Field of the Invention The present invention relates to a novel processes for the preparation of substituted tetralin and substituted indane derivatives. The substituted tetralin and substituted indane derivatives are PPAR alpha agonists, useful for elevating serum levels of high density lipoproteins (HDL), improving levels of intermediate density lipoproteins (IDL), and lowering serum levels of triglycerides, low density lipoproteins (LDL), atherogenic molecules, and/or free fatty acids (FFA). The substituted tetralin and substituted indane compounds are further useful in treating hypertriglyceridemia, raising levels of HDL, lowering levels of LDL, and/or lowering total cholesterol. The present invention is further directed to novel processes for the preparation of intermediates in the preparation of the substituted tetralin and substituted indane derivatives.

Summary of the Invention The present invention is directed to novel processes for the preparation of substituted tetralin and substituted indane derivatives. The substituted tetralin and substituted indane derivatives and their use for the treatment of PPAR alpha-mediated diseases including, but not limited to dyslipidemia, cardiovascular disorders, impaired glucose tolerance, hyperinsulinemia, hyperglycemia, insulin resistance, early, intermediate or late Type Il diabetes (NIDDM), complications thereof and / or Syndrome X are disclosed in U.S. Patent Application 10/688,380, filed October 17, 2003, U.S. Patent Application 10/688,379, filed October 17, 2003 and U.S. Patent Application 10/688,572 filed October 17, 2003, which are incorporated by reference herein in their entirety.

The present invention is directed to a process for the preparation of compounds of formula (L) wherein Q is selected from the group consisting of OH1 OPg2, NH2 and N(Pg3Pg4); wherein Pg2 is a carboxylic acid protecting group; and wherein Pg3 and Pg4 are each independently selected from hydrogen, Ci-8alkyl, C3- scycloalkyl or aryl; or Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3_ioheteroaryl or C3-i0non-aromatic heterocyclic;

each of Ri and R2 is independently H, C-i-βalkyl, (CH2)mNRaRb. (CH2)mOR8j (CH2V1NH(CO)R8 or (CH2)mCO2R8; wherein each of Ra, Rb, and R8 is independently H or Ci-6alkyl; and m is an integer from 1 to 6; alternatively, Ri and R2 are taken together with the carbon atom to which they are attached to form a C3-7cycloalkyl;

n is an integer from 1 to 2; X is S; provided that when n is 1 , X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 position;

R3 is H, C-ι-3alkoxy, Ci-3alkylthio, halo, Ci-6alkyl, NR9R10, NHCOR10, CONHR10 or COOR10; and R3 is ortho or meta to X; provided that R3 is other than CF3; each Rg and R10 is independently Chalky!; R4 is H or -(Ci-5straight chain aikylene)Ri5; wherein R15 is H, C1-7alkyl, [di(Ci-2alkyl)amino](Ci-6alkylene)-, Ci-6alkoxy, C3-7alkenyl or C3-8alkynyl; wherein R4 has no more than 9 carbon atoms; alternatively, R4 is -(straight chain Ci-5alkylene)Ri6; wherein R16 is C3- 6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;

wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl1 Br, I, amino, methyl, ethyl, hydroxy or methoxy; comprising

reacting a compound of formula (III), to yield the corresponding compound of formula (IV), wherein Pg1 is a nitrogen protecting group which is inefrfo~CISO3Hr

reacting the compound of formula (IV) with a suitably substituted compound of formula (V) wherein R4a is R4 other than hydrogen and wherein J is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (Vl); and then reacting the compound of formula (Vl) with CISO3H, to yield the corresponding compound of formula (VII); alternatively, reacting the compound of formula (IV) with CISO3H, to yield the corresponding compound of formula (VII) wherein R4 is hydrogen;

reacting the compound of formula (VII) with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII), to yield a mixture of the corresponding compound of formula (VIII) and the corresponding compound of formula (IX); (VIII) (IX)

(Xl) reacting the compound of formula (VIII), isolated or in a mixture with the compound of formula (IX), with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (Xl); alternatively, reacting the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII), with a reducing agent capable of reducing the disulfide on compound of formula (IX), to yield the corresponding compound of formula (VIII); and then reacting the compound of formula (VIII) with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (Xl);

(Xl) (L) reacting the compound of formula (Xl), to yield the corresponding compound of formula (L).

The present invention is further directed to a process for the preparation of compounds of formula (L)

wherein Q is selected from the group consisting of OH, OPg2, NH2 and N(Pg3Pg4); wherein Pg2 is a carboxylic acid protecting group; and wherein Pg3 and Pg4 are each independently selected from hydrogen, Ci-8alkyl, C3- scycloalkyl or aryl; or Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3-i0heteroaryl or C3-i0non-aromatic heterocyclic;

each of Ri and R2 is independently H, Ci_6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8 or (CH2)mCO2R8; wherein each of Ra, Rb, and R8 is independently H or C-ι-6alkyl; and m is an integer from 1 to 6; alternatively, Ri and R2 are taken together with the carbon atom to which they are attached to form a C3-7cycloalkyl;

n is an integer from 1 to 2; X is S; provided that when n is 1 , X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 position;

R3 is H, C1-3alkoxy, Ci-3alkylthio, halo, C1-6alkyl, NR9R10, NHCOR10, CONHR10, or COOR10; and R3 is ortho or meta to X; provided that R3 is other than CF3; each R9 and R10 is independently Chalky!;

R4 is H or -(C-i-δStraight chain alkylene)R-i5; wherein R15 is H, Chalky!, [di(C1-2alkyl)amino](C1-6alkylene)-, (C-i-salkoxyacylXC-i-βalkylene)-, C-i-βalkoxy, C3-7alkenyl or C3-8alkynyl; wherein R4 has no more than 9 carbon atoms; alternatively, R4 is -(straight chain C1-5alkylene)R16; wherein R-iβ is C3- 6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;

wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy; comprising

reacting a compound of formula (III), to yield the corresponding compound of formula (IV), wherein Pg1 is a nitrogen protecting group which is inert to CISO3H; reacting the compound of formula (IV) with a suitably substituted compound of formula (V) wherein R4a is R4 other than hydrogen and wherein J is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (Vl); and then reacting the compound of formula (Vl) with CISO3H, to yield the corresponding compound of formula (VII); alternatively, reacting the compound of formula (IV) with CISO3H, to yield the corresponding compound of formula (VII) wherein R4 is hydrogen;

/pgi

reacting the compound of formula (VII) with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII), to yield a mixture of the corresponding compound of formula (VIII) and the corresponding compound of formula (IX);

(XlIl) de-protecting the compound of formula (VIII), isolated or in a mixture with the compound of formula (IX), to yield the corresponding compound of formula (XIII); alternatively, de-protecting the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII), to yield a corresponding compound of formula (XII); and then reducing the compound of formula (XII) with a reducing agent capable of reducing the disulfide on compound of formula (XII), to yield the corresponding compound of formula (XIII); alternatively still, reacting the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII), with a reducing agent capable of reducing the disulfide on compound of formula (IX), to yield the corresponding compound of formula (VIII); and then de-protecting the compound of formula (VIII), to yield the corresponding compound of formula (XIII);

(L) reacting the compound of (XIII) with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (L).

The present invention is further directed to a process for the preparation of compounds of formula (L)

wherein Q is selected from the group consisting of OH, OPg2, NH2 and N(Pg3Pg4); wherein Pg2 is a carboxylic acid protecting group; and wherein Pg3 and Pg4 are each independently selected from hydrogen, Ci-8alkyl, C3- scycloalkyl or aryl; or Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3-ioheteroaryl or C3-10non-aromatic heterocyclic;

each of Ri and R2 is independently H, Ci_6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8 or (CH2)mCO2R8; wherein each of Ra, Rb, and R8 is independently H or Chalky!; and m is an integer from 1 to 6; alternatively, Ri and R2 are taken together with the carbon atom to which they are attached to form a C3.7cycloalkyl;

n is an integer from 1 to 2; X is S; provided that when n is 1 , X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 . position;

R3 is H, Ci-3alkoxy, Ci-3alkylthio, halo, Ci-6alkyl, NR9Ri0, NHCOR10, CONHR10 or COOR10; and R3 is ortho or meta to X; provided that R3 is other than CF3; each R9 and Ri0 is independently Ci_6alkyl;

R4 is -(Ci-5straight chain alkylene)Ris; wherein R15 is H, Ci-7alkyl, [di(Ci_ 2alkyl)amino](C1-6alkylene)-, (Ci-3alkoxyacyl)(Ci-6alkylene)-, Ci_6alkoxy, C3- 7alkenyl or C3-salkynyl; wherein R4 has no more than 9 carbon atoms; alternatively, R4 is -(straight chain Ci-5alkylene)Ri6; wherein Ri6 is C3- 6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;

wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy; comprising

reacting a compound of formula (III), to yield the corresponding compound of formula (IV), wherein Pg1 is a nitrogen protecting group which is inert to CISO3H;

reacting the compound of formula (IV) with CISO3H, to yield the corresponding compound of formula (Vila);

(Villa) reacting the compound of formula (Vila) with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (Vila), to yield a mixture of the corresponding compound of formula (Villa) and the corresponding compound of formula (IXa);

de-protecting the compound of formula (Villa), isolated or in a mixture with the compound of formula (IXa), to yield the corresponding compound of formula (XIIIa); and then reacting the compound of formula (XIIIa) with a suitably substituted compound of formula (X), wherein W is Cl, Br or I, in the presence of a base, to yield the corresponding compound of formula (La); alternatively, reacting the compound of formula (IXa), isolated or in a mixture with the compound of formula (Villa), with a reducing agent capable of reducing the disulfide on the compound of formula (IXa), to yield the corresponding compound of formula (Villa); then reacting the compound of formula (Villa) with a suitably substituted compound of formula (X) wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (XIa); and then reacting the compound of formula (XIa), to yield the corresponding compound of formula (La); alternatively still, de-protecting the compound of formula (IXa), isolated or in a mixture with the compound of formula (Villa), to yield the corresponding compound of formula (XIIa); then reacting the compound of formula (XIIa) with a reducing agent capable of reducing the disulfide on the compound of formula (XIIa), to yield the corresponding compound of formula (XIIIa); and then reacting the compound of formula (XIIIa) with a suitably substituted compound of formula (X) wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (La);

reacting the compound of formula (La) with a suitably substituted compound of formula (V) wherein R4a is R4 other than hydrogen and wherein J is Br, Cl or I, to yield the corresponding compound of formula (Lb); alternatively, reacting the compound of formula (La) with a suitably substituted acylating agent capable of attaching an -C(O)-R4b group onto the nitrogen of the compound of formula (La), wherein R4b is selected from (Ci-4 straight chain alkylene)Ri5 or (straight chain Ci-4alkylene)Ri6, in the presence of a base, to yield the corresponding compound of formula (XVIII); and then reacting the compound of formula (XVIII) with a reducing agent capable of reducing the amide on the compound of formula (XVIII), to yield the corresponding compound of formula (Lb).

The present invention is further directed to a process for the preparation of compounds of formula (Lc)

wherein Q is selected from the group consisting of OH, OPg2, NH2 and N(Pg3Pg4); wherein Pg2 is a carboxylic acid protecting group; and wherein Pg3 and Pg4 are each independently selected from hydrogen, Ci-8alkyl, C3- 8cycloalkyl or aryl; or Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3-ioheteroaryl or C3-1onon-aromatic heterocyclic;

each of Ri and R2 is independently H, Ci-6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8 or (CH2)mCO2R8; wherein each of R3, Rb, and R8 is independently H or Ci-6alkyl; and m is an integer from 1 to 6; alternatively, Ri and R2 are taken together with the carbon atom to which they are attached to form a C3-7cycloalkyl;

n is an integer from 1 to 2; X is S; provided that when n is 1 , X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 position;

R3 is H, C1-3alkoxy, Ci-3alkylthio, halo, C1-6alkyl, NR9Rio> NHCORi0, CONHR10 or COORi0; and R3 is ortho or meta to X; provided that R3 is other than CF3; each Rg and Ri0 is independently Chalky!;

R4b is -(Ci-4straight chain alkylene)Ri5; wherein Ri5 is H, Ci-7alkyl, [di(Ci. 2alkyl)amino](Ci-6alkyIene)-, (Ci-3alkoxyacyl)(Ci-6alkylene)-, Ci-6alkoxy, C3. 7alkenyl or C3-8alkynyl; wherein R4b has no more than 8 carbon atoms; alternatively, R4b is -(straight chain Ci-4alkylene)Ri6; wherein Riβ is C3- 6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;

wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy; comprising

reacting a suitably substituted compound of formula (III) with a suitably substituted acylating agent capable of attaching an -C(O)-R4b group onto the nitrogen of the compound of formula (III), in the presence of a base, to yield the corresponding compound of formula (XIV);

reacting the compound of formula (XIV) with CISO3H, to yield the corresponding compound of formula (XV);

reacting the compound of formula (XV) with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (XV), to yield a mixture of the corresponding compound of formula (XVI) and the corresponding compound of formula (XVII);

(XIlIb)

reacting the compound of formula (XVI), isolated or in a mixture with the compound of formula (XVII), with a reducing agent capable of reducing the amide on the compound of formula (XVI), to yield the corresponding compound of formula (XIIIb); alternatively, reacting the compound of formula (XVII), isolated or in a mixture with the compound of formula (XVI), with a reducing agent capable of reducing the amide and the disulfide on the compound of formula (XVII), to yield the corresponding compound of formula (XIIIb);

(Lc) reacting the compound of formula (XIIIb) with a suitably substituted compound of formula (X) wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (Lc).

The present invention is further directed to a process for the preparation of a compound of formula (Lc)

wherein Q is selected from the group consisting of OH, OPg2, NH2 and N(Pg3Pg4); wherein Pg2 is a carboxylic acid protecting group; and wherein Pg3 and Pg4 are each independently selected from hydrogen, Ci-8alkyl, C3- scycloalkyl or aryl; or Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3-i0heteroaryl or C3-ionon-aromatic heterocyclic;

each of Ri and R2 is independently H, Ci-6alkyl, (CH2)mNRaRb, (CH2)mOR8, (CH2)mNH(CO)R8 or (CH2)mCO2R8; wherein each of R3, Rb, and R8 is independently H or Ci-6alkyl; and m is an integer from 1 to 6; alternatively, R1 and R2 are taken together with the carbon atom to which they are attached to form a C3-7cycloalkyl;

n is an integer from 1 to 2; X is S; provided that when n is 1 , X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 position;

R3 is H, Ci-3alkoxy, C1-3alkylthio, halo, Ci-6alkyl, NR9Ri0, NHCOR10, CONHR10 or COOR10; and R3 is ortho or meta to X; provided that R3 is other than CF3; each Rg and Ri0 is independently Ci-6alkyl;

R4b is -(Ci-4straight chain alkylene)Ri5; wherein Ri5 is H, C1-7alkyl, [di(Ci_ 2alkyl)amino](Ci-6alkylene)-, (Ci-3alkoxyacyl)(Ci-6alkylene)-, Ci-6alkoxy, C3- 7alkenyl or C3-8alkynyl; wherein R4b has no more than 8 carbon atoms; alternatively, R4b is -(straight chain Ci-4alkylene)R-i6; wherein Ri6 is C3- 6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;

wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy; comprising

reacting a suitably substituted compound of formula (III) with a suitably substituted acylating agent capable of attaching an -C(O)-R4b group onto the nitrogen of the compound of formula (III), in the presence of a base, to yield the corresponding compound of formula (XlV);

reacting the compound of formula (XIV) with CISO3H, to yield the corresponding compound of formula (XV);

(XIIIb)

reacting the compound of formula (XV) with a reducing agent capable of reducing the chlorosulfonyl group and the amide group on the compound of formula (XV), to yield the corresponding compound of formula (XIIIb);

(Lc) reacting the compound of formula (XIIIb) with a suitably substituted compound of formula (X) wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (Lc).

In an embodiment of the present invention is a process for the preparation of a compound of formula (Ld)

wherein Q3 is OH or OPg2, wherein Pg2 is a carboxylic acid protecting group. In another embodiment of the present invention is a process for the preparation of a compound of formula (Ld) wherein Q3 is OPg2 wherein Pg2 is a carboxylic acid protecting group.

The present invention is further directed to a novel process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt, C-i.6 ester or C-ι-6 amide thereof, wherein each of Ri and R2 is independently H, Ci-6alkyl, (CH2ViNRaRb, (CH2)m0R8, (CH2)mNH(CO)R8 or (CH2)mCO2R8; wherein each of R3, Rb, and R8 is independently H or Chalky!; and m is an integer from 1 to 6; alternatively, Ri and R2 are taken together with the carbon atom to which they are attached to form a C3-7cycloalkyl;

n is an integer from 1 to 2; X is S; provided that when n is 1 , X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R3 is other than hydrogen and bound at the 7 position;

R3 is H, C1-3alkoxy, C1-3alkylthio, halo, Ci-6alkyl, NR9R10, NHCOR10, CONHR10 or COOR10; and R3 is ortho or meta to X; provided that R3 is other than CF3; each Rg and Ri0 is independently C1-6alkyl;

R4 is H or -(C-i-βstraight chain alkylene)Ri5; wherein R1S is H, Ci-7alkyl, [di(C1-2alkyl)amino](Ci-6alkylene)-, (Ci-3alkoxyacyl)(Ci-6alkylene)-, Ci-6alkoxy, C3-7alkenyl or C3-8alkynyl; wherein R4 has no more than 9 carbon atoms; alternatively, R4 is -(straight chain Ci-5alkylene)R16; wherein R16 is C3- 6cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;

c is an integer from 0 to 1 ;

each of R5 and R7 is independently selected from H, Ci-6alkyl, halo, cyano, nitro, CORn, COORn, C-i^alkoxy, Ci-4alkylthio, hydroxy, phenyl, NR11R12 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S; R6 is selected from Ci-6alkyl, halo, cyano, nitro, COR13, COOR13, Ci- 4alkoxy, Ci^alkylthio, hydroxy, phenyl, NR13R14 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;

alternatively, R5 and Re or R6 and R7 may be taken together to be a bivalent moiety, saturated or unsaturated, selected from C3-4alkylene (for example, -(CH2)3- or -(CHb)-I-), C3-4alkenylene (for example, -CH=CH-CH2- or -CH=CH-CH=CH-) or (CHi.2)pN(CHi.2)q; p is an integer from O to 2 and q is an integer from 1 to 3; wherein the sum (p + q) is at least 2;

each R-i 1, R12, R13 and R14 is independently H or Chalky!;

wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I1 amino, methyl, ethyl, hydroxy or methoxy; comprising

reacting a compound of formula (L), wherein Q is selected from the group consisting of OH, OPg2, NH2 and N(Pg3Pg4); wherein Pg2 is a carboxylic acid protecting group; and wherein Pg3 and Pg4 are each independently selected from hydrogen, Chalky!, C3-8cycloalkyl or aryl; or Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3- ioheteroaryl or C3-ionon-aromatic heterocyclic; to yield the corresponding compound of formula (I).

In an embodiment of the present invention is a process for the preparation of a compound of formula (II)

also known as 2-[[2-[ethyl[[[4- (trifluoromethoxy)phenyl]amino]carbonyl]amino]-2,3-dihydro-1 H-inden-5- yl]thio]-2-methyl-propanoic acid or 2-{2-[1-ethyl-3-(4-trifluoromethoxy-phenyl)- ureido]-indan-5-ylsulfanyl}-2-methyl-propionic acid. In another embodiment of the present invention is a process for the preparation of a compound of formula (Ha)

also known as 2-[[(2R)-2~[ethyl[[[4- (trifluoromethoxy)phenyl]amino]carbonyl]amino]-2,3-dihydro-1 H-inden-5- yl]thio]-2~methyl-propanoic acid or 2-{(2R)-[1-ethyl-3-(4-trifluoromethoxy- phenyl)-ureido]-indan-5-ylsulfanyl}-2-methyl-propionic acid.

The present invention is further directed to a process for the preparation of the compound of formula (Le)

wherein Qb is selected from the group consisting of d-βalkoxy, wherein the Ci-6alkoxy is not substituted with amino; comprising

(a) reacting a compound of formula (Ld) with (S)-2-(4- hydroxyphenoxy)propionic acid, in an alcohol; or in acetone, at a temperature in the range of from about 35°C to about O0C; to yield the corresponding (R1S) diastereomeric salt, the compound of formula (XX);

(b) reacting the (R1S) diastereomeric salt, the compound of formula (XX), with an inorganic base, to yield the corresponding compound of formula (Le).

The present invention is further directed to a process for the preparation of the compound of formula (Le)

wherein Qb is selected from the group consisting of Ci-6alkoxy, wherein the Ci-βalkoxy is not substituted with amino; comprising

(a) reacting a compound of formula (Ld) with (R)-2-(4- hydroxyphenoxy)propionic acid, in acetone, at a temperature greater than about 35°C, preferably at a temperature greater than about 45°C; or in THF at about room temperature, to yield the corresponding (R1R) diastereomeric salt, the compound of formula (XXI).

(b) reacting the (R,R) diastereomeric salt, the compound of formula (XXI) with an inorganic base, to yield the corresponding compound of formula (Le).

The present invention is further directed to a process for the preparation of the compound of formula (Lf)

wherein Qb is selected from the group consisting of C-i-βalkoxy, wherein the C-ι-6alkoxy is not substituted with amino; comprising

(a) reacting a compound of formula (Ld) with (S)-2-(4- hydroxyphenoxy)propionic acid, in acetone, at a temperature greater than about 35°C, preferably at a temperature greater than about 45°C; or in THF at about room temperature; to yield the corresponding (S1S) diastereomeric salt, the compound of formula (XXII).

(b) reacting the (S, S) diastereomeric salt, the compound of formula (XXI) with an inorganic base, to yield the corresponding compound of formula (Lf).

The present invention is further directed to a process for the preparation of the compound of formula (Lf)

wherein Qb is selected from the group consisting of C-ι-6alkoxy, wherein

the C-ι-6alkoxy is not substituted with amino; comprising

(a) reacting a compound of formula (Ld) with (R)-2-(4-

hydroxyphenoxy)propionic acid, in an alcohol; or in acetone, at a temperature

in the range of from about 350C to about 0°C; to yield the corresponding (S1R)

diastereomeric salt, the compound of formula (XXIII);

(b) reacting the (S, R) diastereomeric salt, the compound of formula (XXIII) with an inorganic base, to yield the corresponding compound of formula (Lf).

The present invention is further directed to a novel crystalline salt of the compound of formula (Ha), more specifically, an N,N'-dibenzylethylenediamine (benzathine) salt of the compound of formula (Ha). The present invention is further directed to an N,N'-dibenzylethylenediamine salt of the compound of formula (Ha) wherein the ratio of the compound of formula (Ha) to the N1N'- dibenzylethylenediamine is 1 :1. The present invention is further directed to a process for the preparation of the benzathine salt of the compound of formula (Ha).

The present invention is further directed to a compound prepared according to any of the processes described herein.

Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound prepared according to any of the processes described herein. An illustration of the invention is a pharmaceutical composition made by mixing a compound prepared according to any of the processes described herein and a pharmaceutically acceptable carrier. Illustrating the invention is a process for making a pharmaceutical composition comprising mixing a compound prepared according to any of the processes described herein and a pharmaceutically acceptable carrier.

In one embodiment, the pharmaceutical composition comprises the compound:

or a pharmaceutically acceptable salt, Ci-6 ester or Ci-6 amide thereof.

In another embodiment, the pharmaceutical composition comprises the compound:

Exemplifying the present invention are methods of treating a PPAR alpha-mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound prepared according to any of the processes described herein or a pharmaceutical composition as described above. Further exemplifying the present invention are methods of elevating serum levels of high density lipoproteins (HDL), improving levels of intermediate density lipoproteins (IDL), lowering serum levels of triglycerides, low density lipoproteins (LDL), atherogenic molecules, and/or free fatty acids (FFA), treating hypertriglyceridemia, raising levels of HDL, lowering levels of LDL, and/or lowering total cholesterol, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound prepared according to any of the processes described herein or a pharmaceutical composition as described above.

Further exemplifying the invention are methods for treating dyslipidemia, cardiovascular disorders, impaired glucose tolerance, hyperinsulinemia, hyperglycemia, insulin resistance, early, intermediate or late Type Il diabetes (NIDDM), complications thereof, or Syndrome X, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound prepared according to any of the processes described herein or a pharmaceutical composition as described above.

Further exemplifying the invention are methods for the treatment, prevention, or for inhibiting the progression of one or more of the following conditions or diseases: phase I hyperlipidemia; pre-clinical hyperlipidemia; phase Il hyperlipidemia; hypertension; CAD (coronary artery disease); coronary heart disease; hypertriglyceridemia; lowering serum levels of low-density -lipoproteins (LDL), IDL, and/or small-density LDL and other atherogenic molecules, or molecules that cause atherosclerotic complications, thereby reducing cardiovascular complications; elevating serum levels of high-density lipoproteins (HDL); lowering serum levels of triglycerides, LDL, and/or free fatty acids; and/or lowering FPG/HbA1c.

Another example of the invention is the use of a compound prepared according to any of the processes described herein in the preparation of a medicament for treating (a) dyslipidemia, (b) cardiovascular disorders, (c) impaired glucose tolerance, (d) hyperinsulinemia, (e) hyperglycemia, (f) insulin resistance, (g) early Type Il diabetes (NIDDM), (h) intermediate Type Il diabetes (NIDDM), (i) late Type Il diabetes (NIDDM), (j) complications of Type Il diabetes or (k) Syndrome X, in a subject in need thereof. Detailed Description of the Invention "Alkyl" includes optionally substituted straight chain and branched hydrocarbons with at least one hydrogen removed to form a radical group. Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, 1- methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl, octyl, and so on. As used herein, alkyl also includes cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

"Alkenyl" includes optionally substituted straight chain and branched hydrocarbon radicals as above with at least one carbon-carbon double bond (sp2). Alkenyls include ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), isopropenyl (or 1-methylvinyl), but-1-enyl, but-2-enyl, butadienyls, pentenyls, hexa-2,4-dienyl, and so on. Hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penten-4-ynyl, are grouped as alkynyls herein. As used herein, alkenyl also includes cycloalkenyl. Cis and trans or (E) and (Z) forms are included within the invention.

"Alkynyl" includes optionally substituted straight chain and branched hydrocarbon radicals as above with at least one carbon-carbon triple bond (sp). Alkynyls include ethynyl, propynyls, butynyls, and pentynyls. Hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penten- 4-ynyl, are grouped as alkynyls herein. Alkynyl does not include cycloalkynyl.

"Alkoxy" includes an optionally substituted straight chain or branched alkyl group with a terminal oxygen linking the alkyl group to the rest of the molecule. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t- butoxy, pentoxy and so on. "Aminoalkyl", "thioalkyl", and "sulfonylalkyl" are analogous to alkoxy, replacing the terminal oxygen atom of alkoxy with, respectively, NH (or NR), S, and SO2. Heteroalkyl includes alkoxy, aminoalkyl, thioalkyl, and so on. "Aryl" includes phenyl, naphthyl, biphenylyl, tetrahydronaphthyl, indenyl, and so on, any of which may be optionally substituted. Aryl also includes arylalkyl groups such as benzyl, phenethyl, and phenylpropyl. Aryl includes a ring system containing an optionally substituted 6-membered carbocyclic aromatic ring, said system may be bicyclic, bridge, and/or fused. The system may include rings that are aromatic, or partially or completely saturated. Examples of ring systems include indenyl, pentalenyl, 1-4-dihydronaphthyl, indanyl, benzimidazolyl, benzothiophenyl, indolyl, benzofuranyl, isoquinolinyl, and so on.

"Heterocyclyl" includes optionally substituted aromatic and nonaromatic rings having carbon atoms and at least one heteroatom (O, S, N) or heteroatom moiety (SO2, CO, CONH, COO) in the ring. Unless otherwise indicated, a heterocyclic radical may have a valence connecting it to the rest of the molecule through a carbon atom, such as 3-furyl or 2-imidazolyl, or through a heteroatom, such as N-piperidyl or i-pyrazolyl. Preferably a monocyclic heterocyclyl has between 5 and 7 ring atoms, or between 5 and 6 ring atoms; there may be between 1 and 5 heteroatoms or heteroatom moieties in the ring, -and preferably between -1 and 3ror between 1 and 2. A heterocyclyl may be saturated, unsaturated, aromatic (e.g., heteroaryl), nonaromatic, or fused.

Heterocyclyl also includes fused, e.g., bicyclic, rings, such as those optionally condensed with an optionally substituted carbocyclic or heterocyclic five- or six-membered aromatic ring. For example, "heteroaryl" includes an optionally substituted six-membered heteroaromatic ring containing 1 , 2 or 3 nitrogen atoms condensed with an optionally substituted five- or six-membered carbocyclic or heterocyclic aromatic ring. Said heterocyclic five- or six- membered aromatic ring condensed with the said five- or six-membered aromatic ring may contain 1 , 2 or 3 nitrogen atoms where it is a six-membered ring, or 1 , 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur where it is a five-membered ring. Examples of heterocyclyls include thiazoylyl, furyl, thienyl, pyranyl, isobenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrirtiidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolyl, furazanyl, pyrrolidinyl, pyrrolinyl, imdazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, and morpholinyl. For example, preferred heterocyclyls or heterocyclic radicals include morpholinyl, piperazinyl, pyrrolidinyl, pyridyl, cyclohexylimino, thienyl, and more preferably, piperidyl or morpholinyl. Examples illustrating heteroaryl are thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl.

"Acyl" refers to a carbonyl moiety attached to either a hydrogen atom (i.e., a formyl group) or to an optionally substituted alkyl or alkenyl chain, or heterocyclyl.

"Halo" or "halogen" includes fluoro, chloro, bromo, and iodo, and preferably fluoro or chloro as a substituent on an alkyl group, with one or more halo-atoms, such-as-trifluoromethyl, trifluoromethoxy, trifluoromethylthio, difluoromethoxy, or fluoromethylthio.

"Alkanediyl" or "alkylene" represents straight or branched chain optionally substituted bivalent alkane radicals such as, for example, methylene, ethylene, propylene, butylene, pentylene or hexylene.

"Alkenediyl" represents, analogous to the above, straight or branched chain optionally substituted bivalent alkene radicals such as, for example, propenylene, butenylene, pentenylene or hexenylene. In such radicals, the carbon atom linking a nitrogen preferably should be saturated. "Aroyl" refers to a carbonyl moiety attached to an optionally substituted aryl or heteroaryl group, wherein aryl and heteroaryl have the definitions provided above. In particular, benzoyl is phenylcarbonyl.

As defined herein, two radicals, together with the atom(s) to which they are attached may form an optionally substituted 4- to 7-, 5 - to 7-, or a 5- to 6- membered ring carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic. Said rings may be as defined above in the Summary of the Invention section.

"Enantiomer excess" or "ee", usually expressed as a percentage, describes the excess of one enantiomer over the other. The percentage enantiomer excess, ee = 100(Xr-Xs)/(Xr+Xs), where Xr>Xs. Alternatively, ee = 100(2X-1 ), where X is the mole fraction of the dominant enantiomer in the mixture. Please note that Xr and Xs represent the mole fraction of (R)- enantiomer and (S)-enantiomer respectively in the mixture.

"Pharmaceutically acceptable salts, esters, and amides" include carboxylate salts, amino acid addition salts, esters, and amides which are within a reasonable benefit/risk ratio, pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. These salts, esters, and amides may be, for example, Ci- salkyl, C3.8cycloalkyl, aryl, C2-ioheteroaryl, or C2-ionon-aromatic heterocyclic salts, esters, and amides. Salts, free acids, and esters are more preferable than amides on the terminal carboxylate/carboxylic acid group on the left of formula (I). Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, and laurylsulfonate. These may include alkali metal and alkali earth cations such as sodium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine. See example, S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. ScL, 1977, 66:1-19 which is incorporated herein by reference. Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, primary d-βalkyl amines and secondary di(Ci-6alkyl) amines. Secondary amines include 5- or 6- membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms. Preferred amides are derived from ammonia, C-i-3alkyl primary amines, and. di(C1-2alkyl)amines. Representative pharmaceutically acceptable esters of the invention include Ci-7 aikyl, C5-7cycloalkyl, phenyl, and phenyl(C1-6)alkyl esters. Preferred esters include methyl and ethyl esters.

As used herein, all hydrocarbon radicals, whether saturated, unsaturated or aromatic, and whether or not cyclic, straight chain, or branched, and also similarly with all heterocyclic radicals, each radical includes substituted radicals of that type and monovalent, bivalent, and multivalent radicals as indicated by the context. The context will indicate that the substituent is an alkylene or hydrocarbon radical with at least two hydrogen atoms removed (bivalent) or more-hydrogen atoms removed (multivalent). • - -

Radicals or structure fragments as defined herein are understood to include substituted radicals or structure fragments. Hydrocarbyls include monovalent radicals containing carbon and hydrogen such as alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl (whether aromatic or unsaturated), as well as corresponding bivalent (or multi-valent) radicals such as alkylene, alkenylene, phenylene, and so on. Heterocarbyls include monovalent and bivalent (or multi-valent) radicals containing carbon, optionally hydrogen, and at least one heteroatom. Examples of monovalent heterocarbyls include acyl, acyloxy, alkoxyacyl, heterocyclyl, heteroaryl, aroyl, benzoyl, dialkylamino, hydroxyalkyl, and so on. Using "alkyl" as an example, "alkyl" should be understood to include substituted alkyl having one or more substitutions, such as between 1 and 5, 1 and 3, or 2 and 4 substituents. The substituents may be the same (di hydroxy, dimethyl) or different (chlorofluoro, chlorobenzyl- or aminomethyl-substituted). Examples of substituted alkyl include haloalkyl (such as fluoromethyl, chloromethyl, difluoromethyl, perchloromethyl, 2- bromoethyl, trifluoromethyl, and 3-iodocyclopentyl), hydroxyalkyl (such as 5 hydroxymethyl, hydroxyethyl, 2-hydroxypropyl), aminoalkyl (such as aminomethyl, 2-aminoethyl, 3-aminopropyl, and 2-aminopropyl), alkylalkyl, and so on. A di(Ci-6alkyl)amino group includes independently selected alkyl groups, to form, for example, methylpropylamino and isopropylmethylamino, in addition dialkylamino groups having two of the same alkyl group such as l o dimethylamino or diethylamino.

Only stable compounds are intended. For example, where there is an NR11R12 group, and R can be an alkenyl group, the double bond is at least one carbon removed from the nitrogen to avoid enamine formation. Similarly, 15 where -(CH2)p-N-(CH2)q- can be unsaturated, the appropriate hydrogen atom(s) is(are) included or omitted, as shown in -(CH2)-N=(CH)-(CH2)- or -(CH2J-NH- (CH)=(CH)-.

— Unless otherwise noted, -when naming substituents such as X and R3, 20 the following numbering of the indane and tetralin, respectively, will be applied.

As used herein, unless otherwise noted, the term "aprotic solvent" shall mean any solvent that does not yield a proton. Suitable examples include, but 25 are not limited to DMF, dioxane, THF, acetonitrile, pyridine, dichloroethane, dichloromethane, MTBE, toluene, and the like.

As used herein, unless otherwise noted, the term "nitrogen protecting group" shall mean a group which may be attached to a nitrogen atom to protect said nitrogen atom from participating in a reaction and which may be readily removed following the reaction. Suitable nitrogen protecting groups include, but are not limited to carbamates - groups of the formula -C(O)O-R wherein R is for example methyl, ethyl, t-butyl, benzyl, phenylethyl, CH2=CH-CH2-, and 5 the like; amides - groups of the formula -C(O)-R' wherein R' is for example methyl, phenyl, trifluoromethyl, and the like; N-sulfonyl derivatives - groups of the formula -SO2-R" wherein R" is for example tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogen protecting groups may be found in texts such o as T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

As used herein, unless otherwise noted, the term "carboxylic acid protecting group" shall mean a group which may be attached to -C(O)O- portion 5 of the carboxylic acid to protect said carboxylic acid from participating in a reaction and which may be readily removed following the reaction. Suitable carboxylic acid protecting groups include, but are not limited Ci-7alkyl, Cs- 7cycloalkyl, phenyl, phenylC-i^alkyl, and the like. Other suitable carboxylic acid protecting groups may be found in texts such as T.W. Greene & P.G.M. Wuts, o Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

In the process for the preparation of the compounds of formula (I), application of the present invention to a mixture of enantiomers of the compound of formula (L), substantially free of the S enantiomer, will result in the production 5 of a mixture of enantiomers of formula (I), substantially free of the S enantiomer. Similarly, in the process for the preparation of the compounds of formula (I), application of the present invention to a mixture of enantiomers of formula (L), substantially free of the R enantiomer, will result in the production of a mixture of enantiomers of formula (I), substantially free of the R enantiomer. Preferably, the o enantiomeric excess of the desired enantiomer of formula (I) is at least about 90% ee, more preferably, at least about 96% ee, most preferably, about 99% ee. To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term "about". It is understood that whether the term "about" is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value.

One skilled in the art will recognize that wherein a reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.

Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

With reference to substituents, the term "independently" means that when more than one of such substituents is possible, such substituents may be the same or different from each other.

When a particular group is "substituted" (e.g., phenyl, aryl, aralkyl, heteroaryl), that group may have one or more substituents, preferably from one to three substituents, more preferably from one to two substituents, independently selected from the list of substituents.

The term "subject" as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

Abbreviations used in the specification, particularly the Schemes and Examples, are as follows:

In an embodiment of the present invention, in the compound of formula (I), (a) one of Ri and R2 is methyl or ethyl; (b) each of Ri and R2 is methyl; (c) Ri and R2 taken together are cyclobutyl or cyclopentyl; (d) R3 is H; (e) R4 is H or C2-7alkyl; (e) R4 is H or C2-5alkyl; (f) R4 is ethyl; (g) R4 is H; (h) n is 1 ; (i) n is 2; (j) at least one of R5 and R7 is H; (k) R6 is Ci^alkyl, halomethoxy, or halothiomethoxy (i.e -S-(halomethyl)); (I) R6 is t-butyl, isopropyl, trifluoromethyl, trifluoromethoxy, trifluorothiomethoxy (i.e. -S-CF3), difluoromethoxy, or dimethylamino; (m) R3 is H, R4 is C2-7alkyl; (n) R4 is C2-5alkyl; (o) Re is cyclopropylmethyl, isopropyl, isobutyl, methylethylamino, or diethylamino; (p) the (S) enantiomer at the C-2 position on the indane or tetralin; (q) the (R) entantiomer at the C-2 position on the indane or tetralin; (r) where R15 is C-1-7 alkyl, [di(C 1-2 alkyl)amino](Ci-6alkylene), (C-i-salkoxyacylXCi-ealkylene), C-i. 6alkoxy, C3-7alkenyl, or C3-8alkynyl; (s) R6 is trifluoromethylthio or trifluoromethoxy; or (t) any combination of the above.

In another embodiment of the present invention, the compound of formula (I) selected from the group consisting of 2-{6-[1-Ethyl-3-(4- trifluoromethoxyphenyl)ureido]-3-methoxy-5,6,7,8-tetrahydron aphthalen-2- ylsulfanyl}-2-methylpropionic acid; 2-{6-[1 -Ethyl-3-(4- trifluoromethoxyphenyl)ureido]-3-fluoro-5,6,7,8-tetrahydrona phthalen-2- ylsulfanyl}-2-methylpropionic acid; 2-{6-[1 -Ethyl-3-(4- -tr-ifluoromethoxyphenyl)ureido]-3-chloro-5,6,7,8-tetrahydro naphthalen-2- ylsu!fanyl}-2-methylpropionic acid; 2-{6-[1-Ethyl-3-(4- trifluoromethoxyphenyl)ureido]-3-bromo-5,6,7,8-tetrahydronap hthalen-2- ylsulfanyl}-2-methylpropionic acid; 2-{6-[1-Ethyl-3-(4- trifluoromethoxyphenyl)ureido]-3-methyl-5,6,7,8-tetrahydrona phthalen-2- ylsulfanyl}-2-methylpropionic acid; 2-{6-[1 -Ethyl-3-(4- trifluoromethoxyphenyl)ureido]-3-trifluoromethoxy-5, 6,7,8- tetrahydronaphthalen-2-ylsulfaηyl}-2-methylpropionic acid; 2-{6-[1 -Ethyl-3-(4- hydroxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2-ylsulfa nyl}-2- methylpropionic acid; 2-{6-[(4-Aminophenyl)-1 -ethyl-ureido]-5, 6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid and 2-{6-[1 -Ethyl-3- (4-trifluoromethoxyphenyl)ureido]-4-trifluoromethyl-5, 6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid. In another embodiment of the present invention the compound of formula (I) selected from the group consisting of 2-{6~[1 -Ethyl-3-(4- trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen- 2-ylsulfanyl}-2- methylpropionic acid; 2-{6-[3-(4-trifluoromethoxyphenyl)ureido]-5, 6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid; 2-{2-[1 -Ethyl-3-(4- trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2-methylpr opionic acid; 2-{2- [1-Ethyl-3-(4-trifluoromethylsulfanylphenyl)ureido]indan-5-y lsulfanyl}-2- methylpropionic acid; and 2-Methyl-2-{2-[1-propyl-3-(4- trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}propionic acid.

In an embodiment of the present invention c is 0. In another embodiment of the present invention n is 1 and X is bound at the 5-position. In yet another embodiment of the present invention n is 2 and X is bound at the 6- or 7-position, preferably at the 6-position.

In an embodiment of the present invention, wherein n is 1 and R3 is hydrogen or is other than hydrogen and is bound at the 4-, 6- or 7- position, then the -X-C(Ri F^)-C(O)-Q group is bound at the 5-position. In another embodiment of the present invention, wherein n is 1 and R3 is hydrogen or is other than hydrogen and is bound at the 4-, 6- or 7- position, then the -X- C(R1R2J-C(O)-OH group is bound at the 5-position. In an embodiment of the present invention, wherein n is 1 and R3 is other than hydrogen and is bound at the 5-position, then the -X-C(Ri Ra)-C(O)- Q group is bound at the 6-position. In another embodiment of the present invention, wherein n is 1 and R3 is other than hydrogen and is bound at the 5- position, then the -X-C(Ri Ra)-C(O)-OH group is bound at the 6-position.

In an embodiment of the present invention Q is OPg2 or N(Pg3Pg4), wherein Pg2 is a carboxylic acid protecting group as readily understood by one skilled in the art, including, but not limited to, Ci-7alkyl, C5-7cycloalkyl, phenyl, phenylCi-βalkyl, and the like; and Pg3 and Pg4 are each independently selected from hydrogen, C1-8alkyl, C3-8cycloalkyl or aryl; alternatively Pg3 and Pg4 are taken together with the nitrogen atom to which they are bound to form C3- 10heteroaryl or C3-ionon-aromatic heterocyclic, preferably a 5- or 6-membered heterocyclic or heteroaromatic ring moiety containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms. In another embodiment of the present invention Q is OPg2, wherein Pg2 is a carboxylic acid protecting group.

In an embodiment of the present invention Q is selected from the group consisting of hydroxy, unsubstituted C^alkoxy, amino, unsubstituted Ct- 4alkylamino and di(unsubstitutedCi.4alkyl)amino. In another embodiment of the present invention Q is selected from the group consisting of hydroxy, methoxy, ethoxy, ispropyloxy, n-butyloxy, t-butoxy, amino, methylamino and dimethylamino. In yet another embodiment of the present invention Q is C1- 6alkoxy, wherein the C-ι-6alkoxy is not substituted with amino. In yet another embodiment of the present invention, Q is selected from the group consisting of methoxy, ethoxy and t-butoxy.

The present invention is directed to a process for the preparation of compounds of formula (L)

wherein Q, X, R1, R2, R3, n and R4 are as herein defined. The compounds of formula (L) are useful as intermediates in the preparation of compounds of formula (I).

Compounds of formula (L) may be prepared according to the process outlined in Scheme 1.

(Xl)

(L) Scheme 1 Accordingly, a suitably substituted compound of formula (III), a known compound or compound prepared by known methods, is reacted (for example, protected) according to known methods, to yield the corresponding compound of formula (IV), wherein Pgi is a nitrogen protecting group which is inert to CISO3H, such as, Alloc (CH2=CHCH2-O-C(O)-), acetyl (CH3-C(O)-), (C^alkyl)- C(O)-, and the like. For example, the compound of formula (III) is reacted with a suitably selected protecting reagent such as Alloc-CI (CH2=CHCH2-O-C(O)- Cl), AIlOC2O (CH2=CHCH2-OC(O)-O-C(O)O-CH2CH=CH2)1 AcCI (CH3-C(O)-CI), Ac2O (CH3-C(O)-O-C(O)-CH3), and the like. Wherein the compound of formula (III) is reacted with a Alloc-CI, or AIIoC2O, the corresponding protecting group Pgi is Alloc. Preferably, Pgi is selected from Alloc or acetyl.

The compound of formula (IV) is reacted with a suitable substituted compound of formula (V), wherein R48 is R4 other than hydrogen and wherein J is Br, Cl, or I, a known compound or compound prepared by known methods, in the presence of a base such as NaH, n-butyl lithium, LDA, LHMDS, and the like, in a polar aprotic solvent such as THF, dioxane, MTBE, and the like, to yield the corresponding compound of formula (Vl). The compound of formula (Vl) is then reacted with CISO3H, optionally in a polar organic solvent which is inert to CISO3H, such as DCM, DCE, acetonitrile, DMF, to yield the corresponding compound of formula (VII). Alternatively, the compound of formula (IV) is reacted with CISO3H, optionally in a polar organic solvent which is inert to CISO3H, such as DCM, DCE, acetonitrile, DMF, to yield the corresponding compound of formula (VII) wherein R4 is hydrogen.

The compound of formula (VII) is reacted with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII), such as Zn, and the like, in the presence of an acid such as HCI, H2SO4, and the like, in an aprotic solvent such as acetonitrile, THF, dioxane, and the like; or with Zn in the presence of (CH3)2SiCI2 and DMA, in an aprotic organic solvent such as THF, dioxane, acetonitrile, 1 ,2-dichloroethane, and the like; to yield a mixture of the corresponding compound of formula (VIII) and the corresponding compound of formula (IX). Alternatively, wherein the compound of formula (VII) Pgi is tosyl or MTr, the compound of formula (VII) is reacted with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII), such as LiAIH4, and the like, in an organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, at a temperature in the range of from about room temperature to about reflux, preferably at about reflux, to yield the corresponding compound of formula (VIII).

The compound of formula (VIII), isolated or in a mixture with the compound of formula (IX) is reacted with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, a known compound or compound prepared by known methods, in the presence of an organic base which is inert to the compound of formula (X), such as TEA, DIPEA, pyridine, and the like or in the presence of an inorganic base which is inert to the compound of formula (X), such as NaHCO3, Na2CO3, K2CO3, Cs2CO3, and the like, in a polar aprotic solvent such as THF, dioxane, DMF, acetonitrile, and the like, to yield the corresponding compound of formula (Xl). Alternatively, the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII) is reacted with a reducing agent which is capable of reducing the disulfide on the compound of formula (VIII), such as LiAIH4, IJBH4, NaBH4, and the like, in an organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, at a temperature in the range of from about room temperature to about reflux, preferably at about room temperature, to yield the corresponding compound of formula (VIII), which is preferably not isolated. The compound of formula (VIII) is then reacted with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, a known compound or compound prepared by known methods, in the presence of an organic base which is inert to the compound of formula (X), such as TEA, DIPEA, pyridine, and the like or in the presence of an inorganic base which is inert to the compound of formula (X), such as NaHCO3, Na2CO3, K2CO3, Cs2CO3, and the like, in a polar aprotic solvent such as THF, dioxane, DMF, acetonitrile, and the like, to yield the corresponding compound of formula (Xl).

The compound of formula (Xl) is reacted to yield the corresponding compound of formula (L). For example, the compound of formula (Xl) is de- protected according to known methods, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenun Pressm 1973 and T.W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991 , to yield the corresponding compound of formula (L). Compounds of formula (L) may alternatively be prepared according to the process outlined in Scheme 2.

Scheme 2 Accordingly, a suitably substituted compound of formula (III), a known compound or compound prepared by known methods, is reacted (for example, protected) according to known methods, to yield the corresponding compound of formula (IV), wherein Pgi is a nitrogen protecting group which is inert to CISO3H, such as, Alloc (CH2=CHCH2-O-C(O)-), acetyl (CH3-C(O)-), (C1-4alkyl)- C(O)-, and the like. For example, the compound of formula (III) is reacted with a suitably selected protecting reagent such as Alloc-CI (CH2=CHCH2-O-C(O)- Cl), AIIoC2O (CH2=CHCH2-OC(O)-O-C(O)O-CH2CH=CH2), ACCI (CH3-C(O)-CI), Ac2O (CH3-C(O)-O-C(O)-CH3), and the like. Wherein the compound of formula (III) is reacted with a Alloc-CI, or AIIoC2O, the corresponding protecting group Pgi is Alloc. Preferably, Pgi is selected from Alloc or acetyl.

The compound of formula (IV) is reacted with a suitable substituted compound of formula (V), wherein R4a is Ft* other than hydrogen and wherein J is Br, Cl, or I, a known compound or compound prepared by known methods, in the presence of a base such as NaH, n-butyl lithium, LDA, LHMDS, and the like, in a polar aprotic solvent such as THF, dioxane, MTBE, and the like, to yield the corresponding compound of formula (Vl). The compound of formula (Vl) is then reacted with CISO3H, optionally in a polar organic solvent which is inert to CISO3H, such as DCM, DCE, acetonitrile, DMF, to yield the corresponding compound of formula (VII). Alternatively, the compound of formula (IV) is reacted with CISO3H, optionally in a polar organic solvent which is inert to CISO3H, such as DCM, DCE, acetonitrile, DMF, to yield the corresponding compound of formula (VII) wherein R4 is hydrogen.

The compound of formula (VII) is reacted with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII), such as Zn, and the like, in the presence of an acid such as HCI, H2SO4, and the like, in an aprotic solvent such as acetonitrile, THF, dioxane, and the like; or with Zn in the presence of (CH3)2SiCI2 and DMA, in an aprotic organic solvent such as THF, dioxane, acetonitrile, 1 ,2-dichloroethane, and the like; to yield a mixture of the corresponding compound of formula (VIII) and the corresponding compound of formula (IX). Alternatively, wherein the compound of formula (VII) Pgi is tosyl or MTr, the compound of formula (VII) is reacted with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII), such as LiAIH4, and the like, in an organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, at a temperature in the range of from about room temperature to about reflux, preferably at about reflux, to yield the corresponding compound of formula (VIII).

The compound of formula (VIII), isolated or in a mixture with the compound of formula (IX), is de-protected according to known methods, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenun Pressm 1973 and T.W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991 , to yield the corresponding compound of formula (XIII). Alternatively, the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII), is reacted with a reducing agent which is capable of reducing the disulfide on the compound of formula (IX), such as LiAIH4, LiBH4, NaBH4, and the like, in an organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, at a temperature in the range of from about room temperature to about reflux, preferably at about rpom temperature, to yield the corresponding compound of formula (VIII), which is preferably not isolated. The compound of formula (VIII) is then de-protected according to known methods, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenun Pressm 1973 and T.W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991 , to yield the corresponding compound of formula (XIII). Alternatively still, the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII), is de-protected according to known methods, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenun Pressm 1973 and T.W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991, to yield the corresponding compound of formula (XII). The compound of formula (XII) is then reacted with a reducing agent which is capable of reducing the disulfide on the compound of formula (XII), such as LiAIH4, LiBH4, NaBH4, and the like, in an organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, at a temperature in the range of from about room temperature to about reflux, preferably at about room temperature, to yield the corresponding compound of formula (XIII).

The compound of formula (XIII) reacted with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, a known compound or compound prepared by known methods, in the presence of an organic base which is inert to the compound of formula (X), such as TEA, DIPEA, pyridine, and the like or in the presence of an inorganic base which is inert to the compound of formula (X), such as NaHCO3, Na2CO3, K2CO3, Cs2CO3, and the like, in a polar aprotic solvent such as THF, dioxane, DMF, acetonitrile, and the like, to yield the corresponding compound of formula (L).

Compounds of formula (L) wherein R4 is other than hydrogen may alternatively be prepared according to the process outlined in Scheme 3.

-57-

Scheme 3 Accordingly, a suitably substituted compound of formula (III), a known compound or compound prepared by known methods, is reacted (for example, protected) according to known methods, to yield the corresponding compound of formula (IV), wherein Pgi is a nitrogen protecting group which is inert to CISO3H, such as, Alloc (CH2=CHCH2-O-C(O)-), acetyl (CH3-C(O)-), (C1-4alkyl)- C(O)-, and the like. For example, the compound of formula (III) is reacted with a suitably selected protecting reagent such as Alloc-CI (CH2=CHCH2-O-C(O)- Cl), AIlOC2O (CH2=CHCH2-OC(O)-O-C(O)O-CH2CH=CH2), ACCI (CH3-C(O)-CI), Ac2O (CH3-C(O)-O-C(O)-CH3), and the like. Wherein the compound of formula (III) is reacted with a Alloc-CI, or AIIoC2O, the corresponding protecting group Pgi is Alloc. Preferably, Pgi is selected from Alloc or acetyl.

The compound of formula (IV) is reacted with CISO3H, optionally in a polar organic solvent which is inert to CISO3H, such as DCM, DCE, acetonitrile, DMF, to yield the corresponding compound of formula (Vila) (i.e. the corresponding compound of formula (VII) wherein R4 is hydrogen.).

The compound of formula (Vila) is reacted with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (Vila) such as Zn, and the like, in the presence of an acid such as HCI, H2SO4, and the like, in an aprotic solvent such as acetonitrile, THF, dioxane, and the like; or with Zn in the presence of (CH3)2SiCI2 and DMA, in an aprotic organic solvent such as THF, dioxane, acetonitrile, 1 ,2-dichloroethane, and the like; to yield a mixture of the corresponding compound of formula (Villa) (i.e. the corresponding compound of formula (VIII) wherein R4 is hydrogen) and the corresponding compound of formula (IXa) (i.e. the corresponding compound of formula (IXa) wherein R4 is hydrogen).

The compound of formula (Villa), isolated or in a mixture with the compound of formula (IXa) is de-protected according to known methods, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenun Pressm 1973 and T.W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 , to yield the corresponding compound of formula (XIIIa) (i.e. the corresponding compound of formula (XIII) wherein R4 is hydrogen). The compound of formula (XIIIa) is reacted with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, a known compound or compound prepared by known methods, in the presence of an organic base which is inert to the compound of formula (X), such as TEA, DIPEA, pyridine, and the like or in the presence of an inorganic base which is inert to the compound of formula (X), NaHCO3, Na2CO3, K2CO3, CS2CO3, and the like, in a polar aprotic solvent such as THF, dioxane, DMF, acetonitrile, and the like, to yield the corresponding compound of formula (La) (i.e. the corresponding compound of formula (L) wherein R4 is hydrogen). Alternatively, the compound of formula (IXa), isolated or in a mixture with the compound of formula (Villa), is reacted with a reducing agent which is capable of reducing the disulfide on the compound of formula (IXa), such as LiAIH4, LiBH4, NaBH4, and the like, in an organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, at a temperature in the range of from about room temperature to about reflux, preferably at about room temperature, to yield the corresponding compound of formula (Villa). The compound of formula (Villa) is then reacted with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, a known compound or compound prepared by known methods, in the presence of an organic base which is inert to the compound of formula (X), such as TEA, DIPEA, pyridine, and the like or in the presence of an inorganic base which is inert to the compound of formula (X), NaHCO3, Na2CO3, K2CO3, Cs2CO3, and the like, in a polar aprotic solvent such as THF, dioxane, DMF, acetonitrile, and the like, to yield the corresponding compound of formula (XIa) (i.e. the corresponding compound of formula (Xl) wherein R4 is hydrogen). The compound of formula (XIa) is then reacted to yield the corresponding compound of formula (La). For example, the compound of formula (XIa) is de-protected according to known methods, such as those described in Protective Groups in Organic Chemistry. ed. J.F.W. McOmie, Plenun Pressm 1973 and T.W. Green and P.G.M. Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991 , to yield the corresponding compound of formula (La). Alternatively still, the compound of formula (IXa), isolated or in a mixture with the compound of formula (Villa), is de-protected according to known methods, such as those described in Protective Groups in Organic Chemistry. ed. J.F.W. McOmie, Plenun Pressm 1973 and T.W. Green and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 , to yield the corresponding compound of formula (XIIa) (i.e. the corresponding compound of formula (XII) wherein R4 is hydrogen). The compound of formula (XIIa) is then reacted with a reducing agent which is capable of reducing the disulfide on the compound of formula (XIIa), such as LiAIH4, LiBH4, NaBH4, and the like, in an organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, at a temperature in the range of from about room temperature to about reflux, preferably at about room temperature, to yield the corresponding compound of formula (XIIIa) (i.e. the corresponding compound of formula (XIII) wherein R4 is hydrogen). The compound of formula (XIIIa) is then reacted with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, a known compound or compound prepared by known methods, in the presence of an organic base which is inert to the compound of formula (X), such as TEA, DIPEA, pyridine, and the like or in the presence of an inorganic base which is inert to the compound of formula (X), such as NaHCO3, Na2CO3, K2CO3, Cs2CO3, and the like, in a polar aprotic solvent such as THF, dioxane, DMF, acetonitrile, and the like, to yield the corresponding compound of formula (La). The compound of formula (La) is reacted with a suitably substituted compound of formula (V), wherein R43 is R4 other than hydrogen and wherein J is Br, Cl, or I, a known compound or compound prepared by known methods, in the presence of a base such as NaH, n-butyl lithium, LDA, LHMDS, and the like, in a polar aprotic solvent such as THF, dioxane, MTBE, and the like, to yield the corresponding compound of formula (Lb). Alternatively, the compound of formula (La) is reacted with a suitably substituted acylating agent capable of attaching an -C(O)-RzU3 group onto the nitrogen of the compound of formula (La), wherein R4b is selected from (Ci-4 straight chain alkylene)R-|5 or (straight chain Ci-4alkylene)Ri6, in the presence of an organic such as TEA, DIPEA, pyridine, and the like, or in the presence of an inorganic base such as NaHCO3, Na2CO3, K2CO3, Cs2CO3, and the like, in a polar aprotic solvent such as THF, dioxane, DMF, acetonitrile, and the like, to yield the corresponding compound of formula (XVIII); the compound of formula (XVIII) is then reacted with a reducing agent capable of reducing the amide on the compound of formula (XVIII), such as borane, and the like, in a aprotic organic solvent such as THF, dioxane, MTBE, and the like, to yield the corresponding compound of formula (Lb).

Compounds of formula (L) wherein R4 is other than hydrogen, (Ci straight chain alkylene)Ris or (straight chain Cialkylene)Ri6 may be prepared according to the process outlined in Scheme 4.

(Lc) Scheme 4 Accordingly, a suitably substituted compound of formula (III), a known compound or compound prepared by known methods, is reacted with a suitably substituted acylating capable of attaching an -C(O)O-R4b group onto the nitrogen of the compound of formula (III), wherein R4b is selected from (C1-4 straight chain alkylene)R-i5 or (straight chain C1-4 alkylene)Ri6, for example an acid chloride of the formula CI-C(O)-R4I3, a symmetric anhydride of the formula R4b-C(O)-O-C(O)-R4b, and the like, in the presence of an organic base, preferably a tertiary amine base such as TEA, DIPEA, pyridine, and the like, in an aprotic solvent such as THF, DMF, dioxane, ethyl acetate, and the like; or in the presence of an organic or inorganic base such as NaOH, KOH, Na2CO3, NaHCO3, K2CO3, KHCO3, TEA, DIPEA, pyridine, and the like, in a mixture of an aprotic solvent and water, to yield the corresponding compound of formula (XIV).

The compound of formula (XIV) is reacted with CISO3H, optionally in a polar organic solvent which is inert to CISO3H, such as DCM, DCE, acetonitrile, DMF, to yield the corresponding compound of formula (XV).

The compound of formula (XV) is reacted with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (XV), such as Zn, and the like, in the presence of an acid such as HCI, H2SO4, and the like, optionally in an aprotic solvent such as acetonitrile, THF, dioxane, and the like; or-with Zn in the presence of (CH3)2SiCI2 and DMA, in an aprotic organic solvent such as THF, dioxane, acetonitrile, 1 ,2-dichloroethane, and the like; to yield a mixture of the compound of formula (XVI) and the compound of formula (XVII). One skilled in the art will recognize that when the compound of formula (XV) is reacted with a reducing agent capable of reducing the chlorosulfonyl group and the amide group on the compound of formula (XV), such as LiAIH4, and the like, in an organic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, at a temperature in the range of from about room temperature to about reflux, preferably at about reflux, then the compound of formula (XV) is reacted to yield the corresponding compound of formula (XIIIb) in one step. The compound of formula (XVI), isolated or in a mixture with the compound of formula (XVII) is reacted with a reducing agent which is capable of reducing the amide on the compound of formula (XVI), such as LiAIH4, borane, and the like, in an aprotic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, to yield the corresponding compound of formula (XIIIb) (i.e. the corresponding compound of formula (XIII) wherein R4 is other than hydrogen). Wherein the reducing agent is LiAIH4, the compound(s) is reduced at a temperature in the range of from about room temperature to about reflux, preferably at about room temperature. Alternatively, the compound of formula (XVII), isolated or in a mixture with the compound of formula (XVI) is reacted with a reducing agent which is capable of reducing the amide on the compound of formula (XVII) and the disulfide on the compound of formula (XVII), such as LiAIH4, borane, and the like, in an aprotic solvent which is inert to the reducing agent, such as THF, dioxane, and the like, to yield the corresponding compound of formula (XIIIb). Wherein the reducing agent is LiAIH4, the compound(s) is reduced at a temperature in the range of from about room temperature to about reflux, preferably at about room temperature.

The compound of formula (XIIIb) is reacted with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, a known compound or compound prepared by known methods, in the presence of an organic base which is inert to the compound of formula (X), such as TEA, DIPEA, pyridine, and the like or in the presence of an inorganic base which is inert to the compound of formula (X), such as NaHCO3, Na2CO3, K2CO3, Cs2CO3, and the like, in a polar aprotic solvent such as THF, dioxane, DMF, acetonitrile, methanol, ethanol, and the like, to yield the corresponding compound of formula (Lc) (i.e. the corresponding compound of formula (L) wherein R4 is selected from (C2-5 straight chain alkylene)R-|5 or (straight chain C2-5 alkylene)R-|6). The present invention is further directed to a process for the preparation of compounds of formula (I)

wherein R1, R2, X, R3, n, R4, c, R5, R6 and R7 are as herein defined. The compounds of formula (I) are useful as PPAR alpha agonists, more specifically as selective PPAR alpha agonists. PPAR alpha agonists are useful for the treatment, prevention, or inhibiting the progression of one or more of the following conditions or diseases: phase I hyperlipidemia; pre-clinical hyperlipidemia; phase Il hyperlipidemia; hypertension; CAD (coronary artery disease); coronary heart disease; hypertriglyceridemia; lowering serum levels of low-density lipoproteins (LDL), IDL, and/or small-density LDL and other atherogenic molecules, or molecules that cause atherosclerotic complications, thereby reducing cardiovascular complications; elevating serum levels of high- density lipoproteins (HDL); lowering serum levels of triglycerides, LDL, and/or free fatty acids; and/or lowering FPG/HbA1 c.

More specifically, the compound of formula (I) may be prepared by reacting a suitably substituted compound of formula (L) with a suitably substituted isocyanate, a compound of the formula (XIX)

according to known methods. One skilled in the art will recognize that in reacting the compound of formula (L) with a suitably substituted isocyanate, a compound of formula (XIX), it may be necessary or desirable to protect reactive groups on the compound of formula (L), according to known methods. For example, it may be necessary or desirable to protect the carboxylic acid or amide on the compound of formula (L) when Q is OH or NH2, respectively. One skilled in the art will further recognize that wherein the compound of formula (L) Q is OPg2 NH or N(Pg3Pg4), the compound of formula (L) is reacted with a suitably substituted isocyanate, a compound of formula (XIX), according to known methods, to yield an intermediate which is then de-protected according to known methods to yield the corresponding compound of formula (I)-

In an embodiment of the present invention is a process for the preparation of a compound of formula (L) wherein X is S, Ri is methyl, R2 is methyl, Q is OH or OPg2, the -X-C(Ri R2)-C(O)-Q is bound at the 5- position, R3 is hydrogen, n is 1 and R4 is ethyl. In another embodiment of the present invention is a process for the preparation of a compound of formula (L) wherein X is S, Ri is methyl, R2 is methyl, Q is OPg2, Pg2 is t-butyl, the -X-C(RiR2)- C(O)-Q is bound at the 5- position, R3 is hydrogen, n is 1 and R4 is ethyl.

In another embodiment of the present invention is a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt, Chester or Ci-6amide thereof, wherein X is S, Ri is methyl, R2 is methyl, wherein -X-C(Ri R2)-C(O)-OH is bound at the 5- position, R3 is hydrogen, n is 1 , R4 is ethyl, c is O, R5 is hydrogen, Re is trifluoromethoxy and R7 is hydrogen.

The present invention is further directed to a process for the preparation of the compound of formula (Le)

wherein Qb is selected from the group consisting of Ci-βalkoxy, wherein the Ci_6alkoxy is not substituted with amino. Preferably, Qb is unsubstituted Ci_ 6alkoxy, more preferably, Qb is selected from the group consisting of methoxy, ethoxy and t-butoxy.

More specifically, the compound of formula (Le) may be prepared according to the process outlined in Scheme 5.

Scheme 5 Accordingly, a compound of formula (Ld) is reacted with (S)-2-(4- hydroxyphenoxy)propionic acid, in an alcohol such as methanol, ethanol, and the like, preferably ethanol; or in acetone, at a temperature in the range of from about 35°C to about 0°C, to yield the corresponding (R,S) diastereomeric salt, the compound of formula (XX). The (R1S) diastereomeric salt, the compound of formula (XX), is reacted with an inorganic base such as NaOH, KOH, Na2CO3, K2CO3, and the like to yield the corresponding compound of formula (Le). Preferably, the compound of formula (Le) is prepared with an enantiomeric excess in the range of from about 70 %ee to about 90 %ee. One skilled in the art will recognize that wherein a greater %ee is desired, the diasteromeric salt of the compound of formula (Le) may be further re-slurrried in or recrystallized from an organic solvent such as methanol, ethanol, acetone, and the like.

The compound of formula (Le) may alternatively be prepared according to the process outlined in Scheme 6.

Scheme 6 Accordingly, a compound of formula (Ld) is reacted with (R)-2-(4- hydroxyphenoxy)propionic acid, in acetone, at a temperature greater than about 35°C, preferably at a temperature greater than about 45°C; or in THF at about room temperature; to yield the corresponding (R1R) diastereomeric salt, the compound of formula (XXI). The (R1R) diastereomeric salt, the compound of formula (XXI), is reacted with an inorganic base such as NaOH, KOH, Na2CO3, K2CO3, and the like to yield the corresponding compound of formula (Le).

Preferably, the compound of formula (Le) is prepared with an enantiomeric excess in the range of from about 70 %ee to about 90 %ee. One skilled in the art will recognize that wherein a greater %ee is desired, the diasteromeric salt of the compound of formula (Le) may be further re-slurrried in or recrystallized from an organic solvent such as methanol, ethanol, acetone, and the like.

One skilled in the art will further recognize that the S-enantiomer of the compound of formula (Ld), a compound of formula (Lf)

may be similarly prepared by reacting a compound of formula (Ld) with (R)-2-(4-hydroxyphenoxy)propionic acid, in an alcohol such as methanol, ethanol, and the like, preferably ethanol; or in acetone, at a temperature in the range of from about 35°C to about 0°C; to yield the corresponding (S, R) diastereomeric salt which is then reacted with an inorganic base such as NaOH, KOH, Na2CO3, K2CO3, and the like, to yield the corresponding compound of formula (Lf). Alternatively, the S-enantiomer of the compound of formula (Ld) (i.e. the compound of formula (Lf)) may be prepared by reacting a compound of formula (Ld) with (S)-2-(4-hydroxyphenoxy)propionic acid, in acetone, at a temperature greater than about 35°C, preferably at a temperature greater than about 45°C; or in THF at about room temperature; to yield the corresponding (S1S) diastereomeric salt which is then reacted with an inorganic base such as NaOH, KOH, Na2CO3, K2CO3, and the like, to yield the corresponding compound of formula (Lf). The present invention is further directed to a novel crystalline salt of the compound of formula (Ha)

more specifically a crystalline N,N'-dibenzylethylenediamine (benzathine) salt of the compound of formula (Ha). In an embodiment of the present invention is a crystalline N.N'-dibenzylethylenediamine salt of the compound of formula (lla) wherein the ratio of the compound of formula (Ha) to the N,N'-dibenzylethylenediamine is 1 :1.

The crystalline benzathine salt of the compound of formula (lla) may be characterized by the major peaks of its X-ray diffraction peaks, as listed in Table 1, below. The X-ray diffraction pattern was measured as follows. The crystalline benzathine salt of the compound of formula (lla) was backloaded into a conventional X-ray holder. Using an X-Celerator detector, the sample was scanned from 3 to 35 °2Θ at a step size of 0.0165 °2Θ and a time per step of 10.16 seconds. The effective scan speed was 0.2067°/s. Instrument voltage and current settings of 45 kV and 40 mA were employed.

Table 1 : XRD - Compound of formula (Ha) Benzathine Salt

SHEETS MISSING UPON FILING

To a solution of terf-butyl 2-(2-ethylamino-indan-5-ylsulfanyl)-2-methyl- propionate (182 g, 0.544 mol) was added 4-(trifluoromethoxy)phenyl isocyanate (115 g, 0.556 mol) and the reaction temperature was maintained at about 15- 20°C. After addition, the clear solution was stirred for 15 minutes at about 15- 20°C. The solution was used for the next step directly. An analytical sample was obtained as a white solid by simple concentration of a small amount of the crude solution. mp 95.4-97.8°C. Optical rotation: [α]20 D= +3.4 (c 1.0, MeOH). MS (APCI): m/z 280.2(30%), 306.2(100%), 437.3(50%), 483.1(20%). 1H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1 H), 7.61 (d, J = 9.2 Hz, 2H), 7.27 (m, 5H), 4.91 (p, J = 8.2 Hz, 1 H), 3.37 (q, J = 6.8 Hz, 2H), 3.08 (m, 4H), 1.38 (s, 9H), 1.36 (s, 6H), 1.09 (t, J = 6.8 Hz, 3H). 13C NMR (300 MHz, DMSO-d6) δ 15.5, 26.1 , 27.8, 36.6, 38.4, 51.2, 56.8, 80.7, 120.6 (q, J = 225 Hz, OCF3), 121.4, 121.5, 124.9, 129.1 , 132.8, 135.3, 140.2, 142.3, 143.0, 143.3, 154.9, 172.5, FTIR (KBr): 3297, 2974, 2933, 1724, 1636, 1605, 1511 , 1419, 1369, 1270, 1229, 1198, 1148, 1122, 845, 817, 756, 561 cm"1. Elemntal Analysis for C27H33F3N2O4S: Calculated: C, 60.21 ; H, 6.18; N, 5.20; F, 10.58; S, 5.95 Found: C, 59.87; H, 6.22; N, 5.08; F, 10.86; S, 5.94.

Example 10

-81- (R)-(+)-2-(2-f1-Ethyl-3-(4-trifluoromethoxy-phenvn-ureidol-i ndan-5-ylsulfanyl)-2- methyl-propionic acid

To a solution of terf-butyl 2-{2-[1 -ethyl-3-(4-trif luoromethoxy-phenyl)- ureido]-indan-5-ylsulfanyl}-2-methyl-propionate (288 g, 0.534 mol) was added a solution of sulfuric acid (535 g, 5.34 mol) in isopropyl acetate (0.7L) while maintaining the reaction temperature at about 15-20°C. The clear solution was stirred at 15°C for 1 hour after the addition. To the reaction mixture was added cold water (0.94L). After removal of the acidic aqueous layer, the isopropyl acetate layer was washed until the pH of the aqueous layer reached 3. The solution was used in the next step without isolation. An analytical sample was obtained as a white foam by simple concentration of a small amount of the crude solution. mp 57°C. Optical rotation: [α]20D = +7.7 (c 1.0, MeOH). MS (APCI): m/z: 483.1(MH+). 1H NMR (300 MHz1 DMSO-d6) δ 12.43 (br s, 1 H), 8.49 (s, 1 H), 7.61 (d, J = 9.5, 2H), 7.27 (m, 5H), 4.91 (p, J = 8.4 Hz, 1 H), 3.39 (m, 2H), 3.08 (m, 4H), 1.38 (s, 6H), 1.10 (t, J = 6.9 Hz, 3H). 13C NMR (300 MHz, DMSO-d6) 6175.2, 154.9, 143.2, 143.0, 142.3, 140.2, 135.1 , 132.6, 129.4, 125.0, 121.5, 121.3, 120.6 (q, J = 255 Hz, OCF3), 56.8, 51.0, 38.4, 36.5, 26.0, 15.5. FTIR (KBr): 3395, 2977, 2935, 1703, 1641 , 1511 , 1420, 1265, 1200, 1161 , 1016, 841 , 815, 755 cm-1. Elemental Analysis for C2SH2SF3N2O4S:

-82- Calculated: C, 57.25; H1 5.22; N, 5.81 ; F, 11.81 ; S, 6.65. Found: C, 57.00; H1 5.47; N, 5.41 ; F, 11.75; S, 6.23.

Example 11 (R)-(+)-2-(2-ri-Ethyl-3-(4-trifluoromethoxy-phenyl)-ureidol- indan-5-ylsulfanyl)-2- methyl-propionic acid. Λ/,Λ/-dibenzylethylenediamine salt

Seeds preparation: Λ/,Λ/-Dibenzylethylenediamine (0.26 g, 1.08 mmol) was added to t-butyl l o methyl ether solution of 2-{2-[1 -ethyl-3-(4-trif luoromethoxy-phenyl)-ureido]- indan-5-ylsulfanyl}-2-methyl-propionic acid (0.52g, 1.08 mmol). iPrOAc was added to the resulted cloudy solution. The solution was kept in the refrigerator overnight (~20 hours). The solids precipitated were collected by filtration. 1H NMR analysis and the melting point measurement of the isolated solids 15 confirmed the formation of the salt with 1 :1 mole ratio of acid and N, N'- dibenzylethylenediamine. Salt Preparation: A solution of 2-{2-[1-ethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-indan-5- ylsulfanyl}-2-methyl-propionic acid (218.51 g, 0.453 mol) in isopropyl acetate 2 o (859 mL) was cooled to about -5 to 0°C and Λ/,Λ/-dibenzylethylenediamine (112 g, 0.453 mol) was added over 1 hour. The internal reaction temperature was maintained under 0°C. Heptane (513 mL) was added to the solution until the solution became cloudy. The seeds were added while stirring. The cloudy mixture changed to a uniform suspension within one hour. Additional heptane

-83- (60 ml_) was then added. After stirred for 1h, more heptane (180 ml_) was added. The suspension was stirred overnight (18 hours) at 0°C. The solid was filtered and rinsed with a chilled mixture of iPrOAc/heptane (1/2, 90 ml_). The solid was air-dried at the ambient temperature overnight to yield a solid with 99.1 % ee. mp 99-102°C. Optical rotation: [α]20D = +7.7 (c 1.0, MeOH). MS (APCI): m/z 483.8(MH+). 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.63 (m, 2H), 7.28 (m, 15H), 6.99 (br s, 3H), 4.91 (p, J = 8.5 Hz, 1 H), 3.80 (s, 4H), 3.37 (q, J = 6.9 Hz, 2H), 3.05 (d, J = 7.6 Hz, 4H), 2.77 (s, 4H), 1.33 (s, 6H), 1.09 (t, J = 6.9 Hz, 3H). 13C NMR (300 MHz, DMSO-d6) .5176.6, 154.9, 142.9, 142.1 , 141.9, 140.3, 138.8, 134.7, 132.2, 131.3, 128.8, 128.5, 127.4, 124.7, 121.4, 121.4, 120.2 (q, J = 255 Hz, OCF3), 56.8, 52.9, 52.2, 46.7, 38.3, 36.5, 36.4, 27.3, 15.5. FTIR (KBr): 3310(broad), 2972, 2849, 1638, 1606, 1539, 1510, 1458, 1418, 1389, 1351 , 1264, 1244, 1199, 1162, 842, 816, 748, 698.81 , 668 cm"1. Elemental Analysis for C39H45F3N4O4S: Calculated: C 64.80; H 6.27; N, 7.75; F 7.88; S, 4.44 Found: C, 64.65; H, 6.35; N, 7.61 ; F, 8.12, S, 4.51.

Example 12 (SM+V-ferf-Butyl 2-(2-ethylamino-indan-5-ylsulfanvO-2-methyl-propionate, (S)-(- )-2-(4-hvdroxvphenoxv)propionic acid salt

Racemi.c terf-Butyl 2-(2-ethylamino-indan-5-ylsulfanyl)-2-methyI- propionate (0.30 mmol) and (S)-(-)-2-(4-hydroxyphenoxy)propionic acid (0.30 mmol) were mixed into THF (2 ml_) and heated to 50°C to a clear solution. The reaction mixture was then cooled to the ambient temperature and stirred -84- overnight. White crystalline solid precipitated and determined to be the enriched diastereomeric salt (S)-(+)-terM3utyl 2-(2-ethylamino-indan-5- ylsulfanyl)-2-methyl-propionate and (S)-(-)-2-(4-hydroxyphenoxy)propionic acid at 48% ee by chiral HPLC.

Example 13 (SM+Herf-Butyl 2-(2-ethylamino-indan-5-ylsulfanyl)-2-methyl-propionate, (S)-(- )-2-(4-hydroxyphenoxy)propionic acid salt

Racemic tert-Buty\ 2-(2-ethylamino-indan-5-ylsulfanyl)-2-methyl- propionate (17g, 51 mmol) and (S)-(-)-2-(4-hydroxyphenoxy)propionic acid (4.6g, 25 mmol) were dissolved in acetone (55 mL), each separately. The solutions were then mixed and stirred at the ambient temperature overnight. The resulting thick suspension was heated to 55°C for 6h, 40°C for 18h, then heated to 50°C and filtered to yield a solid which was determined to be enriched with the diastereomeric salt (S)-(+)-te/t-Butyl 2-(2-ethylamino-indan-5- ylsulfanyl)-2-methyl-propionate and (S)-(-)-2-(4-hydroxyphenoxy)propionic at 22% ee. The enriched salt was re-crystallized from acetone twice, to yield the title compound salt (S1S) salt in 94%ee. 1H NMR for 94%ee sample (300 MHz, DMSO-d6) δ 7.26 (m, 3H), 6.62 (m, 4H), 4.35 (q, J = 6.8 Hz, 1 H), 3.14 (m, 2H), 3.74 (p, J = 7.2 Hz, 1 H), 2.87 (dd, J = 6.7 Hz, 16.3 Hz, 2H), 2.76 (q, J = 7.3 Hz, 2H), 1 .36 (s, 9H), 1 .35 (s, 6H), 1 .34 (d, J = 6.8 Hz, 3H), 1.10 (t, J = 7.3 Hz, 3H). m.p. for 80%ee sample isolated after first recrystallization as described above: 157-159°C (DSC)

Example 14

-85- 2-(6-π-Ethyl-3-(4-trifluoromethoxyphenyl)ureido1-3-methoxy- 5,6,7,8- tetrahvdronaphthale-2-ylsulfanyl)-2-methylpropionic acid

STEP A. 7-Methoxy-1.2,3,4-tetrahvdronaphthalen-2-ylamine To a solution of 7-methoxy-2-tetralone (12.4 g; 70.7 mmol) dissolved in MeOH (350 ml_) was added ammonium acetate (82 g; 1.06 mol) and the reaction was stirred for 30 min at room temperature. To the reaction was then added sodium cyanoborohydride (21.5 g; 353 mmol) and the reaction was refluxed for 1h. Upon completion of the reaction, the reaction was cooled and the solvent removed under reduced pressure. The residue was diluted with EtOAc and 1N NaOH was added to quench the reaction. The aqueous phase was separated and the organic phase washed with H2O, brine, dried over Na2SO4, filtered, and the solvent removed under reduced pressure to yield 7- methoxy-1 ,2,3,4-tetrahydronapthalen-2-ylamine as a dark oil. MS, m/z: 178 (M+1 ) C11H15NO.

STEP B. N-(7-Methoxy-1 ,2,3,4-tetrahvdronaphthalen-2-yl)-acetamide To a stirred suspension of 7-methoxy-1 ,2,3,4-tetrahydronapthalen-2- ylamine (2.54 g; 14.3 mmol) in CH2CI2 (20 ml_) was added DIEA (3.4 ml_) and the reaction mixture was cooled to 00C. Acetyl chloride (1.22 ml_; 17.1 mmol) was added dropwise at 0°C and the reaction was allowed to warm to room temperature, then stirred for 18 h. The reaction mixture was diluted with CH2CI2, washed with H2O, dried over Na2SO4, filtered and the solvent removed under reduced pressure to yield a crude solid. Purification by flash chromatography (SiO2) eluting with hexanes-EtOAc yielded N-(7-methoxy- 1 ,2,3,4-tetrahydronaphthalen-2-yl)-acetamide as a white solid. MS, m/z: 220 (M+1 ) C13H17NO2.

-86- STEP C. 6-Acetylamino-3-methoxy-5.6,7,8-tetrahvdronaDhthalene-2-sulf onyl chloride To chlorosulfoπic acid (15 ml_), cooled to -100C was added N-(I- methoxy-1 ,2,3,4-tetrahydronaphthalen-2-yl)-acetamide (1.44 g; 6.6 mmol). The reaction mixture was stirred at -10°C for 15 min and quenched carefully by pouring over ice-water. The aqueous phase was extracted with CH2CI2 (3X), the organic extracts combined, dried over Na2SO4, filtered and evaporated under reduced pressure to yield 6-acetylamino-3-methoxy-5, 6,7,8- tetrahydronaphthalene-2-sulfonyl chloride as a white solid. 1H NMR (300 MHz, CDCI3): δ 7.68 (s, 1 H), 6.78 (s, 1 H), 5.53-5.56 (m, 1 H), 4.22-4.31 (m, 1H), 4.00 (s, 3H), 3.18-3.26 (dd, 1H), 2.86-2.90 (m, 2H), 2.67-2.76 (dd, 1H), 2.04-2.12 (m, 1H), 2.00 (s, 1 H), 1.73-1.82 (m, 2H). MS, m/z: 318 (M+1) C13H16CINO4S.

STEP D. N-(6-Mercapto-7-methoxy-1 ,2,3,4-tetrahvdronaphthalen- 2yl)acetamide To a suspension of zinc dust (1.16 g; 17.7 mmol) and dimethylsilyl dichloride (2.4 ml_; 17.7 mmol) in MeCN (40 ml_) was added a solution of 6- acetylamino-3-methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfon yl chloride (1.13 g; 3.55 mmol) in MeCN / DCE (40 / 10 ml_), at room temperature. The reaction suspension was then heated at 810C for 4 h, cooled to room temperature, filtered and the solvent evaporated under reduced pressure. The crude residue was purified by reverse-phase semi-prep HPLC eluting with a MeCN-HgO gradient to yield N-(6-mercapto-7-methoxy-1 ,2,3,4-tetrahydronaphthalen- 2yl)acetamide as a white solid and N-[6-(6-acetylamino-3-methoxy-5,6,7,8- tetrahydronaphthalen-2yldisulfanyl)-7-methoxy-1 ,2,3,4,-tetrahydronaphthalen- 2-yl]acetamide as a tan solid. MS, m/z: 252 (M+1 ; S-H) C13H17NO2S & 501 (M+1 ; S-S) C26H32N2O4S2.

STEP E. 2-(6-Acetylamino-3-methoxy-5.6.7,8-tetrahvdronaphthalen-2- ylsulfanyl)-2-methylpropionic acid tert-butyl ester -87- To a suspension of N-[6-(6-acetylamino-3-methoxy-5,6,7,8- tetrahydronaphthalen-2yldisulfanyl)-7-methoxy-1 ,2,3,4,-tetrahydronaphthalen- 2-yl]acetamide (0.368 g; 0.73 mmol) in MeOH (10 ml_) was added DMF (3 ml_), K2CO3 (0.31 g; 2.26 mmol), tert-butyl 2-bromoisobutyrate (0.66 mL; 2.95 mmol) and NaBH4 (0.28 g; 7.34 mmol) and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was partitioned between EtOAc and H2O, the aqueous phase extracted with EtOAc, the organic extracts combined, washed with H2O, brine, dried over Na2SO4, filtered and the solvent removed under reduced pressure to yield a crude oil, which was purified by reverse- phase semi-prep HPLC eluting with a MeCN-H2O gradient to yield 2-(6- acetylamino-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfa nyl)-2- methylpropionic acid tert-butyl ester as an oil. MS, m/z: 338 (M+1 ) C21H3iNO4S.

STEP F. 2-(6-Ethylamino-3-methoxy-5.6,7.8-tetrahvdronaphthalen-2- ylsulfanyl)-2-methylpropionic acid tert-butyl ester To a solution of 2-(6-acetylamino-3-methoxy-5, 6,7,8- tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid tert-butyl ester (0.68 g; 1.74 mmol) in THF (15 mL) was added a solution of 1.0 M borane-THF (15 mL), dropwise at room temperature. The reaction mixture was allowed to stir for 18 h at room temeperature, then carefully quenched with MeOH (10 mL) and the solvent evaporated under reduced pressure. The residual oil was further azeotroped with MeOH (3x) to yield a mixture of 2-(6-ethylamino- 5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid tert-butyl ester and it's borane complex as an oil. MS, m/z: 380 (M+1 ) C21H33NO3S.

STEP G. 2-1641 -Ethyl-3-(4-trifluoromethoxyphenvnureido1-3-methoxy-5.6.7.8- tetrahvdronaphthalen-2-ylsulfanyl)-2-methylpropionic acid tert butyl ester To a mixture of 2-(6-ethylamino-5,6,7,8-tetrahydro-naphthalen-2- ylsulfanyl)-2-methylpropionic acid tert-butyl ester and borane complex (0.054 g; 0.141 mmol) dissolved in CH2CI2 (2 mL) was added 4-trifluoromethoxyphenyl

-88- isocyanate (0.063 mL; 0.284 mmol) and the reaction mixture as stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the crude residue was purified by reverse-phase semi-prep HPLC eluting with a MeCN-H2O gradient to yield 2-{6-[1-ethyl-3-(4-trifluoromethoxyphenyi)ureido]-3- methoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylp ropionic acid tert butyl ester as an oil. MS, M/Z: 527 ((M-C4H8)+1) C29H37F3N2O5S.

STEP H. 2-(6-π-Ethyl-3-(4-trifluoromethoχyphenyl)ureidol-5.6.7,8- tetrahvdronaphthalen^-ylsulfanyl^-methylpropionic acid To 2-{6-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methoxy- 5, 6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid tert butyl ester (0.02 g; 0.03 mmol) dissolved in CH2CI2 (1.5 mL) was added TFA (1.5 mL) and the reaction mixture was stirred at room temperature for 1.5 h. The solvent was removed under reduced pressure and the residue was purified by reverse- phase semi-prep HPLC eluting with a MeCN-H2O gradient to yield 2-{6-[1ethyl- 3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphth alen-2-ylsulfanyl}- 2-methylpropionic acid as a white solid. - -1H NMR (300 MHz, CD3OD): δ 7.45-7.48 (d, 2H), 7.15-7.18 (m, 3H), 6.71 (s, 1 H), 4.43-4.79 (m, 1 H), 3.75 (s, 3H), 3.43-3.45 (m, 2H), 2.88-3.08 (m, 4H), 1.99-2.03 (m, 2H), 1.38 (s, 6H), 1.25-1.52 (t, 3H). MS, m/z: 526 (M+1 ) C25H29F3N2O5S.

The following compounds were similarly prepared according to the procedure described in Example 14 above with selection and substitution of suitable reagents and reaction conditions.

Example 15 2-(6-r3-(4-terf-Butylphenvπi-ethylureidol-3-methoxy-5,6,7,8 - tetrahvdronaphthalen-2-ylsulfanyl)-2-methylpropionic acid

-89-

Prepared as an oil by replacing 4-trifluoromethoxyphenyl isocyanate with 4-te/f-butylphenyl isocyanate in Step G above. MS, m/z: 499 (M+1 ) C28H38N2O4S.

Example 16 2-l6-ri-Ethyl-3-(4-trifluoromethoxyphenvπureidol-3-fluoro-5 ,6,7,8- tetrahvdronaphthalen^-ylsulfanyl^-methylpropionic acid

- Prepared as a white solid by substituting 7-methoxy-2-tetralone with 7- fluoro-2-tetralone in STEP A above. 1H NMR (300 MHZ, CDCL3): δ 7.46-7.51 (M, 2H), 7.25-7.28 (D, 1 H), 7.17- 7.20 (D, 2H), 6.92-6.95 (D, 1 H), 4.43 (M, 1 H), 3.42-3.49 (M, 2H), 2.90-3.11 (M, 4H), 2.02-2.07 (M, 2H), 1.45 (S, 6H), 1.25-1.31 (T, 3H). MS, m/z: 515 (M+1 ) C24H26F4N2O4S.

Example 17 2-(6-ri-Ethyl-3-(4-trifluoromethoxyphenyl)ureidol-3-chloro-5 ,6,7,8- tetrahvdronaphthalen-2-ylsulfanyl)-2-methylpropionic acid

-90-

Prepared as a white solid by substituting 7-methoxy-2-tetralone with 7- chloro-2-tetralone in STEP A above. MS, m/z: 532 (M+1 ) C24H26CIF3N2O4S.

Example 18 2-(6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido1-3-bromo-5. 6,7,8- tetrahvdronaphthalen-2-ylsulfanyl)-2-methylpropionic acid

Prepared as a white solid by substituting 7-methoxy~2-tetralone with 7- bromo-2-tetralone in STEP A above. 1H NMR (300 MHz1 CDCI3): δ 7.45-7.48 (m, 3H), 7.36 (s, 1 H)1 7.15-7.18 (d, 2H), 4.41-4.79 (m, 1 H), 3.40-3.47 (m, 2H), 2.90-3.07 (m, 4H), 2.01-2.03 (m, 2H), 1.45 (s, 6H), 1.24-1.29 (t, 3H). MS1 m/z: 576 (M+1 ) C24H26BrF3N2O4S.

Example 19 2-{6-π-Ethyl-3-(4-trifluoromethoχyphenyl)ureidol-3-methyl- 5,6,7,8- tetrahvdronaphthalen-2-ylsulfanyl)-2-methylpropionic acid

-91-

Prepared as a white solid by substituting 7-methoxy-2-tetralone with 7- methyl-2-tetralone in STEP A above. 1H NMR (300 MHz, CDCI3): δ 7.45-7.48 (m, 2H), 7.22 (s, 1H), 7.15-7.18 (d, 2H), 7.02 (s, 1 H), 4.41-4.79 (m, 1 H), 3.40-3.47 (m, 2H), 2.85-3.03 (m, 4H), 2.39 (s, 3H), 2.01-2.03 (m, 2H), 1.41 (s, 6H), 1.24-1.29 (t, 3H). MS, m/z: 511 (M+1) C25H29F3N2O4S.

Example 20 2-16-M -Ethyl-3-(4-trifluoromethoxyphenyl)ureido1-3-trifluoromethox y-5, 6,7,8- tetrahvdronaphthalen-2-ylsulfanyl)-2-methylpropionic acid

Prepared as white solid by substituting 7-methoxy-2-tetralone with 7- methyl-2-tetralone in STEP A above. 1H NMR (300 MHz, CDCI3): δ 7.45-7.48 (d, 2H), 7.37 (s, 1 H), 7.12-7.18 (m, 3H), 4.44 (m, 1 H), 3.43-3.48 (m, 2H), 2.97-3.21 (m, 4H), 2.03-2.05 (m, 2H), 1.42 (s, 6H), 1.25-1.30 (t, 3H). MS, m/z: 580 (M+1 ) C25H26F6N2O5S.

Example 21 2-(6-f1-Ethyl-3-(4-trifluoromethoxyphenvπureidol-3-phenyl-5 .6,7,8- tetrahvdronaphthalen-2-ylsulfanyl)-2-methylpropionic acid

-92-

STEP A. 2-(6-Acetylamino-3-phenyl-5,6,7,8-tetrahvdronaphthalen-2-yls ulfanyl>- 2-methylpropionic acid fetf-butyl ester To 2-(6-acetylamino-3-bromo-5,6,7,8-tetrahydronaphthalen-2-ylsu lfanyl}- 2-methylpropionic acid terf-butyl ester (0.135 g; 0.30 mmol) dissolved in toluene (1.5 ml_) was added phenylboronic acid (0.178 g; 1.46 mmol), Pd(PPh3)4 (15 mg; 0.013 mmol) and 2M Na2CO3 (0.61 ml_) and the reaction mixture heated at 950C for 18 h. The reaction mixture was cooled, diluted with EtOAc, washed with H2O (2X), brine, dried over Na2SO4, filtered and the solvent removed under reduced pressure to yield a crude residue which was purified by flash chromatography (SiO2) eluting with a heptane-EtOAc gradient (50→100%) to yield 2-(6-acetylamino-3-phenyl-5,6,7,8-tetrahydronaphthalen-2- ylsulfanyl}-2-methyl-propionic acid te/f-butyl ester as a clear oil. MS, MIZ: 383 ((M-C4H8)+1) C26H33NO3S

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-pheny l-5,6,7,8- tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid, the compound of Example 21 was additionally prepared, as a white solid, according to the procedure described in Example 14, by selecting and substituting suitable reagents in Steps F, G and H, as appropriate. 1H NMR (300 MHz1 CDCI3): δ 7.45-7.48 (d, 2H), 7.29-7.38 (m, 6H), 7.15- 7.18 (d, 2H), 7.10 (s, 1 H), 4.46 (m, 1 H), 3.44-3.49 (m, 2H), 2.98-3.06 (m, 4H), 2.04-2.06 (m, 2H), 1.26-1.30 (t, 3H), 1.14 (s, 6H). MS1 M/Z: 573 (M+1 ) C25H29F3N2O5S

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be

-93- understood that the practice of the invention encompasses ail of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents. -94-