R^u ,R¹² , andR¹³ are each independently selected from the group consisting of hydrogen, optionally substituted C _S alkyl, optionally substituted C₃.₁₀ cycloalkyl, optionally substituted C₃_₁₀ cycloalkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl;

E is selected from the group consisting of a bond, an optionally substituted aromatic and a heteroaromatic ring;

n, n", n'" and n"" are each independently 0, 1, 2, 3, or 4 provided that one selected from the group consisting of n, n", n'" and n"" is 1,2,3, or 4 and further provided that the sum of n, n", n '"and n"" is less than seven, if E represents a bond; or n, n", n'" and n"" are each independently 0, 1, 2, 3, or 4, provided that the sum of n, n", n'"and n"" is greater than 1 and less than five, if E represents an optionally substituted aromatic or optionally substituted heteroaromatic ring;

Y is a a bond and a linker element -X'-X^X³- X is attached to the amidine forming moiety and is independently selected from the group consisting of -(CR¹²R¹³)_Z, -(CR¹² =CR¹³)₂-, and -(C=C)_Z-; provided that one selected from the group consisting of X¹, X² andX³, which is attached to the amidine moiety is selected from the group consisting of -(CR¹²R¹³)_Z;

R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selected from the group consisting of hydrogen, optionally substituted C_MO alkyl, optionally substituted C₂-_!o alkenyl, optionally substituted C_ό-io aryl, optionally substituted C₃-₁₀ cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted bicyclic; or

Two selected from the group consisting of R , R , R⁶, and R⁸ together with the carbon atoms to which they are attached combine to form an optionally substituted 3 to 7 membered carbocyclic or form a bridging ring if the two selected from R², R⁴, R⁶, and R⁸ were not substituents on adjacent carbon atoms, and each of the remaining R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are hydrogen or one of R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ combines with another of R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ which is a substituent on an adjacent carbon atom, to optionally form a bond; or

Two substituents which are attached to the same carbon atom are selected from the group consisting of R² and R³, R⁴ and R⁵, R⁶ and R⁷, and R⁸ and R⁹, together with the carbon atom to which they are both attached combine to form a spirocarbocyclic ring, and each of the remaining R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are hydrogen or one of R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ combines with another of R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ which is a substituent on an adjacent carbon atom, to optionally form a bond;

R¹⁰ is hydrogen or an amino protecting group; provided that when Formula π is a group of the formula: ,wherein R¹⁹, R²⁰, R²¹, and R²² are each independently selected from the group consisting of hydrogen and -s alkyl; or;

Rl9 and R21 optionally together form a bond and R20 and R22 are each independently hydrogen or C^.g alkyl; or

Rl9 and R 1 optionally combine together with the carbon atoms to which they are attached form a C3-.7 carbocyclic ring and R20 and R22 are each independently hydrogen or C _g alkyl; or

Rl9 and R20 together with the carbon atom to which they are attached optionally combine to form a C3-.7 spirocarbocyclic ring and R21 and R 2 are independently hydrogen or C^.g alkyl; or

R21 and R22 together with the carbon atom to which they are attached optionally combine to form a C3.7 spirocarbocyclic and Rl9 and R20 are independently hydrogen or Q. _R alkyl; then R cannot be

Y is -O-, -S-, or -NR⁸*-; Y' is -O- or -S-; R6* and R^* are independently hydrogen, Cj.g alkyl, 03.7 cycloalkyl, C_j.g alkoxy, Cj.g alkylthio, halo C^.g alkylthio, Cj.g alkylsulfinyl, C^.g alkylsulfonyl, C3.7 cycloalkoxy, aryl-Cι_g alkoxy, halo, halo-Cj.g alkyl, halo- C^.g alkoxy, nitro,

-NR¹⁰*R¹¹ \ -CONR¹⁰*R^{l l 5}\ aryl Cμg alkyl, optionally substituted heterocyclyl, optionally substituted phenyl, optionally substituted naphthyl, optionally halo substituted acylamino, cyano, hydroxy, C0R1 *₅ halo Cj.g alkylsulfinyl, or halo C\_ g alkylsulfonyl, or alkoxyalkyl of the formula

CH₃(CH₂)p-O-(CH2)_q-O-; where p is 0, 1, 2, 3, or 4; and q is 1, 2, 3, 4, or 5;

Rl2* i_s C _% alkyl or optionally substituted phenyl;

R⁸* is hydrogen, Cj.g alkyl, halo-Cj.g alkyl, optionally substituted phenyl, optionally substituted heterocyclyl, COO Cj.g alkyl, optionally substituted COaryl, COC^.g alkyl, SO2Cj-. alkyl, optionally substituted SO aryl, optionally substituted phenyl-Cj.g alkyl, CH₃(CH2)p-O-(CH₂)_q-O-;

R9 is hydrogen, halo, Cj.g alkyl, halo Cj.g alkyl, Cj.g alkylthio, halo C _ g alkylthio, C3.7 cycloalkylthio, optionally substituted arylthio or heteroarylthio, C _ g alkoxy, C3.7 cycloalkoxy, optionally substituted aryloxy , optionally substituted heteroaryloxy, or optionally substituted aryl or heteroaryl, C3.7 cycloalkyl, halo C3-.7 cycloalkyl, C3.7 cycloalkenyl, cyano, COOR¹⁰*, CONR¹⁰*RU* or NR¹⁰*RU*, C2-.6 alkenyl, optionally substituted heterocyclyl, optionally substituted aryl C^. alkyl, optionally substituted heteroaryl C^.g alkyl in which the alkyl group can be substituted by hydroxy, or Cj.g alkyl substituted by hydroxy; RIO and R^* are independently hydrogen, C^.g alkyl, optionally substituted aryl C^. alkyl, optionally substituted phenyl, or R^ and RU* together with the nitrogen atom to which they are attached may combine to form a ring with up to six carbon atoms which optionally may be substituted with up to two Cj.g alkyl groups or one carbon atom may be replaced by oxygen or sulfur;

Rl4 and RI" are independently hydrogen, halo, Cj.g alkyl, C3-.7 cycloalkyl, C3-.7 cycloalkoxy, C3-.7 cycloalkylC^.g alkoxy, halo-C^.g alkyl, halo-Cι_g alkoxy, Cj. alkoxy, carbo(C₁_s)alkoxy, optionally substituted aryl, or optionally substituted heteroaryl;

Rl5 and R^ are independently hydrogen, halo, Cj.g alkoxy, C3-.7- cycloalkyl, C3.7 cycloalkylCj.g alkoxy, C^.g alkyl, C3-.7 cycloalkoxy, hydroxy, halo

Cι_ alkoxy, carbo(C₁-₈)alkoxy, optionally substituted phenyl, optionally substituted phenyl-C^.g alkyl, optionally substituted phenyloxy, optionally substituted phenyl-Cι_g alkoxy, (tetrahydropyran-2-yl)methoxy, C^.g alkyl-S(O)_m-, optionally substituted aryl-Ci .g alkyl-S(O)_m-, CH₃(CH2)p-Z¹-(CH₂)q-Z2-, or Z³-(CH₂)q'-Z²-; q' is 0,1,2,3,4, or 5; m' is 0, 1, or 2; and zl and z2 are independently a bond, O, S, SO, SO2, sulphoximino, or

NRlO*;

7? is hydroxy, protected hydroxy, NR^O* RU*, protected amino, SH or protected SH.

As used herein, the formulae, a "C_MO alkyl" group can be an alkyl group which is branched or unbranched, containing up to 10 carbon atoms. Likewise, C_1-n" alkyl is a branched or unbranched alkyl containing up to n" carbon atoms whereing n" is an integer. Examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl. Preferred values of Cι_ιo alkyl are C _ alkyl. The Cι_ιo alkyl group may preferably be methyl or ethyl. The term "optionally substituted C_1-10 alkyl", means that the alkyl group may optionally be substituted at any available carbon atom with from one to three substituents selected from the group consisting of OH, -NH₂ , C_2-4 alkenyl, cyano, - NO₂, halo, halo Ci _g alkyl, and -CONH₂.

The term "C^.g alkylthio" has the meaning known to the artisan. That is that one of the carbon atoms is replaced with a sulfur atom.

The term "C₂._n* alkenyl" wherein n* can be from 3 through 18, as used herein, represents an olefinically unsaturated branched or linear group having from 2 to the specified number of carbon atoms and at least one double bond. Examples of such groups include, but are not limited to, 1-propenyl, 2-propenyl (-CH2-CH=CH2), 1,3- butadienyl, (-CH=CHCH=CH2), 1-butenyl (-CH=CHCH2CH3), hexenyl, pentenyl, and the like. The term "optionally substituted C₂._n* alkenyl" means that the alkenyl substituent may optionally be substituted at any available carbon atom with from one to three substituents selected from the group consisting of OH, -NH₂ , C₂.₄ alkenyl, cyano, -NO₂, halo, halo Cj_g alkyl, and -CONH₂.

The term "C₃-_n** cycloalkenyl", wherein n** is 3 to 10, is an olefinically unsaturated ring having from three to 10 carbon atoms. Such groups include, but are not limited to, cyclohexa-l,3-dienyl, cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, cyclohexa-l,4-dienyl, cyclohepta-l,4-dienyl, cycloocta-l,3,5-trienyl and the like.

An "optionally substituted C₃__n»_* cycloalkenyl means that the alkenyl substituent may optionally be substituted at any available carbon atom with from one to three substituents each independently selected from the group consisting of OH, - NH₂ , C₂- alkenyl, cyano, -NO₂, halo, halo C g alkyl, and -CONH₂.

The term "base" when referring to a process reactant, has the meaning known to the skilled artisan. The term means both soluble and insoluble base. The soluble or insoluble base may be, for example but not limited to, triethyl amine or dimethylaminomethyl polystyrene.

A "C3-.7 cycloalkyl" group is a cycyloalkyl group including but not limited to cyclopropyl, cyclobutyl, cycloheptyl, cyclohexyl or cyclopentyl. A "Cι_g alkoxy" group is one of the above-mentioned Cj.g alkyl groups attached through oxygen to the base molecule, and preferred examples are methoxy and ethoxy.

A "C3..7 cycloalkoxy" group is a C3.7 cycloalkyl group as mentioned above linked through an oxygen atom to the cycloalkyl as, for example, cyclopropyloxy, cyclopentyloxy and cyclohexyloxy.

A "C3.7 cycloalkylCi.g alkoxy" group is a C3.7 cycoalkyl-Cj.g alkyl as mentioned above linked through an oxygen atom to the base molecule as, for example, cyclohexylmethoxy.

O

11

A "carbo(C₁-s)alkoxy" group is a ^1"8 group, for example a carbomethoxy or carboethoxy group.

The term "cyano" has the meaning known to the artisan.

The term "carboxamido" has the meaning known to the artisan.

An "optionally substituted aryl" group is a mononuclear or polynuclear aromatic hydrocarbon group, for example phenyl, aryl-C^.g alkoxy, aryl- -s alkyl-

S(O)_m", aryl-C^.g alkyl, COaryl or naphthyl, which is optionally substituted with from one to three substituents each independently selected from the group consisting of Cj.g alkyl, Cι .g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, amino, and phenyl which is optionally substituted by from one to three substituents each independently selected from the group consisting of Cj_g alkyl, Cj_g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, and amino.

An "optionally substituted phenyl" group is a phenyl which is optionally substituted with from one to three substituents each independently selected from the group consisting of C^. alkyl, C^.g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, amino, and phenyl which is optionally substituted by from one to three substituents each independently selected from the group consisting of Cj.g alkyl, C^.g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, and amino.

An "optionally substituted naphthyl" group is a naphthyl which is optionally substituted with from one to three substituents each independently selected from, the group consisting of C^.g alkyl, Cj. alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, amino, and phenyl which is optionally substituted by from one to three each independently selected from the group consisting of C^.g alkyl, Cι_g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, and amino.

An "optionally substituted COaryl" group is an optionally substituted aryl

w c s oun to t e ase mo ecu e t roug a group o t e ormu a: The optionally substituted aryl group is defined herein above.

A "optionally substituted aryl-Cj-s alkyl-S(O)_m" " group is an optionally substituted aryl which is bound to the base molecule through an alkyl-S(O)_m" group, wherein the S- bonds to the base molecule and m" is 0, 1 or 2. The optionally substituted aryl group is as defined herein above.

An "optionally substituted bicyclic" means a 5 to 10 membered fused bicyclic ring, which ring may be saturated or partially unsaturated to include from 0 to 4 double bonds in the bicyclic ring. The bicyclic ring is optionally substituted with from 0 to three substituents selected from the group consisting of of Cj.g alkyl, Cj.g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4- methylenedioxy, and amino.

The term "optionally substituted aromatic" means a mono- or bicyclic 5 to 10- membered aromatic ring which is attached to the cyclic amidine forming atoms, by the two adjacent carbon atoms of the optionally substituted aromatic ring. To further clarify, the resulting group is a group of the general formula:

The optionally substituted aromatic or heteroaromatic ring is optionally substituted with from 0 to 3 each independently selected from the group consisting of C_ji .g alkyl, Cj.g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, and amino.

The term "optionally substituted heteroaromatic" means a mono- or bicyclic 5 to 10-membered aromatic ring in which from one to three carbon atoms of the aromatic ring, defined above, are replaced with an atom each independently selected from group consisting of N, O, and S, and which heteroaromatic ring is attached to the cyclic amidine forming atoms, by the two adjacent carbon atoms of the optionally substituted heteroaromatic ring. Such group is as illustrated above for optionally substituted aromatic; however, the aromatic ring contains up to three heteroatoms as described herein.

The optionally substituted heteroaromatic ring is optionally substituted with from 0 to 3 each independently selected from the group consisting of C^.g alkyl, C^. alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4- methylenedioxy, and amino.

"Heteroaryl" means a four to a ten membered aromatic mononuclear or binuclear ring system in which from one to three atoms of the ring system are each independently selected from the group consisting of nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, but are not limited to, indolyl, imidazolyl, furanyl, thienyl, isoquinolinyl, benzofuranyl, benzothienyl, pyridyl, quinolinyl, oxazolyl, pyrrolyl, isoxazolyl, pyrimidyl, thiazolyl, and benzimidazolyl. An "optionally substituted heteroaryl" group is a heteroaryl group which is optionally substituted with from one to three substituents each independently selected from the group consisting of Cj_g alkyl, C^.g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, amino, and phenyl which is optionally substituted by from one to three substituents each independently selected from the group consisting of C^. alkyl, Cj.g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, and amino.

"Optionally substituted heterocyclyl" means a four to 10 membered mononuclear or binuclear saturated or partially unsaturated ring system in which from one to three atoms of the ring system are each independently selected from the group consisting of nitrogen, oxygen, and sulfur, and which ring system is optionally substituted with from one to three substituents each independently selected from the group consisting of Cj. alkyl, C^.g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, amino, and phenyl which is optionally substituted by from one to three substituents each independently selected from the group consisting of C _g alkyl, C^.g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, and amino. Examples of heterocyclyl groups include, but are not limited to, piperidinyl, piperazinyl, imidazolidinyl, tetrahydrofuranyl, morpholinyl, homopiperidinyl, tetrahydroquinolinyl, dioxanyl, and tetrahydropyranyl.

An "aryl-C^.g alkyl" group can be, for example, optionally substituted phenyl-

Cj.g alkyl or optionally substituted naphthyl-C^.g alkyl, such optionally substituted phenyl or naphthyl groups being optionally substituted with one or more, preferably one to three, substituents selected from, Cj.g alkyl, Cj.g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro and amino. A preferred aryl-Cj-.g alkyl group is optionally substituted phenyl-(CH2) - where x is 1 or 2, most preferably optionally substituted benzyl. Thus, the alkyl group serves as the link between the phenyl or naphtyl and the base molecule.

An "optionally substituted phenyloxy" is a group wherein the phenyl group is attached to the base molecule through an oxygen, and such phenyl group is optionally substituted with one or more, preferably one to three, substituents selected from, Cχ_ alkyl, C^-. alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro and amino. An "optionally substituted phenyl -s alkoxy" is a group wherein the phenyl group is attached to the base molecule through an alkoxy group, and such phenyl group is optionally substituted with one or more, preferably one to three, substituents selected from, C^.g alkyl, Cχ_g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro and amino.

Of course, it will be understood that "optionally substituted" means that there may be zero non-hydrogen substituents.

An "aryl-Cj.g alkoxy" group can be, for example, optionally substituted phenyl-Ci _g alkoxy or optionally substituted naphthyl-C^.g alkoxy, such optionally substituted groups being optionally substituted with one or more, preferably one to three, substituents selected from, for example, Cι _g alkyl, Cj. alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro and amino. A preferred aryl-C_j.g alkyl group is optionally substituted phenyl-(CH2)_x- where x^" is 1 or 2. Thus, the aryl is linked to the base molecule through the alkoxy group.

A halo group is fluoro, chloro, bromo or iodo, preferably fluoro, chloro, or bromo.

A "halo Ci _g alkyl" or "halo C g alkoxy" or "halo Ci _g alkylthio" is a substituent in which one or more, preferably one to three, hydrogen atoms on the C_j.g alkyl moiety is replaced by a halo atom, preferably chloro, bromo or fluoro. Trifluoromethyl is one preferred haloalkyl group.

An "alkoxyalkoxy" group is of the formula CH3(CH2)p-O-(CH2)q-O-, where p is 0-4 and q is 1-5, preferred examples being those in which p is 0 or 1 and q is 1-3, especially methoxyethoxy, ethoxyethoxy, ethoxypropoxy, or methoxypropoxy.

A "Cι_g acylamino" substituent is preferably of the formula RCONH- where

RCO is any appropriate acid residue, RCO containing from 1-8 carbon atoms. Examples of R include Ci _g alkyl, in particular methyl or ethyl, acetyl being the most preferred acyl group. R can also be aryl Ci _g alkyl, especially benzyl, or R can be halo- Cj_g alkyl, especially trifluoromethyl. A "haloCi.g acylamino" substituent is an acylamino group substituted with from one to three halo. It is preferable that acylamino is substituted with one halo.

The term "spirocarbocyclic" means a ring which is fused to the base molecule through one shared tetravalent carbon atom to form two rings which are annelated by a single carbon atom.

The term "Ci _g alkylsulfinyl" has the meaning known to the artisan. That is _\s^alkyl

I I a group of the formula °

The term "halo Cι _g alkylsulfinyl" means that one of the alkyl groups is substituted with a halo. It is most preferred that the halo group is F or CI.

The term "Ci _g alkylsulfonyl" has the meaning known to the artisan. That is

a group of the formula

The term "halo Cj.g alkylsulfonyl" means that one of the alkyl groups is substituted with a halo. It is preferred that the haloalkylsuflonyl group is CF SO -. The term "sulfoximino" has the meaning known to the artisan. That is, a

NH

II

— s II — group of the formula: °

The "acyl" moiety, alone or in combination, is derived from an alkanoic acid containing from one to eight carbon atoms. The term "acyl" also includes moieties derived from an aryl carboxylic acid.

The term "base molecule" means the moiety to which the named substituent is bound.

As used herein the term "amino protecting group" means any of the conventional amino protecting groups, see, for instance, T. W. Greene, Protective Groups in Organic Synthesis, chapter 7, John Wiley and Sons, New York, 1981, and by J. W. Barton, Protective Groups in Organic Chemistry, chapter 2, J. F. W. McOmie, ed., Plenum Press, New York, 1973. Examples of such groups include but are not intended to be limited to benzyl and substituted benzyl such as 3,4-dimethoxybenzyl, o-nitrobenzyl, and triphenylmethyl; those of the formula -COOR where R includes such groups as methyl, ethyl, propyl, isopropyl, 2,2,2-trichloroethyl, 1 -methyl- 1-phenylethyl, isobutyl, t-butyl, t-amyl, vinyl, allyl, phenyl, benzyl, rj-nitrobenzyl, o-nitrobenzyl, and 2,4-dichlorobenzyl; acyl groups and substituted acyl such as formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, benzoyl, and p_-methoxybenzoyl; and other groups such as methanesulfonyl, p_-toluenesulfonyl, p-bromobenzenesulfonyl, rj-nitrophenylethyl, p-toluenesulfonylaminocarbonyl, and the like. Preferred nitrogen protecting groups are benzyl, acyl, like benzyloxycarbonyl or t-butyloxycarbonyl, or silyl or acetyl phenyloxycarbonyl. It is most preferred that the amino protecting group is a silyl.

The term silyl amino protecting group means an amino protecting group, known to the artisan, which contains a silyl functionality. For example, the term includes, but is not limited to, trimethylsilyl;

The term "protected amino" means that the amino group is substituted with an amino protecting group, as defined herein.

As used herein the term "protected hydroxy" means that the hydroxyl group is substituted with any of the conventional hydroxyl protecting groups, see, for instance, T. W. Greene, Protective Groups in Organic Synthesis, chapter 2, John Wiley and Sons, New York, 1981, and by J. W. Barton, Protective Groups in Organic Chemistry, J. F. W. McOmie, ed., Plenum Press, New York, 1973. Examples of such groups include but are not intended to be limited to acetals, ethers such as silyl ethers and the like; esters such as formate, benzoylformate, acetate, phenoxyacetate and the like; carbonates such as methyl carbonate, ethyl carbonate, isobutylcarbonate, benzyl, nitrobenzyl, and the like; and others such as nitrate, borate, phenylcarbamate, tetrahydropyranyl (THP), trityloxy and the like. The artisan will recognise that the art includes other acceptable protecting groups as provided by the cited references.

As used herein the term "protected SH" means that the thiol group is substituted with any of the conventional thiol protecting groups, see, for instance, T. W. Greene, Protective Groups in Organic Synthesis, chapter 6, John Wiley and Sons, New York, 1981, and by J. W. Barton, Protective Groups in Organic Chemistry. J. F. W. McOmie, ed., Plenum Press, New York, 1973. Examples of such groups include but are not intended to be limited to thioethers like benzylthioether, 4- methylbenzylthioether, p-nitrobenzylthioether, diphenylmethylthioether, substituted methyl derivatives such as methoxymethyl (MOM), isobutoxymethyl, 2- tetrahydropyranyl, thioesters like, acetyl, benzoyl, thiocarbonates like t- butoxycarbonyl, and the like.

The two-stage process, herein described, is very general, employs very mild reaction conditions, is compatible with a very broad range of functionalities, delivers comparably high yields and pure products, thus providing significant advantages over the methods known to the artisan.

The process described herein is compatible to many functionalities present in an organic molecule. For example, the process is appropriate for unprotected hydroxy, unprotected primary or secondary amino, olefinic double bond, cyano, nitro, aromatic halogeno, carboxamido, formyl and carbonyland can be successfully applied, when conventional methods have failed (Chem. Pharm. Bull. 1980, 25, 1394-1402).

Additionally, the process is highly suitable for the synthesis of combinatorial cyclic amidine libraries utilizing all kinds of polymerbound esters.

This process may also be suitable for the synthesis of substituted imidazolines, e.g. 4-alkyl-, 4,4'-dialkyl-, 4,5 dialkyl-, 4,4'spirocycloalkyl-, 4,5-cycloalkylsubsituted 2-imidazolines or 1 ,2-substituted imidazolines. In the latter, however, mixtures of isomers are to be expected, if further substituents (4-or 5-position) are also present.

This process may also be suitable for the synthesis of substituted imidazoles annelated to an optionally substituted aromatic or heteroaromatic ring system, e.g. benzimidazoles, imidazo-[4,5-b]-pyridines, imidazo-[4,5-c]-pyridines, or purines

This process may also be suitable for the synthesis of substituted or unsubstituted tetrahydropyrimi dines, optionally annelated to an optionally substituted aromatic or heteroaromatic ring system.

This process may also be suitable for the synthesis of substituted or unsubstituted hexahydro-l,3-diazepines, optionally annelated to an optionally substituted aromatic or heteroaromatic ring system. The following scheme illustrates different ring systems,but is by no way limited to these:

(Va)

(Vc)

In this scheme A each independently represents N or C-R', provided that not more than two nitrogens are present in the annelated ring and t is 2,3, or 4 depending on the number of carbon atoms in the annelated ring accessible for substitution by R'. R' represents a substituent each independently selected from the group consisting of Cι_ alkyl, Cj.g alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro,

3,4-methylenedioxy, amino, Cj.g alkylcarbonyl, Cj.g alkoxycarbonyl, mono-Cι_g alkylaminocarbonyl, di-Cj.g alkylaminocarbonyl or is defined as for R above.

The process may, in some instances, be improved or accelerated by the addition of Lewis-acids, (e.g. trimethylsilyl trifluoromethane sulfonate, rare earth trifluoromethane sulfonates, A1C1₃, BC1₃, SnCl₄, TiCl₄, ZnCl₂ ), metals(e.g. Cu, rare earth metals) or metal salts (e.g. Cul, or rare earth metal salts) catalysis, e.g. rare earth metals and their salts to the reaction mixture. Sometimes Lewis acid catalysis (e.g. Sc(HI) trifluoromethane sulfonate) may be advantageously used or required, to induce cyclisation to the amidine product.

The process for the preparation of the necessary intermediates involves the aminolysis of a carboxylic acid ester by an appropriate diamine. For further clarification, this process is illustrated by Scheme IV.

The carboxylic acid moiety is esterified by a lower alkanol (e.g. methanol, ethanol) or with alcohols, which may also be residues of polymers. The residues of polymers are those known in to the artisan. The residues of polymers are for example, polystyrene based resins, like Merrifield-, Wang- , Tentagel-resins and the like, or polyethylene glycol or monoethers of polyethylene glycol. The esterified carboxylic acid moiety is contacted with about an equimolar amount or an excess of diamine. If an excess of diamine is used, the excess may be up to about 100 fold molar excess. It is preferable that the diamine excess is about 2 to about twenty fold molar excess. It is especially preferable that the diamine excess is about 4 to about 10 fold molar excess. The product of this process is an carboxamide of Formula I or a carboxamide of Formula I. This stage of the process includes the use of solvents or mixtures of solvents, like water, alcohols, ethers, halogenated hydrocarbons, dimethyl formamide, dimethyl sulphoxide, hexamethyl phosphoric acid triamide, dimethyl propylene urea, dimethyl ethylene urea, acetonitrile, aliphatic, cycloaliphatic or aromatic hydrocarbons, and the like.

The term "ethers" means for example, but not limited to ethers such as t-butyl methyl ether, tetrahydrofuran, dioxane, and the like. The term halogenated hydrocarbons means, for example, but not limited to, chloroform, dichloromethane, trichloroethene and the like. The term "aromatic hydrocarbons" means, for example, but not limited to benzene, toluene, xylene and the like. The term "aliphatic hydrocarbons" means, for example, but not limited to pentane, hexane, iso-hexane, octane, petroleum ether and the like. The term "cycloaliphatic hydrocarbons" means, for example, but not limited to cyclopentane, cyclohexane, decaline and the like.

The process may be advantageously run in diamine/water mixtures, containing up to about 100 equivalents of water, which is calculated in respect to the starting ester. It is preferable that the diamine/water mixture contains about 10 equivalents of water. It is especially preferred that the diamine/water mixture contains from about 1 to 1.5 equivalents of water. The process may be advantageously run also without any solvents in neat diamine.

The optimum reaction temperature for the claimed process depends on the reactivity of the ester and other putatively sensitive functionalities present in the molecule. Typically, the reaction temperature may range from about -10°C to about 250°C or at the reflux temperature of the reaction mixture. A preferable reaction temperature is from about ambient temperature to about 120°C. An especially preferred reaction temperature is from about 50 to about 70°C.

An advantage of using neat diamine reaction conditions for the claimed process is that no practical amount of dimerisation product is detectable.

The skilled artisan will readily recognise that, the above mentioned amino alkyl carboxamides are also accessible by other methods known in the art. For example, amino alkyl carboxamides can be prepared using the reaction of an activated carboxylic acid derivative, like an acid chloride or an activated imidazolide with an appropriate diamine. A disadvantage of these reaction conditions using an activated carboxylic acid derivative, an acid chloride or an activated imidazolide is the potential for extended dimerisation even at low temperatures (J. Org. Chem. 1987,52,2592- 2594). In these cases monoprotection of the diamine prior to aminolysis of the activated carboxylic acid derivative may be advantageous. The product of this process is an aminoalkyl carboxamide of Formula I or a carboxamide of Formula I' in which R¹⁰ is an amino protecting group. Deprotection of the amino group prior to the cyclisation step producing an amidine of Formula II or of Formula II' may be not required, if the so said amino protecting group is a silyl amino protecting group, e.g. trimethyl silyl.

The amino alkyl carboxamides, thus obtained and serve as the starting materials for the process claimed herein. The carboxamides are cyclized, with or without purification. Cyclisation is induced by a silylating agent or a mixture of silylating agents, optionally in the presence of an soluble or insoluble organic or inorganic base. The soluble or insoluble base may be, for example but not limited to, triethyl amine,pyridine, collidine,lutidine, DBN, DBU or basic polymer resins like dimethylaminomethyl polystyrene or piperidinylmethyl polystyrene or the like and a solvent. Useful silylating reagents are available to the artisan as described in FLUKA Chemika "Silylating Agents" (1995) ISBN 3-905617-08-0 and the literature cited therein.

The silylating agents which are especially preferred are trimethyl silyl halogenides, TMS-X (wherein TMS-X means trimethyl silyl chloride, trimethyl silyl bromide or trimethyl silyl iodide) or hexamethyl disilazane, HMDS or trimethyl silyl diethylamine, TMS-DEA or N,O -bis trimethylsilyl acetamide, or N,O -bis trimethylsilyl trifluoroacetamide, or trimethylsilyl imidazole or mixtures of them. Suitable silylating reagentsmay advantageously generated in situ, for example but not limited to, by contacting TMS-C1 with an inorganic iodide or bromide salt or an organic compound like imidazole. In the most prefered embodiment of the process, the silylation reaction is carried out either in neat HMDS or a mixtures of HMDS and other silylating agents as cited above. For example, especially preferred HMDS mixtures include but are not limited to, HMDS/TMS-Cl 99/1 or HMDS/TMS-Cl 98/2. It is especially preferred that the HMDS is used without additional base and solvent. A preferred reaction temperature for HMDS is about 50°C to reflux of the mixture. It is especially preferred that the temperature is 70°C to 90°C.

Another preferred embodiment of the claimed process is that the silylation is done in methylene chloride with excess TMS-C1 or TMS-I. It is especially preferred that the silylation is done in TMS-I in presence of triethyl amine or dimethylaminomethyl polystyrene. When the silylation is done in TMS-I in the in presence of triethyl amine or dimethylaminomethyl polystyrene the reaction is most preferably run at about ambient temperature.

It is an especially preferred embodiment of the claimed invention that the process is completed using TMS-I. The TMS-I can be obtained commercially or may be generated in situ. It is particularly preferred that the TMS-I is generated in situ by addition of sodium iodide to TMS-CL

In some cases, dependent of the structure of the starting material, if TMS-X is used as the cyclizing reagent, an excess of TMS-X reagent has to be added in several portions within a period of time to ensure complete conversion. The period of time for making such additions of TMS-X may be up to about 2 weeks. It is most preferred that the reaction time is less than one day.

In some cases, when using TMS-X as cyclizing reagent, it is desired to add excessive reagent in several portions within a period of time (up to about a week) to ensure complete conversion. It can be particularly advantageous to generate the silylating agent, TMS-I, in situ. Some standard references which provide general information regarding the generation of TMS-I include, but are not limited to, Jung, M.E; Martinelli, MJ, in "Encyclopedia of reagents for Organic Synthesis" (Edited by L. Paquette), 1995, vol. 4, p2854 (Wiley); and Colvin, E. "Silcon in Organic Chemistry", 1981, Chapter 18 (Buttterworths).

One embodiment of the claimed process, as described in Scheme I, affords numerous advantages over similar methods known in the art. The transformation can be achieved in high yield and under mild conditions, whereas, methods known in the art typically require the use of extreme conditions or reagents.

Scheme I

The substituents illustrated by Scheme I are as defined herein by Formulas I and E.

Likewise, a further embodiment of the claimed process can be illustrated by Scheme II: Scheme II

The R group which appears in Scheme π is as defined for Formula I, herein.

Likewise, a further embodiment of the claimed process can be illustrated by Scheme HI:

Scheme III

The substituents illustrated in Scheme HI are as defined herein as follows: Y, Y' and Y" independently are as defined as Y above, and R_{l 5} Rι\ and Ri" independently are as defined as R] above. 25

For further clarification, the process for preparing the intermediates of

Formula I can be prepared using the process illustrated by Scheme IV:

As illustrated by Scheme IV, the substituents have the meaning defined for

Formula I herein. Y¹ represents halogen, N-imidazole

— N

or -O- R^{1 ]} . The R^{1 λ} substituent is selected from the group consisting of CH₃, CH₂CH₃, and an alcoholic hydroxy groups containing polymer resin.

Certain process features and conditions within the scope of this invention are preferred. The following conditions, invention embodiments, and compound characteristics listed in tabular form may be independently combined to produce a variety of preferred intermediates and process conditions. The following list of embodiments of this invention is not intended to limit the scope of this invention in any way. Some prefered characteristics of the process claimed herein are: i) the silylating agent is selected from the group consisting of TMS-X and

HMDS; ii) the silylating agent is TMS-I; iii) the silylating agent is TMS-I and is generated in situ; iv) R¹⁰ is hydrogen; v) the product of the claimed process is a compound of Formula II; vi) R is selected from the group consisting of optionally substituted C _S alkyl, optionally substituted C₃.₁₀ cycloalkyl, optionally substituted C₃.₁₀ cycloalkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl vii) n, n", n'" and n"" are each 1; viii) n and n'" are each 1; ix) n and n" are each 0, n'" is 1; x) n and n" are each 0, n'" and n"" are each 1, R², R³, R⁸, R⁹ are each hydrogen OΓ C_HO alkyl; xi) R¹ is hydrogen; xii) n is 0, n", n'", and n"" are each 1; R² and R⁶ along with the carbon to which they are bound combine to form an aromatic benzofused ring, R⁸ and

R⁹ are each hydrogen;

By virtue of their acidic moieties, some of the compounds of Formula II include the pharmaceutically acceptable base addition salts thereof. Such salts may be prepared following the amidine formation process described herein. Such salts include those derived from inorganic bases such as ammonium and alkali and alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, as well as salts derived from basic organic amines such as aliphatic and aromatic amines, aliphatic diamines, hydroxy alkamines, and the like. Such bases useful in preparing the salts of this invention thus include ammonium hydroxide, potassium carbonate, sodium bicarbonate, calcium hydroxide, methylamine, diethylamine, ethylenediamine, cyclohexylamine, ethanolamine and the like.

Because of a basic moiety, some of the compounds of Formula II can also exist as pharmaceutically acceptable acid addition salts. The salt may optionally be prepared following the amidine formation process described herein. Acids commonly employed to form such salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, methanesulfonic, oxalic, para- bromophenylsulfonic, carbonic, succinic, citric, benzoic, acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, mono-hydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, heptanoate, propiolate, oxalate, malonate, succmate, suberate, sebacate, fumarate, maleate, 2-butyne-l,4 dioate, 3- hexyne-2, 5-dιoate, benzoate, chlorobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hippurate, β-hydroxybutyrate, glycollate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like salts.

The artisan appreciates that, in some instances, desired isomeπc forms may be obtained using separation methods which are generally known.

Preparations and Examples

The following examples and preparations are provided merely to further illustrate the invention. The scope of the invention is not limited or m any way to be construed as merely consisting of the following examples. In the following examples and preparations, melting point, nuclear magnetic resonance spectra, mass spectra, high pressure liquid chromatography over silica gel, gas chromatography, N,N- dimethylformamide, palladium on charcoal, tetrahydrofuran, ethyl acetate, thin layer chromatography and elemental analysis are abbreviated M.Pt. or m.p., NMR, MS, HPLC, GC, DMF, Pd/C, THF, EtOAc, TLC and EA respectively. The terms "EA", "TLC", "NMR", and "MS", when being utilised m the preparations, indicate that the data indicated was consistent with the desired structure. Reported melting points are uncorrected and yields are not optimised.

Example 1

Aminolysis of Ethyl Benzoate: A mixture of 1 mMol of ethyl benzoate and 4 to 10 mMol of the corresponding neat diamine was stirred at 90 °C for 20 h. After cooling the residue was purified via flash chromatography on silica gel using a methylene chloride/ethanolic ammonia gradient 95:5 to 80:20. Yields were in the range of 80 to 100% Example la Cyclisation Method A:

The foregoing ω-amino alkyl amide was dissolved in neat hexamethylene disilazane (HMDS) containing 2% of trimethyl chlorosilane (TMS-C1) (approx. 1,5ml of silylating agent/1 mMol of amide). The mixture was stirred at 100 °C, until TLC check (methylene chloride/ethanolic ammonia 9:1) showed nearly complete conversion (16 to 48 h). After cooling the mixture was diluted with ethanol and evaporated. The residue was dissolved in methylene chloride, coated on silica gel, and purified via flash chromatography on silica gel using a methylene chloride/ethanolic ammonia gradient 99:1 to 80:20. Yields and physical data as indicated in table 1 :

Table 1

Structure (free base) MS (M+1 ) Yield (%)

Method B:

The foregoing ω-amino alkyl amide (1 mMol) was dissolved in 20 ml of dry methylene and lg (3 mequiv.) of dimethylaminomethyl polystyrene together with 3 mMol of trimethyl iodo silane (TMS-I) were added. The mixture was stirred at ambient temperature, until TLC check (methylene chloride/ethanolic ammonia 9:1) showed nearly complete conversion (2 to 18 d). If conversion was incomplete after 3 d the same amount of basic resin and TMS-I was added. The slurry was filtered off, the remaining resin was thoroughly rinsed with methylene chloride and ethanol, and the collected filtrates were evaporated. The residue was coated on silica gel and purified via flash chromatography, either on silica gel or ALOX using a methylene chloride/ethanolic ammonia gradient 99:1 to 80:20. Analyticallly pure samples were obtained via prep. HPLC on RP-18 silica gel using an acetonitrile/water gradient. Yields and physical data as indicated in table 2:

Table 2

Structure (hydro iodide) MS (M+1) of Yield (%) free base

299.2 68

'catalyzed by scandium triflate see below Synthesis of Midaglizole

163 g (0,605 Mol) of the amide was suspended in 400 ml of HMDS and stirred at 110 °C for 33 h. The heterogenous mixture was cooled and poured into 11 of ice cold ethanol. The solution was evaporated to dryness and the residue dissolved in 550 ml of acetone. After cooling the crystalline precipitate was collected and the mother liquor concentrated to half of the volume. A second crop of off white crystalls was collected. The remaining mother liquor was evaporated to dryness and the remaining dark brown oil was dissolved in methanol and stirred with 2 g of charcoal for 30 min. After filtration the firtrate was evaporated and recrystallized from hot acetone. The collected crops of crystalls were pooled and finally recrystallized from acetone. Yield: 151,4 g of colorless crystalls (100% of theory). Mp.: 120-122 °C

Synthesis of 2-Phenylbenzimidazole by scandium triflate catalyzed cyclisation et yl

A mixture of 106 mg (0.5 mMol) of the 2-aminophenyl benzamide, 500 mg (1.5 mMol equiv.) of diethylaminomethyl polystyrene resin, 215 μl (1.5 mMol) of TMS-I and 25 mg (0.05 mMol) of scandium triflate Sc(OSO₂CF₃)₃ in 10 ml of dry methylene chloride was stirred under argon at ambient temperature for 16 h. Another amount of 500 mg (1.5 mMol equiv.) of diethylaminomethyl polystyrene resin, 215 μl (1.5 mMol) of TMS-I and 50 mg (0.1 mMol) of scandium triflate Sc(OSO₂CF₃)₃was added and stirring continued for 16 hours. The mixture was made alkaline with aqueous 2 N NaOH and the pH adjusted to 14 by 8 N NaOH. The mixture was filtered and the resin thoroughly rinsed with water and ethyl acetate. The phases were separated, the collected organic phases washed to neutral, dried with sodium sulfate and brought to dryness. Yield 70 mg (72%) of material, which was essentially pure according to NMR.

Example 3 Cyclisation by Diethylamino trimethylsilan (TMS-DEA)

A solution of 82 mg (0,5 mMol) of 2-aminoethyl benzamide and 500 μl of TMS- DEA was stirred for 5 d at ambient temperature, evaporated and purified by flash chromatography. 50% yield of 2-phenyl-4,5-dihydroimidazole.

A solution of 82 mg (0,5 mMol) of 2-aminoethyl benzamide in 500 μl of neat TMS-DEA was stirred for 3 h atlOO °C, evaporated and purified by flash chromatography. 89% yield of 2-phenyl-4,5-dihydroimidazole.

Example 4

Synthesis of 6-(4,5-Dihydro-lH-imidazoI-2-yl)-7-(2-methoxyethoxy)-4- methylchromen-2-one. A solution of the starting amide (200 mg; 0.62 mmol) in CH₂C1 (2 mL), under an inert atmosphere of nitrogen, is sequentially treated with Nal (215 mg, 1.43 mmol, 2.3 eq.), and Et₃N (0.2 mL, 1.43 mmol, 2.3 eq.). After cooling the resulting suspension to 0 °C, TMSCl (0.18 mL, 1.43 mmol, 2.3 eq.) is added and the reaction mixture allowed to warm to room temperature. The progress of the reaction is followed by HPLC. After 42 h, 2.3 eq. of Nal, Et₃N, and TMSCl are added, and the reaction is stirred at room temperature until consumption of the starting amide. After adding water (2 mL) a precipitate appears. It is filtered, washed with water, and dried under reduced pressure, to give 167 mg of the title compound most likely as its hydroiodide salt. This material is then suspended in 1/1 v/v CH₂Cl /H₂O and treated with NaOH 0.5 N until the aqueous phase reaches a basic pH. The CH C1₂ layer is then concentrated to dryness providing 114 mg of the title compound (61% based on the starting amide). This compound has been found to be very clean by NMR spectroscopy.

Example 5

Generation of Imidazoline Libraries: A sixty-well reaction block, each well containing 800 mg of Wang resin esterified biphenyl carboxylic acid derivative was charged with 2 ml of neat ethylene diamine per well gently stirred for 16 h at 65 °C. After filtration, the resin was thoroughly washed with ethanol (1x5 ml, 3x1,5 ml) and the collected filtrates evaporated in a SpeedVac. Each of the residues was mixed with 3 ml of HMDS, containing 2% of TMS-C1 and stirred under argon at 100 °C for 16 h. All volatiles were removed in a vacuum, the residues dissolved in methanol and coated on silica gel. Purification was done by parallel flash chromatography on silica gel using a methylene chloride/ethanolic ammonia gradient 100 to 90:10. Yields were in the range of 30 to 80%.

Preparation 1: 2-Aminoethyl 3-(2-Methoxyethoxy)-5-methyl-5,6,7,8- tetrahydronaphthyl-2-carboxamide

A solution of 120 mg (0.43 mmol) methyl 3-(2-methoxyethoxy)-5-methyl-5,6,7,8- tetrahydronaphthyl-2-carboxylate in 1 ml 1,2-diaminoethane was stirred at 85 °C for 16 h under an argon atmosphere. After removal of the solvent in vacuo the title compound was obtained by chromatography (silica gel, dichloromethane / 10% ethanolic ammonia 95:5). Yield: 90 mg (69 %); MS 306 (M⁺)

The following intermediates were prepared in the same manner: Preparation la

2-Aminoethyl 3-(2-Methoxyethoxy)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2- carboxamide

from 200 mg (0.72 mmol) methyl 3-(2-methoxyethoxy)-6,7,8,9-tetrahydro-5H- benzocycloheptene-2-carboxylate;

Yield: 160 mg (73 %); MS 306 (VT -K)

Preparation lb

2-Aminoethyl 2-Ethoxycarbonyl-6-(2-methoxyethoxy)-3,4-dihydro-lH- isoquinoline-7-carboxamide

from 135 mg (0.4 mmol) methyl 2-ethoxycarbonyl-6-(2-methoxyethoxy)-3,4-dihydro- lH-isoquinoline-7-carboxylate at room temperature; Yield: 40 mg (27 %); MS 366 (M⁺+l)

Preparation lc

2-Aminoethyl 3-(2,2,3,3,3-Pentafluoropropoxy)-5,6,7,8-tetrahydronaphthalene-2- carboxamide

from 250 mg (7.10 mmol) ethyl 3-(2,2,3,3,3-pentafluoropropoxy)-5,6,7,8- tetrahydronaphthalene-2-carboxylate; yield: 0.11 g (42 %); MS 366 (M +^τ)Λ

Preparation Id

2-AminoethyI 7-(2-Methoxyethoxy)-4-methyl-2-oxo-2H-benzo[b]pyran-6- carboxamide (R = H)

from of 8.2 g (28.0 mmol) methyl 7-(2-methoxyethoxy)-4-methyl-2-oxo-2H- benzo[b]pyran-6-carboxylate in 70 ml 1,2-diaminoethane for 2 days at room temperature;

Yield: 7.4 g (82 %); MS 320 (NT -K)

Preparation le

2-Aminoethyl 3,4-Dimethyl-7-(2-methoxyethoxy)-2-oxo-2H-benzo[b]pyran-6- carboxamide (R = CH3) from 0.46 g (1.37 mmol) methyl 3,4-dimethyl-7-(2-methoxyethoxy)-2-oxo-2H- benzo[b]pyran-6-carboxylate in 4 ml 1,2-diaminoethane for 3 days at room temperature;

Yield: 0.23 g (50 %); MS 334 (M⁺)

Preparation If

2-AminoethyI 7-(2-Methoxyethoxy)-2,2,3,4-tetramethyl-2H-benzo[b]pyran-6- carboxamide

from 125 mg (0.36 mmol) propyl 7-(2-methoxyethoxy)-2,2,3,4-tetramethyl-2H- benzo[b]pyran-6-carboxylate;

Yield: 60 mg (48 %); MS 349 (WT ^■++, l)

Example 6: 2-(3-(2-Methoxyethoxy)-5-methyl-5,6,7,8-tetrahydronaphthalen-2-yl)- 4,5-dihydro-lH-imidazole

To a solution of 90 mg (0.29 mmol) 2-aminoethyl 3-(2-methoxyethoxy)-5-methyl- 5,6,7,8-tetrahydronaphthyl-2-carboxamide in 5 ml dry dichloromethane were added 290 mg (0.88 mmol) diethylaminomethyl-polystyrene and 0.126 ml (0.88 mmol) trimethylsilyl iodide. The mixture was stirred for 48 h at room temperature, and the resin was filtered and washed with dichloromethane and ethanol, successively. After removal of the solvent under reduced pressure chromatography on silica gel with dichloromethane / 10% ethanolic ammonia 95:5 afforded the title imidazoline.

Yield: 60 mg (71 %); beige crystalline solid, m.p. 60-61 °C; MS 288 (M⁺)

The following Examples were prepared in the same manner:

Example 7: 2-(3-(2-Methoxyethoxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten- 2-yl)-4,5-dihydro-lH-imidazole

from 140 mg (0.46 mmol) of 2-aminoethyl 3-(2-methoxyethoxy)-6,7,8,9-tetrahydro- 5H-benzocycloheptene-2-carboxamide, 0.195 ml (1.37 mmol) trimethylsilyl iodide, and 458 mg (1.37 mmol) diethylaminomethyl-polystyrene for 16 h at room temperature; Yield: 93 mg (71 %); beige resin; MS 288 (NT +Λ)

Example 8: Ethyl 7-(4,5-Dihydro-lH-imidazol-2-yl)-6-(2-methoxyethoxy)-3,4- dihydro-lH-isoquinoline-2-carboxylate

from 40 mg (0.11 mmol) 2-aminoethyl 2-ethoxycarbonyl-6-(2-methoxyethoxy)-3,4- dihydro-lH-isoquinoline-7-carboxamide, 110 mg (0.33 mmol) diethylaminomethyl- polystyrene, and 0.047 ml (0.33 mmol) trimethylsilyl iodide for 64 h at room temperature;

Yield: 16 mg (42 %); pale yellow oil; MS 347 (M⁺)

Example 9: 2-(3-(2,2,3,3,3-Pentafluoropropoxy)-5,6,7,8-tetrahydronaphthalen- 2-yl)-4,5-dihydro- lH-imidazole

from 110 mg (0.30 mmol) 2-aminoethyl 3-(2,2,3,3,3-pentafluoropropoxy)-5,6,7,8- tetrahydronaphthalene-2-carboxamide, 300 mg (0.90 mmol) diethylaminomethyl- polystyrene, and 0.129 ml (0.90 mmol) trimethylsilyl iodide;

Yield: 70 mg (67 %); pale yellow resin; MS 348 (M⁺)

Example 10: 2-(7-(2-Methoxyethoxy)-4-methyl-2-oxo-2H-benzo[b]pyran-6-yl)- 4,5-dihydro- lH-imidazole

from 7.3 g (22.8 mmol) 2-aminoethyl 7-(2-methoxyethoxy)-4-methyl-2-oxo-2H- benzo[b]pyran-6-carboxamide with 23.3 g (70.0 mmol) diethylaminomethyl- polystyrene resin and 10 ml (70.0 mmol) trimethylsilyl iodide in 300 ml dry dichloromethane for 18 h at room temperature;

Yield: 4.40 g (64 %); pale yellow crystals, m.p. 150-152 °C; MS 302 (M⁺)

Example 11: 2-(3,4-Dimethyl-7-(2-methoxyethoxy)-2-oxo-2H-benzo[b]pyran-6- yl)-4,5-dihydro-lH-imidazole

from 0.23 g (0.69 mmol) 2-aminoethyl 3,4-dimethyl-7-(2-methoxyethoxy)-2-oxo-2H- benzo[b]pyran-6-carboxamide with 690 mg (2.07 mmol) diethylaminomethyl- polystyrene resin and 0.294 ml (2.07 mmol) trimethylsilyl iodide in 10 ml dry dichloromethane for 3 days at room temperature;

Yield: 0.11 g (51 %); colorless crystals, m.p. 174-176 °C; MS 316 (M⁺)

Example 12: 2-(7-(2-Methoxyethoxy)-2,2,3,4-tetramethyl-2H-benzo[b]pyran-6- yl)-4,5-dihydro-lH-imidazole Hydroiodide

HI

from 60 mg (0.17 mmol) 2-aminoethyl 7-(2-methoxyethoxy)-2,2,3,4-tetramethyl-2H- benzo[b]pyran-6-carboxamide with 172 mg (0.52 mmol) diethylaminomethyl- polystyrene resin and 0.074 ml (0.52 mmol) trimethylsilyl iodide in 10 ml dry dichloromethane for 7 days at room temperature; Example 13: 2-(3-Phenyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4,5-dihydro-lH- imidazole Hydroiodide (R = H)

Step A: 2-Aminoethyl 3-Phenyl-5,6,7,8-tetrahydronaphthalene-2- carboxamide (R = H)

A solution of 0.24 g (0.85 mmol) of the ester from the previous step and 15.3 mg (0.85 mmol) water in 4 ml neat ethylenediamine (EDA) was stirred at 100 °C, until the reaction was nearly complete (after 3 days) as detected by TLC (dichloromethane / ethanolic ammonia 9:1). After cooling the mixture was diluted with toluene and the excess EDA and water were removed azeotropically. The title amide was obtained from the residue via flash chromatography on silica gel using a dichloromethane / ethanolic ammonia gradient 100 to 90:10. Yield: 203 mg (81 %); yellow powder; MS 295.3 (M⁺+l) Step B: 2-(3-Phenyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4,5-dihydro-lH- imidazole Hydroiodide (R = H)

To a solution of 0.2 g (0.68 mmol) of the aminoethyl amide in 7 ml dichloromethane were added 3 equivalents of diethylaminomethyl-polystyrene and 40 mg (0.2 mmol) of trimethylsilyl iodide. The mixture was stirred at room temperature for 3 days. Another two equivalents of base and TMS iodide were added, stirring was continued, and after 7days the reaction was nearly complete as detected by TLC (dichloromethane / ethanolic ammonia 4:1). The resin was removed by filtration and thoroughly rinsed with dichloromethane and methanol. The combined filtrates were concentrated under reduced pressure, and the residue was purified via prep. HPLC on RP-18 silica gel using an acetonitrile / water gradient. Yield: 118 mg (43 %); yellow oil; MS 277.2 (M⁺+l)

The following Examples were prepared in the same manner using the corresponding benzeneboronic acids:

Example 14: 2-(3-(4-Methylphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl)-4,5- dihydro-lH-imidazole Hydroiodide (R = CH₃)

Step A: 2-Aminoethyl 3-(4-Methylphenyl)-5,6,7,8-tetrahydronaphthalene-

2-carboxamide (R = CH₃)

Yield: 0.27 g (81 %); yellow oil

Step B: 2-(3-(4-MethylphenyI)-5,6,7,8-tetrahydronaphthalen-2-yI)-4,5- dihydro-lH-imidazole Hydroiodide (R = CH₃)

The reaction was complete after 10 days at room temperature. Yield: 165 mg (45 %); yellow oil; MS 291.0 (M⁺+l)

Example 15: 2-(3-(4-MethoxyphenyI)-5,6,7,8-tetrahydronaphthalen-2-yl)-4,5- dihydro-lH-imidazole Hydroiodide (R = OCH₃)

Step A: 2-Aminoethyl 3-(4-Methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-

2-carboxamide (R = OCH₃)

Yield: 0.24 g (57 %); yellow oil

Step B: 2-(3-(4-Methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl)-4,5- dihydro-lH-imidazole Hydroiodide (R = OCH₃)

The reaction was complete after 11 days at room temperature. Yield: 12.9 mg (4 %); yellow oil; MS 307.2 (MM)

Example 16: 2-(3-(4-Chlorophenyl)-5,6,7,8-tetrahydronaphthalen-2-yl)-4,5- dihydro-lH-imidazole Hydroiodide (R = CI)

Step A: 2-Aminoethyl 3-(4-Clorophenyl)-5,6,7,8-tetrahydronaphthaIene-2- carboxamide (R = CI)

Yield: 0.37 g (71 %); yellow powder; MS 329.1 (M⁺+l)

Step B: 2-(3-(4-Chlorophenyl)-5,6,7,8-tetrahydronaphthalen-2-yl)-4,5- dihydro-lH-imidazole Hydroiodide (R = CI)

The reaction was complete after 7 days at room temperature. Yield: 148 mg (30 %); yellow oil; MS 311.0 and 313.0 (M⁺+l) Example 17: 2-(3-(2-(N,N-Dimethylamino)ethoxy)-5,6,7,8- tetrahydronaphthalen-2-yl)-4,5-dihydro-lH-imidazole Dihydroiodide (R¹ = R² : CH₃)

Step A: 2-Aminoethyl 3-(2-(N,N-Dimethylamino)ethoxy)-5,6,7,8- tetrahydronaphthalene-2-carboxamide (R¹ = R² = CH₃)

A mixture of 0.49 g (1.68 mmol) of the ester from the previous step, 8 ml neat ethylenediamine (EDA), and 30.3 mg (1.68 mmol) water was heated at 100 °C for 24 h. The excess of EDA was removed in vacuo, and the evaporation was repeated after dilution with toluene. The residue was coated on silica gel and purified via flash chromatography using a dichloromethane / ethanolic ammonia gradient 100 to 90:10 as an eluent. Yield: 0.22 g (43 %); yellow oil

Step B: 2-(3-(2-(N,N-Dimethylamino)ethoxy)-5,6,7,8- tetrahydronaphthalen-2-yl)-4,5-dihydro-lH-imidazole Dihydroiodide (R¹ = R² = CH₃) To a solution of 0.22 g (0.72 mmol) of the amide from the previous step in 7 ml dichloromethane were added 3 equivalents of diethylaminomethyl-polystyrene, and 0.44 g (2.2 mmol) of trimethylsilyl iodide. The mixture was stirred at ambient temperature for 6 d until the reaction was nearly complete as detected by TLC (dichloromethane /ethanolic ammonia 9:1). The resin was removed by filtration, thoroughly rinsed with dichloromethane and ethanol, and the combined filtrates were concentrated in vacuo. The residue was purified via prep. HPLC on RP-18 silica gel using an acetonitrile / water gradient to give the title imidazoline. Yield: 66.5 mg (17 %); yellow oil which solidified upon standing; MS 288.1 (M⁺+l)

The following Examples were prepared in the same manner starting with the corresponding 2-chloroethylamine hydrochlorides:

Example 18: 2-(3-(2-(MorphoIin-4-yI)ethoxy)-5,6,7,8-tetrahydronaphthaIen-2- yl)-4,5-dihydro-lH-imidazole Dihydroiodide (R¹ - R² = -CH₂CH₂OCH₂CH₂-)

Step A: 2-Aminoethyl 3-(2-(Morpholin-4-yl)ethoxy)-5,6,7,8- tetrahydronaphthalene-2-carboxamide

(R¹ - R² = -CH2CH2OCH2CH2-)

Yield: 0.91 g (95 %); yellow oil

Step B: 2-(3-(2-(Morpholin-4-yl)ethoxy)-5,6,7,8-tetrahydronaphthalen-2- yl)-4,5-dihydro-lH-imidazole Dihydroiodide (R¹ - R² = -CH₂CH2OCH₂CH₂-)

Yield: 0.46 g (30 %); yellow oil; MS 330.1 (M⁺+l) Example 19: 2-(3-(2-(N,N-Diisopropylamino)ethoxy)-5,6,7,8- tetrahydronaphthalen-2-yl)-4,5-dihydro-lH-imidazole Dihydroiodide (R¹ = R² CH(CH₃)₂)

Step A: 2-Aminoethyl 3-(2-(N,N-Diisopropylamino)ethoxy)-5,6,7,8- tteettrraahhyyddrroonnaapphhtthhaalleennee--22--ccaarrbbooxxaamide (R¹ = R² = CH(CH₃)₂)

Yield: 0.77 g (87 %); brownish oil

StepB:2-(3-(2-(N,N-Diisopropylamino)ethoxy)-5,6,7,8-tetrahydronaphthalen-2- yl)-4,5-dihydro-lH-imidazole Dihydroiodide (R¹ = R² = CH(CH₃)₂)

Yield: 0.23 g (18 %); yellow oil; MS 344.3 (M⁺+l)

The following compounds are prepared utilizing the method as described by Preparation *(4) and the process substantially as described by Examples 13 to 19: Example 20

2-(2'-(2"-methoxy-ethoxy)-5',6',7',8',9',10'-hexahydro-benzocyclooctene-3'-yl)- 4,5-dihydro- lH-imidazole

Example 21

2-(2'-(2"-methoxy-ethoxy)-6',7'-dihydro-5H-benzocyclopentene-3'-yl)-4,5- dihydro-lH-imidazole

Example 22

2-(6'-(2"-methoxy-ethoxy)-2'-spiro-2'"-[l'",3'"]dioxolane-3',4'-dihydro-lH- naphth-7 ' -yl)-4,5-dihydro- lH-imidazole

Example 23

2-(l',3'-ethano-2'(ethoxycarbonyl)-6'(2"methoxy-ethoxy)-l',2',3',4'- tetrahydroisoquinolin-7'-yl)-4,5-dihydro-lH-imidazole

Etooα

Claims

1. A a process for preparing a compound of Formula -3,

comprising contacting a compound of the Formula I:

with a silylating agent or for preparing a compound of Formula II' :

comprising contacting a compound of the Formula I': with a silylating reagent

wherein

R is independently selected from the group consisting of hydrogen, optionally substituted C _S alkyl, optionally substituted C₃-₁₀ cycloalkyl, optionally substituted

R^! is hydrogen or optionally substituted Cι-₁₈ alkyl, optionally substituted C₃-₁₀ cycloalkyl, optionally substituted C₃-₁₀ cycloalkenyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;

X is selected from the group consisting of a bond and a linker element -X'-X^X³-; when X and Y are each -X^]-X²-X³- and each of X¹, X², and X³ are (CR¹²R¹³)_Z or

(CR^I2R¹³)_Z> then X and Y optionally together combine and along with the nitrogen and carbon to which they are each respectively attached optionally form a fused C₄.₁₈ heterocychc πng;

X¹ is attached to the amidme forming moiety and is independently selected from the group consisting of

-(C CRI ¹²R¹³)_Z, -(CR¹² =CR¹³)_Z , and -(C≡C)_Z

X² and X^J- are each independently selected from the group consisting of - (CR¹²R¹³)_Z ,

-(CR¹² =CR¹³)_Z , -(C=C)_Z -, -O-, -NR¹¹-, -CONR¹¹-, -NRⁿCO-, -S-, -SO-, -SO₂-, - NRⁿSO₂- , and -SO₂NRⁿ, provided that, if one of X² and X³ is a selected from the group consisting of -O-, -NR¹¹-, -S-, -SO-, and -SO -, then the other remaining X²or X³ is selected from the group consisting of -(CR¹²R¹³)_Z , -(CR¹² =CR¹³)_Z •, -(C=C)_Z. ; z is independently 1 to 18; z'is independently 0 to 18; z" and z'" are each independently 0 to 3;

R^π ,R¹² , andR¹³ are each independently selected from the group consisting of hydrogen, optionally substituted Cι_-18 alkyl, optionally substituted C₃-_!o cycloalkyl, optionally substituted C₃-₁₀ cycloalkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl;

1 7 1

Y is a a bond and a linker element -X -X -X -;

X¹ is attached to the amidine forming moiety and is independently selected from the group consisting of -(CR¹²R¹³)_Z, -(CR¹² =CR¹³)₂-, and -(C≡C)_Z-; provided that one selected from the group consisting of X¹, X² andX^J, which is attached to the amidine moiety is selected from the group consisting of -(CR¹²R¹³)_Z;

R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selected from the group consisting of hydrogen, optionally substituted C^o alkyl, optionally substituted C -₁₀ alkenyl, optionally substituted C₆_₁₀ aryl, optionally substituted C₃-₁₀ cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted bicyclic; or

Two selected from the group consisting of R², R⁴, R⁶, and R⁸ together with the carbon atoms to which they are attached combine to form an optionally substituted 3 to 7 membered carbocyclic or form a bridging ring if the two selected from R², R⁴, R⁶, and R⁸ were not substituents on adjacent carbon atoms, and each of the remaining R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are hydrogen or one of R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ combines with another of R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ which is a substituent on an adjacent carbon atom, to optionally form a bond; or

Two substituents which are attached to the same carbon atom are selected from the group consisting of R² and R³, R⁴ and R⁵, R⁶ and R⁷, and R⁸ and R⁹, together with the carbon atom to which they are both attached combine to form a spirocarbocyclic ring,

T ^*-! Λ S Λ "7 R and each of the remaining R , R , R , R , R , R , R , and R are hydrogen or one of R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ combines with another of R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R which is a substituent on an adjacent carbon atom, to optionally form a bond;

R¹⁰ is hydrogen or an amino protecting group; provided that when Formula π is a group of the formula:

,wherein R , R , R , and R are each independently selected from the group consisting of hydrogen and C]-₈ alkyl; or;

Rl9 and R^l optionally together form a bond and R^O and R^2 are each independently hydrogen or C^.g alkyl; or

Rl9 and R21 optionally combine together with the carbon atoms to which they are attached form a C3-.7 carbocyclic ring and R20 nd R22 are each independently hydrogen or Cj.g alkyl; or

Rl9 and R 0 together with the carbon atom to which they are attached optionally combine to form a C3-.7 spirocarbocyclic ring and R21 and R22 are independently hydrogen or C^.g alkyl; or R21 and R22 together with the carbon atom to which they are attached optionally combine to form a 03.7 spirocarbocyclic and Rl9 _and R20 are independently hydrogen cr i o alkyl; then R cannot be

Y is -O-, -S-, or -NR⁸*-; Y' is -O- or -S-;

R6* and R^* are independently hydrogen, C^.g alkyl, C3-.7 cycloalkyl, C_j-.g alkoxy, Cj_g alkylthio, halo C}-.g alkylthio, Cι_g alkylsulfinyl, C^. alkylsulfonyl, C3-.7 cycloalkoxy, aryl-C^.g alkoxy, halo, halo-Cj.g alkyl, halo- C^.g alkoxy, nitro,

-NR^R^{1 1}*, -CONR¹⁰*Rⁿ*, aryl Ci .g alkyl, optionally substituted heterocyclyl, optionally substituted phenyl, optionally substituted naphthyl, optionally halo substituted acylamino, cyano, hydroxy, COR 12 _; halo C}_g alkylsulfinyl, or halo C _ g alkylsulfonyl, or alkoxyalkyl of the formula

CH₃(CH2)p-O-(CH₂)_q-O-; where p is 0, 1, 2, 3, or 4; and q is 1, 2, 3, 4, or 5; Rl2* is C alkyl or optionally substituted phenyl;

R° is hydrogen, Cj.g alkyl, halo-Cι_g alkyl, optionally substituted phenyl, optionally substituted heterocyclyl, COO Cj.g alkyl, optionally substituted COaryl, COCj.g alkyl, SO2Ci_ alkyl, optionally substituted SO₂ aryl, optionally substituted phenyl-Cι _g alkyl, CH3(CH₂)p-O-(CH₂)q-O-;

R9* is hydrogen, halo, C alkyl, halo Cj.g alkyl, C^.g alkylthio, halo C_j_ g alkylthio, C3.7 cycloalkylthio, optionally substituted arylthio or heteroarylthio, C\_ g alkoxy, C3-.7 cycloalkoxy, optionally substituted aryloxy , optionally substituted heteroaryloxy, or optionally substituted aryl or heteroaryl, C3.7 cycloalkyl, halo C3.7 cycloalkyl, C3.7 cycloalkenyl, cyano, COOR¹⁰*, CONR¹⁰*RU * or R10*R11*_J C2-6 alkenyl, optionally substituted heterocyclyl, optionally substituted aryl Cι_g alkyl, optionally substituted heteroaryl Cj. alkyl in which the alkyl group can be substituted by hydroxy, or Cj.g alkyl substituted by hydroxy;

RIO and RI 1 are independently hydrogen, C^.g alkyl, optionally substituted aryl Cχ-.g alkyl, optionally substituted phenyl, or RIO* and R 1* together with the nitrogen atom to which they are attached may combine to form a ring with up to six carbon atoms which optionally may be substituted with up to two Cj.g alkyl groups or one carbon atom may be replaced by oxygen or sulfur;

Rl4 and Rl" are independently hydrogen, halo, C _% alkyl, C3.7 cycloalkyl, C3-.7 cycloalkoxy, 03.7 cycloalkylCι_g alkoxy, halo-Cj.g alkyl, halo-C^.g alkoxy, Cι_g alkoxy, carbo(C₁_₈)alkoxy, optionally substituted aryl, or optionally substituted heteroaryl;

R!5 and Rl7 are independently hydrogen, halo, Cj_ alkoxy, C3.7- cycloalkyl, C3.7 cycloalkylCj.g alkoxy, Cj.g alkyl, C3.7 cycloalkoxy, hydroxy, halo C j_ alkoxy, carbo(Cι-₈)alkoxy, optionally substituted phenyl, optionally substituted phenyl-Cι_g alkyl, optionally substituted phenyloxy, optionally substituted phenyl-Cj.g alkoxy, (tetrahydropyran-2-yl)methoxy, Cj.g alkyl-S(O)_m-, optionally substituted aιyl-Cι_g alkyl-S(O)_m-, CH₃(CH₂)p-Z¹-(CH2)q-Z2-, or Z³-(CH₂)q'-Z²-; q' is 0,1,2,3,4, or 5; m' is O, 1, or 2; and

Z and Z are independently a bond, O, S, SO, SO2, sulphoximino, or

NRlO*;

7? is hydroxy, protected hydroxy, NR 0* R! 1*, protected amino, SH or protected SH.

2. A process of claim 1 wherein R¹⁰ is hydrogen.

3. A process of Claim 1 wherein R is hydrogen.

4. A process of Claim 1 wherein the silylating agent is selected from the group consisting of TMS-C1, TMS-I and HMDS.

5. A process of Claim 4 wherein the silylating agent is TMS-I and the TMS-I is generated in situ.

6. A process of Claim 2 wherein n, n" are each 1 and n'" is 0.

7. A process of Claim 4 wherein the process reactants include both a silylating agent and a base.

8. A process of Claim 7 wherein the base is triethyl amine or dimethylaminomethyl polystyrene.

9. A process for preparing a compound of Formula II' :

comprising contacting a compound of the Formula I' : with a silylating agent wherein

R is independently selected from the group consisting of hydrogen, optionally substituted C_{M S} alkyl, optionally substituted C₃-₁₀ cycloalkyl, optionally substituted C₃__!o cycloalkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl;

R¹ , R¹ and R¹ are each independently selected from the group consisting of hydrogen and optionally substituted C ₈ alkyl, optionally substituted C₃-₁₀ cycloalkyl, optionally substituted C₃-₁₀ cycloalkenyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl; X is selected from the group consisting of a bond and a linker element -X'-X^X³-; X¹ is attached to the amidine forming moiety and is independently selected from the group consisting of

-(CR¹²R¹³)_Z, -(CR¹² =CR¹³) _Z >, and -(C≡C)_Z-;

X andX - are each independently selected from the group consisting of - (CR¹²R¹³)_Z.,

-(CR¹² =CR¹³)_Z-, -(C=C)_Z-, -O-, -NR¹¹-, -CONR¹¹-, -NRⁿCO-, -S-, -SO-, -SO₂-, - NR¹ 'SO₂- , and -SO₂NRⁿ, provided that, if one of X² and X³ is a selected from the group consisting of -O-, -NR -, -S-, -SO-, and -SO -, then the other remaining X or X³ is selected from the group consisting of -(CR¹²R¹³)_Z., -(CR¹² =CR¹³)_Z», -(C=C)_Z-; z is independently 1 to 18; z'is independently 0 to 18; z" and z'" are each independently 0 to 3; R¹¹ ,R¹² , andR¹³ are each independently selected from the group consisting of hydrogen, optionally substituted C_MS alkyl, optionally substituted C₃-₁₀ cycloalkyl, optionally substituted C₃-₁₀ cycloalkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl;

Y, Y', and Y" are each independently selected from the group consisting of a bond and a linker element -X¹-X²-X³-;

X¹ is attached to the amidine forming moiety and is independently selected from the group consisting of -(CR¹²R¹³)_Z, -(CR¹² =CR¹³)_Z-, and -(C≡C)_Z...; provided that one selected from the group consisting of X^!, X² andX³, which is attached to the amidine moiety is selected from the group consisting of -(CR¹²R¹³)z; and

R¹⁰ is hydrogen or a silyl amino protecting group.

10. A a process for preparing a compound of Formula π,

comprising contacting a compound of the Formula I:

with a silylating agent or for preparing a compound of Formula II':

comprising contacting a compound of the Formula I' :

with a silylating reagent

wherein

R is independently selected from the group consisting of hydrogen, optionally substituted C_{M S} alkyl, optionally substituted C₃-₁₀ cycloalkyl, optionally substituted

C₃-!o cycloalkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl;

R¹ is hydrogen or optionally substituted C_M8 alkyl, optionally substituted C₃-₁₀ cycloalkyl, optionally substituted C₃-_]0 cycloalkenyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;

X is selected from the group consisting of a bond and a linker element -X^!-X²-X³-;

X^I is attached to the amidine forming moiety and is independently selected from the group consisting of

-(CR¹²R¹³)_Z, -(CR¹² =CR¹³)_Z-, and -(C≡C)_Z-; X² andX³- are each independently selected from the group consisting of -

(CR¹²R¹³)_Z-,

-(CR¹² =CR¹³)_Z<., -(C≡C)_Z.», -O-, -NR¹¹-, -CONR¹¹-, -NRⁿCO-, -S-, -SO-, -SO₂-, -

NRⁿSO₂- , and -SO₂NRⁿ, provided that, if one of X² and X³ is a selected from the group consisting of -O-, -NR¹¹-, -S-, -SO-, and -SO₂-, then the other remaining X²or

X³ is selected from the group consisting of -(CR¹²R¹³)_Z., -(CR¹²=CR¹³)_Z-, -(C=C)_Z-; z is independently 1 to 18; z'is independently 0 to 18; z" and z'" are each independently 0 to 3;

R¹¹ ,R¹² , andR¹³ are each independently selected from the group consisting of hydrogen, optionally substituted C ₈ alkyl, optionally substituted C₃.₁₀ cycloalkyl, optionally substituted C₃-₁₀ cycloalkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl;

Y is a a bond and a linker element -X'-X²-X³-;

X¹ is attached to the amidine forming moiety and is independently selected from the group consisting of -(CR¹²R¹³)_Z, -(CR¹² =CR¹³)_Z», and -(C_≡C)_Z-; provided that one selected from the group consisting of X¹, X² andX³, which is attached to the amidine moiety is selected from the group consisting of -(CR¹²R¹³)_Z; R , R , R , R , R , R , R and R are each independently selected from the group consisting of hydrogen, optionally substituted C _O alkyl, optionally substituted C₂-₁₀ alkenyl, optionally substituted C₆-₁₀ aryl, optionally substituted C₃-₁₀ cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted bicyclic; or

Two substituents which are attached to the same carbon atom are selected from the group consisting of R² and R³, R⁴ and R⁵, R⁶ and R⁷, and R⁸ and R⁹, together with the carbon atom to which they are both attached combine to form a spirocarbocyclic ring, and each of the remaining R , R , R , R , R , R , R , and R are hydrogen or one of R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ combines with another of R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ which is a substituent on an adjacent carbon atom, to optionally form a bond;

R¹⁰ is hydrogen or an amino protecting group; provided that when Formula II is a group of the formula:

are each independently selected from the group consisting of hydrogen and C s alkyl; or;

Rl9 and R21 optionally together form a bond and R20 and R22 are each independently hydrogen or Cj.g alkyl; or Rl9 and R21 optionally combine together with the carbon atoms to which they are attached form a 03.7 carbocyclic ring and R 0 and R 2 are each independently hydrogen or Cj_g alkyl; or

Rl9 and R20 together with the carbon atom to which they are attached optionally combine to form a 03.7 spirocarbocyclic ring and R21 and R22 are independently hydrogen or Cj.g alkyl; or

R2 and R22 together with the carbon atom to which they are attached optionally combine to form a 03.7 spirocarbocyclic and R 9 and R 0 are independently hydrogen or £\ o alkyl; then R cannot be

Y is -O-, -S-, or -NR⁸*-; Y' is -O- or -S-;

R6* and R^* are independently hydrogen, C^.g alkyl, C3.7 cycloalkyl, C_j.g alkoxy, C^.g alkylthio, halo Cj.g alkylthio, Cj. alkylsulfinyl, C^. alkylsulfonyl, C3-.7 cycloalkoxy, aryl-C^.g alkoxy, halo, halo-C^_g alkyl, halo- C^.g alkoxy, nitro,

-NR¹⁰*R^π*, -CONR^R^{1 1}*, aryl C g alkyl, optionally substituted heterocyclyl, optionally substituted phenyl, optionally substituted naphthyl, optionally halo substituted acylamino, cyano, hydroxy, COR 12 _? halo Cj.g alkylsulfinyl, or halo C\_ g alkylsulfonyl, or alkoxyalkyl of the formula

CH₃(CH₂)_p-O-(CH2)_q-O-; where p is 0, 1, 2, 3, or 4; and q is 1, 2, 3, 4, or 5;

Rl2 is Cj. alkyl or optionally substituted phenyl;

R⁸* is hydrogen, C^.g alkyl, halo-Cj.g alkyl, optionally substituted phenyl, optionally substituted heterocyclyl, COO C^.g alkyl, optionally substituted COaryl, COCι_g alkyl, SO2Ci_g alkyl, optionally substituted SO aryl, optionally substituted phenyl-Ci.g alkyl, CH₃(CH2)p-O-(CH₂)_q-O-;

R9* is hydrogen, halo, C^.g alkyl, halo Cj.g alkyl, C^.g alkylthio, halo C\_ g alkylthio, C3-.7 cycloalkylthio, optionally substituted arylthio or heteroarylthio, C\_ g alkoxy, C3-.7 cycloalkoxy, optionally substituted aryloxy , optionally substituted heteroaryloxy, or optionally substituted aryl or heteroaryl, 03, cycloalkyl, halo C3.7 cycloalkyl, C3.7 cycloalkenyl, cyano, COORl°*, CONR1°*RH* or NR10*R11 *, C2-.6 alkenyl, optionally substituted heterocyclyl, optionally substituted aryl C^-.g alkyl, optionally substituted heteroaryl Cι_g alkyl in which the alkyl group can be substituted by hydroxy, or C^_g alkyl substituted by hydroxy;

RIO and RI 1* are independently hydrogen, Cj_g alkyl, optionally substituted aryl Cj.g alkyl, optionally substituted phenyl, or Rl" and R 1* together with the nitrogen atom to which they are attached may combine to form a ring with up to six carbon atoms which optionally may be substituted with up to two Cj.g alkyl groups or one carbon atom may be replaced by oxygen or sulfur; Rl4 and Rl6 are independently hydrogen, halo, Cχ_g alkyl, 03.7 cycloalkyl, C3.7 cycloalkoxy, 03.7 cycloalkylCi.g alkoxy, halo-Cj.g alkyl, halo-Cj.g alkoxy, Cχ_g alkoxy, carbo(C₁-₈)alkoxy, optionally substituted aryl, or optionally substituted heteroaryl;

Rl5 and Rl are independently hydrogen, halo, Cj.g alkoxy, C3-.7- cycloalkyl, C3.7 cycloalkylCi.g alkoxy, Cj.g alkyl, 03.7 cycloalkoxy, hydroxy, halo Cj_g alkoxy, carbo(C₁-₈)alkoxy, optionally substituted phenyl, optionally substituted phenyl-Cj.g alkyl, optionally substituted phenyloxy, optionally substituted phenyl-Cι_g alkoxy, (tetrahydropyran-2-yl)methoxy, C^.g alkyl-S(O)_m-, optionally substituted aryl-Ci .g alkyl-S(O)_m-, CH₃(CH2)p-Zl-(CH2)_q-Z2-, or Z³-(CH₂)q'-Z -; q' is 0,1,2,3,4, or 5; m' is 0, 1, or 2; and

Zl and Z2 are independently a bond, O, S, SO, SO2, sulphoximino, or

NRl0*_;

7? is hydroxy, protected hydroxy, NRIO* R! 1*, protected amino, SH or protected SH.