2-acylaminopropoanol-type glucosylceramide synthase inhibitors

Description

BACKGROUND OF THE INVENTION

Gangliosides, such as GM1, GM2 and GM3, are glycosphingolipids (GSLs) comprised of ceramide and at least one acidic sugar. Gangliosides are generally found in the outer leaflet of the plasma membrane (Nojri et al., Proc. Natl. Acad. ScL USA 83:782 (1986)). Gangliosides are involved in cell signaling and act as modulators of receptor activity (Yamashita et al., Proc. Natl. Acad. ScL USA 100(6):3445 (2003)). A number of GSLs are derived from glucosylceramide, which is enzymatically formed from ceramide and UDP-glucose. The formation of glucosylceramide is catalyzed by glucosylceramide synthase.

It has been found that the level of GSLs controls a variety of cell functions, such as growth, differentiation, adhesion between cells or between cells and matrix proteins, binding of microorganisms and viruses to cells, and metastasis of tumor cells. In addition, the glucosylceramide precursor, ceramide, may cause differentiation or inhibition of cell growth and be involved in the functioning of vitamin D₃, tumor necrosis factor-α, interleukins, and apoptosis. Sphingols, precursors of ceramide, and products of ceramide catabolism have also been shown to influence many cell systems, possibly by inhibiting protein kinase C.

Defects in GSL metabolizing enzymes can cause serious disorders. For example, Tay-Sachs, Gaucher's, and Fabry's diseases result from enzymatic defects in the GSL degradative pathway and the accumulation of GSL. In particular, GM1 accumulates in the nervous system leading to mental retardation and liver enlargement. In Tay-Sachs, GM2 accumulates in brain tissue leading to mental retardation and blindness. These observations suggest that inhibitors of glycosylceramide synthase can be effective in treating lysosomal diseases such as Tay-Sachs, Gaucher's, and Fabry's diseases. Indeed, glucosylceramide synthase inhibitors have been described for this purpose (see U.S. Pat. Nos. 6,569,889; 6,255,336; 5,916,911; 5,302,609; 6,660,749; 6,610,703; 5,472,969; and 5,525,616).

Recently it has been disclosed that the interruption of the insulin induced signaling cascade may be associated with elevated levels of GM3. It has also been suggested that the cytokine tumor necrosis factor-α (TNF-α), implicated in insulin resistance, results in increased expression of GM3 (Tagami et al., J. Biol. Chem. 277(5):3085 (2002)). Also, it has been disclosed that mutant mice lacking GM3 synthase, and thus lacking in GM3, are protected from insulin resistance caused by a high-fat diet (Yamashita et al., Proc. Natl. Acad. Sc. USA 100:3445-3449 (2003)). These observations suggest that inhibitors of glycosylceramide synthase can be effective in treating diabetes. Indeed, inhibitors of glucosylceramide synthase have been proposed for treating Type 2 diabetes (see WO 2006/053043).

Therefore, agents which inhibit glucosylceramide synthesis, or reduce intracellular content of GSLs, such as GM3, have the potential to treat conditions associated with altered GSL levels and/or GSL precursor levels. There is a need for additional agents which can act as glucosylceramide synthase inhibitors.

SUMMARY OF THE INVENTION

It has now been discovered that 2-acylaminopropoanol derivatives represented by Structural Formula (I) below can effectively inhibit glycosphingolipid synthesis, such as GM3 synthesis. As such, these compounds can be used for treating diabetes or lysosomal storage diseases, such as Tay-Sachs, Gaucher's or Fabry's disease. In addition, a number of these compounds were tested and found to significantly inhibit glycosphingolipid synthesis in animal tissues and to have high metabolic stability at the liver. These compounds can also be used for a subject having polycystic kidney disease (PKD). Based upon this discovery, novel 2-acylaminopropoanol derivatives, pharmaceutical compositions comprising the 2-acylaminopropoanol derivatives, and methods of treatment using the 2-acylaminopropoanol derivatives are disclosed herein.

In one embodiment, the present invention is directed to compounds represented by Structural Formula (I):

embedded image

and pharmaceutically acceptable salts thereof, wherein:

R¹is a substituted or unsubstituted aryl group;

Y is —H, a hydrolyzable group, or a substituted or unsubstituted alkyl group.

Alternatively, X is —O—, —S— or —NR⁷—; and R⁴is a substituted or unsubstituted aliphatic group, or substituted or unsubstituted aryl group;

Alternatively, X is —(CR⁵R⁶)_n—; and R⁴is a substituted or unsubstituted cyclic alkyl group, or a substituted or unsubstituted cyclic alkenyl group, a substituted or unsubstituted aryl group, —CN, —NCS, —NO₂or a halogen;

Alternatively, X is a covalent bond; and R⁴is a substituted or unsubstituted aryl group;

n is 1, 2, 3, 4, 5 or 6;

In another embodiment, the present invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound represented by Structural Formula (1) or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention is directed to a method of treating a subject having type 2 diabetes, comprising administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof.

A method of treating a subject having renal hypertrophy or hyperplasia associated with diabetic nephropathy is also included in the invention. The method comprises administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof.

A method of decreasing plasma TNF-α in a subject in need thereof is also included in the present invention. The method comprises administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof.

A method of lowering blood glucose levels in a subject in need thereof is also included in the present invention. The method comprises administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof.

A method of decreasing glycated hemoglobin levels in a subject in need thereof is also included in the present invention. The method comprises administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof.

A method of inhibiting glucosylceramide synthase or lowering glycosphingolipid concentrations in a subject in need thereof is also included in the present invention. The method comprises administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof.

A method of treating a subject with Tay-Sachs, Gaucher's or Fabry's disease is also included in the present invention. The method comprises administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof.

A method of treating a subject with polycystic kidney disease is also included in the present invention. The method comprises administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof.

Also, included in the present invention is the use of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament. The medicament is for treating a subject having type 2 diabetes; for treating a subject having renal hypertrophy or hyperplasia associated with diabetic nephropathy; for decreasing plasma TNF-α in a subject in need thereof; for lowering blood glucose levels in a subject in need thereof; for decreasing glycated hemoglobin levels in a subject in need thereof; for inhibiting glucosylceramide synthase or lowering glycosphingolipid concentrations in a subject in need thereof; or for treating a subject with Tay-Sachs, Gaucher's or Fabry's disease. Alternatively, the medicament is for treating a subject having polycystic kidney disease.

The compounds of the invention are inhibitors of glucosylceramide synthesis. As such, they can be used for treating various disorders associated with GSL metabolism, including diabetes and lysosomal storage diseases. The compounds of the invention can effectively inhibit glucosylceramide synthesis and at the same time have high metabolic stability at the liver. For example, the compounds of the invention can have a clearance value of less than 50%, and commonly less than 30%, at the liver relative to hepatic blood flow.

The present invention has many advantages. In particular, the present invention provides a treatment for PKD that addresses the underlying disease state, rather than simply ameliorating symptoms that are associated with PKD. Such compounds may reduce the need for kidney dialysis or transplant in patients suffering from PKD.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the invention is directed to a compound represented by Structural Formula (I), or a pharmaceutically acceptable salt thereof. A first set of values and preferred values for the variables in Structural Formula (I) is provided in the following paragraphs:

R¹is a substituted or unsubstituted aryl group, such as a substituted or unsubstituted phenyl group. Preferably, R¹is an aryl group optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl, Ar¹, —OR³⁰, —O(haloalkyl), —SR³⁰, —NO₂, —CN, —NCS, —N(R³¹)₂, —NR³¹C(O)R³⁰, —NR³¹C(O)OR³², —N(R³¹)C(O)N(R³¹)₂, —C(O)R³⁰, —C(S)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰, —C(O)N(R³¹)₂, —S(O)₂R³⁰, —SO₂N(R³¹)₂, —S(O)R³², —SO₃R³⁰, —NR³¹SO₂N(R³¹)₂, —NR³¹SO₂R³², —V_o—Ar¹, —V_o—OR³⁰, —V_o—O(haloalkyl), —V_o—SR³⁰, —V_o—NO₂, —V_o—CN, —V_o—N(R³¹)₂, —V_o—NR³¹C(O)R³⁰, —V_o—NR³¹CO₂R³², —V_o—N(R³¹)C(O)N(R³¹)₂, —V_o—C(O)R³⁰, —V_o—C(S)R³⁰, —V_o—CO₂R³⁰, —V_o—OC(O)R³⁰, —V_o—C(O)N(R³¹)₂—, —V_o—S(O)₂R³⁰, —V_o—SO₂N(R³¹)₂, —V_o—S(O)R³², —V_o—SO₃R³⁰, —V_o—NR³¹SO₂N(R³¹)₂, —V_o—NR³¹SO₂R³², —O—V_o—Ar¹, —O—V₁—N(R³¹)₂, —S—V_o—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_o—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —NR³¹C(O)—V_o—N(R³¹)₂, —NR³¹C(O)—V_o—Ar¹, —C(O)—V_o—N(R³¹)₂, —C(O)—V_o—Ar¹, —C(S)—V_o—N(R³¹)₂, —C(S)—V_o—Ar¹, —C(O)O—V₁—N(R³¹)₂, —C(O)O—V_o—Ar¹, —O—C(O)—V₁—N(R³¹)₂, —O—C(O)—V_o—Ar¹, —C(O)N(R³¹)—V₁—N(R³¹)₂, —C(O)N(R³¹)—V_o—Ar¹, —S(O)₂—V_o—N(R³¹)₂, —S(O)₂—V_o—Ar¹, —SO₂N(R³¹)—V₁—N(R³¹)₂, —SO₂N(R³¹)—V_o—Ar¹, —S(O)—V_o—N(R³¹)₂, —S(O)—V_o—Ar¹, —S(O)₂—O—V₁—N(R³¹)₂, —S(O)₂—O—V_o—Ar¹, —NR³¹SO₂—V_o—N(R³¹)₂, —NR³¹SO₂—V_o—Ar¹, —O—[CH₂]_p—O—, —S—[CH₂]_p—S—, or —[CH₂]_q—. More preferably, R¹is an aryl group, such as a phenyl group, optionally substituted with one or more halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹, —V_o—OR³⁰, —V_o—N(R³¹)₂, —V_o—Ar¹, —O—V_o—Ar¹, —O—V₁—N(R³¹)₂, —S—V_o—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_o—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —O—[CH₂]_p—O—, —S—[CH₂]_p—S—, or —[CH₂]_q—. More preferably, R¹is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl, aryloxy, —OH, C1-C6 alkoxy, —O—[CH₂]_p—O—, and —[CH₂]_q—. Even more preferably, R¹is a phenyl group optionally substituted with —OH, —OCH₃, —OC₂H₅or —O—[CH₂]_p—O—. Even more preferably, R¹is

embedded image

where r is 1, 2, 3 or 4, preferably 1 or 2.

Y is —H, a hydrolyzable group, or a substituted or unsubstituted alkyl group. Examples of hydrolyzable groups include —C(O)R, —C(O)OR, —C(O)NRR′, C(S)R, —C(S)OR, —C(O)SR or —C(S)NRR′. Preferably, Y is —H, —C(O)R, —C(O)OR or —C(O)NRR′; more preferably, —H.

R²and R³are each independently —H, a substituted or unsubstituted aliphatic group, or a substituted or unsubstituted aryl group, or R²and R³taken together with the nitrogen atom of N(R²R³) form a substituted or unsubstituted non-aromatic heterocyclic ring. Preferably, R²and R³taken together with the nitrogen atom of N(R²R³) form a 5- or 6-membered, optionally-substituted non-aromatic heterocyclic ring. More preferably, —N(R²R³) is an optionally substituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group. Even more preferably, —N(R²R³) is an unsubstituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group, preferably an unsubstituted pyrrolidinyl group.

Suitable substituents for the aliphatic and aryl groups represented by R²and R³, and suitable substituents for the non-aromatic heterocyclic ring represented by N(R²R³) each independently include halogen, alkyl, haloalkyl, —OR⁴⁰, —O(haloalkyl), —SR⁴⁰, —NO₂, —CN, —N(R⁴¹)₂, —NR⁴¹C(O)R⁴⁰, —NR⁴¹C(O)OR⁴², —N(R⁴¹)C(O)N(R⁴¹)₂, —C(O)R⁴⁰, —C(S)R⁴⁰, —C(O)OR⁴⁰, —OC(O)R⁴⁰, —C(O)N(R⁴¹)₂, —S(O)₂R⁴⁰, —SO₂N(R⁴¹)₂, —S(O)R⁴², —SO₃R⁴⁰, Ar², V₂—Ar², —V₂—OR⁴⁰, —V₂—O(haloalkyl), —V₂—SR⁴⁰, —V₂—NO₂, —V₂—CN, —V₂—N(R⁴¹)₂, —V₂—NR⁴¹C(O)R⁴⁰, —V₂—NR⁴¹CO₂R⁴², —V₂—N(R⁴¹)C(O)N(R⁴¹)₂, —V₂—C(O)R⁴⁰, —V₂—C(S)R⁴⁰, —V₂—CO₂R⁴⁰, —V₂—OC(O)R⁴⁰, —V₂—C(O)N(R⁴¹)₂—, —V₂—S(O)₂R⁴⁰, —V₂—SO₂N(R⁴¹)₂, —V₂—S(O)R⁴², —V₂—SO₃R⁴⁰, —O—V₂—Ar²and —S—V₂—Ar². Preferably, suitable substituents for the aliphatic and aryl groups represented by R²and R³, and suitable substituents for the non-aromatic heterocyclic ring represented by N(R²R³) each independently include halogen, alkyl, haloalkyl, —OR⁴⁰, —O(haloalkyl), —SR⁴⁰, —NO₂, —CN, —N(R⁴¹)₂, —C(O)R⁴⁰, —C(S)R⁴⁰, —C(O)OR⁴⁰, —OC(O)R⁴⁰, —C(O)N(R⁴¹)₂, Ar², V₂—Ar², —V₂—OR⁴⁰, —V₂—O(haloalkyl), —V₂—SR⁴⁰, —V₂—NO₂, —V₂—CN, —V₂—N(R⁴¹)₂, —V₂—C(O)R⁴⁰, —V₂—C(S)R⁴⁰, —V₂—CO₂R⁴⁰, —V₂—OC(O)R⁴⁰, —O—V₂—Ar²and —S—V₂—Ar². More preferably, suitable substituents for the aliphatic and aryl groups represented by R²and R³, and suitable substituents for the non-aromatic heterocyclic ring represented by N(R²R³) each independently include halogen, C1-C10 alkyl, C1-C10 haloalkyl, —O(C1-C10 alkyl), —O(phenyl), —O(C1-C10 haloalkyl), —S(C1-C10 alkyl), —S(phenyl), —S(C1-C10 haloalkyl), —NO₂, —CN, —NH(C1-C10 alkyl), —N(C1-C10 alkyl)₂, —NH(C1-C10 haloalkyl), —N(C1-C10 haloalkyl)₂, —NH(phenyl), —N(phenyl)₂, —C(O)(C1-C10 alkyl), —C(O)(C1-C10 haloalkyl), —C(O)(phenyl), —C(S)(C1-C10 alkyl), —C(S)(C1-C10 haloalkyl), —C(S)(phenyl), —C(O)O(C1-C10 alkyl), —C(O)O(C1-C10 haloalkyl), —C(O)O(phenyl), phenyl, —V₂-phenyl, —V₂—O-phenyl, —V₂—O(C1-C10 alkyl), —V₂—O(C1-C10 haloalkyl), —V₂—S-phenyl, —V₂—S(C1-C10 alkyl), —V₂—S(C1-C10 haloalkyl), —V₂—NO₂, —V₂—CN, —V₂—NH(C1-C10 alkyl), —V₂—N(C1-C10 alkyl)₂, —V₂—NH(C1-C10 haloalkyl), —V₂—N(C1-C10 haloalkyl)₂, —V₂—NH(phenyl), —V₂—N(phenyl)₂, —V₂—C(O)(C1-C10 alkyl), —V₂—C(O)(C1-C10 haloalkyl), —V₂—C(O)(phenyl), —V₂—C(S)(C1-C10 alkyl), —V₂—C(S)(C1-C10 haloalkyl), —V₂—C(S)(phenyl), —V₂—C(O)O(C1-C10 alkyl), —V₂—C(O)O(C1-C10 haloalkyl), —V₂—C(O)O(phenyl), —V₂—OC(O)(C1-C10 alkyl), —V₂—OC(O)(C1-C10 haloalkyl), —V₂—OC(O)(phenyl), —O—V₂-phenyl and —S—V₂-phenyl. Even more preferably, suitable substituents for the aliphatic and aryl groups represented by R²and R³, and suitable substituents for the non-aromatic heterocyclic ring represented by N(R²R³) each independently include halogen, C1-C5 alkyl, C1-C5 haloalkyl, hydroxy, C1-C5 alkoxy, nitro, cyano, C1-C5 alkoxycarbonyl, C1-C5 alkylcarbonyl, C1-C5 haloalkoxy, amino, C1-C5 alkylamino and C1-C5 dialkylamino.

X is —(CR⁵R⁶)_n-Q-; Q is —O—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —C(S)S—, —C(O)NR⁷—, —NR⁷—, —NR⁷C(O)—, —NR⁷C(O)NR⁷—, —OC(O)—, —SO₃—, —SO—, —S(O)₂—, —SO₂NR⁷—, or —NR⁷SO₂—; and R⁴is —H, a substituted or unsubstituted aliphatic group, or a substituted or unsubstituted aryl group. Preferably, Q is —O—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —C(S)S—, —C(O)NR⁷—, —NR⁷C(O)NR⁷—, —OC(O)—, —SO₃—, —SO—, —S(O)₂—, —SO₂NR⁷— or —NR⁷SO₂—. More Preferably, Q is —O—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —C(S)S—, —C(O)NR⁷— or —OC(O)—. Even more preferably, Q is —O—, —S—, —C(O)— or —C(S)—.

Alternatively, X is —O—, —S— or —NR⁷—; and R⁴is a substituted or unsubstituted aliphatic group, or substituted or unsubstituted aryl group.

In another alternative, X is —(CR⁵R⁶)_n—; and R⁴is a substituted or unsubstituted cyclic alkyl (e.g., C3-C8) group, or a substituted or unsubstituted cyclic alkenyl (C3-C8) group, a substituted or unsubstituted aryl group, —CN, —NCS, —NO₂or a halogen.

In another alternative, X is a covalent bond; and R⁴is a substituted or unsubstituted aryl group.

Preferably, R⁴is an optionally substituted aliphatic, such as a lower alkyl, or aryl group. More preferably, R⁴is an optionally substituted aryl or lower arylalkyl group. Even more preferably, R⁴is selected from the group consisting of:

embedded image

wherein each of rings A-Z5 is optionally and independently substituted; and each x is independently 0 or 1, specifically x is 0. Even more preferably, R⁴is an optionally substituted

embedded image

group. Alternatively, R⁴is an optionally substituted phenyl group. Alternatively, R⁴is an aryl group substituted with Ar³, such as a phenyl group substituted with Ar³. It is noted that, as shown above, rings A-Z5 can be attached to variable “X” of Structural Formula (I) through —(CH₂)_x— at any ring carbon of rings A-Z5 which is not at a position bridging two aryl groups. For example, R⁴represented by

embedded image

means that R⁴is attached to variable “X” through either ring J or ring K.

Preferred substituents for each of the aliphatic group and the aryl group represented by R⁴, including lower alkyl, arylalkyl and rings A-Z5, include halogen, alkyl, haloalkyl, Ar³, Ar³—Ar³, —OR⁵⁰, —O(haloalkyl), —SR⁵⁰, —NO₂, —CN, —NCS, —N(R⁵¹)₂, —NR⁵¹C(O)R⁵⁰, —NR⁵¹C(O)OR⁵², —N(R⁵¹)C(O)N(R⁵¹)₂, —C(O)R⁵⁰, —C(S)R⁵⁰, —C(O)OR⁵⁰, —OC(O)R⁵⁰, —C(O)N(R⁵¹)₂, —S(O)₂R⁵⁰, —SO₂N(R⁵¹)₂, —S(O)R⁵², —SO₃R⁵⁰, —NR⁵¹SO₂N(R⁵¹)₂, —NR⁵¹SO₂R⁵², —V₄—Ar³, —V—OR⁵⁰, —V₄—O(haloalkyl), —V₄—SR⁵⁰, —V₄—NO₂, —V₄—CN, —V₄—N(R⁵¹)₂, —V₄—NR⁵¹C(O)R⁵⁰, —V₄—NR⁵¹CO₂R⁵², —V₄—N(R⁵¹)C(O)N(R⁵¹)₂, —V₄—C(O)R⁵⁰, —V₄—C(S)R⁵⁰, —V₄—CO₂R⁵⁰, —V₄—OC(O)R⁵⁰, —V₄—C(O)N(R⁵¹)₂—, —V₄—S(O)₂R⁵⁰, —V₄—SO₂N(R⁵¹)₂, —V₄—S(O)R⁵², —V₄—SO₃R⁵⁰, —V₄—NR⁵¹SO₂N(R⁵¹)₂, —V₄—NR⁵¹SO₂R⁵², —O—V₄—Ar³, —O—V₅—N(R⁵¹)₂, —S—V₄—Ar³, —S—V₅—N(R⁵¹)₂, —N(R⁵¹)—V₄—Ar³, —N(R⁵¹)—V₅—N(R⁵¹)₂, —NR⁵¹C(O)—V₄—N(R⁵¹)₂, —NR⁵¹C(O)—V₄—Ar³, —C(O)—V₄—N(R⁵¹)₂, —C(O)—V₄—Ar³, —C(S)—V₄—N(R⁵¹)₂, —C(S)—V₄—Ar³, —C(O)O—V₅—N(R⁵¹)₂, —C(O)O—V₄—Ar³, —O—C(O)—V₅—N(R⁵¹)₂, —O—C(O)—V₄—Ar³, —C(O)N(R⁵¹)—V₅—N(R⁵¹)₂, —C(O)N(R⁵¹)—V₄—Ar³, —S(O)₂—V₄—N(R⁵¹)₂, —S(O)₂—V₄—Ar³, —SO₂N(R⁵¹)—V₅—N(R⁵¹)₂, —SO₂N(R⁵¹)—V₄—Ar³, —S(O)—V₄—N(R⁵¹)₂, —S(O)—V₄—Ar³, —S(O)₂—O—V₅—N(R⁵¹)₂, —S(O)₂—O—V₄—Ar³, —NR⁵¹SO₂—V₄—N(R⁵¹)₂, —NR⁵¹SO₂—V₄—Ar³, —O—[CH₂]_p′—O—, —S—[CH₂]_p′—S—, and —[CH₂]_q′—. More preferably, substituents for each of the aliphatic group and the aryl group represented by R⁴, including lower alkyl, arylalkyl and rings A-Z5, include halogen, C1-C10 alkyl, C1-C10 haloalkyl, Ar³, Ar³—Ar³, —OR⁵⁰, —O(haloalkyl), —SR⁵⁰, —NO₂, —CN, —N(R⁵¹)₂, —NR⁵¹C(O)R⁵⁰, —C(O)R⁵⁰, —C(O)OR⁵⁰, —OC(O)R⁵⁰, —C(O)N(R⁵¹)₂, —V₄—Ar³, —V—OR⁵⁰, —V₄—O(haloalkyl), —V₄—SR⁵⁰, —V₄—NO₂, —V₄—CN, —V₄—N(R⁵¹)₂, —V₄—NR⁵¹C(O)R⁵⁰, —V₄—C(O)R⁵⁰, —V₄—CO₂R⁵⁰, —V₄—OC(O)R⁵⁰, —V₄—C(O)N(R⁵¹)₂—, —O—V₄—Ar³, —O—V₅—N(R⁵¹)₂, —S—V₄—Ar³, —S—V₅—N(R⁵¹)₂, —N(R⁵¹)—V₄—Ar³, —N(R⁵¹)—V₅—N(R⁵¹)₂, —NR⁵¹C(O)—V₄—N(R⁵¹)₂, —NR⁵¹C(O)—V₄—Ar³, —C(O)—V₄—N(R⁵¹)₂, —C(O)—V₄—Ar³, —C(O)O—V₅—N(R⁵¹)₂, —C(O)O—V₄—Ar³, —O—C(O)—V₅—N(R⁵¹)₂, —O—C(O)—V₄—Ar³, —C(O)N(R⁵¹)—V₅—N(R⁵¹)₂, —C(O)N(R⁵¹)—V₄—Ar³, —O—[CH₂]_p′—O— and —[CH₂]_q′—. More preferably, substituents for each of the aliphatic group and the aryl group represented by R⁴, including lower alkyl, arylalkyl and rings A-Z5, include halogen, cyano, nitro, C1-C10 alkyl, C1-C10 haloalkyl, amino, C1-C10 alkylamino, C1-C10 dialkylamino, aryl, aryloxy, hydroxy, C1-10 alkoxy, —O—[CH₂]_p—O— or —[CH₂]_q—. Even more preferably, substituents for each of the aliphatic group and the aryl group represented by R⁴, including lower alkyl, arylalkyl and rings A-Z5, include halogen, cyano, amino, nitro, Ar³, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy and C1-C6 haloalkoxy. Even more preferably, substituents for each of the aliphatic and aryl groups represented by R⁴, including lower alkyl, arylalkyl and rings A-Z5, include —OH, —OCH₃, —OC₂H₅and —O—[CH₂]_p′—O—. Preferably, phenyl ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C10 alkyl, C1-C10 haloalkyl, amino, C1-C10 alkylamino, C1-C10 dialkylamino, —OR⁵⁰, —Ar³, —V₄—Ar³, —V—OR⁵⁰, —O(C1-C10 haloalkyl), —V₄—O(C1-C10 haloalkyl), —O—V₄—Ar³, —O—[CH₂]_p—O— and —[CH₂]_q—. More preferably, phenyl ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C10 alkyl, C1-C10 haloalkyl, amino, C1-C10 alkylamino, C1-C10 dialkylamino, aryl, aryloxy, hydroxy, C1-10 alkoxy, —O—[CH₂]_p—O— and —[CH₂]_q—. Even more preferably, phenyl ring A is optionally substituted with one or more substituents selected from the group consisting of —OH, —OCH₃and —OC₂H₅. Specifically, when R⁴is phenyl ring A, at least one of the substituents of ring A is at the para position.

R⁵and R⁶are each independently —H, —OH, —SH, a halogen, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted lower alkylthio group, or a substituted or unsubstituted lower aliphatic group. Preferably, R⁵and R⁶are each independently —H; —OH; a halogen; or a lower alkoxy or lower alkyl group. More preferably, R⁵and R⁶are each independently —H, —OH or a halogen. Even more preferably, R⁵and R⁶are each independently —H.

Each R⁷is independently —H, a substituted or unsubstituted aliphatic group, or a substituted or unsubstituted aryl group, or R⁷and R⁴taken together with the nitrogen atom of NR⁷R⁴form a substituted or unsubstituted non-aromatic heterocyclic group. Preferably, each R⁷is independently —H, an aliphatic group or phenyl. Even more preferably, each R⁷is independently —H or C1-C6 alkyl.

Each n is independently 1, 2, 3, 4, 5 or 6. Preferably, each n is independently 1, 2, 3 or 4. Alternatively, each n is independently 2, 3, 4 or 5.

Each p is independently 1, 2, 3 or 4, preferably 1 or 2.

Each q is independently 3, 4, 5 or 6, preferably 3 or 4.

Each p′ is independently 1, 2, 3 or 4, preferably 1 or 2.

Each q′ is independently 3, 4, 5 or 6, preferably 3 or 4.

Each V_ois independently a C1-C10 alkylene group, preferably C1-C4 alkylene group.

Each V₁is independently a C2-C10 alkylene group, specifically C2-C4 alkylene group.

Each V₂is independently a C1-C4 alkylene group.

Each V₄is independently a C1-C10 alkylene group, preferably a C1-C4 alkylene group.

Each V₅is independently a C2-C10 alkylene group, preferably a C2-C4 alkylene group.

Each Ar¹is an aryl group optionally and independently substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy and haloalkyl. Preferably, Ar¹is an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. More preferably, Ar¹is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

Each Ar²is an aryl group optionally and independently substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino.

Each Ar³is independently an aryl group, such as phenyl, each optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy and haloalkyl. Preferably, Ar³is independently an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C10 alkyl, C1-C10 haloalkyl, hydroxy, C1-C10 alkoxy, nitro, cyano, C1-C10 alkoxycarbonyl, C1-C10 alkylcarbonyl, C1-C10 haloalkoxy, amino, C1-C10 alkylamino and C1-C10 dialkylamino. Even more preferably, Ar³is independently an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 alkoxy, nitro, cyano, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, C1-C4 haloalkoxy, amino, C1-C4 alkylamino and C1-C4 dialkylamino.

Each R³⁰is independently hydrogen; an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl and alkylcarbonyl. Preferably, each R³⁰is independently hydrogen; an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or an C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C1 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl and C1-C6 alkylcarbonyl. More preferably, each R³⁰is independently hydrogen; a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or an C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C1 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl and C1-C6 alkylcarbonyl.

Each R³¹is independently R³⁰, —CO₂R³⁰, —SO₂R³⁰or —C(O)R³⁰, or —N(R³¹)₂taken together is an optionally substituted non-aromatic heterocyclic group. Preferably, each R³¹is independently R³⁰, or —N(R³¹)₂is an optionally substituted non-aromatic heterocyclic group.

Each R³²is independently an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl and alkylcarbonyl. Preferably, each R³²is independently an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C1 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl and C1-C6 alkylcarbonyl. More preferably, each R³²is independently a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy and C1-C6 haloalkyl; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C1 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl and C1-C6 alkylcarbonyl.

Each R⁴⁰is independently hydrogen; an aryl group, such as a phenyl group, optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino.

Each R⁴¹is independently R⁴⁰, —CO₂R⁴⁰, —SO₂R⁴⁰or —C(O)R⁴⁰, or —N(R⁴¹)₂taken together is an optionally substituted non-aromatic heterocyclic group.

Each R⁴²is independently an aryl group, such as a phenyl group, optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino.

Each R⁵⁰is independently hydrogen; an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl. Preferably, each R⁵⁰is independently hydrogen; an aryl group, such as a phenyl group, optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino.

Each R⁵¹is independently R⁵⁰, —CO₂R⁵⁰, —SO₂R⁵⁰or —C(O)R⁵⁰, or —N(R⁵¹)₂taken together is an optionally substituted non-aromatic heterocyclic group. Preferably, each R⁵¹is independently R⁵⁰, or —N(R³¹)₂is an optionally substituted non-aromatic heterocyclic group.

Each R⁵²is independently an aryl group optionally substituted with one or two substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl. Preferably, each R⁵²is independently an aryl group, such as a phenyl group, optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino and C1-C6 dialkylamino.

R and R′ are each independently —H; a lower aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —CN, —NCS, —NO₂, —NH₂, lower alkoxy, lower haloalkoxy and aryl; or an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —CN, —NCS, —NO₂, —NH₂, lower alkoxy, lower haloalkoxy, lower aliphatic group and lower haloaliphatic group; or R and R′ taken together with the nitrogen atom of NRR′ form a non-aromatic heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of: halogen; —OH; —CN; —NCS; —NO₂; —NH₂; lower alkoxy; lower haloalkoxy; lower aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —CN, —NCS, —NO₂, —NH₂, lower alkoxy, lower haloalkoxy and aryl; and aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —CN, —NCS, —NO₂, —NH₂, lower alkoxy, lower haloalkoxy, lower aliphatic group and lower haloaliphatic group. Preferably, R and R′ are each independently —H; a lower aliphatic group; a lower aliphatic group substituted with phenyl; or an aryl group. More preferably, R and R′ are each independently —H, C1-C4 alkyl, phenyl or benzyl.

A second set of values for the variables in Structural Formula (I) is provided in the following paragraphs:

Y is —H, —C(O)R, —C(O)OR or —C(O)NRR′, preferably —H.

R¹is an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, Ar¹, —OR³⁰, —O(haloalkyl), —SR³⁰, —NO₂, —CN, —NCS, —N(R³¹)₂, —NR³¹C(O)R³⁰, —NR³¹C(O)OR³², —N(R³¹)C(O)N(R³¹)₂, —C(O)R³⁰, —C(S)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰, —C(O)N(R³¹)₂, —S(O)₂R³⁰, —SO₂N(R³¹)₂, —S(O)R³², —SO₃R³⁰, —NR³¹SO₂N(R³¹)₂, —NR³¹SO₂R³², —V_o—OR³⁰, —V_o—O(haloalkyl), —V_o—SR³⁰, —V_o—NO₂, —V_o—CN, —V_o—N(R³¹)₂, —V_o—NR³¹C(O)R³⁰, —V_o—NR³¹CO₂R³², —V_o—N(R³¹)C(O)N(R³¹)₂, —V_o—C(O)R³⁰, —V_o—C(S)R³⁰, —V_o—CO₂R³⁰, —V_o—OC(O)R³⁰, —V_o—C(O)N(R³¹)₂—, —V_o—S(O)₂R³⁰, —V_o—SO₂N(R³¹)₂, —V_o—S(O)R³², —V_o—SO₃R³⁰, —V_o—NR³¹SO₂N(R³¹)₂, —V_o—NR³¹SO₂R³², —O—V_o—Ar¹, —O—V₁—N(R³¹)₂, —S—V_o—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_o—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —NR³¹C(O)—V_o—N(R³¹)₂, —NR³¹C(O)—V_o—Ar¹, —C(O)—V_o—N(R³¹)₂, —C(O)—V_o—Ar¹, —C(S)—V_o—N(R³¹)₂, —C(S)—V_o—Ar¹, —C(O)O—V₁—N(R³¹)₂, —C(O)O—V_o—Ar¹, —O—C(O)—V₁—N(R³¹)₂, —O—C(O)—V_o—Ar¹, —C(O)N(R³¹)—V₁—N(R³¹)₂, —C(O)N(R³¹)—V_o—Ar¹, —S(O)₂—V_o—N(R³¹)₂, —S(O)₂—V_o—Ar¹, —SO₂N(R³¹)—V₁—N(R³¹)₂, —SO₂N(R³¹)—V_o—Ar¹, —S(O)—V_o—N(R³¹)₂, —S(O)—V_o—Ar¹, —S(O)₂—O—V₁—N(R³¹)₂, —S(O)₂—O—V_o—Ar¹, —NR³¹SO₂—V_o—N(R³¹)₂, —NR³¹—SO₂—V_o—Ar¹, —O—[CH₂]_p—O—, —S—[CH₂]_p—S— and —[CH₂]_q—.

Values and preferred values for the remainder of the variables of Structural Formula (I) are each independently as described above for the first set of values.

A third set of values for the variables in Structural Formula (I) is provided in the following four paragraphs.

Y is —H, —C(O)R, —C(O)OR or —C(O)NRR′, preferably —H.

R¹is an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, Ar¹, —OR³⁰, —O(haloalkyl), —SR³⁰, —NO₂, —CN, —NCS, —N(R³¹)₂, —NR³¹C(O)R³⁰, —NR³¹C(O)OR³², —N(R³¹)C(O)N(R³¹)₂, —C(O)R³⁰, —C(S)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰, —C(O)N(R³¹)₂, —S(O)₂R³⁰, —SO₂N(R³¹)₂, —S(O)R³², —SO₃R³⁰, —NR³¹SO₂N(R³¹)₂, —NR³¹SO₂R³², —V_o—Ar¹, —V_o—OR³⁰, —V_o—O(haloalkyl), —V_o—SR³⁰, —V_o—NO₂, —V_o—CN, —V_o—N(R³¹)₂, —V_o—NR³¹C(O)R³⁰, —V_o—NR³¹CO₂R³², —V_o—N(R³¹)C(O)N(R³¹)₂, —V_o—C(O)R³⁰, —V_o—C(S)R³⁰, —V_o—CO₂R³⁰, —V_o—OC(O)R³⁰, —V_o—C(O)N(R³¹)₂—, —V_o—S(O)₂R³⁰, —V_o—SO₂N(R³¹)₂, —V_o—S(O)R³², —V_o—SO₃R³⁰, —V_o—NR³¹SO₂N(R³¹)₂, —V_o—NR³¹SO₂R³², —O—V_o—Ar¹, —O—V₁—N(R³¹)₂, —S—V_o—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_o—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —NR³¹C(O)—V_o—N(R³¹)₂, —NR³¹C(O)—V_o—Ar¹, —C(O)—V_o—N(R³¹)₂, —C(O)—V_o—Ar¹, —C(S)—V_o—N(R³¹)₂, —C(S)—V_o—Ar¹, —C(O)O—V₁—N(R³¹)₂, —C(O)O—V_o—Ar¹, —O—C(O)—V₁—N(R³¹)₂, —O—C(O)—V_o—Ar¹, —C(O)N(R³¹)—V₁—N(R³¹)₂, —C(O)N(R³¹)—V_o—Ar¹, —S(O)₂—V_o—N(R³¹)₂, —S(O)₂—V_o—Ar¹, —SO₂N(R³¹)—V₁—N(R³¹)₂, —SO₂N(R³¹)—V_o—Ar¹, —S(O)—V_o—N(R³¹)₂, —S(O)—V_o—Ar¹, —S(O)₂—O—V₁—N(R³¹)₂, —S(O)₂—O—V_o—Ar¹, —NR³¹SO₂—V_o—N(R³¹)₂, —NR³¹SO₂—V_o—Ar¹, —O—[CH₂]_p—O—, —S—[CH₂]_p—S— and —[CH₂]_q—.

R²and R³taken together with the nitrogen atom of N(R²R³) form a 5- or 6-membered, optionally-substituted non-aromatic heterocyclic ring. Examples of suitable substituents for the non-aromatic heterocyclic ring represented by —NR²R³are as described in the first set of values for Structural Formula (I).

Values and preferred values for the remainder of the variables of Structural Formula (I) are as described above for the first set of values.

A fourth set of values for the variables in Structural Formula (I) is provided in the following paragraphs:

Y is —H, —C(O)R, —C(O)OR or —C(O)NRR′, preferably —H.

R¹is an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, Ar¹, —OR³⁰, —O(haloalkyl), —SR³⁰, —NO₂, —CN, —NCS, —N(R³¹)₂, —NR³¹C(O)R³⁰, —NR³¹C(O)OR³², —N(R³¹)C(O)N(R³¹)₂, —C(O)R³⁰, —C(S)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰, —C(O)N(R³¹)₂, —S(O)₂R³⁰, —SO₂N(R³¹)₂, —S(O)R³², —SO₃R³⁰, —NR³¹SO₂N(R³¹)₂, —NR³¹SO₂R³², —V_o—Ar¹, —V_o—OR³⁰, —V_o—O(haloalkyl), —V_o—SR³⁰, —V_o—NO₂, —V_o—CN, —V_o—N(R³¹)₂, —V_o—NR³¹C(O)R³⁰, —V_o—NR³¹CO₂R³², —V_o—N(R³¹)C(O)N(R³¹)₂, —V_o—C(O)R³⁰, —V_o—C(S)R³⁰, —V_o—CO₂R³⁰, —V_o—OC(O)R³⁰, —V_o—C(O)N(R³¹)₂—, —V_o—S(O)₂R³⁰, —V_o—SO₂N(R³¹)₂, —V_o—S(O)R³², —V_o—SO₃R³⁰, —V_o—NR³¹SO₂N(R³¹)₂, —V_o—NR³¹SO₂R³², —O—V_o—Ar¹, —O—V₁—N(R³¹)₂, —S—V_o—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_o—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —NR³¹C(O)—V_o—N(R³¹)₂, —NR³¹C(O)—V_o—Ar¹, —C(O)—V_o—N(R³¹)₂, —C(O)—V_o—Ar¹, —C(S)—V_o—N(R³¹)₂, —C(S)—V_o—Ar¹, —C(O)O—V₁—N(R³¹)₂, —C(O)O—V_o—Ar¹, —O—C(O)—V₁—N(R³¹)₂, —O—C(O)—V_o—Ar¹, —C(O)N(R³¹)—V₁—N(R³¹)₂, —C(O)N(R³¹)—V_o—Ar¹, —S(O)₂—V_o—N(R³¹)₂, —S(O)₂—V_o—Ar¹, —SO₂N(R³¹)—V₁—N(R³¹)₂, —SO₂N(R³¹)—V_o—Ar¹, —S(O)—V_o—N(R³¹)₂, —S(O)—V_o—Ar¹, —S(O)₂—O—V₁—N(R³¹)₂, —S(O)₂—O—V_o—Ar¹, —NR³¹SO₂—V_o—N(R³¹)₂, —NR³¹SO₂—V_o—Ar¹, —O—[CH₂]_p—O—, —S—[CH₂]_p—S— and —[CH₂]_q—.

R²and R³taken together with the nitrogen atom of N(R²R³) form a 5- or 6-membered, optionally-substituted non-aromatic heterocyclic ring.

R⁵and R⁶are each independently —H, —OH, a halogen, a lower alkoxy group or a lower alkyl group.

Values and preferred values of the remainder of the variables of Structural Formula (I) are each independently as described above for the first set of values.

A fifth set of values for the variables in Structural Formula (I) is provided in the following paragraphs:

Y is —H, —C(O)R, —C(O)OR or —C(O)NRR′, preferably —H.

R¹is an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, Ar¹, —OR³⁰, —O(haloalkyl), —SR³⁰, —NO₂, —CN, —NCS, —N(R³¹)₂, —NR³¹C(O)R³⁰, —NR³¹C(O)OR³², —N(R³¹)C(O)N(R³¹)₂, —C(O)R³⁰, —C(S)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰, —C(O)N(R³¹)₂, —S(O)₂R³⁰, —SO₂N(R³¹)₂, —S(O)R³², —SO₃R³⁰, —NR³¹SO₂N(R³¹)₂, —NR³¹SO₂R³², —V_o—Ar¹, —V_o—OR³⁰, —V_o—O(haloalkyl), —V_o—SR³⁰, —V_o—NO₂, —V_o—CN, —V_o—N(R³¹)₂, —V_o—NR³¹C(O)R³⁰, —V_o—NR³¹CO₂R³², —V_o—N(R³¹)C(O)N(R³¹)₂, —V_o—C(O)R³⁰, —V_o—C(S)R³⁰, —V_o—CO₂R³⁰, —V_o—OC(O)R³⁰, —V_o—C(O)N(R³¹)₂—, —V_o—S(O)₂R³⁰, —V_o—SO₂N(R³¹)₂, —V_o—S(O)R³², —V_o—SO₃R³⁰, —V_o—NR³¹SO₂N(R³¹)₂, —V_o—NR³¹SO₂R³², —O—V_o—Ar¹, —O—V₁—N(R³¹)₂, —S—V_o—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_o—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —NR³¹C(O)—V_o—N(R³¹)₂, —NR³¹C(O)—V_o—Ar¹, —C(O)—V_o—N(R³¹)₂, —C(O)—V_o—Ar¹, —C(S)—V_o—N(R³¹)₂, —C(S)—V_o—Ar¹, —C(O)O—V₁—N(R³¹)₂, —C(O)O—V_o—Ar¹, —O—C(O)—V₁—N(R³¹)₂, —O—C(O)—V_o—Ar¹, —C(O)N(R³¹)—V₁—N(R³¹)₂, —C(O)N(R³¹)—V_o—Ar¹, —S(O)₂—V_o—N(R³¹)₂, —S(O)₂—V_o—Ar¹, —SO₂N(R³¹)—V₁—N(R³¹)₂, —SO₂N(R³¹)—V_o—Ar¹, —S(O)—V_o—N(R³¹)₂, —S(O)—V_o—Ar¹, —S(O)₂—O—V₁—N(R³¹)₂, —S(O)₂—O—V_o—Ar¹, —NR³¹SO₂—V_o—N(R³¹)₂, —NR³¹SO₂—V_o—Ar¹, —O—[CH₂]_p—O—, —S—[CH₂]_p—S— and —[CH₂]_q—.

R²and R³taken together with the nitrogen atom of N(R²R³) form a 5- or 6-membered, optionally-substituted non-aromatic heterocyclic ring.

R⁴is an aliphatic or aryl group each optionally substituted with one or more substituents. Examples of suitable substituents are as described above for the first set of values.

R⁵and R⁶are each independently —H, —OH, a halogen, a lower alkoxy group or a lower alkyl group.

Values and preferred values of the remainder of the variables of Structural Formula (I) are each independently as described above for the first set of values.

A sixth set of values for the variables in Structural Formula (I) is provided in the following paragraphs:

Y is —H, —C(O)R, —C(O)OR or —C(O)NRR′, preferably —H.

R¹is an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, Ar¹, —OR³⁰, —O(haloalkyl), —SR³⁰, —NO₂, —CN, —NCS, —N(R³¹)₂, —NR³¹C(O)R³⁰, —NR³¹C(O)OR³², —N(R³¹)C(O)N(R³¹)₂, —C(O)R³⁰, —C(S)R³⁰, —C(O)OR³⁰, —OC(O)R³⁰, —C(O)N(R³¹)₂, —S(O)₂R³⁰, —SO₂N(R³¹)₂, —S(O)R³², —SO₃R³⁰, —NR³¹SO₂N(R³¹)₂, —NR³¹SO₂R³², —V_o—Ar¹, —V_o—OR³⁰, —V_o—O(haloalkyl), —V_o—SR³⁰, —V_o—NO₂, —V_o—CN, —V_o—N(R³¹)₂, —V_o—NR³¹C(O)R³⁰, —V_o—NR³¹CO₂R³², —V_o—N(R³¹)C(O)N(R³¹)₂, —V_o—C(O)R³⁰, —V_o—C(S)R³⁰, —V_o—CO₂R³⁰, —V_o—OC(O)R³⁰, —V_o—C(O)N(R³¹)₂—, —V_o—S(O)₂R³⁰, —V_o—SO₂N(R³¹)₂, —V_o—S(O)R³², —V_o—SO₃R³⁰, —V_o—NR³¹SO₂N(R³¹)₂, —V_o—NR³¹SO₂R³², —O—V_o—Ar¹, —O—V₁—N(R³¹)₂, —S—V_o—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_o—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —NR³¹C(O)—V_o—N(R³¹)₂, —NR³¹C(O)—V_o—Ar¹, —C(O)—V_o—N(R³¹)₂, —C(O)—V_o—Ar¹, —C(S)—V_o—N(R³¹)₂, —C(S)—V_o—Ar¹, —C(O)O—V₁—N(R³¹)₂, —C(O)O—V_o—Ar¹, —O—C(O)—V₁—N(R³¹)₂, —O—C(O)—V_o—Ar¹, —C(O)N(R³¹)—V₁—N(R³¹)₂, —C(O)N(R³¹)—V_o—Ar¹, —S(O)₂—V_o—N(R³¹)₂, —S(O)₂—V_o—Ar¹, —SO₂N(R³¹)—V₁—N(R³¹)₂, —SO₂N(R³¹)—V_o—Ar¹, —S(O)—V_o—N(R³¹)₂, —S(O)—V_o—Ar¹, —S(O)₂—O—V₁—N(R³¹)₂, —S(O)₂—O—V_o—Ar¹, —NR³¹SO₂—V_o—N(R³¹)₂, —NR³¹SO₂—V_o—Ar¹, —O—[CH₂]_p—O—, —S—[CH₂]_p—S— and —[CH₂]_q—.

R²and R³taken together with the nitrogen atom of N(R²R³) form a 5- or 6-membered, optionally-substituted non-aromatic heterocyclic ring.

R⁴is an optionally substituted cyclic alkyl group, or an optionally substituted cyclic alkenyl group, an optionally substituted aryl group, —CN, —NCS, —NO₂or a halogen. Examples of suitable substituents are as described above for the first set.

R⁵and R⁶are each independently —H, —OH, a halogen, a lower alkoxy group or a lower alkyl group.

Values and preferred values of the remainder of the variables of Structural Formula (I) are each independently as described above for the first set of values.

A seventh set of values and preferred values for the variables in Structural Formula (I) is provided in the following paragraphs:

Values and preferred values of R¹, Y, R², R³, R⁵and R⁶are each independently as described above for the sixth set.

R⁴is an optionally substituted cyclic alkyl group, or an optionally substituted cyclic alkenyl group, or an optionally substituted aryl group, specifically optionally substituted aryl group. Examples of suitable substituents are as described above for the first set.

Values and preferred values of the remainder of the variables of Structural Formula (I) are each independently as described above for the first set of values.

In a second embodiment, the compound of the invention is represented by Structural Formula (II), (III), (IV), (V), (VI), (VII) or (VIII):

embedded image

or a pharmaceutically acceptable salt thereof. A first set of values for the variables of Structural Formulas (II)-(VIII) is provided in the following paragraphs:

R¹is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹, —V_o—OR³⁰, —V_o—N(R³¹)₂, —V_o—Ar¹, —O—V_o—Ar¹, —O—V₁—N(R³¹)₂, —S—V_o—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_o—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —O—[CH₂]_p—O—, —S—[CH₂]_p—S— and —[CH₂]_q—. Preferably, R¹is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl, aryloxy, —OH, C1-C6 alkoxy, —O—[CH₂]_p—O— and —[CH₂]_q—.

Ar¹is an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Preferably, Ar¹is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

Each R³¹is independently R³⁰, or —N(R³¹)₂is an optionally substituted non-aromatic heterocyclic group. Examples of suitable substituents are as described above in the first set of values for Structural Formula (I).

R²and R³taken together with the nitrogen atom of N(R²R³) form a 5- or 6-membered, optionally-substituted non-aromatic heterocyclic ring. Examples of suitable substituents for the non-aromatic heterocyclic ring represented by —NR²R³are as described above in the first set of values for Structural Formula (I).

R⁴is an aliphatic or aryl group each optionally substituted with one or more substituents described above in the first set of values for Structural Formula (I).

R⁵and R⁶for Structural Formulas (II), (III) and (V) are each independently —H, —OH, a halogen, a lower alkoxy group or a lower alkyl group.

For Structural Formula (VIII), R⁷is —H or C1-C6 alkyl, preferably —H.

Values and preferred values of the remainder of the variables of Structural Formulas (II)-(VIII) are each independently as described above in the first set of values for Structural Formula (I).

A second set of values for the variables in Structural Formulas (II)-(VIII) is provided in the following paragraphs:

R¹is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹, —V_o—OR³⁰, —V_o—N(R³¹)₂, —V_o—Ar¹, —O—V_o—Ar¹, —O—V₁—N(R³¹)₂, —S—V_o—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_o—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —O—[CH₂]_p—O—, —S—[CH₂]_p—S—, or —[CH₂]_q—. Preferably, R¹is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl, aryloxy, —OH, C1-C6 alkoxy, —O—[CH₂]_p—O— and —[CH₂]_q—.

Each R³¹is independently R³⁰, or —N(R³¹)₂is an optionally substituted non-aromatic heterocyclic group.

—N(R²R³) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C5 alkyl, C1-C5 haloalkyl, hydroxyl, C1-C5 alkoxy, nitro, cyano, C1-C5 alkoxycarbonyl, C1-C5 alkylcarbonyl or C1-C5 haloalkoxy, amino, C1-C5 alkylamino and C1-C5 dialkylamino.

R⁴is an aliphatic or aryl group each optionally substituted with one or more substituents. Examples of suitable substituents are described above in the first set of values for Structural Formula (I).

R⁵and R⁶for Structural Formulas (II), (III) and (V) are each independently —H, —OH, a halogen, a lower alkoxy group or a lower alkyl group.

For Structural Formula (VIII), R⁷is —H or C1-C6 alkyl, preferably —H.

Values and preferred values of the remainder of the variables of Structural Formulas (II)-(VIII) are each independently as described above in the first set of values for Structural Formula (I).

A third set of values for the variables in Structural Formulas (II)-(VIII) is provided in the following paragraphs:

R¹is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹, —V_o—OR³⁰, —V_o—N(R³¹)₂, —V_o—Ar¹, —O—V_o—Ar¹, —O—V₁—N(R³¹)₂, —S—V_o—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_o—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —O—[CH₂]_p—O —, —S—[CH₂]_p—S—, or —[CH₂]_q—. Preferably, R¹is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl, aryloxy, —OH, C1-C6 alkoxy, —O—[CH₂]_p—O— and —[CH₂]_q—.

Each R³¹is independently R³⁰, or —N(R³¹)₂is an optionally substituted non-aromatic heterocyclic group.

R⁴is an optionally substituted aryl or an optionally substituted lower arylalkyl group. Example of suitable substituents are as described in the first set of values for Structural Formula (I).

R⁵and R⁶for Structural Formulas (II), (III) and (V) are each independently —H, —OH, a halogen, a lower alkoxy group or a lower alkyl group.

For Structural Formula (VIII), R⁷is —H.

Preferably, Q in Structural Formula (II) is —O—, —S—, —C(O)—, —C(S)—, —NR⁷(CO)— or —C(O)NR⁷—

A fourth set of values for the variables in Structural Formulas (II)-(VIII) is provided in the following paragraphs:

R¹is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹, —V_o—OR³⁰, —V_o—N(R³¹)₂, —V_o—Ar¹, —O—V_o—Ar¹, —O—V₁—N(R³¹)₂, —S—V_o—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_o—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —O—[CH₂]_p—O—, —S—[CH₂]_p—S—, or —[CH₂]_q—. Preferably, R¹is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl, aryloxy, —OH, C1-C6 alkoxy, —O—[CH₂]_p—O— and —[CH₂]_q—.

Ar¹is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

Each R³¹is independently R³⁰, or —N(R³¹)₂is an optionally substituted non-aromatic heterocyclic group.

—N(R²R³) is a pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group, which is optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C5 alkyl, C1-C5 haloalkyl, hydroxyl, C1-C5 alkoxy, nitro, cyano, C1-C5 alkoxycarbonyl, C1-C5 alkylcarbonyl or C1-C5 haloalkoxy, amino, C1-C5 alkylamino and C1-C5 dialkylamino.

R⁴is an optionally substituted aryl or an optionally substituted lower arylalkyl group. Examples of suitable substitutents for R⁴are as provided above in the first set of values for Structural Formula (I). Preferably, R⁴is selected from the group consisting of:

embedded image

Each of rings A-Z5 is optionally and independently substituted.

For Structural Formula (VIII), R⁷is —H.

Values and preferred values of the remainder of the variables of Structural Formulas (II)-(VIII) are each independently as described above in the first set of values for Structural Formula (I). When the compound of the invention is represented by Structural Formula (III) or (IV), or a pharmaceutically acceptable salt thereof, n is 1, 2, 3 or 4. Alternatively, when the compound of the invention is represented by Structural Formula (V) or (VI), or a pharmaceutically acceptable salt thereof, n is 3, 4 or 5.

A fifth set of values for the variables in Structural Formulas (II)-(VIII) independently is as defined in the first set, second set, third set, fourth set, fifth set, sixth set or seventh set of values for the variables for Structural Formula (I).

In a third embodiment, the compound of the invention is represented by Structural Formula (IX) or (X):

embedded image

or a pharmaceutically acceptable salt thereof. A first set of values for the variables in Structural Formulas (IX) and (X) is defined in the following paragraphs:

R¹is a phenyl group optionally substituted with one or more substituents. Examples of suitable substituents include halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹, —V_o—OR³⁰, —V_o—N(R³¹)₂, —V_o—Ar¹, —O—V_o—Ar¹, —O—V₁—N(R³¹)₂, —S—V_o—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_o—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —O—[CH₂]_p—O—, —S—[CH₂]_p—S—, and —[CH₂]_q—; preferably, R¹is a phenyl group optionally substituted with one or more substituents selected from the group consisting of —OH, —OCH₃, —OC₂H₅and —O—[CH₂]_p—O—.

Phenyl ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C10 alkyl, C1-C10 haloalkyl, amino, C1-C10 alkylamino, C1-C10 dialkylamino, —OR⁵⁰, —Ar³, —V₄—Ar³, —V—OR⁵⁰, —O(C1-C10 haloalkyl), —V₄—O(C1-C10 haloalkyl), —O—V₄—Ar³, —O—[CH₂]_p′—O— and —[CH₂]_q′—.

Ar³is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

Each R⁵⁰is independently hydrogen; a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or an C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

For Structural Formula (IX), n is 1, 2, 3 or 4. For Structural Formula (X), n is 3, 4 or 5.

Values and preferred values of the remainder of the variables of Structural Formulas (IX) and (X) are each independently as defined above in the first set of values for Structural Formula (I).

A second set of values and preferred values for the variables in Structural Formulas (IX) and (X) is as defined in the following paragraphs:

R¹is a phenyl group optionally substituted with one or more substituents selected from the group consisting of —OH, —OCH₃, —OC₂H₅and —O—[CH₂]_p—O—.

—N(R²R³) is pyrrolidinyl.

Phenyl ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C10 alkyl, C1-C10 haloalkyl, amino, C1-C10 alkylamino, C1-C10 dialkylamino, aryl, aryloxy, hydroxy, C1-C10 alkoxy, —O—[CH₂]_p′—O— and —[CH₂]_q′—. Preferably, phenyl ring A is optionally substituted with one or more substituents selected from the group consisting of —OH, —OCH₃or —OC₂H₅.

For Structural Formula (IX), n is 1, 2, 3 or 4. For Structural Formula (X), n is 3, 4 or 5.

Values and preferred values of the remaining variables of Structural Formulas (IX) and (X) are each independently as described above in the first set of values for Structural Formula (I).

A third set of values for the variables in Structural Formulas (IX) and (X) independently is as defined in the first set, second set, third set, fourth set or fifth set, of values for Structural Formulas (II)-(VIII).

In a fourth embodiment, the compound of the invention is represented by Structural Formula (XI), (XII) or (XIII):

embedded image

or a pharmaceutically acceptable salt thereof. A first set of values and preferred values for the variables of Structural Formulas (XI)-(XIII) is defined in the following paragraphs:

R¹is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹, —V_o—OR³⁰, —V_o—N(R³¹)₂, —V_o—Ar¹, —O—V_o—Ar¹, —O—V₁—N(R³¹)₂, —S—V_o—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_o—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —O—[CH₂]_p—O—, —S—[CH₂]_p—S—, or —[CH₂]_q—. Preferably, R¹is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl, aryloxy, —OH, C1-C6 alkoxy, —O—[CH₂]_p—O— and —[CH₂]_q—.

R²and R³taken together with the nitrogen atom of N(R²R³) form a 5- or 6-membered, optionally-substituted non-aromatic heterocyclic ring. Examples of suitable substituents for the non-aromatic heterocyclic group represented by —NR²R³are as described above in the first set of values for Structural Formula (I).

R⁴is an optionally substituted aryl group. Examples of suitable substituents for R⁴are as provided above in the first set of values for Structural Formula (I).

R⁵and R⁶for Structural Formula (XI) are each independently —H, —OH, a halogen, a lower alkoxy group or a lower alkyl group.

Values and preferred values of the remainder of the variables of Structural Formulas (XI)-(XIII) are each independently as described above in the first set of values for Structural Formula (I).

A second set of values and preferred values for the variables of Structural Formulas (XI)-(XIII) is defined in the following paragraphs:

R¹is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹, —V_o—OR³⁰, —V_o—N(R³¹)₂, —V_o—Ar¹, —O—V_o—Ar¹, —O—V₁—N(R³¹)₂, —S—V_o—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_o—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —O—[CH₂]_p—O—, —S—[CH₂]_p—S—, or —[CH₂]_q—. Preferably, R¹is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl, aryloxy, —OH, C1-C6 alkoxy, —O—[CH₂]_p—O—, and —[CH₂]_q—.

Ar¹is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

Each R³¹is independently R³⁰, or —N(R³¹)₂is an optionally substituted non-aromatic heterocyclic group.

R⁴is an optionally substituted aryl group. Suitable substituents and preferred substitutents are as provided above in the first set of values for Structural Formula (I). Preferably, R⁴is selected from the group consisting of:

embedded image

Each of rings A-Z5 is optionally and independently substituted. Preferably, each of rings A-Z5 is optionally and independently substituted with one or more substituents selected from Ar³and Ar³—Ar³wherein values and preferred values of Ar³are as described above for the first set of values for Structural Formula (I). Preferably, Ar³is an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C10 alkyl, C1-C10 haloalkyl, hydroxy, C1-C10 alkoxy, nitro, cyano, C1-C10 alkoxycarbonyl, C1-C10 alkylcarbonyl, C1-C10 haloalkoxy, amino, C1-C10 alkylamino and C1-C10 dialkylamino. More preferably, Ar³is an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 alkoxy, nitro, cyano, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, C1-C4 haloalkoxy, amino, C1-C4 alkylamino and C1-C4 dialkylamino.

R⁵and R⁶for Structural Formula (XI) are each independently —H, —OH, a halogen, a lower alkoxy group or a lower alkyl group.

Values and preferred values of the remainder of the variables of Structural Formulas (XI)-(XIII) are each independently as described above in the first set of values for Structural Formula (I).

A third set of values for the variables of Structural Formulas (XI)-(XIII) is defined in the following paragraphs:

R¹is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹, —V_o—OR³⁰, —V_o—N(R³¹)₂, —V_o—Ar¹, —O—V_o—Ar¹, —O—V₁—N(R³¹)₂, —S—V_o—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_o—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —O—[CH₂]_p—O—, —S—[CH₂]_p—S—, or —[CH₂]_q—. Preferably, R¹is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl, aryloxy, —OH, C1-C6 alkoxy, —O—[CH₂]_p—O—, and —[CH₂]_q—.

Ar¹is a phenyl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.

Each R³¹is independently R³⁰, or —N(R³¹)₂is an optionally substituted non-aromatic heterocyclic group.

—N(R²R³) is an unsubstituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group.

R⁴is a biaryl group, such as a biphenyl group, optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, amino, nitro, Ar³, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy and C1-C6 haloalkoxy.

R⁵and R⁶for Structural Formula (XI) are each independently —H, —OH, a halogen, a lower alkoxy group or a lower alkyl group, preferably —H.

Values and preferred values of the remainder of the variables of Structural Formulas (XI)-(XIII) are each independently as described above in the first set of values for Structural Formula (I).

A fourth set of values for the variables of Structural Formulas (XI)-(XIII) is defined in the following paragraphs:

R¹is a phenyl group optionally substituted with one or more substituents selected from the group consisting of —OH, —OCH₃, —OC₂H₅and —O—[CH₂]_p—O—,

Preferably, R¹is

embedded image

where r is 1, 2, 3 or 4, preferably 1 or 2.

—N(R²R³) is an unsubstituted pyrrolidinyl group.

R⁵and R⁶for Structural Formula (XI) are each independently —H, —OH, a halogen, a lower alkoxy group or a lower alkyl group, preferably —H.

n is an integer from 1 to 4.

Values and preferred values of the remainder of the variables of Structural Formulas (XI)-(XIII) are each independently as described above in the first set of values for Structural Formula (I).

A fifth set of values preferred values for the variables of Structural Formulas (XI)-(XIII) is defined in the following paragraphs:

R¹is a phenyl group optionally substituted with one or more substituents selected from the group consisting of —OH, —OCH₃, —OC₂H₅and —O—[CH₂]_p—O—.

Preferably R¹is

embedded image

where r is 1, 2, 3 or 4, preferably 1 or 2.

—N(R²R³) is pyrrolidinyl.

R⁴is

embedded image

optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, amino, nitro, Ar³, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy and C1-C6 haloalkoxy.

n is 1.

R⁵and R⁶for Structural Formula (XI) are each independently —H, —OH, a halogen, a lower alkoxy group or a lower alkyl group, preferably —H.

Values and preferred values of the remainder of the variables of Structural Formulas (XI)-(XIII) are each independently as described above in the first set of values for Structural Formula (I).

A sixth set of values for the variables in Structural Formulas (XI)-(XIII) independently is as defined in the first set, second set, third set, fourth set, fifth set, sixth set or seventh set of values for Structural Formula (I).

In a fifth embodiment, the compound of the invention is represented by Structural Formula (XIV) or (XV):

embedded image

or a pharmaceutically acceptable salt thereof. A first set of values and preferred values for the variables in Structural Formulas (XIV) and (XV) is as defined in the following paragraphs:

R¹is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, —OR³⁰, —SR³⁰, —N(R³¹)₂, Ar¹, —V_o—OR³⁰, —V_o—N(R³¹)₂, —V_o—Ar¹, —O—V_o—Ar¹, —O—V₁—N(R³¹)₂, —S—V_o—Ar¹, —S—V₁—N(R³¹)₂, —N(R³¹)—V_o—Ar¹, —N(R³¹)—V₁—N(R³¹)₂, —O—[CH₂]_p—O—, —S—[CH₂]_p—S—, or —[CH₂]_q—. Preferably, R¹is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, aryl, aryloxy, —OH, C1-C6 alkoxy, —O—[CH₂]_p—O—, and —[CH₂]_q—.

Each R³¹is independently R³⁰, or —N(R³¹)₂is an optionally substituted non-aromatic heterocyclic group.

k is 0, 1, 2, 3, 4, 5 or 6.

R⁸is —H, or an optionally substituted aryl or an optionally substituted lower alkyl group. Examples of suitable substituents are as described for the first set of values for Structural Formula (I). Preferably, R⁸is selected from the group consisting of:

embedded image

Each of rings A-Z5 is optionally and independently substituted. Examples of suitable substituents for R⁸are as provided above in the first set of values for R⁴in Structural Formula (I). More preferably, R⁸is a

embedded image

group. Alternatively R⁸is an aryl group substituted with Ar³, such as a phenyl group substituted with Ar³, where values and preferred values of Ar³are as described above in Structural Formula (I).

Values and preferred values of the remainder of the variables of Structural Formulas (XIV) and (XV) are each independently as described above in the first set of values for Structural Formula (I).

A second set of values for the variables in Structural Formulas (XIV) and (XV) is defined in the following paragraphs:

Each R³¹is independently R³⁰, or —N(R³¹)₂is an optionally substituted non-aromatic heterocyclic group.

—N(R²R³) is an unsubstituted pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl group, preferably an unsubstituted pyrrolidinyl group.

Values and preferred values for k and R⁸are as provided above in the first set of values for Structural Formulas (XIV) and (XV).

Values and preferred values of the remainder of the variables of Structural Formulas (XIV) and (XV) are each independently as described above in the first set of values for Structural Formula (I).

A third set of values for the variables in Structural Formulas (XIV) and (XV) is defined in the following paragraphs:

R¹is a phenyl group optionally substituted with one or more substituents selected from the group consisting of —OH, —OCH₃, —OC₂H₅and —O—[CH₂]_p—O—.

Preferably R¹is

embedded image

where r is 1, 2, 3 or 4, preferably 1 or 2.

—N(R²R³) is pyrrolidinyl.

Values and preferred values for k and R⁸are each independently as provided above in the first set of values for Structural Formulas (XIV) and (XV).

Values and preferred values of the remainder of the variables of Structural Formulas (XIV) and (XV) are each independently as described above in the first set of values for Structural Formula (I).

A fourth set of values for the variables in Structural Formulas (XIV)-(XV) is as defined in the first set, second set, third set, fourth set, fifth set, sixth set or seventh set for Structural Formula (I).

In a sixth embodiment, the compound of the invention is represented by Structural Formula (XXI):

embedded image

or a pharmaceutically acceptable salt thereof. A first set of values and preferred values for the variables in Structural Formula (XXI) is as defined in the following paragraphs:

Each of A and B independently is halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

k′ is 0, 1 or 2.

k″ is 0, 1 or 2. Preferably, k″ is 0 or 1. More preferably k″ is 1.

m′ is 0, 1 or 2. Preferably, m′ is 1.

Values and preferred values for the remainder of the variables of Structural Formula (XXI) are each independently as described above in the first set of values for Structural Formula (I).

A second set of values for the variables in Structural Formula (XXI) is provided in the following paragraphs:

Y is —H, —C(O)R, —C(O)OR or —C(O)NRR′, preferably —H.

Values and preferred values for A, B, k′, k″ and m′ are each independently as described above in the first set of values for Structural Formula (XXI).

Values and preferred values for the remainder of the variables of Structural Formula (XXI) are each independently as described above in the first set of values for Structural Formula (I).

A third set of values for the variables in Structural Formula (XXI) is provided in the following paragraphs:

R³⁰is independently hydrogen; an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Preferably, R³⁰is independently hydrogen; a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. More preferably, R³⁰is independently hydrogen; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Even more preferably, R³⁰is independently hydrogen, or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkoxy, C1-C6 haloalkoxy and hydroxy.

Values and preferred values for A, B, Y, k′, k″ and m′ are each independently as described above in the second set of values for Structural Formula (XXI).

Values and preferred values for the remainder of the variables of Structural Formula (XXI) are each independently as described above in the first set of values for Structural Formula (I).

A fourth set of values for the variables in Structural Formula (XXI) is provided in the following paragraphs:

Y is —H.

Values and preferred values for R³⁰, A, B, k′, k″ and m′ are each independently as described above in the third set of values for Structural Formula (XXI).

Values and preferred values for the remainder of the variables of Structural Formula (XXI) are each independently as described above in the first set of values for Structural Formula (I).

In a seventh embodiment, the compound of the invention is represented by Structural Formula (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX) or (XXXI):

embedded image

or a pharmaceutically acceptable salt thereof. A first set of values and preferred values for the variables in Structural Formulas (XXII)-(XXXI) is as defined in the following paragraphs:

Each of A and B independently is halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

Each R³⁰is independently hydrogen; a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. Preferably, R³⁰is independently hydrogen; or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl. More preferably, R³⁰is independently hydrogen, or a C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkoxy, C1-C6 haloalkoxy and hydroxy.

Each k′ is independently 0, 1 or 2.

Each k″ is independently 0, 1 or 2.

Each m′ is independently 0, 1 or 2. Preferably, each m′ is 1.

Each n is independently 1, 2, 3, 4, 5 or 6. Preferably, each n in Structural Formulas (XXV) and (XXVI) is independently 1, 2, 3 or 4, and each n in Structural Formulas (XXIII) or (XXIV) is independently 2, 3, 4 or 5.

Values and preferred values for the remainder of the variables of Structural Formulas (XXII)-(XXXI) are each independently as described above in the first set of values for Structural Formula (I).

A second set of values for the variables in Structural Formulas (XXII)-(XXXI) is provided in the following paragraphs:

Each R⁴in Structural Formulas (XXII)-(XXVIII) is independently an aliphatic or aryl group each optionally substituted with one or more substituents described above in the first set of values for Structural Formula (I). Preferably, each R⁴in Structural Formulas (XXII)-(XXVIII) is independently an optionally substituted aryl or an optionally substituted lower arylalkyl group. Examples of suitable substituents are as described in the first set of values for Structural Formula (I).

Each R⁴in Structural Formulas (XXIX)-(XXXI) is independently an aryl group optionally substituted with one or more substituents described above in the first set of values for Structural Formula (I).

R⁵and R⁶in Structural Formulas (XXII), (XXIII), (XV) and (XXIX) are each independently —H, —OH, a halogen, a C1-C6 alkoxy group or a C1-C6 alkyl group.

For Structural Formula (XXVIII), R⁷is —H or C1-C6 alkyl, preferably —H.

Values and preferred values for A, B, R³⁰, k′, k″, m′ and n are each independently as described above in the first set of values for the variables in Structural Formulas (XXII)-(XXXI). Preferably, each n in Structural Formulas (XXV) and (XXVI) is independently 1, 2, 3 or 4, and each n in Structural Formulas (XXIII) or (XXIV) is independently 2, 3, 4 or 5.

Values and preferred values for the remainder of the variables of Structural Formulas (XXII)-(XXXI) are each independently as described above in the first set of values for Structural Formula (I).

A third set of values for the variables in Structural Formulas (XXII)-(XXXI) is provided in the following paragraphs:

Each R⁴in Structural Formulas (XXII)-(XXVIII) is independently an optionally substituted aryl or an optionally substituted lower arylalkyl group. Example of suitable substituents are as described in the first set of values for Structural Formula (I). Each R⁴in Structural Formulas (XXIX)-(XXXI) is independently an aryl group optionally substituted with one or more substituents described above in the first set of values for Structural Formula (I).

R⁵and R⁶for Structural Formulas (XXII), (XXIII), (XXV) and (XXIX) are each independently —H, —OH, a halogen, a lower alkoxy group or a lower alkyl group.

For Structural Formula (XXVIII), R⁷is —H.

Q in Structural Formula (XXII) is —O—, —S—, —C(O)—, —C(S)—, —NR⁷(CO)— or —C(O)NR⁷—.

Values and preferred values for the remainder of the variables of Structural Formulas (XXII)-(XXXI) are each independently as described above in the first set of values for Structural Formula (I).

A fourth set of values for the variables in Structural Formulas (XXII)-(XXXI) is provided in the following paragraphs:

Each R⁴in Structural Formulas (XXII)-(XXVIII) is independently selected from the group consisting of:

embedded image

wherein each x is independently 0 or 1, and each of rings A-Z5 is optionally and independently substituted.

Each R⁴in Structural Formulas (XXIX)-(XXXI) is independently selected from the group consisting of:

embedded image

wherein each of rings A-Z5 is optionally and independently substituted. Preferably, each R⁴in Structural Formulas (XXII)-(XXXI) is independently monocyclic.

Example of suitable substituents for rings A-Z5 are as described in the first set of values for Structural Formula (I).

Preferably, in Structural Formulas (XXIX)-(XXXI), each of rings A-Z5 is optionally and independently substituted with one or more substituents selected from Ar³and Ar³—Ar³wherein values and preferred values of Ar³are as described above for the first set of values for Structural Formula (I). Preferably, Ar³is an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C10 alkyl, C1-C10 haloalkyl, hydroxy, C1-C10 alkoxy, nitro, cyano, C1-C10 alkoxycarbonyl, C1-C10 alkylcarbonyl, C1-C10 haloalkoxy, amino, C1-C10 alkylamino and C1-C10 dialkylamino. More preferably, Ar³is an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 alkoxy, nitro, cyano, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, C1-C4 haloalkoxy, amino, C1-C4 alkylamino and C1-C4 dialkylamino.

Values and preferred values for R⁵, R⁶, R⁷, R³⁰, Q, k′, k″, m′ and n are each independently as described above in the third set of values for the variables in Structural Formulas (XXII)-(XXXII). Preferably, each n in Structural Formulas (XXV) and (XXVI) is independently 1, 2, 3 or 4, and each n in Structural Formulas (XXIII) or (XXIV) is independently 2, 3, 4 or 5.

Values and preferred values for the remainder of the variables of Structural Formulas (XXII)-(XXXI) are each independently as described above in the first set of values for Structural Formula (I).

A fifth set of values for the variables in Structural Formulas (XXII)-(XXXI) is provided in the following paragraphs:

Each R⁴in Structural Formulas (XXII)-(XXVIII) is independently

embedded image

wherein x is 0 or 1.

Each R⁴in Structural Formulas (XXIX)-(XXXI) is independently

embedded image

Each ring A is optionally substituted. Example of suitable substituents for rings A are as described in the first set of values for Structural Formula (I).

Preferably, ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, amino, nitro, Ar³, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy and C1-C6 haloalkoxy.

Ar³is an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy, C1-C4 alkoxy, nitro, cyano, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, C1-C4 haloalkoxy, amino, C1-C4 alkylamino and C1-C4 dialkylamino.

Values and preferred values for A, B, R⁵, R⁶, R⁷, R³⁰, k′, k″, m′ and n are each independently as described above in the fourth set of values for the variables in Structural Formulas (XXII)-(XXXI).

Values and preferred values for the remainder of the variables of Structural Formulas (XXII)-(XXXI) are each independently as described above in the first set of values for Structural Formula (I).

A sixth set of values for the variables other than A, B, k′, k″ and m′ in Structural Formulas (XXII)-(XXXI) is as defined in the first set, second set, third set, fourth set, fifth set, sixth set or seventh set of values for the variables for Structural Formula (I), and values and preferred values for A, B, k′, k″ and m′ are each independently as described above in the first set of values for the variables in Structural Formulas (XXII)-(XXXI).

In an eighth embodiment, the compound of the invention is represented by Structural Formula (XXXII) or (XXXIII):

embedded image

or a pharmaceutically acceptable salt thereof. A first set of values and preferred values for the variables in Structural Formulas (XXXII)-(XXXIII) is as defined in the following paragraphs:

Each of A and B independently is halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

Each k′ is independently 0, 1 or 2.

Each k″ is independently 0, 1 or 2.

Each m′ is independently 0, 1 or 2.

Each q is independently 0, 1, 2, 3, 4, 5 or 6.

Each R⁸independently is —H, or an optionally substituted aryl or an optionally substituted lower alkyl group. Examples of suitable substituents are as described for the first set of values for Structural Formula (I). Preferably, each R⁸independently is selected from the group consisting of:

embedded image

group. Alternatively, each R⁸is independently an aryl group substituted with Ar³, such as a phenyl group substituted with Ar³, where values and preferred values of Ar³are as described above in Structural Formula (I).

Values and preferred values for the remainder of the variables of Structural Formulas (XXXII)-(XXXIII) are each independently as described above in the first set of values for Structural Formula (I).

In one preferred embodiment, each k in Structural Formulas (XXI)-(XXXIII) is independently 0 or 1. Preferably, when k′ is 1, each A independently is positioned at a meta position of the phenyl ring.

In another preferred embodiment, each k″ in Structural Formulas (XXI)-(XXXIII) is independently 0 or 1, more preferably 1.

In yet another preferred embodiment, each m′ in Structural Formulas (XXI)-(XXXIII) is independently 1.

In yet another preferred embodiment, each k in Structural Formulas (XXI)-(XXXIII) is independently 0 or 1; and each k″ in Structural Formulas (XXI)-(XXXIII) is independently 0 or 1, more preferably 1.

In yet another preferred embodiment, in Structural Formulas (XXI)-(XXXIII).

Each R³⁰is independently hydrogen or a C1-C6 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C3 alkylamino, C1-C3 dialkylamino, C1-C3 alkoxy, nitro, cyano, hydroxy, C1-C3 haloalkoxy, C1-C3 alkoxycarbonyl and C1-C3 alkylcarbonyl;

each k′ in Structural Formulas (XXI)-(XXXIV) is independently 0 or 1. Preferably, when k′ is 1, each A independently is positioned at a meta position of the phenyl ring; and

each k″ in Structural Formulas (XXI)-(XXXIV) is independently 0 or 1, preferably 1.

In yet another preferred embodiment, in Structural Formulas (XXI)-(XXXIII):

Each —OR³⁰is independently —OH or —O—C1-C6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C3 C1-C3 alkoxy, hydroxy and C1-C3 haloalkoxy;

each k′ in Structural Formulas (XXI)-(XXXIII) is independently 0 or 1. Preferably, when k′ is 1, each A is independently positioned at a meta position of the phenyl ring; and

each k″ in Structural Formulas (XXI)-(XXXIII) is independently 0 or 1, preferably 1.

In one more preferred embodiment, the compound of the invention is represented by Structural Formula (XVIA) or (XVIB):

embedded image

or a pharmaceutically acceptable salt thereof, wherein: Q is —O—, —C(O)— or —NH, specifically, —O— or —C(O)—; r and s are each independently 1, 2, 3 or 4; each n independently is 1, 2, 3, 4, 5 or 6; and R⁴has values and preferred values provided above in the first set of values for Structural Formula (I).

In another more preferred embodiment, the compound of the invention is represented by Structural Formula (XVIC) or (XVID):

embedded image

or a pharmaceutically acceptable salt thereof, wherein:

Q is —O—, —C(O)— or —NH, specifically, —O— or —C(O)—;

r and s are each independently 1, 2, 3 or 4;

each n independently is 1, 2, 3, 4, 5 or 6;

R⁴has values and preferred values provided above in the first set of values for Structural Formula (I); and

B is halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy. Preferably, B is halogen, hydroxy, C1-C5 alkoxy or C1-C5 haloalkoxy.

In another more preferred embodiment, the compound of the invention is represented by Structural Formula (XVII), (XVIII), (XIX) or (XIX):

embedded image

or a pharmaceutically acceptable salt thereof, wherein phenyl ring A is optionally substituted; each n is 1, 2, 3, 4, 5, or 6; and k is 0, 1 or 2. Values and preferred values of suitable substituents of phenyl ring A are as described above in the first set of values for Structural Formula (I).

In all of the embodiments described above for Structural Formulas (XXI)-(XXXIII) and (XVIC)-(XVID), the heterocyclic ring represented by

embedded image

can be replaced with a bridged heterobicyclic ring comprising 5-12 ring carbon atoms and 1 or 2 nitrogen atoms. The invention also includes compounds represented by Structural Formulas (XXI)-(XXXIII) and (XVIC)-(XVID) with this replacement of

embedded image

with a bridged heterobicyclic ring comprising 5-12 ring carbon atoms and 1 or 2 nitrogen atoms. Values, including preferred values, for the variables other than B, k″ and m′ in Structural Formulas (XXI)-(XXXIII) and (XVIC)-(XVID) are as defined above with respect to Structural Formulas (XXI)-(XXXIIII) and (XVIC)-(XVID).

Similarly, in all of the embodiments described above for Structural Formulas (I)-(XX), the non-aromatic heterocyclic ring represented by —NR²R³can be a bridged heterobicyclic ring comprising 5-12 ring carbon atoms and 1 or 2 nitrogen atoms.

Examples of bridged eterobicyclic ring comprising 5-12 ring carbon atoms and 1 or 2 nitrogen atoms include

embedded image

The bridged bicyclic ring carbon atoms can be optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, —OH, —SH, —O(C1-C6 alkyl), —S(C1-C6 alkyl), —O(C1-C6 haloalkyl), —S(C1-C6 haloalkyl), C1-C6 alkyl, C1-C6 haloalkyl, amino, C1-C6 alkylamino and C1-C6 dialkylamino. Alternatively, the bridged bicyclic ring carbon atoms can be optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —O(C1-C6 alkyl) and —O(C1-C6 haloalkyl). The bridged bicyclic ring nitrogen atoms can be optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl and phenyl, the alkyl being optionally substituted with halogen, cyano, nitro, —OH, —SH, —O(C1-C6 alkyl), —S(C1-C6 alkyl), —O(C1-C6 haloalkyl), —S(C1-C6 haloalkyl), phenyl, amino, C1-C6 alkylamino and C1-C6 dialkylamino, and the phenyl being optionally substituted with halogen, cyano, nitro, —OH, —SH, —O(C1-C6 alkyl), —S(C1-C6 alkyl), —O(C1-C6 haloalkyl), —S(C1-C6 haloalkyl), C1-C6 alkyl, C1-C6 haloalkyl, amino, C1-C6 alkylamino and C1-C6 dialkylamino. Alternatively, the bridged bicyclic ring nitrogen atoms can be optionally substituted with C1-C6 alkyl that is optionally substituted with halogen, —OH, —O(C1-C6 alkyl) and —O(C1-C6 haloalkyl).

In another embodiment, the compound of the invention is represented by a structural formula selected from Structural Formulas (I)-(VIII) and (XI)-(XV), wherein values, including preferred values, of the variables in the structural formulas, other than R³⁰, R³¹and R³²for the substituents of R¹, are independently as defined in each embodiment described above for Structural Formulas (I)-(VIII) and (XI)-(XV). In this embodiment, each R³⁰is independently: i) hydrogen; ii) an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; or iii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, phenyl, phenylamino, diphenylamino, aryloxy, benzoyl, phenoxycarbonyl, alkylamino, dialkylamino, alkoxy, alkoxycarbonyl and alkylcarbonyl. Each R³¹is independently R³⁰, —CO₂R³⁰, —SO₂R³⁰or —C(O)R³⁰, or —N(R³¹)₂taken together is an optionally substituted non-aromatic heterocyclic group. Each R³²is independently: i) an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkylcarbonyl and haloalkoxy and haloalkyl; or ii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, phenyl, phenylamino, diphenylamino, aryloxy, benzoyl, phenoxycarbonyl, alkylamino, dialkylamino, alkoxy, alkoxycarbonyl and alkylcarbonyl. Each of the phenyl, phenylamino, diphenylamino, aryloxy, benzoyl, phenoxycarbonyl for the substituents of the alkyl group represented by R³⁰and R³²is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 alkoxy, C1-C5 haloalkoxy, C1-C5 alkylamino, C1-C5 dialkylamino, (C1-C5 alkoxy)carbonyl and (C1-C5 alkyl)carbonyl. Each of the alkylamino, dialkylamino, alkoxy, alkoxycarbonyl and alkylcarbonyl for the substituents of the alkyl group represented by R³⁰and R³²is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, phenyl, C1-C5 alkoxy, C1-C5 haloalkoxy, phenylamino, C1-C5 alkylamino, C1-C5 dialkylamino, diphenylamino, (C1-C5 alkoxy)carbonyl, (C1-C5 alkyl)carbonyl, benzoyl and phenoxycarbonyl.

Specific examples of the compounds of the invention are shown below:

embedded image

and pharmaceutically acceptable salts thereof.

Other specific examples of the compounds of the invention include compounds shown in Tables 1 and 2 and those exemplified in the examples below, stereoisomers thereof, and pharmaceutically acceptable salts thereof.

Also included are solvates, hydrates or polymorphs of the disclosed compounds herein. Thus, it is to be understood that when any compound is referred to herein by name and structure, solvates, hydrates and polymorphs thereof are included.

The compounds of the invention may contain one or more chiral centers and/or double bonds and, therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. When compounds of the invention are depicted or named without indicating the stereochemistry, it is to be understood that both stereomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and stereoisomeric mixtures are encompassed. For example, the compound represented by Structural Formula (I) below has chiral centers 1 and 2. Accordingly, the compounds of the invention depicted by Structural Formula (I) include (1R,2R), (1R,2S), (1S,2R) and (1S,2S) stereoisomers and mixtures thereof.

embedded image

As used herein, a racemic mixture means about 50% of one enantiomer and about 50% of is corresponding enantiomer relative to all chiral centers in the molecule. The invention encompasses all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures of the compounds of the invention.

In some preferred embodiments, the compounds of the invention are (1R,2R) stereoisomers.

Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically - or enantiomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.

Included in the invention are pharmaceutically acceptable salts of the compounds disclosed herein. The disclosed compounds have basic amine groups and therefore can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention include salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic, and tartaric acids). Compounds of the invention with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates [e.g. (+)-tartrates, (−)-tartrates or mixtures thereof including racemic mixtures], succinates, benzoates and salts with amino acids such as glutamic acid.

When the stereochemistry of the disclosed compounds is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure. Percent optical purity by weight is the ratio of the weight of the enatiomer over the weight of the enantiomer plus the weight of its optical isomer.

As used herein, the term “hydrolyzable group” means an amide, ester, carbamate, carbonate, ureide, or phosphate analogue, respectively, that either: 1) does not destroy the biological activity of the compound and confers upon that compound advantageous properties in vivo, such as improved water solubility, improved circulating half-life in the blood (e.g., because of reduced metabolism of the prodrug), improved uptake, improved duration of action, or improved onset of action; or 2) is itself biologically inactive but is converted to a biologically active compound. Examples of hydrolyzable amides include, but are not limited to, lower alkyl amides, α-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, aminoacids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.

An “aliphatic group” is non-aromatic, consists solely of carbon and hydrogen and may optionally contain one or more units of unsaturation, e.g., double and/or triple bonds. An aliphatic group may be straight chained, branched or cyclic. When straight chained or branched, an aliphatic group typically contains between about one and about twenty carbon atoms, typically between about one and about ten carbon atoms, more typically between about one and about six carbon atoms. When cyclic, an aliphatic group typically contains between about three and about ten carbon atoms, more typically between about three and about seven carbon atoms. A “substituted aliphatic group” is substituted at any one or more “substitutable carbon atom”. A “substitutable carbon atom” in an aliphatic group is a carbon in an aliphatic group that is bonded to one or more hydrogen atoms. One or more hydrogen atoms can be optionally replaced with a suitable substituent group. A “haloaliphatic group” is an aliphatic group, as defined above, substituted with one or more halogen atoms. Suitable substituents on a substitutable carbon atom of an aliphatic group are the same as those for an alkyl group.

The term “alkyl” used alone or as part of a larger moiety, such as “alkoxy”, “haloalkyl”, “arylalkyl”, “alkylamine”, “cycloalkyl”, “dialkyamine”, “alkylamino”, “dialkyamino” “alkylcarbonyl”, “alkoxycarbonyl” and the like, includes as used herein means saturated straight-chain, cyclic or branched aliphatic group. As used herein, a C1-C6 alkyl group is referred to “lower alkyl.” Similarly, the terms “lower alkoxy”, “lower haloalkyl”, “lower arylalkyl”, “lower alkylamine”, “lower cycloalkylalkyl”, “lower dialkyamine”, “lower alkylamino”, “lower dialkyamino” “lower alkylcarbonyl”, “lower alkoxycarbonyl” include straight and branched saturated chains containing one to six carbon atoms.

The term “alkoxy” means —O-alkyl; “hydroxyalkyl” means alkyl substituted with hydroxy; “aralkyl” means alkyl substituted with an aryl group; “alkoxyalkyl” mean alkyl substituted with an alkoxy group; “alkylamine” means amine substituted with an alkyl group; “cycloalkylalkyl” means alkyl substituted with cycloalkyl; “dialkylamine” means amine substituted with two alkyl groups; “alkylcarbonyl” means —C(O)—R*, wherein R* is alkyl; “alkoxycarbonyl” means —C(O)—OR*, wherein R* is alkyl; and where alkyl is as defined above.

The terms “amine” and “amino” are used interchangeably throughout herein and mean —NH₂, —NHR or —NR₂, wherein R is alkyl.

“Cycloalkyl” means a saturated carbocyclic ring, with from three to eight carbons.

The terms “haloalkyl” and “haloalkoxy” mean alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term “halogen” means F, Cl, Br or I. Preferably the halogen in a haloalkyl or haloalkoxy is F.

The term “acyl group” means —C(O)R, wherein R is an optionally substituted alkyl group or aryl group (e.g., optionally substituted phenyl). R is preferably an unsubstituted alkyl group or phenyl.

An “alkylene group” is represented by —[CH₂]_z—, wherein z is a positive integer, preferably from one to eight, more preferably from one to four.

As used herein, the term “alkenyl” refers to a straight or branched hydrocarbon group that contains one or more double bonds between carbon atoms. Suitable alkenyl groups include, e.g., n-butenyl, cyclooctenyl and the like. An alkenyl group may be substituted.

The term “aryl group” used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, includes carbocyclic aromatic rings and heteroaryl rings. The term “aromatic group” may be used interchangeably with the terms “aryl”, “aryl ring” “aromatic ring”, “aryl group” and “aromatic group”. An aromatic group typically has six—fourteen ring atoms. A “substituted aryl group” is substituted at any one or more substitutable ring atom.

Carbocyclic aromatic rings have only carbon ring atoms (typically six to fourteen) and include monocyclic aromatic rings such as phenyl and fused polycyclic aromatic ring systems in which two or more carbocyclic aromatic rings are fused to one another. Examples include 1-naphthyl, 2-naphthyl, 1-anthracyl.

The term “heteroaryl”, “heteroaromatic”, “heteroaryl ring”, “heteroaryl group” and “heteroaromatic group”, used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy”, refers to aromatic ring groups having five to fourteen ring atoms selected from carbon and at least one (typically 1-4, more typically 1 or 2) heteroatom (e.g., oxygen, nitrogen or sulfur). They include monocyclic rings and polycyclic rings in which a monocyclic heteroaromatic ring is fused to one or more other carbocyclic aromatic or heteroaromatic rings. Examples of monocyclic heteroaryl groups include furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl(e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5-oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl), tetrazolyl (e.g., tetrazolyl) and thienyl (e.g., 2-thienyl, 3-thienyl. Examples of monocyclic six-membered nitrogen-containing heteraryl groups include pyrimidinyl, pyridinyl and pyridazinyl. Examples of polycyclic aromatic heteroaryl groups include carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzisoxazolyl.

The term “non-aromatic heterocyclic group”, used alone or as part of a larger moiety as in “non-aromatic heterocyclylalkyl group”, refers to non-aromatic ring systems typically having five to twelve members, preferably five to seven, in which one or more ring carbons, preferably one or two, are each replaced by a heteroatom such as N, O, or S. A non-aromatic heterocyclic group can be monocyclic or fused bicyclic. A “nitrogen-containing non-aromatic heterocyclic group” is a non-aromatic heterocyclic group with at least one nitrogen ring atom.

Examples of non-aromatic heterocyclic groups include (tetrahydrofuranyl (e.g., 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl), [1,3]-dioxalanyl, [1,3]-dithiolanyl, [1,3]-dioxanyl, tetrahydrothienyl (e.g., 2-tetrahydrothienyl, 3-tetrahydrothieneyl), azetidinyl (e.g., N-azetidinyl, 1-azetidinyl, 2-azetidinyl), oxazolidinyl (e.g., N-oxazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl), morpholinyl (e.g., N-morpholinyl, 2-morpholinyl, 3-morpholinyl), thiomorpholinyl (e.g., N-thiomorpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl), pyrrolidinyl (e.g., N-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl) piperazinyl (e.g., N-piperazinyl, 2-piperazinyl), piperidinyl (e.g., N-piperidinyl), 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), thiazolidinyl (e.g., 4-thiazolidinyl), diazolonyl and N-substituted diazolonyl. The designation “N” on N-morpholinyl, N-thiomorpholinyl, N-pyrrolidinyl, N-piperazinyl, N-piperidinyl and the like indicates that the non-aromatic heterocyclic group is attached to the remainder of the molecule at the ring nitrogen atom.

A “substitutable ring atom” in an aromatic group is a ring carbon or nitrogen atom bonded to a hydrogen atom. The hydrogen can be optionally replaced with a suitable substituent group. Thus, the term “substitutable ring atom” does not include ring nitrogen or carbon atoms which are shared when two aromatic rings are fused. In addition, “substitutable ring atom” does not include ring carbon or nitrogen atoms when the structure depicts that they are already attached to a moiety other than hydrogen.

An aryl group may contain one or more substitutable ring atoms, each bonded to a suitable substituent. Examples of suitable substituents on a substitutable ring carbon atom of an aryl group include halogen, alkyl, haloalkyl, Ar^A, —OR^A, —O(haloalkyl), —SR^A, —NO₂, —CN, —N(R^B)₂, —NR^BC(O)R^A, —NR^BCO₂R^C, —N(R^B)C(O)N(R^B)₂, —C(O)R^A, —CO₂R^A, —S(O)₂R^A, —SO₂N(R^B)₂, —S(O)R^C, —NR^BSO₂N(R^B)₂, —NR^BSO₂R^C, —V_A—Ar^A, —V_A—OR^A, —V—O(haloalkyl), —V_A—SR^A, —V_A—NO₂, —V_A—CN, —V_A—N(R^B)₂, —V_A—NR^BC(O)R^A, —V_A—NR^BCO₂R^C, —V_A—N(R^B)C(O)N(R^B)₂, —V_A—C(O)R^A, —V_A—CO₂R^A, —V_A—S(O)₂R^A, —V_A—SO₂N(R^B)₂, —V_A—S(O)R^C, —V_A—NR^BSO₂N(R^B)₂, —V_A—NR^BSO₂R^C, —O—V_A—Ar^A, —O—V_B—N(R^B)₂, —S—V_A—Ar^A, —S—V_B—N(R^B)₂, —N(R^B)—V_B—Ar^A, —N(R^B)—V_B—N(R^B)₂, —NR^BC(O)—V_A—N(R^B)₂, —NR^BC(O)—V_A—Ar^A, —C(O)—V_A—N(R^B)₂, —C(O)—V_A—Ar^A, —CO₂—V_B—N(R^B)₂, —CO₂—V_A—Ar^A, —C(O)N(R^B)—V_B—N(R^B)₂, —C(O)N(R^B)—V_A—Ar^A, —S(O)₂—V_A—N(R^B)₂, —S(O)₂—V_A—Ar^A, —SO₂N(R^B)—V_B—N(R^B)₂, —SO₂N(R^b)—V_A—Ar^A, —S(O)—V_A—N(R^B)₂, —S(O)—V_A—Ar^A, —NR^BSO₂—V_A—N(R^B)₂or —NR^BSO₂—V_A—Ar^A; or two adjacent substituents, taken together, form a methylenedioxy, ethylenedioxy or —[CH₂]₄— group.

Each V_Ais independently a C1-C10 alkylene group.

Each V_Bis independently a C2-C10 alkylene group.

Ar^Ais a monocyclic aromatic group each substituted with zero, one or two groups independently selected from halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy or haloalkyl.

Each R^Ais independently i) hydrogen; ii) an aromatic group substituted with zero, one or two groups represented by halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy or haloalkyl; or iii) an alkyl group optionally substituted with halogen, hydroxyl, alkoxy, nitro, cyano, alkoxycarbonyl, alkylcarbonyl or haloalkoxy.

Each R^Bis independently R^A, —CO₂R^A, —SO₂R^Aor —C(O)R^A; or —N(R^B)₂taken together is an optionally substituted non-aromatic heterocyclic group.

Each R^Cis independently: i) an aromatic group substituted with zero, one or two groups represented by halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy or haloalkyl; or ii) an alkyl group optionally substituted with halogen, hydroxyl, alkoxy, nitro, cyano, alkoxycarbonyl, alkylcarbonyl or haloalkoxy.

An alkyl or a non-aromatic heterocyclic group (including, but not limited to, non-aromatic heterocyclic groups represented by —N(R³¹)₂, —N(R⁴¹)₂, —N(R⁵¹)₂and —N(R^B)₂) may contain one or more substituents. Examples of suitable substituents for an alkyl or a ring carbon of a non-aromatic heterocyclic group include those listed above for a substitutable carbon of an aryl and the following: ═O, ═S, ═NNHR^C, ═NN(R^C)₂, ═NNHC(O)R^C, ═NNHCO₂(alkyl), ═NNHSO₂(alkyl), ═NR^C, spiro cycloalkyl group, fused cycloalkyl group or a monocyclic non-aromatic nitrogen-containing heterocyclic group attached by a ring nitrogen atom (e.g., N-piperidinyl, N-pyrrolidinyl, N-azepanyl, N-morpholinyl, N-thiomorphinyl, N-piperazinyl or N-diazepanyl group). Each R^Cis independently selected from hydrogen, an unsubstituted alkyl group or a substituted alkyl group. Examples of substituents on the alkyl group represented by R^Cinclude amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl. Preferred substituents for an alkyl or a ring carbon of a non-aromatic heterocyclic group include C1-C2 alkyl, —OH, N-pyrrolidinyl, N-piperidinyl, N-(4-alkyl)piperazinyl, N-morpholinyl or N-pyrrolyl.

Suitable substituents on the nitrogen of a non-aromatic heterocyclic group or heteroaryl group include —R^D, —N(R^D)₂, —C(O)R^D, —CO₂R^D, —C(O)C(O)R^D, —C(O)CH₂C(O)R^D, —SO₂R^D, —SO₂N(R^D)₂, —C(═S)N(R^D)₂, —C(═NH)—N(R^D)₂, and —NR^DSO₂R^D; wherein R^Dis hydrogen, an alkyl group, a substituted alkyl group, phenyl (Ph), substituted Ph, —O(Ph), substituted —OPh), CH₂(Ph), substituted CH₂(Ph), or an unsubstituted heteroaryl or heterocyclic ring. Examples of substituents on the alkyl group or the phenyl ring represented by R^Dinclude amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl. Preferred substituents on a substitutable nitrogen atom of a nitrogen-containing heteroaryl or nitrogen-containing non-aromatic heterocyclic group include C1-C2 alkyl, C1-C2 hydroxyalkyl, or benzyl optionally substituted with halogen, nitro, cyano, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy or C1-C2 haloalkoxy.

In some specific embodiments, non-aromatic heterocyclic groups (including, but not limited to, non-aromatic heterocyclic groups represented by —N(R³¹)₂, —N(R⁴¹)₂, —N(R⁵¹)₂and —N(R^B)₂) each independently are optionally substituted with one or more substituents selected from the group consisting of halogen, ═O, ═S, ═N(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, (C1-C6 alkoxy)carbonyl, (C1-C6 alkyl)carbonyl, C1-C6 haloalkoxy, amino, (C1-C6 alkyl)amino and (C1-C6 dialkyl)amino. In some more specific embodiments, the non-aromatic heterocyclic groups each independently are optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano, (C1-C6 alkoxy)carbonyl, (C1-C6 alkyl)carbonyl, C1-C6 haloalkoxy, amino, (C1-C6 alkyl)amino and (C1-C6 dialkyl)amino.

Inhibitors of glucosylceramide synthase can be used to treat diabetes, such as type 2 diabetes (see WO 2006/053043, the entire teachings of which are incorporated herein by reference). As such, the disclosed compounds, which are inhibitors of glucosylceramide synthase, can be used to treat diabetes, e.g., type 2 diabetes and renal hypertrophy or hyperplasia associated with diabetic nephropathy, by administration of a therapeutically effective amount of a compound of the invention to a subject in need of such treatment.

Inhibitors of glucosylceramide synthase, such as GM3 synthase, have been shown to be useful for treating lysosomal storage diseases (see, for example, U.S. Pat. Nos. 6,569,889; 6,255,336; 5,916,911; 5,302,609; 6,660,749; 6,610,703; 5,472,969; 5,525,616, the entire teachings of which are incorporated herein by reference). As such, the disclosed compounds, which are inhibitors of glucosylceramide synthase, can be used to treat lysosomal storage diseases, such as Tay-Sachs, Gaucher's or Fabry's disease, by administration of a therapeutically effective amount of a compound of the invention to a subject in need of such treatment.

In an alternative embodiment of the present invention, the compounds of the present invention can be used for: treating disorders involving cell growth and division, including cancer, collagen vascular diseases, atherosclerosis, and the renal hypertrophy of diabetic patients (see U.S. Pat. Nos. 6,916,802 and 5,849,326, the entire teachings of which are incorporated herein by reference); inhibiting the growth of arterial epithelial cells (see U.S. Pat. Nos. 6,916,802 and 5,849,326); treating patients suffering from infections (see Svensson, M. et al., “Epithelial Glucosphingolipid Expression as a Determinant of Bacterial Adherence and Cytokine Production,” Infect. and Immun., 62:4404-4410 (1994), the entire teachings of which are incorporated herein by reference); preventing the host, i.e., patient, from generating antibodies against the tumor (see Inokuchi, J. et al., “Antitumor Activity in Mice of an Inhibitor of Glycosphingolipid Biosynthesis,” Cancer Lett., 38:23-30(1987), the entire teachings of which are incorporated herein by reference); and treating tumors (see Hakomori, S. “New Directions in Cancer Therapy Based on Aberrant Expression of Glycosphingolipids: Anti-adhesion and Ortho-Signaling Therapy,” Cancer Cells 3:461-470 (1991), Inokuchi, J. et al., “Inhibition of Experimental Metastasis of Murine Lewis Long Carcinoma by an Inhibitor of Glucosylceramide Synthase and its Possible Mechanism of Action,” Cancer Res., 50:6731-6737 (1990) and Ziche, M. et al., “Angiogenesis Can Be Stimulated or Repressed in In Vivo by a Change in GM3:GD3 Ganglioside Ratio,” Lab. Invest., 67:711-715 (1992), the entire teachings of which are incorporated herein by reference).

In an alternative embodiment, the compounds of the invention can be used for a vaccine-like preparation (see, for example, U.S. Pat. Nos. 6,569,889; 6,255,336; 5,916,911; 5,302,609; 6,660,749; 6,610,703; 5,472,969; 5,525,616). Here, cancer cells are removed from the patient (preferably as completely as possible), and the cells are grown in culture in order to obtain a large number of the cancer cells. The cells are then exposed to the inhibitor for a time sufficient to deplete the cells of their GSLs (generally 1 to 5 days) and are reinjected into the patient. These reinjected cells act like antigens and are destroyed by the patient's immunodefense system. The remaining cancer cells (which could not be physically removed) will also be attacked by the patient's immunodefense system. In a preferred embodiment, the patient's circulating gangliosides in the plasma are removed by—plasmapheresis, since the circulating gangliosides would tend to block the immunodefense system.

In an alternative embodiment of the present invention, the compounds of the present invention can be used for treating a subject having polycystic kidney disease (PKD). As shown in Example 4, Applicants have discovered that a certain glucosylceramide synthase inhibitors can reduce the growth of cyst formation and/or growth in an animal modeled PKD (see for example, U.S. Provisional Application No. 60/997,803, filed Oct. 5, 2007, the entire teachings of which are incorporated herein by reference).

As used herein a subject is a mammal, preferably a human, but can also be an animal in need of veterinary treatment, such as a companion animal (e.g., dogs, cats, and the like), a farm animal (e.g., cows, sheep, pigs, horses, and the like) or a laboratory animal (e.g., rats, mice, guinea pigs, and the like). Subject and patient are used interchangeably. A subject “in need of treatment” includes a subject with chronic renal failure.

“Treatment” or “treating” refers to both therapeutic and prophylactic treatment.

An “effective amount” of a pharmaceutical composition disclosed above is a quantity that results in a beneficial clinical outcome of or exerts an influence on, the condition being treated with the pharmaceutical composition compared with the absence of treatment. The administering amount of a pharmaceutical composition disclosed above to the subject will depend on the degree, severity, and type of the disease or condition, the amount of therapy desired, and the release characteristics of the pharmaceutical composition. It will also depend on the subject's health, size, weight, age, sex, and tolerance to drugs. An effective amount of an active agent is an amount sufficient to have the desired effect for the condition being treated, which can either be treatment of an active disease state or prophylactically inhibiting the active disease state from appearing or progressing. For example, an effective amount of a compound for treating a polycystic kidney disease is the quantity of compound that results in a slowing in the progression of the polycystic kidney disease, a reversal of the polycystic kidney disease state, the reduction of new cyst formation (partial or complete inhibition of cystogenesis), a reduction in cyst mass, a reduction in the size and number of cysts, and/or a reduction in the severity of the symptoms associated with the polycystic kidney disease (PDK).

Typically, the pharmaceutical compositions of the invention are administered for a sufficient period of time to achieve the desired therapeutic effect. Dosages may range from 0.1 to 500 mg/kg body weight per day. In one embodiment, the dosing range is 1-20 mg/kg/day. The compound of the invention may be administered continuously or at specific timed intervals. For example, the compound of the invention may be administered 1, 2, 3, or 4 times per day, such as, e.g., a daily or twice-daily formulation. Commercially available assays may be employed to determine optimal dose ranges and/or schedules for administration. For example, assays for measuring blood glucose levels are commercially available (e.g., OneTouch® Ultra®, Lifescan, Inc. Milpitas, Calif.). Kits to measure human insulin levels are also commercially available (Linco Research, Inc. St. Charles, Mo.). Additionally, effective doses may be extrapolated from dose-response curves obtained from animal models (see, e.g., Comuzzie et al., Obes. Res. 11 (1):75 (2003); Rubino et al., Ann. Surg. 240(2):389 (2004); Gill-Randall et al., Diabet. Med. 21 (7):759 (2004), the entire teachings of which are incorporated herein by reference). Therapeutically effective dosages achieved in one animal model can be converted for use in another animal, including humans, using conversion factors known in the art (see, e.g., Freireich et al., Cancer Chemother. Reports 50(4):219 (1996), the entire teachings of which are incorporated herein by reference) and Table A below for equivalent surface area dosage factors.

From:

Mouse
Rat
Monkey
Dog
Human

(20 g)
(150 g)
(3.5 kg)
(8 kg)
(60 kg)

To: Mouse
1
½
¼
⅙
1/12

To: Rat
2
1
½
¼
1/7

To: Monkey
4
2
1
⅗
⅓

To: Dog
6
4
⅗
1
½

To: Human
12
7
3
2
1

Typically, the pharmaceutical compositions of the invention can be administered before or after a meal, or with a meal. As used herein, “before” or “after” a meal is typically within two hours, preferably within one hour, more preferably within thirty minutes, most preferably within ten minutes of commencing or finishing a meal, respectively.

In one embodiment, the method of the present invention is a mono-therapy where the pharmaceutical compositions of the invention are administered alone. Accordingly, in this embodiment, the compound of the invention is the only pharmaceutically active ingredient in the pharmaceutical compositions.

In another embodiment, the method of the invention is a co-therapy with other therapeutically active drugs known in the art for treating the desired diseases or indications, such as one or more known drugs for treating, diabetes, lysosomal diseases, tumors, etc.

In a particular embodiment, the method of the invention is a combination therapy for treating diabetes, such as Type 2 diabetes. The combination therapy comprise any of the compounds of the invention described herein and at least one other compound suitable for treating diabetes. Examples of drugs or compounds used to treat type 2 diabetes include: insulin (e.g., Novolin®, Novolog®, Velosulin®); sulfonylureas (e.g., Diabinese®, Glucotrol®, Glucotrol XL®, (Diabeta®, Amaryl®, Orinase®, Tolinase®, Micronase® and Glynase®); metformin; [alpha]-glucosidase inhibitors (e.g., Glyset®); thiazolidinediones (e.g., Actos® and Avandia®); nateglinide (Starlix®); repaglinide (Prandin®) and combination drugs such as Avandamet® (Avandia® and metformin).

In another embodiment, the method of the invention is a combination therapy for treating polycystic kidney disease (PDK). Any of the compounds of the invention described herein are co-administered either simultaneously as a single dosage form or consecutively as separate dosage forms with other agents that ease the symptoms and/or complications associated with PKD. The associated symptoms with PKD include pain, headaches, urinary tract infections and high blood pressure. Examples of the agents that can be co-administered with the compounds of the invention include, but are not limited to, over-the counter pain medications, antibiotics, antimicrobials, thiazide diuretics, angiotensin-converting enzyme inhibitors, angiotensin II antagonists such as losartan, and calcium channel blockers such as diltiazem. Examples of pain medications include acetaminophen, aspirin, naproxen, ibuprofen and COX-2 selective inhibitors such as rofecoxib, celecoxib and valdecoxib. Examples of antibiotics and antimicrobials include cephalosporins, penicilin derivatives, aminoglycosidesm ciprofloxacin, erythromycin, chloramphemicol, tetracycline, ampicillin, gentamicin, sulfamethoxazole, trimethoprim and ciprofloxacin, streptomycin, rifamycin, amphotericin B, griseofulvin, cephalothin, cefazolin, fluconazole, clindamycin, erythromycin, bacitracin, vancomycin and fusidic acid Examples of thiazide diuretics include bendroflumethiazide, chlorothiazide, chlorthalidone, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, metolazone, polythiazide, quinethazone and trichlormethiazide. Examples of angiotensin-converting enzyme inhibitors include benazepril, captopril, cilazapril, enalapril, enalaprilat, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril.

The pharmaceutical compositions of the invention optionally include one or more pharmaceutically acceptable carriers and/or diluents therefor, such as lactose, starch, cellulose and dextrose. Other excipients, such as flavoring agents; sweeteners; and preservatives, such as methyl, ethyl, propyl and butyl parabens, can also be included. More complete listings of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5^thEd., Pharmaceutical Press (2005)).

The carriers, diluents and/or excipients are “acceptable” in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof. The pharmaceutical compositions can conveniently be presented in unit dosage form and can be prepared by any suitable method known to the skilled artisan. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing into association the compounds disclosed herein with the carriers, diluents and/or excipients and then, if necessary, dividing the product into unit dosages thereof.

The pharmaceutical compositions of the invention can be formulated as a tablet, sachet, slurry, food formulation, troche, capsule, elixir, suspension, syrup, wafer, chewing gum or lozenge. A syrup formulation will generally consist of a suspension or solution of the compounds of the invention described herein or salt in a liquid carrier, for example, ethanol, glycerine or water, with a flavoring or coloring agent. Where the composition is in the form of a tablet, one or more pharmaceutical carriers routinely used for preparing solid formulations can be employed. Examples of such carriers include magnesium stearate, starch, lactose and sucrose. Where the composition is in the form of a capsule, the use of routine encapsulation is generally suitable, for example, using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule, pharmaceutical carriers routinely used for preparing dispersions or suspensions can be considered, for example, aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell.

Though the above description is directed toward routes of oral administration of pharmaceutical compositions consistent with embodiments of the invention, it is understood by those skilled in the art that other modes of administration using vehicles or carriers conventionally employed and which are inert with respect to the compounds of the invention may be utilized for preparing and administering the pharmaceutical compositions. For example, the pharmaceutical compositions of the invention may also be formulated for rectal administration as a suppository or retention enema, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. Also, the pharmaceutical compositions of the invention can be formulated for injection, or for transdermal or transmucosal administration. Illustrative of various modes of administration methods, vehicles and carriers are those described, for example, in Remington's Pharmaceutical Sciences, 18^thed. (1990), the disclosure of which is incorporated herein by reference.

The invention is illustrated by the following examples which are not intended to be limiting in any way.

EXEMPLIFICATION
Example 1
General Methods for the Preparation of Compounds of the Invention

A general method for the synthesis of final compounds is depicted in Scheme 1. A general method for the preparation of the compounds of the invention involves the reaction of the amine of type EVII with the appropriate reagent. The amine type EVII, such as (1R,2R)-2-amino-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl) propan-1-ol, can be prepared according to the preparation of intermediate 4 of U.S. Pat. No. 6,855,830 (the entire teachings of which are incorporated herein by reference), or by using the general synthetic procedures depicted in schemes 2-5. Final amide compounds, EIX can be prepared by reaction of the amine EVII with the corresponding acylating agent using standard reaction conditions for the formation of an amide. The urea compounds, EIIX can be prepared by reaction of the amine EVII with the corresponding isocyanate. The carbamates, EX can be prepared by reaction of the amine EVII with the corresponding chloroformate.

embedded image

Example 1A
Synthesis of the Compounds of the Invention: General Methods for the Preparation of Amide Analogs

Method 1

A mixture of Compound EVII (1 mmol), such as (1R,2R)-2-amino-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol, prepared according to the preparation of intermediate 4 of U.S. Pat. No. 6,855,830 (the entire teachings of which are incorporated herein by reference) or using the methods depicted in schemes 2,3,4 and 5, an acid (1.2 mmol), DCC (dicyclohexylcarbodiimide, 1.2 mmol) and HOBT (1-hydroxy benzotriazole, 1.2 mmol) was dissolved in CH₂Cl₂(5 ml). The mixture was stirred at room temperature and monitored by TLC (thin liquid chromatography) for completion. After completion the mixture was filtered and purified by column chromatography using, for example, a mixture of (CH₂Cl₂/MeOH/NH₄OH).

Method 2

A mixture of Compound EVII (1 mmol), such as (1R,2R)-2-amino-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol, prepared according to the preparation of intermediate 4 of U.S. Pat. No. 6,855,830 (the entire teachings of which are incorporated herein by reference) or using the methods depicted in schemes 2,3,4 and 5, an acid and DCC (dicyclohexylcarbodiimide, 1.2 mmol) was dissolved in CHCl₃(5 ml). The mixture was placed in the microwave reactor (T=120° C., time=1 min) and it was then filtered and purified by column chromatography using, for example, a mixture of (CH₂Cl₂/MeOH/NH₄OH).

Method 3

A mixture of Compound EVII (1 mmol), such as (1R,2R)-2-amino-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol, prepared according to the preparation of intermediate 4 of U.S. Pat. No. 6,855,830 (the entire teachings of which are incorporated herein by reference) or using the methods depicted in schemes 2,3,4 and 5, an acid chloride (1.2 mmol) and K₂CO₃(2 mmol) was suspended in THF (5 ml). The mixture was stirred at room temperature and monitored by TLC for completion. After completion, the mixture was filtered and purified by column chromatography using, for example, a mixture of (CH₂Cl₂/MeOH/NH₄OH).

Method 4

Compound EVII, such as (1R,2R)-2-amino-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3-pyrrolidin-1-yl-propan-1-ol, prepared according to the preparation of intermediate 4 of U.S. Pat. No. 6,855,830 (the entire teachings of which are incorporated herein by reference) or using the methods depicted in schemes 2,3,4 and 5, was coupled with a variety of N-hydroxysuccinamide esters in methylene chloride under an atmosphere of nitrogen, for example, for 18 to 24 hours depending on the ester used.

Preparation of N-Hydroxysuccinamide Esters

Various mono- and di-keto acids were coupled with N-hydroxysuccinamide in the presence of N,N¹-dicyclohexylcarbodiimide in ethyl acetate under an atmosphere of nitrogen for 18 hours. The products were filtered to remove the dicyclohexylurea. The identity of these esters was confirmed by ¹H NMR and the crude material was then used in the preparation of amide analogs without further purification.

Example 1B
Alternative Synthetic Method for the Preparation of Intermediate EVII. Synthetic Route 1

An alternative general synthesis of Compound EVII is depicted in Scheme 2. Treatment of (R)-2-(benzyloxycarbonylamino)-3-hydroxypropanoic acid with EDCI and N,O-dimethylhydroxyamine gave the weinreb amide EI in excellent yield. The primary alcohol was protected as the TBDMS ether EII in excellent yield by reaction with TBDMSCl in DMF. Reaction of EII with a grignard at low temperature gave EIII in good to excellent yields. Steroselective reduction of EIII and with L-selectride at −70 C gave EIV in good to excellent yield and selectivity. Compound EV was obtained in good to excellent yields after deprotection with acetic acid. Reaction with mesylate chloride and a suitable amine produced EVI in good to excellent yield. Finally, deprotection to the primary amine EVII was done in the microwave oven using NaOH aqueous solution in methanol at 150° C. for one to three minutes depending on the specific compound.

embedded image

Example 1B
Alternative Synthetic Method for the Preparation of Intermediate EVII. Synthetic Route 2

An alternative general synthesis of Compound EVII is depicted in Scheme 3. Intermediate AI was obtained with excellent diastereoselectivity (96:4) by reduction of compound A with LiAlH₄followed by reaction with an aldehyde in the presence of CuI and Me₂S. Mesylate intermediate AIII was obtained by reaction with Amberlyst 15 followed by reaction with MsCl in pyridine. The final compound EVII was obtained by reaction with pyrrolidine and removal of the CBz by hydrogenation.

embedded image

Example 1B
Alternative Synthetic Method for the Preparation of Intermediate EVII. Synthetic Route 3

A general alternative route for synthesis of compound EVII is depicted in Scheme 4. Intermediate EIV was obtain as shown in Scheme 4 was cycled into oxazolidinone B using sodium hydride in a DMF/THF solution. Deprotection of the primary alcohol by reaction with nBu₄NF, followed by formation of the tosylate by reaction with tosyl chloride in pyridine, finally, displacement of the tosylate by an appropriate amine afforded compound B1 in good to excellent yield. Hydrolysis of the oxazolidinone with LiOH in a water ethanol mixture gave compound EVII.

embedded image

Example 1B
Alternative Synthetic Method for the Preparation of Intermediate EVII. Synthetic Route 4

An alternative general synthesis of Compound EVII is depicted in Scheme 5. An aldehyde (2 equiv) is condensed with the chiral morpholinone in toluene with removal of water to provide the fused cycloadduct 2. Treatment of 2 with hydrogen chloride in an alcohol solvent such as methanol provides amino acid 3. Removal of the N-benzyl functionality can be accomplished with hydrogen in the presence of a palladium catalyst to afford 4. Cyclization of 4 with triphosgene and base provides ester 5. The ester functionality can be reduced with sodium borohydride, and the resulting alcohol converted to an appropriate leaving group (i.e. tosylate or iodide). Reaction of 6 with a suitable amine in the presence of excess base (e.g. K₂CO₃) in a polar solvent (e.g. DMSO or CH₃CN) affords 7. Final deprotection under basic conditions affords Compound EVII analogs suitable for conversion to the desired amide final products.

embedded image

Example 1C
Preparation of Compound EVII Using Scheme 2
Preparation of EII: (R)-benzyl 3,8,8,9,9-pentamethyl-4-oxo-2,7-dioxa-3-aza-8-siladecan-5-ylcarbamate

Imidazole (1.8 g, 26.5 mmol) was added to a solution of (R)-benzyl 3-hydroxy-1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (3 g, 10.6 mmol) in DMF (dimethyl formamide, 15 mL) followed by TBDMSiCl (tert-butyldimethylsilyl chloride, 2.4 g, 15.95 mmol). The reaction stirred for 12 hrs at room temperature under nitrogen atmosphere and was quenched with aqueous ammonium chloride (100 ml). The aqueous layer was extracted with methylene chloride (200 mL) and ethyl acetate (100 mL) and the organic layers were washed with brine and concentrated. The crude product was purified by column chromatography using 10% EtOAc (ethylacetate)-hexanes to give an oil (3 g, 74% yield). ¹H NMR (400 MHz, CDCl₃) δ=0 (s, 6H), 0.9 (s, 9H), 3.2 (s, 3H), 3.8 (s, 3H), 3.8-3.9 (m, 2H), 4.8 (broad s, 1H), 5.1 (q, 2H), 5.7 (d, 1H), 7.2-7.4 (m, 5H).

Preparation of EIII: (R)-benzyl 3-(tert-butyldimethylsilyloxy)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-oxopropan-2-ylcarbamate

(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)magnesium bromide (26 g, 78 mmol) dissolved in 40 mL of THF (tetrahydrofuran) under a nitrogen atmosphere was cooled down to −70° C. and (R)-benzyl 3,8,8,9,9-pentamethyl-4-oxo-2,7-dioxa-3-aza-8-siladecan-5-ylcarbamate (12.3 g, 31 mmol) dissolved in THF (13 ml) were added dropwise. The reaction mixture was allowed to warm up to −15° C. and left to react for 12 hrs followed by stirring at room temperature for 2 hrs. After cooling the reaction mixture to −40° C. it was quenched using aqueous ammonium chloride and the aqueous layer was extracted with EtOAc dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography using 25% EtOAc-hexanes to give pure product (13 g, 88% yield). ¹H NMR (400 MHz, CDCl₃) δ=0 (d, 6H), 0.9 (s, 9H), 4.0-4.2 (m, 2H), 4.4 (s, 2H), 4.5 (s, 2H), 5.2 (s, 2H), 5.4 (m, 1H), 6.1 (d, 1H), 7 (d, 1H), 7.4-7.7 (m, 7H).

Preparation of EIV: benzyl (1R,2R)-3-(tert-butyldimethylsilyloxy)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxypropan-2-ylcarbamate

(R)-benzyl 3-(tert-butyldimethylsilyloxy)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-oxopropan-2-ylcarbamate (3.1 g, 6.6 mmol) were dissolved in THF (25 ml) and cooled down to −70° C. under nitrogen atmosphere. L Selectride (13.2 ml of 1M solution in THF, 13 mmol) was added dropwise while keeping the temperature at −70° C. After 1 hour, the reaction was quenched with a 1M aqueous solution of potassium tartrate (13 ml) and extracted with EtOAc. The organic layer was evaporated down and the product was purified by column chromatography using 2.5% EtOAc-2% acetone-methylene chloride. The desired diastereomer was obtained in 80% yield (2.5 g). ¹H NMR (400 MHz, CDCl₃) δ=0 (d, 6H), 0.9 (s, 9H), 3.5 (broad s, 1H), 3.7-3.9 (m, 2H), 4.2 (s, 4H), 4.9 (broad s, 1H), 5.0 (d, 2H), 5.4 (d, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.2-7.4 (m, 5H).

Preparation of EV: benzyl (1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1,3-dihydroxypropan-2-ylcarbamate

Benzyl (1R,2R)-3-(tert-butyldimethylsilyloxy)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxypropan-2-ylcarbamate (0.5 g) was dissolved in a 4 ml mixture of Acetic acid/THF/water (3/1/1) and left to stir over night. The crude was evaporated down and the product azeotropically dried with EtOAc (10 ml). The crude product was purified by column chromatography using 50% EtOAc-hexane. The pure product was obtained in 74% yield (0.28 g). ¹H NMR (400 MHz, CDCl₃) δ=3.4-3.8 (m, 4H), 4.1 (broad s, 4H), 4.8 (s, 1H), 4.9 (broad s, 2H), 5.7 (broad s, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.2-7.4 (m, 5H).

General Procedure for Preparation of EVI and EVII

Benzyl (1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1,3-dihydroxypropan-2-ylcarbamate was dissolved in excess pyridine, cooled to −15° C. and one equivalent of methanosulfonyl chloride was added to the mixture. Mixture was stirred about half an hour, and ten equivalents of the amine were added. The reaction mixture was allowed to warm up to room temperature and then heated at 50° C. overnight. The crude was evaporated down and the product was purified by column chromatography using a mixture of methanol/methylene chloride/ammonium hydroxide. The pure compound EVI was then de-protected by hydrolysis in the microwave, using aqueous NaOH (40% in weight)/methanol solution as solvent and heating the mixture to 150° C. for about 15 minutes to give the free amines of the type EVI. The final product was purified by silica-gel column chromatography using a mixture of methanol/methylene chloride/ammonium hydroxide.

Examples of EVII Compounds
i) (1R,2R)-2-amino-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-3-morpholinopropan-1-ol

embedded image

¹H NMR (400 MHz, CDCl₃) δ=2.3 (dd, 2H), 2.4 (dd, 2H), 2.5-2.6 (m, 2H), 3.2 (m, 1H), 3.6-3.7 (m, 4H), 4.2 (s, 4H), 4.4 (d, 1H), 6.5-6.9 (m, 3H); MS for C₁₅H₂₂N₂O₄m/z 294.8 [M+H].

ii) (1R,2R)-2-amino-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-3-(piperidin-1-yl)propan-1-ol

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.4 (broad s, 2H), 1.7 (m, 4H), 2.2-2.6 (m, 6H), 3.2 (m, 1H), 4.2 (s, 4H), 4.5 (s, 1H), 6.7-6.9 (m, 3H).

Example 1D
Preparation of Substituted Phenoxy Propionic Acids
Example 1D1
Preparation of 3-(4-methoxyphenoxy)propionic acid
i) 3-(4-methoxyphenoxy)propionitrile

A 740 g (5.96 mol, 1 eq.) sample of 4-methoxyphenol was charged to a 3 necked 5 L flask under nitrogen. Triton B (50 mL of a 30% wt. solution in methanol) was charged to the flask, and stirring initiated via an overhead stirrer. Acrylonitrile (2365 mL, 35.76 mol, 6 eq.) was then charged to the reaction flask in a single portion, and the reaction mixture heated at 78° C. for 36 h. HPLC analysis indicated that the reaction was complete at this point. Solvents were removed via rotary evaporation, and the resulting oil was chased with toluene to remove excess acrylonitrile. The crude material was recrystallized from TBME (tert-butyl methyl ether) 10 volumes relative to the crude weight), and dried in a vacuum oven to give 945 g of 3-(4-methoxyphenoxy)propionitrile as white crystals (Yield: 89.48%). ¹H NMR (450 MHz, CDCl₃): δ=2.72 (t, 2 H; CH₂CN); δ=3.83 (s, 3 H; OCH₃); δ=4.05 (t, 2H; OCH₂); 6=6.70 (m, 4H; Ar—H); ¹³C NMR (112.5 MHz, CDCl₃): d=18.843 (CH₂CN); 55.902 (OCH₃); 63.699 (OCH₂); 114.947 (CH₃OCCH); 116.183 (CH₂OCCH); 117.716 (CN); 151.983 (CH₃OC); 154.775 (CH₂OC).

ii) 3-(4-methoxyphenoxy)propionic acid

A 945 g (5.34 mol, 1 eq.) sample of 1 (3-(4-methoxyphenoxy)propionitrile was charged to a 22 L round bottom flask equipped with an overhead stirrer under N₂. To the stirred solids, 4 L of concentrated HCl was slowly added, followed by 2 L of H₂O. The reaction mixture was heated to 100° C. for 3.5 h, at which point the reaction was complete by HPLC analysis. The reaction was cooled to 10° C. by the addition of ice to the reaction mixture, and was filtered. The dried solids gave 920 g of crude 3-(4-methoxyphenoxy)propionic acid. The crude material was dissolved in 5 L of 6 wt. % sodium carbonate (such that pH=9), and 2 L of DCM (dichloromethane) was added to the reaction vessel. After stirring thoroughly, the organic layer was separated and discarded via a separatory funnel, and the aqueous layer charged back into the 22 L flask. The pH of the aqueous layer was carefully adjusted to 4.0, by slow addition of 6 M HCl. The precipitated solids were filtered, and dried in a vacuum oven to give 900 g of 3-(4-methoxyphenoxy)propionic acid as a white solid (Yield: 86.04%). ¹H NMR (450 MHz, CDCl₃); δ=2.78 (t, 2H; CH₂COOH); 3.70 (s, 3H; OCH₃); 4.18 (t, 2H; OCH₂); 6.78 (m, 4 H; Ar—H); ¹³C NMR (112.5 MHz, CDCl₃): δ=34.703 (CH₂COOH); 55.925 (OCH₃); 64.088 (OCH₂); 114.855 (CH₃OCCH); 115.984 (CH₂OCCH); 152.723 (CH₃OC); 154.302 (CH₂OC); 177.386 (COOH).

Example 1D2
Preparation of 3-(4-(3-oxobutyl)phenoxy)propanoic acid

embedded image

Step 1: a mixture of 4-(p-hydroxyphenol)-2-butanone (1.032 g), triton B (400 μL), acrylonitrile (4 mL) and MeOH (0.8 mL) was heated at 70° C. for 20 hours. The mixture was cooled to room temperature and the solvent was removed to dryness. 3-(4-(3-oxobutyl)phenoxy)propanenitrile was obtained as a white solid (0.572 g) after purification by column chromatography using ethyl acetate/hexane.

Step 2: 3-(4-(3-oxobutyl)phenoxy)propanenitrile (0.478 g) was suspended in HCl (37%, 5 mL) and placed in the microwave reactor (T=110° C., 5 min). The mixture was poured onto iced water (20 g), filtered, and the solid was washed with water (2×5 mL). After column chromatography purification using a mixture of methylene chloride/methanol, 3-(4-(3-oxobutyl)phenoxy)propanoic acid was obtained as a white solid (0.3 g). ¹H NMR (CDCl₃, 400 mHz, ppm); 2.2 (s, 3H), 2.7 (t, 2H), 2.85 (m, 4H), 4.25 (t, 2H), 6.8 (d, 2H), 7.1 (d, 2H).

Example 1D3
Preparation of 3-(4-(2-methoxyethyl)phenoxy)propanoic acid

embedded image

Step 1: a mixture of 4-(2-methoxy ethyl) phenol (1.547 g, 10.3 mmol), propiolic acid tert-butyl ester (1.367 g, 10.8 mmol) and N-methyl morpholine (1.18 mL, 10.8 mmol) in CH₂Cl₂(15 mL) was stirred at room temperature for 24 hours. The mixture was absorbed on SiO₂(20 g) and purified by column chromatography using a mixture of methylene chloride/hexane. The product was obtained as a two to one mixture of (E)/(Z)-tert-butyl 3-(4-(2-methoxyethyl)phenoxy)acrylate isomers (2.0 g).

Step 2: (E)/(Z)-tert-butyl 3-(4-(2-methoxyethyl)phenoxy)acrylate (0.57 g) was suspended in a mixture of THF (5 mL)/HCl (2 M, 5 mL) and placed in the microwave reactor (T=100° C., 15 sec). THF was removed by rotary evaporation and the mixture was extracted with CH₂Cl₂(10 mL). (E)/(Z)-3-(4-(2-methoxyethyl)phenoxy)acrylic acid was obtained as a white solid after purification by column chromatography using a mixture of hexane/ethyl acetate.

Step 3: (E)/(Z)-3-(4-(2-methoxyethyl)phenoxy)acrylic acid (0.3 g) was dissolved in EtOH (10 mL) and Pd/C (5%, degussa type E101, 40 mg) was added. The mixture was hydrogenated at atmospheric pressure for 2 hours and then filtered and the solvent removed to dryness. After purification by column chromatography using a mixture of hexane/ethyl acetate, 3-(4-(2-methoxyethyl)phenoxy)propanoic acid was obtained as a white solid (0.236 g). ¹H NMR (CDCl₃, 400 mHz, ppm); 2.85 (t, 4H), 3.35 (s, 3H), 3.55 (t, 2H), 4.25 (t, 2H), 6.85 (d, 2H), 7.1 (d, 2H).

Example 1D4
Preparation of 3-(4-(3-methylbutanoyl)phenoxy)propanoic acid

Step 1: 3-phenoxypropionic acid (5.0 g, 30 mmol) was dissolved in MeOH (12 mL) and H₂SO₄(18 M, 3 drops) was added. The mixture was place in the microwave reactor (T: 140° C., t: 5 min). The solvent was evaporated, the mixture was partitioned in EtOAc (30 mL) and NaOH (2N, 20 mL). The organic phase was dried over MgSO₄, filtered, and evaporated to give methyl 3-phenoxypropanoate (5.0 g, 27.7 mmol, 92.5%).

Step 2: aluminum chloride (1.1 g, 8.34 mmol) was added to a cold solution (0° C.) solution of methyl 3-phenoxypropanoate (1.0 g, 5.56 mmol) and tert-butylacetyl chloride (1.25 mL, 8.34 mmol) in CH₂Cl₂(9 mL) and the reaction mixture was stirred overnight. The mixture was evaporated and the residue was diluted with EtOAc (30 mL) and then washed with water (2×20 mL). The organic phase was removed and purified with silica chromatography using of a gradient hexanes/EtOAc (100:0→0:100) to give methyl 3-phenoxypropanoate (600 mg, 2.27 mmol, 40%).

Step 3: a solution of methyl 3-phenoxypropanoate (200 mg, 0.76 mmol) in 2 mL of HCl (37%) was placed in a microwave reactor (T: 120° C., t: 5 min). The mixture was poured into iced water (2 g) and washed with EtOH (3×10 mL). The organic phase was combined and evaporated. The crude product was purified with silica gel chromatography using of a gradient hexanes/EtOAc (100:0→0:100) to give 3-(4-(3-methylbutanoyl)phenoxy)propanoic acid (120 mg, 0.48 mmol, 63%).

Example 2
Preparation of Compounds of the Invention

The exemplary compounds shown in Example 2 and Tables 1-3 can be prepared by following scheme 1 described above, Detailed synthetic description of certain compounds also are described below as examples.

Example 2E1
Preparation of Hemi-Hydrate of Compound 163 N-[2-Hydroxy-2-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-pyrrolidin-1-ylmethyl-ethyl]-3-(4-methoxy-phenoxy)-propionamide

embedded image

Compound 163 was prepared by following Scheme 1A above. 3-(4-methoxyphenoxy)propanoic acid (see Example 1D1, 34.47 g, 169 mmol, 96% purity by HPLC), DCC (34.78 g, 169 mmol) and N-hydroxysuccinimide (19.33, 169 mmol) were combined as dry powders and methylene chloride (500 mL) was added. The suspension was mechanically stirred overnight, ambient temperature, under a nitrogen atmosphere. HPLC analysis showed complete conversion of the acid to the NHS ester (N-hydroxy succinyl ester). To the mixture was added (1R,2R)-2-amino-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3-pyrrolidin-1-yl-propan-1-ol (50 g, 169 mmol) and stirring continued for 2.5 hours. HPLC showed conversion to the product and loss of both the NHS ester and step 5 amine. The reaction mixture was vacuum filtered on a Buchner funnel to remove DCC urea. The solid urea was washed with 500 mL of methylene chloride. The organic layers were combined, placed in a separatory funnel, and treated with 500 mL of 1.0M NaOH. The layers were separated, and the cloudy organic layer was recharged into a separatory funnel and treated with a 6% HCl solution (adjusted to pH=0.03-0.34, 100 mL of solution). Two clear layers formed. The resultant biphasic solution was poured into an Erlenmeyer flask and cautiously neutralized to a pH of 7.2-7.4 with a saturated solution of sodium bicarbonate (approx 200 mL of solution). The organic layer was separated from the aqueous layer, dried over sodium sulfate and evaporated to yield 83.6 g of yellow oil (theoretical yield: 77.03 g). The oil was dissolved in isopropyl alcohol (500 mL) with heating and transferred to a 1 L round bottom flask equipped with a mechanical stirrer and heating mantel. The solution was heated to 50° C. and the mechanical stirrer was set to a rate of 53-64 rpm. Tartaric acid (25.33 g, 168 mmol) was dissolved in deionized water (50 mL) and added to the stirred solution at 50° C. Once the solution turned from milky white to clear, seed crystals were added to the mixture and crystallization immediately began (temperature jumped to 56° C.). After 20 minutes, the mixture was set to cool to a temperature of 35° C. (cooling took 1.15 hours). Heating was removed and the solution was allowed to stir for 12 hours. The resulting thick slurry was filtered on a Buchner funnel. Any remaining solid in the flask was washed onto the funnel using ice-cold isopropyl alcohol (100 mL). The material was transferred to a drying tray and heated to 48° C. under vacuum for 3 days (after two days the material weighed 76 g and after three days it weighed 69.3 g). The solid was analyzed by LC and shown to be 98.1% pure (AUC), the residual solvent analysis showed the material to possess 3472 ppm of isopropyl alcohol, and the DSC (differential scanning calorimetery) showed a melting point of 134.89° C. A total of 69.3 g of white solid was collected (65.7% overall yield). ¹H NMR (400 MHz, CDCl₃) δ=1.8 (M, 4H), 2.4-2.6 (m, 4H), 2.6 (m, 1H), 2.85 (m, 2H), 3.0 (m, 1H), 3.65 (s, 3H), 3.8 (m, 2H), 3.86 (2, 2H), 4.18 (br s, 5H), 4.6 (s, 1H), 6.6-6.8(m, 7 H), 7.8 (d, 1H); MS for C₂₉H₄₀N₂O₁₃m/z 457.3 [M+H] for main peak (free-base).

Example 2E2
Preparation of Compound 247: N-((1R,2R)-1-hydroxy-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)-3-(p-tolyloxy)propanamide

Compound 247 was prepared by reaction of (1R,2R)-2-amino-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-1-ol as the amine, prepared according to scheme 3 with 3-(4-methylphenoxy)propionic acid using method 1.

Preparation of A: (R)-benzyl 4-formyl-2,2-dimethyloxazolidine-3-carboxylate

embedded image

N,O-dimethylhydroxylamine hydrochloride (45 g, 0.46 mmol, 1.5 eq) and N-methyl morpholine (84 mL, 0.765 mol, 2.5 eq.) were added slowly to a cold (−15° C. suspension of d-CBz serine (73.0 g, 0.305 mol) in CH₂Cl₂(560 mL) keeping the temperature below −5° C. The mixture was cooled back to ˜−15° C. and EDCI (62 g, 0.323 mol, 1.05 eq) was added. The mixture was stirred for 5 hours keeping the temperature below 5° C. The solvent was removed by rotary evaporation and the mixture was partitioned between HCl (1 M, 300 mL) and EtOAc (500 mL). The organic layer was separated and washed with HCl (1 M, 2×100 mL) and then sat. NaHCO₃(2×150 mL). The mixture was dried over MgSO₄, filtered and then the solvent was removed by rotary evaporation. (R)-benzyl 3-hydroxy-1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate was re-dissolved in a mixture of acetone (375 mL) and 2,2-dimethoxy propane (375 mL) and boron trifluoride ethereate (3 mL) was added. The mixture was stirred at room temperature for 5 hours and then triethyl amine (3 mL) was added. The solvent was removed to dryness and (R)-benzyl 4-(methoxy(methyl)carbamoyl)-2,2-dimethyloxazolidine-3-carboxylate was obtained as a white solid (73.0 g, 74% yield from both steps) after purification by column chromatography using a mixture of hexane/EtOAc/acetone.

¹H NMR (CDCl₃, 400 mHz, ppm); 1.5 (s, 2 H), 1.6 (s, 3H), 1.7 (s, 2H), 1.75 (s, 3H), 3.14 (s, 3 H), 3.24 (2 H), 3.4 (3 H), 3.76 (s, 2 H), 4.0 (m, 1.7 H), 4.16 (m, 1 H), 4.2 (m, 1.7), 4.78 (m, 1 H), 4.88 (m, 0.6 H), 5.06 (q, 2 H), 5.18 (q, 1 H), 7.4 (m, 8 H).

Preparation of AI: (R)-benzyl 4-((R)-hydroxy(4-methoxyphenyl)methyl)-2,2-dimethyloxazolidine-3-carboxylate

embedded image

A solution of LiALH₄(1 M, 20 mL, 20 mmol) was added dropwise to a cold (−15° C.) solution of (R)-benzyl 4-(methoxy(methyl)carbamoyl)-2,2-dimethyloxazolidine-3-carboxylate (12.2 g, 37.9 mmol) in THF (75 mL). The mixture was stirred for 30 min keeping the temperature below 0° C. A saturated solution of KHSO₄(100 mL) was added slowly to the mixture and it was warmed to room temperature. The mixture was filtered and the solvent was removed to dryness. (R)-benzyl 4-formyl-2,2-dimethyloxazolidine-3-carboxylate was obtained as a clear oil (9.161 g, 92% yield) after purification by column chromatography (SiO₂, using a mixture of hexane/EtOAc).

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (m, 6 H), 4.15 (m, 2H), 4.4 (m, 1H), 5.15, (s, 1H), 5.2 (m, 1H), 7.3 (m, 5H), 9.6 (m, 1H).

1,2-dibromoethane (0.2 mL) was added slowly to a hot (65° C.) solution of magnesium turnings (0.91 g, 37 mmol) in THF (14 mL), followed by the dropwise addition of a solution of 4-bromo anisole (4 mL, 32 mmol) in THF (14 mL). The mixture was refluxed for 2 hours and then cooled to room temperature. The grignard solution was added dropwise to a suspension of CuI (6.8 g, 36 mmol) in a mixture of Me₂S (20 mL)/THF (100 mL) at −78° C. The mixture was warmed slowly to −45° C. and stirred for 30 min keeping the temperature between −45 to −35° C. The mixture was cooled back to −78° C., and a solution of the Garner's aldehyde [(R)-benzyl 4-formyl-2,2-dimethyloxazolidine-3-carboxylate](3.20 g, 12.6 mmol) in THF (15 mL) was added dropwise. The mixture was stirred at low temperature overnight (15 h, T max=10° C.). The reaction mixture was quenched with NH₄Cl (sat. 100 mL) and extracted with EtOAc (50 mL). The solvent was removed to dryness and the mixture was purified by column chromatography (SiO₂, using a mixture of hexane/EtOAc/acetone) and the product was obtained as a colorless oil (1.697 g, 36% yield).

Preparation of AII: benzyl (1R,2R)-1,3-dihydroxy-1-(4-methoxyphenyl)propan-2-ylcarbamate

embedded image

A mixture of benzyl 4-(hydroxy-(4-methoxyphenyl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (1.679 g, 4.5 mmol) and amberlyst 15 (1.85 g) in MeOH (20 mL) was stirred at room temperature for 2 days. The mixture was centrifuged and the solid was washed with MeOH (2×40 mL). The solvent was removed to dryness and after purification by column chromatography (SiO₂using a mixture of CH₂Cl₂/EtOAc) the product was obtained as a white solid (1.26 g, 84% yield).

Preparation of AIV: Synthesis of Compound 289: benzyl (1R,2R)-1-hydroxy-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-ylcarbamate

embedded image

Mesityl chloride (0.28 mL, 3.6 mmol) was added slowly to a cold (−10° C.) solution of benzyl (1R,2R)-1,3-dihydroxy-1-(4-methoxyphenyl)propan-2-ylcarbamate (1.07 g, 3.23 mmol) in pyridine (1.5 mL). The mixture was stirred for 30 min and then pyrrolidine (2.7 mL, 33 mmol) was added slowly to the mixture. The mixture was heated to 45° C. for 6 hours and then the solvent was removed to dryness. After purification by column chromatography (SiO₂, using a mixture of CH₂Cl₂, MeOH, NH₄OH), the product was obtained as a clear oil (0.816 g, 66% yield).

Preparation of EVII: (1R,2R)-2-amino-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-1-ol as the amine was prepared by the procedures described below

embedded image

A mixture of benzyl (1R,2R)-1-hydroxy-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-ylcarbamate (0.10 g, 0.26 mmol) and Pd/C (5%, 21 mg) in EtOH (1 mL)/HCl (1 M, 50 μL) was degassed and hydrogen gas was added. The mixture was hydrogenated at atmospheric pressure for two hours. The mixture was filtered over celite and the solvent was removed to dryness. The product was obtained as a colorless oil (63.5 mg, 85% yield).

embedded image

Preparation of Compound 247: N-((1R,2R)-1-hydroxy-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)-3-(p-tolyloxy)propanamide

¹H NMR (CDCl₃, 400 mHz, ppm); 1.75 (br, 4H), 2.3 (s, 3H), 2.65 (br, 6H), 2.85 (m, 2H), 3.75 (s, 3H), 4.1 (m, 2H), 4.25 (m, 1H), 5.05 (sd, 1H), 6.5 (br, 1H), 6.8 (m, 4H), 7.1 (d, 2H), 7.2 (d, 2H). M/Z for C₂₄H₃₂N₂O₄[M−H]⁻=413.

Example 2E3
Preparation of Compound 251: N-((1R,2R)-1-hydroxy-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(trifluoromethyl)phenyl)acetamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.75 (br, 4H), 2.55 (br, 4H), 2.85 (m, 2H), 3.5 (s, 2H), 3.8 (s, 3H), 4.2 (m, 1H), 5.05 (sd, 1H), 5.8 (d, 1H), 6.8 (d, 2H), 7.1 (d, 2H), 7.2 (d, 2H), 7.55 (d, 2H). M/Z for C₂₃H₂₇F₃N₂O₃[M−H]⁻=437.

Example 2E4
Preparation of Compound 5: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)benzo[b]thiophene-2-carboxamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.7 (br, 4H), 3.0 (m, 2H), 4.25 (s, 4H), 4.45 (m, 1H), 5.05 (sd, 1H), 6.6 (br, 1H), 6.85 (s, 2H), 6.95 (s, 1H), 7.4 (m, 2H), 7.7 (s, 1H), 7.85 (m, 2H). M/Z for C₂₄H₂₆N₂O₄S [M−H]⁻=439.

Example 2E5
Preparation of Compound 11: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(phenylthio)acetamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.5 (br, 4H), 2.8 (br, 2H), 3.6 (q, 2H), 4.1.5 (m, 1H), 4.2 (s, 4H), 5.9 (sd, 1H), 6.7 (m, 2H), 6.8 (s, 1H), 7.2 (m, 7H). M/Z for C₂₃H₂₈N₂O₄S [M−H]⁻=429.

Example 2E6
Preparation of Compound 12: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)biphenyl-4-carboxamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.7 (br, 4H), 3.0 (m, 2H), 4.25 (s, 4H), 4.4 (br, 1H), 5.05 (sd, 1H), 6.6 (sd, 1H), 6.85 (m, 2H), 6.95 (s, 1H), 7.45 (m, 3H), 7.6 (m, 4H), 7.75 (m, 2H). M/Z for C₂₈H₃₀N₂O₄[M−H]⁻=459.

Example 2E7
Preparation of Compound 19: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)benzo[b]thiophene-5-carboxamide

embedded image

¹H NMR (d₆-dmso, 400 mHz, ppm); 1.6 (br, 4H), 2.4 (br, 5H), 2.65 (m, 1H), 4.15 (s, 4H), 4.25 (m, 1H), 4.75 (sd, 1H), 5.6 (br, 1H), 6.7 (m, 3H), 7.5 (sd, 1H), 7.7 (sd, 1H), 7.8 (sd, 1H), 7.85 (sd, 1H), 8.0 (sd, 1H), 8.2 (s, 1H). M/Z for C₂₄H₂₆N₂O₄S [M−H]⁻=439.

Example 2E8
Preparation of Compound 23: 2-(biphenyl-4-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.5 (br, 4H), 2.8 (d, 2H), 3.55 (s, 2H), 4.2 (m, 5H), 4.85 (sd, 1H), 5.95 (br, 1H), 6.6 (m, 1H), 6.75 (m, 2H), 7.2 (sd, 2H), 7.4 (m, 1H), 7.5 (st, 2H), 7.6 (m, 4H). M/Z for C₂₉H₃₂N₂O₄[M−H]⁻=473.

Example 2E9
Preparation of Compound 24: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-phenoxyphenyl)acetamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.6 (br, 4H), 2.8 (sd, 2H), 3.45 (s, 2H), 4.15 (m, 1H), 4.25 (s, 4H), 4.85 (sd, 1H), 5.9 (br, 1H), 6.6 (m, 1H), 6.7 (s, 1H), 6.8 (m, 1H), 7.15 (m, 7H), 7.4 (m, 2H). M/Z for C₂₉H₃₂N₂O₅[M−H]⁻=489.

Example 2E10
Preparation of Compound 25: (S)—N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-hydroxy-3-phenylpropanamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.65 (br, 7H), 3.1 (dd, 2H), 4.2 (m, 6H), 4.8 (sd, 1H), 6.6 (m, 1H), 6.8 (m, 3H), 7.3 (m, 5H). M/Z for C₂₄H₃₀N₂O₅[M−H]⁻=427.

Example 2E11
Preparation of Compound 27: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-phenoxypropanamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.7 (br, 6H), 2.9 (m, 2H), 4.2 (m, 7H), 4.95 (sd, 1H), 6.45 (m, 1H), 6.75 (s, 1H), 6.85 (m, 3H), 6.95 (t, 1H), 7.2 (m, 3H). M/Z for C₂₄H30N₂O₅[M−H]⁻=427.

Example 2E12
Preparation of Compound 31: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxo-2-phenylacetamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.8 (br, 4H), 3.0 (m, 2H), 4.2 (s, 4H), 4.3 (m, 1H), 5.05 (sd, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.35 (m, 1H), 7.45 (t, 2H), 7.6 (t, 1H) 8.2 (d, 2H). M/Z for C₂₃H₂₆N₂O₅[M−H]⁻=411.

Example 2E13
Preparation of Compound 32: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(phenylthio)propanamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.4 (t, 2H), 2.7 (br, 4H), 2.8 (m, 2H), 3.1 (m, 2H), 4.2 (m, 5H), 4.9 (sd, 1H), 5.95 (br, 1H), 6.8 (m, 3H), 7.2 (m, 1H), 7.3 (m, 3H). M/Z for C₂₄H₃₀N₂O₄S [M−H]⁻=443.

Example 2E14
Preparation of Compound 35: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-o-tolylacetamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.1 (s, 3H), 2.5 (br, 4H), 2.75 (m, 2H), 3.5 (s, 2H), 4.1 (m, 1H), 4.25 (s, 4H), 4.8 (sd, 1H), 5.75 (br, 1H), 6.5 (d, 1H), 6.65 (s, 1H), 6.75 (d, 1H), 7.1 (d, 1H), 7.2 (m, 3H). M/Z for C₂₄H₃₀N₂O₄[M−H]⁻=411.

Example 2E15
Preparation of Compound 36: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-m-tolylacetamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.35 (s, 3H), 2.5 (br, 4H), 2.75 (m, 2H), 3.45 (s, 2H), 4.1 (m, 1H), 4.25 (s, 4H), 4.85 (sd, 1H), 5.8 (br, 1H), 6.55 (d, 1H), 6.75 (m, 2H), 6.9 (d, 2H), 7.1 (sd, 1H), 7.2 (m, 1H). M/Z for C₂₄H₃₀N₂O₄[M−H]⁻=411.

Example 2E16
Preparation of Compound 39: 2-(benzylthio)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.7 (br, 4H), 2.9 (m, 2H), 3.0 (m, 2H), 3.3 (d, 1H), 3.55 (d, 1H), 4.2 (m, 5H), 5.05 (sd, 1H), 6.85 (s, 2H), 6.9 (s, 1H), 7.1 (sd, 2H), 7.3 (m, 3H). M/Z for C₂₄H₃₀N₂O₄S [M−H]⁻=443.

Example 2E17
Preparation of Compound 47: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(pyridin-3-yl)phenyl)acetamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.6 (br, 4H), 2.8 (sd, 2H), 3.55 (s, 2H), 4.15 (m, 1H), 4.2 (s, 4H), 4.85 (sd, 1H), 5.85 (br, 1H), 6.6 (d, 1H), 6.75 (m, 2H), 7.25 (d, 3H), 7.4 (m, 1H), 7.6 (sd, 2H), 7.9 (sd, 1H), 8.6 (sd, 1H), 8.85 (s, 1H). M/Z for C₂₈H₃₁N₃O₄[M−H]⁻=474.

Example 2E18
Preparation of Compound 48: 2-(4′-chlorobiphenyl-4-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.75 (br, 4H), 2.55 (br, 4H), 2.8 (sd, 2H), 3.55 (s, 2H), 4.15 (m, 1H), 4.2 (s, 4H), 4.85 (sd, 1H), 5.8 (br, 1H), 6.6 (d, 1H), 6.75 (m, 2H), 7.2 (d, 2H), 7.4 (m, 2H), 7.55 (sd, 4H). M/Z for C₂₉H₃₁C1N₂O₄[M−H]⁻=508.

Example 2E19
Preparation of Compound 51: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(3-(trifluoromethyl)phenyl)acetamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.55 (br, 4H), 2.8 (sd, 2H), 3.55 (s, 2H), 4.15 (m, 1H), 4.25 (s, 4H), 4.85 (sd, 1H), 5.8 (br, 1H), 6.6 (d, 1H), 6.75 (m, 2H), 7.35 (d, 1H), 7.45 (m, 2H), 7.55 (sd, 1H). M/Z for C₂₄H₂₇F₃N2O₄[M−H]⁻=465.

Example 2E20
Preparation of Compound 53: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(3-fluorophenyl)acetamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.55 (br, 4H), 2.8 (sd, 2H), 3.50 (s, 2H), 4.15 (m, 1H), 4.25 (s, 4H), 4.85 (sd, 1H), 5.8 (br, 1H), 6.6 (d, 1H), 6.75 (m, 1H), 6.8 (d, 1H), 6.85 (d, 1H), 6.9 (d, 1H), 7.0 (t, 1H), 7.3 (sq, 1H). M/Z for C₂₃H₂₇FN₂O₄[M−H]⁻=415.

Example 2E21
Preparation of Compound 54: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(3-methoxyphenoxy)propanamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.65 (br, 6H), 2.85 (m, 2H), 3.80 (s, 3H), 4.2 (m, 7H), 4.95 (sd, 1H), 6.45 (m, 4H), 6.75 (s, 2H), 6.85 (s, 1H), 7.2 (t, 1H). M/Z for C₂₅H₃₂N₂O₆[M−H]⁻=457.

Example 2E22
Preparation of Compound 55: 3-(2,5-dichlorophenoxy)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)propanamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.65 (br, 6H), 2.8 (m, 2H), 4.1 (m, 1H), 4.25 (m, 6H), 4.95 (sd, 1H), 6.3 (br, 1H), 6.75 (s, 2H), 6.8 (s, 1H), 6.9 (m, 2H), 7.25 (m, 1H). M/Z for C₂₄H₂₈Cl₂N₂O₅[M−H]⁻=496.

Example 2E23
Preparation of Compound 57: 3-(4-chlorophenoxy)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)propanamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.75 (br, 4H), 2.65 (br, 6H), 2.8 (m, 2H), 4.2 (m, 7H), 4.95 (sd, 1H), 6.3 (br, 1H), 6.8 (m, 5H), 7.2 (m, 2H). M/Z for C₂₄H₂₉C1N₂O₅[M−H]⁻=461.

Example 2E24
Preparation of Compound 58: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-fluorophenoxy)propanamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.75 (br, 4H), 2.65 (br, 6H), 2.8 (m, 2H), 4.2 (m, 7H), 4.95 (sd, 1H), 6.4 (br, 1H), 6.8 (m, 5H), 7.0 (m, 2H). M/Z for C₂₄H₂₉FN₂O₅[M−H]⁻=445.

Example 2E25
Preparation of Compound 59: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(p-tolyloxy)propanamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.75 (br, 4H), 2.3 (s, 3H), 2.65 (br, 6H), 2.8 (m, 2H), 4.2 (m, 7H), 4.95 (sd, 1H), 6.45 (br, 1H), 6.75 (m, 4H), 6.85 (s, 1H), 7.1 (m, 2H). M/Z for C₂₅H₃₂N₂O₅[M−H]⁻=441.

Example 2E26
Preparation of Compound 60: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(2-fluorophenoxy)propanamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.75 (br, 4H), 2.65 (br, 6H), 2.75 (m, 2H), 4.2 (m, 7H), 4.95 (sd, 1H), 6.35 (br, 1H), 6.7 (s, 2H), 6.85 (s, 1H), 6.95 (m, 2H), 7.05 (m, 2H). M/Z for C₂₄H₂₉FN₂O₅[M−H]⁻=445.

Example 2E27
Preparation of Compound 61: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-methoxyphenoxy)propanamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.75 (br, 4H), 2.65 (br, 6H), 2.75 (m, 2H), 3.8 (s, 3H), 4.1 (m, 2H), 4.2 (br, 5H), 4.95 (sd, 1H), 6.45 (br, 1H), 6.8 (m, 7H). M/Z for C₂₅H₃₂N₂O₆[M−H]⁻=457.

Example 2E28
Preparation of Compound 188: N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-ethylphenoxy)propanamide (2R,3R)-2,3-dihydroxysuccinate

embedded image

¹H NMR (D₂O, 400 mHz, ppm); 0.93 (t, 3H), 1.75 (br, 2H), 1.86 (br, 2H), 2.35 (q, 2H), 2.4 (br, 2H), 2.9 (br, 2H), 3.25 (m, 2H), 3.4 (br, 2H), 3.9 (br, 6H), 4.3 (br, 3H), 4.6 (br, 1H), 6.6 (m, 5H), 7.0 (d, 2H). M/Z for C₂₆H₃₄N₂O₅.C₄H₆O₆[M−H]⁻=454.

Example 2E29
Preparation of Compound 189: N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-propionylphenoxy)propanamide (2R, 3R)-2,3-dihydroxysuccinate

embedded image

¹H NMR (D₂O, 400 mHz, ppm); 0.93 (t, 3H), 1.75 (br, 2H), 1.86 (br, 2H), 2.45 (br, 2H), 2.8 (q, 2H), 2.9 (br, 2H), 3.25 (m, 2H), 3.4 (br, 2H), 3.9 (br, 6H), 4.3 (br, 3H), 4.6 (br, 1H), 6.5 (d, 1H), 6.5 (d, 2H), 6.7 (d, 2H), 7.7 (d, 2H). M/Z for C₂₇H₃₄N₂O₆.C₄H₆O₆[M−H]⁻=483.

Example 2E30
Preparation of Compound 193: N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-(3-oxobutyl)phenoxy)propanamide (2R, 3R)-2,3-dihydroxysuccinate

embedded image

¹H NMR (D₂O, 400 mHz, ppm); 1.75 (br, 2H), 1.86 (br, 2H), 1.94 (s, 3H), 2.45 (br, 2H), 2.6 (m, 4H), 2.9 (br, 2H), 3.25 (m, 2H), 3.4 (br, 2H), 3.9 (br, 6H), 4.3 (br, 3H), 4.6 (br, 1H), 6.6 (m, 5H), 7.0 (d, 2H). M/Z for C₂₈H₃₆N₂O₆.C₄H₆O₆[M−H]⁻=497.

Example 2E31
Preparation of Compound 202: N-((1R, R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-(2-methoxyethyl)phenoxy)propanamide (2R, R)-2,3-dihydroxysuccinate

embedded image

¹H NMR (D₂O, 400 mHz, ppm); 1.75 (br, 2H), 1.86 (br, 2H), 2.45 (br, 2H), 2.62 (t, 2H), 2.9 (br, 2H), 3.1 (s, 3H), 3.25 (m, 2H), 3.4 (br, 4H), 3.9 (br, 6H), 4.3 (br, 3H), 4.6 (br, 1H), 6.6 (m, 5H), 7.0 (d, 2H). M/Z for C₂₇H₃₆N₂O₆.C₄H₆O₆[M−H]⁻=485.

Example 2E32
Preparation of Compound 63: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(3′-methoxybiphenyl-4-yl)acetamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.7 (br, 4H), 2.5 (br, 4H), 2.75 (m, 2H), 3.5 (br, 2H), 3.9 (sd, 3H), 4.2 (m, 5H), 4.95 (sd, 1H), 5.9 (br, 1H), 6.5-7.6 (m, 11H). M/Z for C₃₀H₃₄N₂O₅[M−H]⁻=503.

Example 2E33
Preparation of Compound 127: N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-(4-ethoxyphenyl)-4-oxobutanamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.4 (t, 3H), 1.8 (br, 4H), 2.7 (br, 6H), 3.2 (m, 2H), 4.05 (q, 2H), 4.2 (m, 2H), 4.25 (m, 5H), 4.95 (sd, 1H), 6.05 (br, 1H), 6.9 (m, 5H), 7.95 (d, 2H). M/Z for C₂₇H₃₄N₂O₆[M−H]⁻=483.

Example 2E34
Preparation of Compound 154: N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-(4-methoxyphenyl)-4-oxobutanamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.8 (br, 4H), 2.7 (br, 6H), 3.2 (m, 1H), 3.45 (s, 3H), 3.9 (s, 3 H), 4.2 (m, 5H), 4.95 (sd, 1H), 6.05 (br, 1H), 6.9 (m, 5H), 7.95 (d, 2H). M/Z for C₂₆H₃₂N₂O₆[M−H]⁻=469.

Example 2E35
Preparation of Compound 181: N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-isopropoxyphenyl)-6-oxohexanamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm); 1.4 (d, 6H), 1.8 (br, 8H), 2.15 (br, 2H), 2.8 (br, 10H), 4.25 (m, 5H), 4.65 (m, 1H), 4.95 (sd, 1H), 6.05 (br, 1H), 6.9 (m, 5H), 7.95 (d, 2H). M/Z for C₃₀H₄₀N₂O₆[M−H]⁻=525.

Example 2E36
Preparation of Compound 191: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5-(4-methoxyphenyl)-5-oxopentanamide (2R,3R)-2,3-dihydroxysuccinate

embedded image

¹H NMR (D₂O, 400 mHz, ppm); 1.40 (br, 1H), 1.53 (br, 1H), 1.75 (br, 2H), 1.91 (br, 2H), 1.98 (m, 1H), 2.15 (m, 1H) 2.45 (m, 2H), 2.95 (m, 2H), 3.35 (dd, 2H), 3.4 (m, 2H), 3.68 (br, 5H), 3.77 (br, 2H), 4.3 (br, 3H), 4.68 (br, 1H), 6.47 (d, 1H), 6.65 (d, 2H), 6.85 (d, 2H), 7.63 (d, 2H). M/Z for C₂₇H₃₄N₂O₆.C₄H₆O₆[M−H]=483.

Example 2E37
Preparation of Compound 265: N-((1R,2R)-1-(benzo[δ][1,3]dioxol-5-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5-(4-isopropoxyphenyl)-5-oxopentanamide (2S,3S)-2,3-dihydroxysuccinate

embedded image

¹H NMR (400 MHz, CD₃OD) δ 1.30 (sd, 6H), 1.70-1.85 (m, 2H), 2.04 (br, 4H), 2.09-2.26 (m, 2H), 2.64-2.82 (m, 2H), 3.31-3.48 (m, 5H), 4.37 (s, 2H), 4.43 (br, 1H), 4.68 (m, 1H), 4.71 (sd, 1H), 5.76 (s, 2H), 6.66 (d, 1H), 6.82-6.95 (m, 4H), 7.84 (d, 2H); MS for C₂₈H₃₆N₂O₆.C₄H₆O₆: [M−H]⁻ 645.

Example 2E38
Preparation of Compound 267: N-((1R,2R)-1-(benzo[δ][1,3]dioxol-5-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide (2S,3S)-2,3-dihydroxysuccinate

embedded image

¹H NMR (400 MHz, CD₃OD) δ 1.49 (br, 4H), 2.03 (br, 4H), 2.89 (t, 2H), 3.33-3.46 (m, 6H), 3.84 (s, 3H), 4.37 (s, 2H), 4.43 (d, 1H), 4.76 (br, 1H), 5.81 (s, 2H), 6.68 (d, 1H), 6.81 (d, 1H), 6.88 (s, 1H), 6.96 (d, 2H), 7.92 (d, 2H); MS for C₂₇H₃₄N₂O₆.C₄H₆O₆: [M−H]⁻ 633.

Example 2E39
Preparation of Compound 268: N-((1R,2R)-1-(benzo[δ][1,3]dioxol-5-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-(4-isopropoxyphenyl)-7-oxoheptanamide (2S,3S)-2,3-dihydroxysuccinate

embedded image

¹H NMR (400 MHz, CD₃OD) δ 1.15-1.18 (m, 2H), 1.30 (d, 6H), 1.40-1.45 (m, 2H), 1.57-1.65 (m, 2H), 2.03 (br, 4H), 2.12-2.17 (m, 2H), 2.88 (t, 2H), 3.33-3.48 (m, 5H), 4.38 (s, 2H), 4.42 (d, 1H), 4.67 (m, 1H), 4.78 (d, 1H), 5.83 (d, 2H), 6.71 (d, 1H), 6.82 (d, 1H), 6.89 (s, 1H), 6.92 (d, 2H), 7.90 (d, 2H); MS for C₃₀H₄₀N₂O₆.C₄H₆O₆: [M−H]⁻ 675.

Example 2E40
Preparation of Compound 197: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-(4-methoxyphenoxy)butanamide (2S,3S)-2,3-dihydroxysuccinate

embedded image

¹H NMR (400 MHz, CD₃OD) δ 1.78-1.91 (m, 2H), 2.00 (br, 4H), 2.32 (t, 2H), 3.33-3.47 (m, 6H), 3.69 (s, 3H), 3.72 (t, 2H), 4.11 (br, 4H), 4.37 (s, 2H), 4.41 (d, 1H), 4.72 (d, 1H), 6.69-6.86 (m, 7H); MS for C₂₆H₃₄N₂O₆.C₄H₆O₆: [M−H]⁻ 621.

Example 2E41
Preparation of Compound 187: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-(3-methylbutanoyl)phenoxy)propanamide (2S,3S)-2,3-dihydroxysuccinate

embedded image

¹H NMR (400 MHz, CD₃OD) δ 0.95 (d, 6H), 2.00 (br, 4H), 2.17 (m, 2H), 2.66 (t, 2H), 2.78 (d, 2H), 3.34-3.44 (m, 5H), 4.12-4.17 (m, 6H), 4.40 (s, 2H), 4.45 (d, 1H), 4.73 (sd, 1H), 6.67 (d, 1H), 6.79 (d, 1H), 6.86 (s, 1H), 6.93 (d, 2H), 7.91 (d, 2H); MS for C₂₉H₃₈N₂O₆.C₄H₆O₆: [M−H]⁻ 661.

Example 2E42
Preparation of Compound 83: 2-(4-chlorophenoxy)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ 1.76 (br, 4H), 2.63 (br, 4H), 2.78 (dd, 1H), 2.89 (dd, 1H), 4.24 (s, 4H), 4.27 (br, 1H), 4.36 (q, 2H), 4.94 (d, 1H), 6.71 (d, 1H), 6.77-6.82 (m, 4H), 6.86 (d, 1H), 7.24 (s, 1H); MS for C₂₃H₂₇C1N₂O₅: [M−H]⁻ 447.

Example 2E43
Preparation of Compound 87: 2-(3,4-dichlorophenoxy)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ 1.78 (br, 4H), 2.67 (br, 4H), 2.79 (dd, 1H), 2.92 (dd, 1H), 4.25 (br, s, 5H), 4.35 (q, 2H), 4.95 (d, 1H), 6.71-6.84 (m, 5H), 7.01 (d, 1H), 7.34 (d, 1H); MS for C₂₃H₂₆Cl₂N₂O₅: [M−H]⁻ 482.

Example 2E44
Preparation of Compound 86: N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(3-phenoxyphenyl)acetamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ 1.72 (br, 4H), 2.57 (br, 4H), 2.75-2.80 (m, 2H), 3.45 (s, 2H), 4.11-4.13 (m, 1H), 4.23 (s, 4H), 4.84 (d, 1H), 5.86 (d, 1H), 6.55 (dd, 1H), 6.71 (d, 1H), 6.74 (d, 1H), 6.80 (br, 1H), 6.85 (dd, 1H), 6.92 (dd, 1H), 6.98 (d, 1H), 7.14 (t, 1H), 7.28-7.36 (m, 2H); MS for C₂₉H₃₂N₂O₅: [M−H]⁻ 489.

Example 2E45
Preparation of Compound 280: 2-(3,4-difluorophenyl)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ 1.80 (br, 4H, 2.68 (br, 4H), 2.84 (d, 2H), 3.45 (s, 2H), 4.17 (m, 1H), 4.25 (s, 4H), 4.88 (d, 1H), 5.88 (d, 1H), 6.65 (d, 1H), 6.79 (d, 1H), 6.95 (m, 1H), 6.95 (t, 1H), 7.13 (q, 1H); MS for C₂₃H₂₆F₂N₂O₄: [M−H]⁻ 434.

Example 2E46
Preparation of Compound 103: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(trifluoromethoxy)phenyl)acetamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ 1.65 (br, 4H), 2.48 (br, 4H), 2.69 (d, 2H), 3.40 (s, 2H), 4.08 (m, 1H), 4.17 (s, 4H), 4.80 (s, 1H), 5.84 (t, 1H), 6.55 (d, 1H), 6.66 (s, 1H), 6.70 (d, 1H), 7.10 (t, 3H); MS for C₂₄H₂₇F₃N₂O₅: [M−H]⁻ 481.

Example 2E47
Preparation of Compound 90: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5-(thiophen-2-yl)isoxazole-3-carboxamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ 1.82 (br, 4H), 2.73-2.81 (m, 4H), 2.89-2.93 (m, 1H), 3.02-3.07 (m, 1H), 4.23 (s, 4H), 4.41 (br, 1H), 5.07 (s, 1H), 5.30 (d, 1H), 6.74 (s, 1H), 6.83 (t, 2H), 6.90 (s, 1H), 7.12-7.14 (m, 2H), 7.47 (d, 1H), 7.52 (d, 1H); MS for C₂₃H₂₅N₃O₅S: [M−H]⁻ 456.

Example 2E48
Preparation of Compound 92: 3-(3-chloro-4-methoxyphenyl)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)propanamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ 1.77 (br, 4H), 2.38 (t, 2 H), 2.60 (br, 4H), 2.8 (m, 4H), 3.86 (s, 3H), 4.20 (br, 1H), 4.24 (s, 4H), 4.87 (s, 1H), 5.80 (d, 1H), 6.66 (d, 1H), 6.8 (m, 3H), 7.00 (d, 1H), 7.18 (s, 1H); MS for C₂₅H₃₁C1N₂O₅: [M−H]⁻ 475.

Example 2E49
Preparation of Compound 96: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-(trifluoromethyl)phenyl)propanamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ 1.73 (br, 4H), 2.4 (m, 2H), 2.53 (m, 4H), 2.7 (m, 2H), 2.90-2.97 (m, 2H), 4.17 (br, 1H), 4.23 (s, 4H), 4.89 (s, 1H), 5.83 (br, 1H), 6.68 (d, 1H), 6.79 (d, 2H), 7.24 (d, 2H), 7.50 (d, 2H); MS for C₂₅H₂₉F₃N₂O₅: [M−H]⁻ 479.

Example 2E50
Preparation of Compound 101: 4-(benzo[d]thiazol-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)butanamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ 1.77 (br, 4H), 2.10-2.15 (m, 2H), 2.24-2.27 (m, 2H), 2.64-2.67 (m, 4H), 2.79-2.83 (m, 2H), 3.02 (t, 2H), 4.18 (s, 4H), 4.26 (br, 1H), 4.92 (d, 1H), 6.12 (br, 1H), 6.75-6.81 (m, 2H), 6.86 (s, 1H), 7.37 (t, 1H), 7.45 (t, 1H), 7.85 (d, 1H), 7.92 (d, 1H); MS for C₂₆H₃₁N₃O₄S: [M−H]⁻ 482.

Example 2E51
Preparation of Compound 102: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(2,3-dihydrobenzo[β][1,4]dioxine-6-sulfonamido)hexanamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ 1.15-1.20 (m, 2H), 1.38-1.50 (m, 4H), 1.77 (br, 4H), 2.08 (q, 2H), 2.63-2.66 (m, 4H), 2.79 (d, 2H), 2.87 (t, 2H), 4.2 (m, 9H), 4.91 (br, 1H), 5.93 (br, 1H), 6.77 (q, 2H), 6.84 (s, 1H), 6.93 (d, 1H), 7.31 (d, 1H), 7.37 (s, 1H); MS for C₂₉H₃₉N₃O₈S: [M−H]⁻ 590.

Example 2E52
Preparation of Compound 104: N-(5-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-ylamino)-5-oxopentyl)benzamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ 1.47-1.52 (m, 2H), 1.59-1.69 (m, 2H), 1.77 (br, 4H), 2.15-2.21 (m, 2H), 2.62-2.65 (m, 4H), 2.81 (br, 2H), 3.30-3.42 (m, 2H), 4.19-4.23 (m, 5H), 4.94 (br, 1H), 5.98 (br, 1H), 6.76 (br, 1H), 6.78-6.86 (m, 3H), 7.40-7.50 (m, 3H), 7.80 (d, 2H); MS for C₂₇H₃₅N₃O₅: [M−H]⁻ 482.

Example 2E53
Preparation of Compound 281: N1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-N5-(thiazol-2-yl)glutaramide

embedded image

¹H NMR (400 MHz, CDCl₃) δ 1.74 (br, 4H), 1.97-2.03 (m, 2H), 2.20-2.26 (m, 2H), 2.40-2.45 (m, 2H), 2.64-2.68 (m, 5H), 2.88 (m 1H), 4.20 (s, 4H), 4.26-4.29 (m, 1H), 4.83 (d, 1H), 6.12 (br, 1H), 6.74-6.79 (m, 2H), 6.85 (s, 1H), 6.95 (d, 1H), 7.41 (d, 1H); MS for C₂₃H₃₀N₄O₅S: [M−H]⁻ 475.

Example 2E54
Preparation of Compound 282: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5-(3,4-dimethoxyphenyl)-5-oxopentanamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ 1.76 (br, 4H), 1.92-2.00 (m, 2H), 2.21-2.26 (m, 2H), 2.60-2.65 (m, 4H), 2.70-2.95 (m, 4H), 3.93 (d, 6H), 4.17-4.23 (m, 5H), 4.90 (d, 1H), 5.96 (br, 1H), 6.75-6.79 (m, 2H), 6.85 (s, 1H), 6.87 (d, 1H), 7.50 (s, 1H), 7.55 (d, 1H); MS for C₂₈H₃₆N₂O₇: [M−H]⁻ 513.

Example 2E55
Preparation of Compound 283: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5-oxo-5-p-tolylpentanamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ 1.77 (br, 4H), 1.96-2.02 (m, 2H), 2.21-2.26 (m, 2H), 2.40 (s, 3H), 2.63-2.80 (m, 4H), 2.82-2.95 (m, 4H), 4.18-4.23 (m, 5H), 4.91 (d, 1H), 5.94 (br, 1H), 6.74-6.77 (m, 2H), 6.85 (s, 1H), 7.26 (d, 2H), 7.81 (d, 2H); MS for C₂₇H₃₄N₂O₅: [M−H]⁻ 467.

Example 2E56
Preparation of Compound 113: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5-oxo-5-phenylpentanamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ 1.76 (br, 4H), 1.95-2.01 (m, 2H), 2.22-2.25 (m, 2H), 2.62-2.63 (m, 4H), 2.78-2.95 (m, 4H), 4.17-4.22 (m, 5H), 4.91 (sd, 1H), 5.99 (br, 1H), 6.77 (st, 2H), 6.85 (s, 1H), 7.44-7.58 (m, 3H), 7.92 (d, 2H); MS for C₂₆H₃₂N₂O₅: [M−H]⁻ 453.

Example 2E57
Preparation of Compound 284: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5-(4-isopropoxyphenyl)-5-oxopentanamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ 1.36 (d, 6H), 1.75 (br, 4H), 1.90-2.02 (m, 2H), 2.20-2.25 (m, 2H), 2.60-2.66 (m, 4H), 2.70-2.86 (m, 4H), 4.17 (s, 4H), 4.22 (br, 1H), 4.62-4.65 (m, 1H), 4.89 (sd, 1H), 6.07 (d, 1H), 6.77 (s, 2H), 6.85 (s, 1H), 6.87 (d, 2H), 7.86 (d, 2H); MS for C₂₉H₃₈N₂O₆: [M−H]⁻ 511.

Example 2E58
Preparation of Compound 140: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxy-3,5-dimethylphenyl)-6-oxohexanamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ 1.61-1.63 (m, 4H), 1.77 (br, 4H), 2.16 (t, 2H), 2.32 (s, 6H), 2.61-2.67 (m, 4H), 2.74-2.89 (m, 2H), 2.91 (t, 2H), 3.75 (s, 3H), 4.21 (br, 5H), 4.90 (sd, 1H), 5.93 (br, 1H), 6.75-6.82 (m, 2H), 6.85 (sd, 1H), 7.61 (s, 2H); MS for C₃₀H₄₀N₂O₆: [M−H]⁻ 525.

Example 2E59
Preparation of Compound 141: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ 1.62-1.64 (m, 4H), 1.76 (br, 4H), 2.17 (t, 2H), 2.61-2.65 (m, 4H), 2.72-2.79 (m, 2H), 2.89 (t, 2H), 3.86 (s, 3H), 4.20 (br, 5H), 4.89 (d, 1H), 6.01 (br, 1H), 6.77 (q, 2H), 6.85 (s, 1H), 6.91 (d, 2H), 7.90 (d, 2H); MS for C₂₈H₃₆N₂O₆: [M−H]⁻ 497.

Example 2E60
Preparation of Compound 155: 6-(4-tert-butylphenyl)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-oxohexanamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ 1.34 (s, 9H), 1.63-1.65 (m, 4H), 1.77 (br, 4H), 2.17 (t, 2H), 2.64-2.66 (br, 4H), 2.75 (dd, 1H), 2.2.81 (dd, 1H), 2.91 (t, 2H), 4.20 (br, 5H), 4.90 (d, 1H), 6.02 (br, 1H), 6.77-6.82 (q, 2H), 6.85 (d, 1H), 7.46 (d, 2H), 7.86 (d, 2H); MS for C₃₁H₄₂N₂O₅: [M−H]⁻ 523.

Example 2E61
Preparation of Compound 156: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-(4-methoxyphenyl)-7-oxoheptanamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ 1.25-1.30 (m, 2H), 1.55-1.70 (m, 4H), 1.77 (br, 4H), 2.13 (t, 2H), 2.61-2.66 (m, 4H), 2.74-2.82 (m, 2H), 2.88 (t, 2H), 3.86 (s, 3H), 4.20 (br, 5H), 4.90 (d, 1H), 5.93 (br, 1H), 6.78 (q, 2H), 6.85 (s, 1H), 6.91 (d, 2H), 7.92 (d, 2H); MS for C₂₉H₃₈N₂O₆: [M−H]⁻ 511.

Example 2E62
Preparation of Compound 144: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-8-(4-methoxyphenyl)-8-oxooctanamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ 1.25-1.33 (m, 4H), 1.54 (m, 2H), 1.68 (t, 2H), 1.78 (br, 4H), 2.11 (br, 2H), 2.65 (br, 4H), 2.76-2.11 (m, 4H), 3.86 (s, 3H), 4.21 (br, 5H), 4.90 (br, 1H), 6.02 (d, 1H), 6.78-6.84 (m, 3H), 6.91 (d, 2H), 7.92 (d, 2H); MS for C₃₀H₄₀N₂O₆: [M−H]⁻ 525.

Example 2E63
Preparation of Compound 159: 7-(4-chlorophenyl)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-oxoheptanamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ 1.26-1.37 (m, 2H), 1.57 (m, 2H), 1.68 (m, 2H), 1.77 (br, 4H), 2.13 (t, 2H), 2.62-2.65 (m, 4H), 2.76-2.82 (m, 2H), 2.90 (t, 2H), 4.20 (br, 5H), 4.90 (d, 1H), 5.93 (d, 1H), 6.78 (q, 2H), 6.85 (s, 1H), 7.42 (d, 2H), 7.87 (d, 2H); MS for C₂₈H₃₅C1N₂O₅: [M−H]⁻ 515.

Example 2E64
Preparation of Compound 160: 7-(4-tert-butylphenyl)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-oxoheptanamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ 1.27-1.34 (m, 11H), 1.56-1.71 (m, 4H), 1.77 (br, 4H), 2.13 (t, 2H), 2.63-2.66 (m, 4H), 2.76-2.819 (m, 2H), 2.91 (t, 2H), 4.20 (br, 5H), 4.90 (sd, 1H), 5.90 (d, 1H), 6.81 (q, 2H), 6.85 (s, 1H), 7.46 (d, 2H), 7.88 (d, 2H); MS for C₃₂H₄₄N₂O₅: [M−H]⁻ 537.

Example 2E65
Preparation of Compound 168: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-7-(4-methoxyphenyl)-7-oxoheptanamide (2S,3S)-2, 3-dihydroxysuccinate

embedded image

¹H NMR (400 MHz, CD₃OD) δ 1.15-1.19 (m, 2H), 1.40-1.47 (m, 2H), 1.60 (m, 2H), 2.02 (br, 4H), 2.09-2.21 (m, 2H), 2.90 (t, 2H), 3.35-3.49 (m, 5H), 3.83 (s, 3H), 4.12 (br, 4H), 4.38 (s, 2H), 4.43 (m, 1H), 4.74 (sd, 1H), 6.71 (d, 1H), 6.79 (dq, 1H), 6.86 (sd, 1H), 6.96 (d, 2H), 7.92 (d, 2H); MS for C₂₉H₃₈N₂O₆.C₄H₆O₆: [M−H]⁻ 661.

Example 2E66
Preparation of Compound 162: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-(4-isopropoxyphenyl)-4-oxobutanamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ 1.35 (d, 6H), 1.77 (br, 4H), 2.52-2.56 (m, 2H), 2.64-2.83 (m, 6H), 3.09-3.36 (m, 2H), 4.22 (br, 5H), 4.63-4.66 (m, 1H), 4.89 (sd, 1H), 6.13 (d, 1H), 6.78 (s, 2H), 6.88 (t, 3H), 7.90 (d, 2H); MS for C₂₈H₃₆N₂O₆: [M−H]⁻ 497.

Example 2E67
Preparation of Compound 176: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-4-oxo-4-(4-(trifluoromethyl)phenyl)butanamide (2S,3S)-2,3-dihydroxysuccinate

embedded image

¹H NMR (400 MHz, CD₃OD) δ 2.08 (br, 4H), 2.54-2.72 (m, 2H), 3.24-3.48 (m, 6H), 4.19 (s, 4H), 4.29 (m, 4H), 4.74 (sd, 1H), 6.76 (d, 1H), 6.86 (d, 1H), 6.92 (s, 1H), 7.81 (d, 2H), 8.13 (d, 2H); MS for C₂₆H₂₉F₃N₂O₅.C₄H₆O₆: [M−H]⁻ 657.

Example 2E68
Preparation of Compound 65 (Genz-528152-1): 2-(3′-chlorobiphenyl-4-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ 1.70 (br, 4H), 2.54 (br, 4H), 2.72-2.81 (m, 2H), 3.53 (s, 2H), 4.12-4.23 (m, 5H), 4.85 (d, 1H), 5.82 (d, 1H), 6.58 (dd, 1H), 6.70 (sd, 1H), 6.73 (d, 1H), 7.19 (d, 1H), 7.32-7.34 (m, 1H), 7.38 (t, 1H), 7.46-7.49 (m, 1H), 7.52 (d, 2H), 7.59 (d, 1H); C₂₉H₃₁C1N₂O₄: [M−H]⁻ 507.

Example 2E69
Preparation of Compound 262: N-[2-Hydroxy-2-(4-methoxy-phenyl)-1-pyrrolidin-1-ylmethyl-ethyl]-3-(4-methoxy-phenoxy)-propionamide

embedded image

¹H NMR (CDCl₃400 mHz, ppm); 1.75 (m, 4H), 2.55 (m, 2H), 2.65 (m, 4H), 2.85 (m, 2H), 3.8 (s, 6H), 4.1 (m, 2H), 4.25 (m, 1H), 5.0 (d, 1H), 6.5 (br. d, 1H), 6.8 (m, 4H), 7.25 (m, 4H). M/Z for C₂₄H₃₂N₂O₅[M−H]⁺ 429.

Example 2E70
Preparation of Compound 270: 5-(4-Isopropoxy-phenyl)-5-oxo-pentanoic acid [2-hydroxy-2-(4-methoxy-phenyl)-1-pyrrolidin-1-ylmethyl-ethyl]amide

embedded image

¹H NMR (CDCl₃400 mHz, ppm); 1.4 (d, 6H), 1.8 (m, 4H), 2.0 (m, 2H), 2.2 (m, 2H), 2.6 (m, 4H), 2.8 (m, 4H), 3.75 (s, 3H), 4.25 (m, 1H), 4.65 (m, 1H), 5.0 (d, 1H), 5.95 (br. d, 1H), 6.85 (m, 4H), 7.25 (m, 2H), 7.9 (m, 2H). M/Z for C₂₄H₃₂N₂O₅[M−H]⁺ 483.3.

Example 2E71
Preparation of Compound 285: 7-(4-Methoxy-phenyl)-7-oxo-heptanoic acid [2-hydroxy-2-(4-methoxy-phenyl)-1-pyrrolidin-1-ylmethyl-ethyl]-amide

embedded image

¹H NMR (CDCl₃400 mHz, ppm); 1.25 (m, 2H), 1.6 (m, 4H), 1.8 (m, 4H), 2.15 (m, 2H), 2.65 (m, 4H), 2.85 (m, 4H), 3.75 (s, 3H), 3.9 (s, 3H), 4.2 (m, 1H), 5.0 (d, 1H), 5.9 (br. d, 1H), 6.85 (d, 2H), 6.95 (d, 2H), 7.2 (d, 2H), 7.95 (d, 2H). M/Z for C₂₄H₃₂N₂O₅[M−H]⁺ 483.3

Example 2E72
Preparation of Compound 262: N-[2-Hydroxy-2-(4-methoxy-phenyl)-1-pyrrolidin-1-ylmethyl-ethyl]-3-(4-methoxy-phenoxy)-propionamide

embedded image

Example 2E73
Preparation of Compound 270: 5-(4-Isopropoxy-phenyl)-5-oxo-pentanoic acid [2-hydroxy-2-(4-methoxy-phenyl)-1-pyrrolidin-1-ylmethyl-ethyl]amide

embedded image

Example 2E74
Preparation of Compound 305

embedded image

¹H NMR (CDCl₃400 mHz, ppm); 1.25 (m, 14 H), 1.6 (m, 4H), 1.8 (m, 4H), 2.1 (t, 2H), 2.6 (t, 2H), 2.8 (m, 6H), 4.2 (m, 5H), 4.9 (d, 1H), 6.0 (br d, 1H), 6.8 (m, 3H), 7.2 (m, 1H), 7.5 (m, 1H), 8.4 (m, 2H). M/Z for C₂₄H₃₂N₂O₅[M−H]⁺ 538.

Example 2E75
Preparation of Compound 320: Octanoic acid [2-hydroxy-2(4-methoxy-phenyl)-1-Pyrrolidin1-ylmethyl-ethyl]-amide

embedded image

¹H NMR (CDCl₃400 mHz, ppm); 0.9 (t, 3H), 1.2 (m, 8H), 1.5 (m, 2H), 1.8 (m, 4H), 2.1 (t, 2H), 2.65 (m, 4H), 2.8 (d, 2H), 3.8 (s, 3H), 4.2 (m, 1H), 4.95 (d, 1H), 5.9 (br d, 1H), 6.9 (2s, 2H), 7.25 (m, 2H). M/Z for C₂₂H₃₆N₂O₃[M−H]⁺ 377.4.

Example 2E76
Preparation of Cyclic Amide Analogs

embedded image

Cyclic amide analogs were prepared according to Scheme 6. 2-Amino-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3-pyrrolidin-1-yl-propan-1-ol was prepared according to the preparation of intermediate 4 of U.S. Pat. No. 6,855,830 B2. This amine was coupled with various nitriles in potassium carbonate and glycerol, under an atmosphere of nitrogen, for example, at 115° C. for 18 hours. Compound 323 characterized by the following structural formula was prepared by following Scheme 6. Compound 323 was purified by column chromatography using a mixture of methanol and methylene chloride.

embedded image

¹H NMR (CDCl₃400 mHz, ppm); 0.95 (t, 3H), 1.35 (m, 2H), 1.6 (m, 2H), 1.8 (m, 4H), 2.7 (m, 6H), 2.8 (m, 2H), 4.2 (m, 5H), 5.4 (d, 1H), 6.85 (m, 3H), 7.2 (m, 2H), 7.9 (d, 2H). M/Z for C₂₄H₃₂N₂O₅[M−H]⁺ 421.54.

Example 2E77
Preparation of N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5-(4-(2-methoxyethoxy)phenyl)-5-oxopentanamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm): 1.25 (t, 3H), 1.8 (br, 4H), 1.95 (m, 2H), 2.05 (t, 3H), 2.25 (m, 2H), 3.65 (m, 4H), 2.90 (m, 4H), 3.4 (s, 4H), 3.8 (m, 2H), 4.15 (m, 9H), 4.95 (br, 1H), 5.95 (br, 1H), 6.88-6.95 (m, 5H), 7.9 (m, 2H). M/Z for C₂₉H₃₈N₂O₇[M+H]=527.

Example 2E78
Preparation of N-((1R,2R)-1-(4-chlorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-methoxyphenoxy)propanamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm): 1.76 (br, 4H), 2.52-2.57 (sq, 2H), 2.60-2.73 (br, 4H), 2.88-2.96 (st, 2H), 3.8 (s, 3H), 3.96-4.0 (m, 1H), 4.06-4.11 (1H), 4.21-4.24 (m, 1H), 5.07 (d, 1H), 6.57 (bd, 1H), 6.77-6.87 (sq, 4H), 7.20-7.27 (sd, 6H). M/Z for C₂₃H₂₉C1N₂O₄[M+H]=433.

Example 2E79
Preparation of N-((1R,2R)-1-(4-chlorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm): 1.54-1.62 (br, 4H), 1.79 (br, 4H), 2.14 (t, 2H), 2.63-2.69 (br, 4H), 2.83-2.89 (m, 4H), 3.88 (s, 3H), 4.24 (br, 1H), 5.03 (d, 1H), 5.93 (d, 1H), 6.93 (d, 2H), 7.26-7.32 (m, 4H), 7.93 (d, 2H). M/Z for C₂₆H₃₃ClN₂O₄[M+H]=473.

Example 2E80
Preparation of N-((1R,2R)-1-hydroxy-1-(4-methoxy-3-methylphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm): 1.77 (br, 4H), 1.91-2.0 (m, 2H), 2.18 (s, 3H), 2.2-2.25 (m, 2H), 2.62-2.69 (m, 4H), 2.77-2.89 (m, 4H), 3.75 (s, 3H), 3.88 (s, 3H), 4.23 (m, 1H), 4.96 (sd, 1H), 5.93 (br, 1H), 6.75 (br, 1H), 6.94 (d, 2H), 7.1 (br, 2H), 7.88 (m, 2H). M/Z for C₂₈H₃₈N₂O₅[M+H]=483.

Example 2E81
Preparation of N-((1R,2R)-1-hydroxy-1-(4-methoxy-3-methylphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(trifluoromethoxy)phenyl)acetamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm): 1.73 (br, 4H), 2.20 (s, 3H), 2.55 (br, 4H), 2.81 (st, 2H), 3.46 (s, 2H), 3.82 (s, 3H), 4.15 (m, 1H), 4.92 (sd, 1H), 5.85 (br, 1H), 672 (d, 1H), 6.95 (sd, 1H), 7.00 (br, 1H), 7.2 (m, 4H). M/Z for C₂₄H₂₉F₃N₂O₄[M+H]=467.

Example 2E82
Preparation of N-((1R,2R)-1-hydroxy-3-(pyrrolidin-1-yl)-1-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propan-2-yl)octanamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm): 0.9 (t, 3H), 1.2 (rm, 11H), 1.5 (bm, 8H), 1.8 (br, 4H), 2.1 (m, 2H), 2.65 (m, 4 H), 2.90 (m, 2H), 4.2 (m, 1H), 5.05 (d, 1H), 5.85 (br, 1H), 7.2 (m, 3H). M/Z for C₂₃H₃₂F₄N₂O₄[M+H]=477.

Example 2E83
Preparation of N-((1R,2R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(trifluoromethoxy)phenyl)acetamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm): 1.75 (br, 4H), 2.55 (br, 4H), 2.85 (m, 2H), 3.45 (s, 2H), 4.1 (m, 1H), 5.0 (d, 1H), 5.85 (br, 1H), 6.8-6.95 (3H), 7.1-7.20 (4H). M/Z for C₂₃H₂₃F₅N₂O₅[M+H]=503.

Example 2E84
Preparation of N-((1R,2R)-1-hydroxy-1-(4-(2-phenoxyethoxy)phenyl)-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm): 1.6 (m, 4H), 1.8 (m, 4H), 2.15 (t, 2H), 2.7 (m, 4H), 2.85 (m, 4H), 3.8 (s, 3H), 4.25 (m, 1H), 4.3 (s, 3H), 5.0 (d, 1H), 5.95 (br, 1H), 6.9 (m, 7H), 7.2 (m, 4H), 7.95 (m, 2H). M/Z for C₃₄H₄₂N₂O₆[M+H]=575.

Example 2E85
Preparation of N-((1R,2R)-1-(4-(cyclobutylmethoxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm): 1.6 (br, 4H), 1.9 (m, 9H), 2.05 (m, 5H), 2.75-3.0 (m, 9H), 3.8 (m, 5H), 4.3 (m, 1H), 5.0 (m, 1H), 6.2 (br, 1H), 6.9 (m, 4H), 7.25 (m, 2H), 7.9 (m, 2H). M/Z for C₃₁H₄₂N₂O₅[M+H]=523.

Example 2E86
Preparation of N-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm): 1.6 (m, 8H), 1.8 (m, 10H), 2.15 (t, 2H), 2.65 (m, 4H), 2.8 (d, 2H), 2.9 (m, 5H), 2.95 (s, 3H), 4.0 (t, 2H), 4.15 (m, 1H), 4.45 (t, 1H), 4.55 (t, 1H), 4.95 (br, 2H), 5.9 (br, 1H), 6.90 (m, 4H), 7.20 (m, 2H), 7.95 (m, 2H), 8.05 (br, 1H). M/Z for C₃₀H₄₁FN₂O₅[M+H]=529.

Example 2E87
Preparation of N-((1R,2R)-1-hydroxy-3-(pyrrolidin-1-yl)-1-(4-(3-(p-tolyloxy)propoxy)phenyl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm): 1.65 (m, 4H), 1.8 (m, 4H), 2.15 (t, 2H), 2.25 (t, 2H), 2.3 (s, 3H), 2.65 (m, 4H), 2.8 (m, 2H), 2.9 (t, 2H), 3.85 (s, 3H), 4.15 (m, 4H), 4.25 (m, 1H), 4.95 (br, 1H), 6.85 (br, 1H), 6.8-6.95 (m, 6H), 7.05 (m, 2H), 7.2 (m, 2H), 7.95 (2H). M/Z for C₃₆H₄₆N₂O₆[M+H]=603.

Example 2E88
Preparation of N-((1R,2R)-1-(4-butoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm): 1.0 (t, 3H), 1.5 (m, 2H), 1.65 (m, 4H), 1.8 (m, 6H), 2.15 (t, 2H), 2.65 (m, 4H0, 2.8 (m, 2H), 2.9 (t, 2H), 3.85 (s, 3H), 3.9 (t, 2H), 4.15 (m, 1H), 4.95 (br, 1H), 5.90 (br, 1H), 6.8-6.95 (m, 4H), 7.2 (br, 2H), 7.90 (br, 2H). M/Z for C₃₀H₄₂N₂O₅[M+H]=511.

Example 2E89
Preparation of N-((1R,2R)-1-(4-(hexyloxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-5-(4-(2-methoxyethoxy)phenyl)-5-oxopentanamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm): 0.95 (t, 3H), 1.35 (m, 4H), 1.45 (m, 2H), 1.7 (m, 6H), 1.95 (m, 2H), 2.20 (m, 2H), 2.65 (m, 4H), 2.85 (m, 4H), 3.45 (s, 3H), 3.75 (m, 2H), 3.90 (t, 2H), 4.15 (m, 2H), 4.25 (m, 1H), 4.95 (m, 1H), 6.0 (br, 1H), 6.8 (m, 2H), 6.9 (m, 2H), 7.2 (m, 2H), 7.90 (m, 2H). M/Z for C₃₃H₄₈N₂O₆[M+H]=569.

Example 2E90
Preparation of N-((1R,2R)-1-(4-(hexyloxy)phenyl)-1-hydroxy-3-((S)-3-hydroxypyrrolidin-1-yl)propan-2-yl)-3-(4-methoxyphenoxy)propanamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm): 0.95 (t, 3H), 1.35 (m, 4H), 1.45 (m, 2H), 1.75 (m, 3H), 2.1 (m, 1H), 2.4 (m, 1H), 2.55 (t, 2H), 2.75 (m, 3H), 2.85 (m, 1H), 3.0 (m, 1H), 3.75 (s, 3H), 3.90 (t, 2H), 4.05 (m, 2H), 4.1 (m, 1H), 4.15 (m, 1H), 5.0 (br, 1H), 6.6 (br, 1H), 6.8 (m, 6H), 7.2 (m, 2H). M/Z for C₂₉H₄₂N₂O₆[M+H]=515.

Example 2E91
Preparation of 2-(4′-chlorobiphenyl-4-yl)-N-((1R,2R)-3-((R)-3-fluoropyrrolidin-1-yl)-1-hydroxy-1-(4-isopropoxyphenyl)propan-2-yl)acetamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm): 1.15 (m, 6H), 2.10 (m, 2H), 2.4 (q, 1H), 2.5-2.75 (m, 4H), 2.95 (m, 2H), 3.55 (d, 2H), 4.15 (m, 1H), 4.45 (m, 1H), 4.85 (br, 1H), 5.10 (m, 1H), 5.9 (br, 1H), 6.75 (m, 2H), 7.05 (br, 2H), 7.20 (m, 2H), 7.4 (m, 2H), 7.5 (m, 4H). M/Z for C₃₀H₃₄ClFN₂O₃[M+H]=528.

Example 2E92
Preparation of N-((1R,2R)-1-hydroxy-3-((S)-3-hydroxypyrrolidin-1-yl)-1-(4-isopropoxyphenyl)propan-2-yl)-3-(4-methoxyphenoxy)propanamide

embedded image

¹H NMR (CDCl₃, 400 mHz, ppm): 1.35 (d, 6H), 1.7 (m, 1H), 2.1 (m, 1H), 2.45 (m, 1H), 2.55 (t, 2H), 2.7-2.9 (m, 4H), 3.0 (m, 1H), 3.8 (s, 3H), 4.05 (m, 1H), 4.15 (m, 1H), 4.20 (m, 1H), 4.35 (m, 1H), 4.5 (m, 1H), 4.95 (d, 1H), 6.55 (br, 1H), 6.75-6.85 (m, 6H), 7.2 (m, 2H). M/Z for C₂₆H₃₆N₂O₆[M+H]=473.

Example 2E93
Preparation of N-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-((R)-3-hydroxypyrrolidin-1-yl)propan-2-yl)-5-(4-methoxyphenyl)-5-oxopentanamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.7-2.2 (m, 12 H), 2.4 (dd, 1H), 2.65-2.9 (m, 6H), 3.0 (dd, 1H), 3.90 (s, 3H), 3.91 (dd, 2H), 4.1-4.22 (m, 1H), 4.3-4.4 (m, 1H), 4.4 (dd, 1H), 4.6 (dd, 1H), 4.91 (d, 1H), 6.19 (d, 1H), 6.83 (d, 2H), 6.92 (d, 2H), 7.22 (d, 2 H), 7.9 (d, 2H); MS for C₂₉H₃₉FN₂O₆m/z 531[M+H].

Example 2E94
Preparation of N-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-((R)-3-hydroxypyrrolidin-1-yl)propan-2-yl)-8-methoxyoctanamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.2-1.34 (m, 6H), 1.45-1.6 (m, 4H), 1.7-1.8 (m, 1H), 1.86-1.95 (m, 4H), 2.0-2.2 (m, 4), 2.4-2.5 (m, 2H), 2.7-2.8 (m, 4H), 2.98 (dd, 1H), 3.3 (s, 3H), 3.53 (dd, 1H), 4.0 (dd, 2H), 4.1-4.2 (m, 1H), 4.3-4.4 (m, 1H), 4.5 (dd, 1H), 4.58 (dd, 1H), 4.9 (d, 1H), 5.9 (d, 1H), 6.85 (d, 2H), 7.22 (d, 2H); MS for C₂₆H₄₃FN₂O₅m/z 483 [M+H]

Example 2E95
Preparation of N-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-((R)-3-hydroxypyrrolidin-1-yl)propan-2-yl)-4-(4-methoxyphenoxy)butanamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.6-2.2 (m, 9H), 2.3-2.5 (m, 4H), 2.6-2.8 (m, 5), 2.9 (dd, 1H), 3.7 (s, 3H), 3.85 (dd, 2H), 3.95 (dd, 2H), 4.2-4.3 (m, 2H), 4.5 (dd, 1H), 4.6 (dd, 1H), 4.9 (d, 1H), 6.0 (d, 1H), 6.7-7 (m, 6H), 7.1-7.2 (d, 2H); MS for C₂₈H₃₉FN₂O₆m/z 519 [M+H].

Example 2E96
Preparation of N-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-((R)-3-hydroxypyrrolidin-1-yl)propan-2-yl)-3-(4-methoxyphenoxy)propanamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.6-1.7 (m, 1H), 1.8-2 (m, 4H), 2.1-2.2 (m, 1), 2.4-2.5 (m, 1H), 2.6 (t, 2H), 2.7-2.85 (m, 4H), 3.0 (dd, 1H), 3.7 (s, 3H), 4.0 (t, 2H), 4.1-4.3 (m, 4H), 4.5 (dd, 1H), 4.6 (dd, 1H) 4.98 (d, 1H), 6.6 (d, 1H), 6.7-6.9 (m, 6H), 7.1-7.22 (d, 2H); MS for C₂₇H₃₇FN₂O₆m/z 505[M+H].

Example 2E97
Preparation of N-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-((R)-3-hydroxypyrrolidin-1-yl)propan-2-yl)-7-(4-methoxyphenyl)-7-oxoheptanamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.1-1.4 (m, 3H), 1.5-2.0 (m, 12H), 2.1-2.2 (dd, 4H), 2.4-2.90 (m, 10H), 3.0 (dd, 1H), 3.75 (s, 3H), 3.9 (dd, 2H), 4.1-4.2 (m, 1H), 4.3-4.4.5 (m, 2H), 4.57 (dd, 1H), 4.9 (d, 1H), 5.9 (d, 1H), 6.8 (d, 2H), 6.9 (d, 2H), 7.2 (d, 2H), 7.9 (d, 2H); MS for C₃₁H₄₃FN₂O₆m/z 559[M+H].

Example 2E98
Preparation of N-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-((R)-3-hydroxypyrrolidin-1-yl)propan-2-yl)-6-(4-methoxyphenyl)-6-oxohexanamide

embedded image

¹H NMR (400 MHz, CD₃OD) δ=1.4-1.6 (m, 4H), 1.6-1.8 (m, 5H), 2.0-2.2 (m, 1H), 2.2-2.3 (m, 2H), 2.4-2.6 (m, 3H), 2.7-3.0 (m, 5H), 3.8 (s, 3H), 3.9 (dd, 1H), 4.1-4.25 (m, 1H), 4.3-4.38 (m, 1H), 4.4 (dd, 1H), 4.5 (dd, 1H), 6.8 (d, 2H), 7.1 (d, 2H), 7.2 (d, 2H), 8 (d, 2H); MS for C₃₀H₄₁FN₂O₆m/z 545[M+H]

Example 2E99
Preparation of N-((1S,2R)-1-(5-chlorothiophen-2-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-methoxyphenoxy)propanamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.7 (broad s, 4H), 2.5-2.7 (m, 7H), 2.8 (dd, 1H), 2.94 (dd, 1H), 3.77 (s, 3H) 4.1-4.2 (m, 2H), 4.3-4.35 (m, 1H), 5.18 (d, 1H), 6.55 (d, 1H), 6.66 (d, 1H), 6.67 (d, 1H), 6.7-6.9 (m, 4H); MS for C₂₁H₂₇ClN₂O₄S m/z 439[M+H].

Example 2E100
Preparation of N-((1 S,2R)-1-hydroxy-1-(3-methylthiophen-2-yl)-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-methoxyphenoxy)propanamide 2,2,2-trifluoroacetate

embedded image

¹H NMR (400 MHz, CD₃OD) δ=1.8-2.2 (m, 4H), 2.24 (s, 3H) 2.5-2.8 (m, 2H), 3.0-3.2 (m, 2H), 3.5 (dd, 2H), 3.7 (s, 3H), 3.6-3.8 (m, 2H), 4.0-4.2 (m, 2H), 4.5 (dd, 1H), 5.2 (s, 1H), 6.8 (d, 1H), 6.84 (broad s, 4H), 7.2 (d, 1H); MS for C₂₂H₃₀N₂O₄S m/z 419[M+H].

Example 2E101
Preparation of Compound 257: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-morpholinopropan-2-yl)-3-(4-methoxyphenoxy)propanamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ=2.4-2.6 (m, 7H), 2.7 (dd, 1H), 3.5-3.7 (m, 4H), 3.8 (s, 3H), 4-4.2 (m, 2H), 4.2 (s, 4H), 4.2-4.3 (m, 1H), 4.9 (d, 1H), 6.5 (d, 1H), 6.7-6.9 (m, 7H); MS for C₂₅H₃₂N₂O₇m/z 473.1 [M+H].

Example 2E102
Preparation of Compound 261: N-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(piperidin-1-yl)propan-2-yl)-3-(4-methoxyphenoxy)propanamide

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.4 (br, 2H), 1.6 (br, 4H), 2.2-2.8 (m, 6H), 3.8 (s, 3H), 4.0-4.2 (m, 2H), 4.2 (s, 4H), 4.2-4.3 (m, 1H), 4.9 (s, 1H), 6.4 (d, 1H), 6.7-6.9 (m, 7H); MS for C₂₅H₃₄N₂O₆m/z 471.1 [M+H].

Example 2B1
Preparation of Compound 6: 1-benzyl-3-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)urea

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.4-2.6 (m, 5H), 2.6-2.7 (dd, 1H), 4.0 (m, 1H), 4.2 (s, 4H), 4.3 (m, 2H), 4.8 (d, 1H), 4.86 (d, 1H), 5.0 (br, 1H), 6.6-6.9 (m, 3H), 7.2-7.4 (m, 5 H); MS for C₂₃H₂₉N₃O₄m/z 412.2 [M+H].

Example 2B2
Preparation of Compound 17: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-fluorobenzyl)urea

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.6 (s, 4H), 2.4-2.6 (m, 6H), 3.9 (m, 1H), 4.0-4.1 (m, 2H), 4.13 (s, 4H), 4.7 (d, 1H), 5.4 (d, 1H), 6.6-7.1 (m, 7H); MS for C₂₃H₂₈FN₃O₄m/z 430.2 [M+H].

Example 2B3
Preparation of Compound 40: 1-(4-bromobenzyl)-3-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)urea

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.4-2.8 (m, 6H), 4.0 (m, 1H), 4.1-4.2 (m, 2H) 4.2 (s, 4H), 4.8 (d, 1H), 5.3 (d, 1H), 5.6-5.8 (br, 1H), 6.8-7.0 (m, 3H), 7.0 (d, 2H), 7.4 (d, 2H); MS for C₂₃H₂₈BrN₃O₄m/z 490 [M], 491 [M+H], 492 [M+2].

Example 2B4
Preparation of Compound 41: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-methoxybenzyl)urea

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.6 (s, 4H), 2.4-2.6 (m, 6H), 3.7 (s, 3H), 3.9 (m, 1H), 4.1 (d, 2H), 4.2 (s, 4H), 4.7 (d, 1H), 5.2 (d, 1H), 5.5-5.7 (br, 1H), 6.6-6.8 (m, 5H), 7.1 (d, 2H); MS for C₂₄H₃₁N₃O₅m/z 442.2 [M+H].

Example 2B5
Preparation of Compound 80: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(3-methoxybenzyl)urea

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.4-2.6 (m, 6H), 3.8 (s, 3H), 4.0 (m, 1H), 4.1-4.2 (s, 6H), 4.8 (d, 1H), 5.1 (d, 1H), 5.2-5.4 (br, 1H), 6.6-6.8 (m, 6H), 7.2 (dd, 1H); MS for C₂₄H₃₁N₃O₅m/z 442.2 [M+H].

Example 2B6
Preparation of Compound 42: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-methylbenzyl)urea

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.6 (s, 4H), 2.3 (s, 3H), 2.4-2.6 (m, 6H), 4.0 (m, 1H), 4.2 (d, 2H), 4.21 (s, 4H), 4.7 (d, 1H), 5.2 (d, 1H), 5.4-5.6 (br, 1H), 6.7-7.1 (m, 7H); MS (for C₂₄H₃₁N₃O₄m/z 426.2 [M+H].

Example 2B7
Preparation of Compound 43: 1-(4-chlorobenzyl)-3-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)urea

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.5-2.7 (m, 6H), 4.0 (m, 1H), 4.2 (s, 6H), 4.8 (d, 1H), 5.2 (d, 1H), 5.4-5.5 (br, 1H), 6.7-6.9 (m, 3H), 7.1 (d, 2H), 7.3 (d, 2H); MS for C₂₃H₂₈N₃ClO₄m/z 446 [M+H], 447.5 [M+2].

Example 2B8
Preparation of Compound 10: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-((S)-1-phenylethyl)urea

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.4 (d, 3H), 1.6 (s, 4H), 2.2-2.5 (m, 4H), 2.5 (dd, 1H), 2.6 (dd, 1H), 3.9 (m, 1H), 4.2 (s, 4H), 4.5 (m, 1H), 4.8 (d, 1H), 5.0 (d, 1H), 5.1-5.3 (br, 1H), 6.6-6.9 (m, 3H), 7.2-7.4 (m, 5H); MS for C₂₄H₃₁N₃O₄m/z 426.2 [M+H].

Example 2B9
Preparation of Compound 286: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(®-1-phenylethyl)urea

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.3 (d, 3H), 1.7 (s, 4H), 2.2-2.6 (m, 6H), 3.9 (m, 1H), 4.2 (s, 4H), 4.6-4.7 (m, 2H), 5.3 (d, 1H), 5.6-5.7 (br, 1H), 6.6 (d, 1H), 6.7 (d, 1H), 6.8 (s, 1H), 7.2-7.4 (m, 5H); MS for C₂₄H₃₁N₃O₄m/z 426.0 [M+H].

Example 2B10
Preparation of Compound 69: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(naphthalen-2-yl)urea

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.6 (s, 4H), 2.4-2.8 (m, 6H), 4.1 (s, 5H), 4.8 (s, 1H), 6.0 (d, 1H), 6.7 (s, 2H), 6.9 (s, 1H), 7.1-7.8 (m, 7H); MS for C₂₆H₂₉N₃O₄m/z 448.1 [M+H].

Example 2B11
Preparation of Compound 288: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(naphthalen-1-yl)urea

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.6 (s, 4H), 2.4 (s, 4H), 2.6 (d, 2H), 4.1 (m, 1H), 4.2 (s, 4H), 4.8 (d, 1H), 5.4 (d, 1H), 6.5 (d, 1H), 6.6 (d, 1H), 6.7 (s, 1H), 7.2-7.6 (m, 3H), 7.7 (d, 1H), 7.8 (d, 1H), 8.0 (d, 1H); MS for C₂₆H₂₉N₃O₄m/z 448.1 [M+H].

Example 2B12
Preparation of Compound 71: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-((S)-1-(naphthalen-1-yl)ethyl)urea

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.4 (s, 4H), 1.5 (d, 3H), 2.3 (s, 4H), 2.4 (dd, 1H), 2.6 (dd, 1H), 3.9 (br, 1H), 4.2 (s, 4H), 4.7 (s, 1H), 5.0 (d, 1H), 5.3 (br, 1H), 5.5 (br, 1H), 6.6 (m, 3H), 7.4-7.6 (m, 4H), 7.7 (d, 1H), 7.8 (d, 1H), 8.1 (d, 1H); MS for C₂₈H₃₃N₃O₄m/z 476.2 [M+H].

Example 2B13
Preparation of Compound 70: 1-(biphenyl-4-yl)-3-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)urea

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.6-2.8 (m, 6H), 4.1 (br, 1H), 4.2 (s, 4H), 4.9 (br, 1H), 5.9 (d, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.2-7.6 (m, 9H); for C₂₈H₃₁N₃O₄m/z 474.1 [M+H].

Example 2B14
Preparation of Compound 81: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-(trifluoromethyl)phenyl)urea

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.4-2.7 (m, 6H), 4.0 (br, 1H), 4.2 (s, 4H), 4.8 (br, 1H), 5.9 (br, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.3 (d, 2H), 7.5 (d, 2H); MS for C₂₃H₂₆F₃N₃O₄m/z 465.97 [M+H].

Example 2B15
Preparation of Compound 68: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(3-(trifluoromethyl)phenyl)urea

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.5-2.9 (m, 6H), 4.0 (br, 1H), 4.2 (s, 4H), 4.8 (br, 1H), 5.9 (br, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.2-7.6 (m, 4H); MS for C₂₃H₂₆F₃N₃O₄m/z 466.0 [M+H].

Example 2B16
Preparation of Compound 82: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.4-2.7 (m, 6H), 4.0 (br, 1H), 4.2 (s, 4H), 4.8 (br, 1H), 5.9 (br, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.0 (d, 2H), 7.2 (d, 2H); MS for C₂₃H₂₆F₃N₃O₅m/z 481.5 [M], 482.5 [M+H].

Example 2B17
Preparation of Compound 133: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(4-(2-methylthiazol-4-yl)phenyl)urea

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.4-2.7 (m, 6H), 2.7 (s, 3H), 4.1 (br, 1H), 4.2 (s, 4H), 4.8 (br, 1H), 5.9 (d, 1H), 6.8 (s, 2H), 6.9 (s, 1H), 7.2 (s, 1H), 7.3 (d, 2H), 7.7 (d, 2H); MS for C₂₆H₃₀N₄O₄S m/z 494.9 [M+H].

Example 2B18
Preparation of Compound 7: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-dodecylurea

embedded image

¹H NMR (400 MHz, CDCl₃) δ=0.9 (t, 3H), 1.3 (br, 18H), 1.4 (m, 2H), 1.8 (s, 4H), 2.5-2.7 (m, 6H), 3.1 (q, 2H), 4.0 (m, 1H), 4.3 (s, 4H), 4.4 (br, 1H), 4.76 (d, 1H), 4.8 (d, 1H), 6.7-6.8 (dd, 2H), 6.9 (s, 1H); MS for C₂₈H₄₇N₃O4 m/z 489.7 [M+H], 490.9 [M+2].

Example 2B19
Preparation of Compound 287: 1-((1R,2R)-1-(2,3-dihydrobenzo[β][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-3-(2-(thiophen-2-yl)ethyl)urea

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.7 (s, 4H), 2.5-2.7 (m, 6H), 3.0 (t, 2H), 3.8 (q, 2H), 4.0 (m, 1H), 4.2 (s, 4H), 4.8 (d, 2H), 4.9 (d, 1H), 6.7-6.8 (m, 3H), 6.9 (d, 1H), 6.9 (dd-1H), 7.1 (d, 1H); MS for C₂₂H₂₉N₃O4S m/z 432.1 [M+H].

Example 2B20
Preparation of 1-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-((R)-3-hydroxypyrrolidin-1-yl)propan-2-yl)-3-(4-methoxybenzyl)urea 2,2,2-trifluoroacetate

embedded image

¹H NMR (400 MHz, CD₃OD) δ=1.8-2.2 (m, 6H), 3.2-3.3 (dd, 2H), 3.4-3.7 (m, 3H), 3.8 (s, 3H), 3.82-4.1 (m, 4H), 4.3 (dd, 2H), 4.4 (dd, 1H), 4.5 (dd, 2H), 4.8 (dd, 1H), 6.8 (d, 2H), 6.9 (d, 2H), 7 (m, 2H), 7.3 (d, 2H); MS for C₂₆H₃₆FN₃O₅m/z 491[M+H].

Example 2B21
Preparation of 1-(4-chlorobenzyl)-3-((1R,2R)-1-(4-(4-fluorobutoxy)phenyl)-1-hydroxy-3-((R)-3-hydroxypyrrolidin-1-yl)propan-2-yl)urea

embedded image

¹H NMR (400 MHz, CDCl₃) δ=1.6-1.8 (m, 3H), 1.8-2 (m, 5H), 2-2.2 (m, 2H), 2.2-2.3 (m, 2H), 2.8-2.4 (m, 5H), 2.9 (m, 1H), 3.9-4.0 (m, 3), 4.1-4.4 (m, 3H), 4.5 (t, 1H), 4.6-4.7 (m, 1H), 4.75 (d, 1H), 6.8 (d, 2H), 7.1 (d, 2H), 7.15-7.3 (m, 4H); MS for C₂₅H₃₃ClFN₃O₄m/z 494[M+H].

Example 3
GM3 ELISA Assay

B16-FO cells from ATCC (American Tissue Culture Collection) were grown in DMEM media (ATCC) with 10% Fetal Bovine Serum (Hyclone) and Pen/Step/Glutamine (Biowhittaker). 4000 cells per well were plated on collagen coated plates (BD) and allowed to attach for 6 hours in an incubator (37 degrees, 5% CO2). After 6 hours the compounds and controls were added to the wells, the plates mixed and returned to the incubator for 2 days. Day of assay the cells were fixed for 20 minutes with 1% formaldehyde and then washed with Tris Buffered Saline (TBS) 3 times, 150 μl of TB S was left in the wells and 50 μl of goat serum (Invitrogen) was added, the plates mixed and incubated for 1 hour at room temperature. The plates were flicked and the cells incubated with the monoclonal Antibody to GM3 (NeuAc) (Cosmo) for 45 minutes as room temperature. The plates were then washed 3 times with TBS, leaving 150 μl of TBS in the wells and Peroxidase AffinPure F (ab′) 2 frag Gt Anti-mouse IgM, μ Chain Specific (Jackson Immno Research) was added in 50 μl, the plates mixed and incubated for 45 minutes at room temperature. The plates were washed 3 times with TBS, flicked and blotted and 100 μl of Quantablu (Pierce) was added to the wells and incubated for 1 hour then read on a Fluorometer at Ex 325 and Em 420. The data was then analyzed using standard programs.

The results of the GM3 Elisa assay are summarized in Tables 1 and 2. In Tables 1 and 2, IC50 values are indicated as “A,” “B,” C,” “D,” and “E” for those of less than or equal to 0.1 μm; those of greater than 0.1 μm, and less than or equal to 1 μm; those of greater than 1 μm, and less than or equal to 3 μm; those of greater than 3 μm, and less than or equal to 10 μm; those of greater than 10 μm, respectively. As shown in Tables 1, 2 and 3, numerous compounds of the invention were shown to be inhibitors of GM3.

TABLE 1

IC 50 Values from GM3 Elisa Assay

Z—R*
Compound
IC50_uM_Mean

embedded image

1
B

embedded image

2
C

embedded image

3
C

embedded image

4
B

embedded image

5
B

embedded image

6
B

embedded image

7
A

embedded image

8
B

embedded image

9
B

embedded image

10
B

embedded image

11
A

embedded image

12
B

embedded image

13
B

embedded image

14
B

embedded image

15
B

embedded image

16
D

embedded image

17
A

embedded image

18
B

embedded image

19
B

embedded image

20
B

embedded image

21
A

embedded image

22
C

embedded image

23
A

embedded image

24
B

embedded image

25
B

embedded image

26
B

embedded image

27
A

embedded image

28
A

embedded image

29
A

embedded image

30
B

embedded image

31
B

embedded image

32
A

embedded image

33
A

embedded image

34
C

embedded image

35
C

embedded image

36
B

embedded image

37
B

embedded image

38
B

embedded image

39
A

embedded image

40
A

embedded image

41
A

embedded image

42
A

embedded image

43
A

embedded image

44
B

embedded image

45
B

embedded image

46
B

embedded image

47
B

embedded image

48
A

embedded image

49
A

embedded image

50
B

embedded image

51
B

embedded image

52
B

embedded image

53
C

embedded image

54
A

embedded image

55
A

embedded image

56
A

embedded image

57
A

embedded image

58
B

embedded image

59
A

embedded image

60
A

embedded image

61
A

embedded image

62
B

embedded image

63
A

embedded image

64
A

embedded image

65
A

embedded image

66
A

embedded image

67
A

embedded image

68
B

embedded image

69
B

embedded image

70
A

embedded image

71
B

embedded image

72
B

embedded image

73
A

embedded image

74
B

embedded image

75
B

embedded image

76
B

embedded image

77
A

embedded image

78
B

embedded image

79
A

embedded image

80
B

embedded image

81
B

embedded image

82
A

embedded image

83
A

embedded image

84
C

embedded image

85
A

embedded image

86
A

embedded image

87
A

embedded image

88
B

embedded image

89
B

embedded image

90
B

embedded image

91
B

embedded image

92
A

embedded image

93
A

embedded image

94
C

embedded image

95
A

embedded image

96
A

embedded image

97
B

embedded image

98
D

embedded image

99
B

embedded image

100
A

embedded image

101
A

embedded image

102
C

embedded image

103
A

embedded image

104
B

embedded image

105
B

embedded image

106
B

embedded image

107
D

embedded image

108
B

embedded image

109
A

embedded image

110
A

embedded image

111
B

embedded image

112
B

embedded image

113
B

embedded image

114
B

embedded image

115
A

embedded image

116
B

embedded image

117
B

embedded image

118
B

embedded image

119
A

embedded image

120
B

embedded image

121
D

embedded image

122
D

embedded image

123
C

embedded image

124
C

embedded image

125
B

embedded image

126
D

embedded image

127
B

embedded image

128
C

embedded image

129
B

embedded image

130
C

embedded image

131
A

embedded image

132
D

embedded image

133
D

embedded image

134
C

embedded image

135
C

embedded image

136
A

embedded image

137
A

embedded image

138
A

embedded image

139
A

embedded image

140
A

embedded image

141
A

embedded image

142
A

embedded image

143
A

embedded image

144
A

embedded image

145
B

embedded image

146
B

embedded image

147
B

embedded image

148
A

embedded image

149
B

embedded image

150
C

embedded image

151
B

embedded image

152
A

embedded image

153
B

embedded image

154
B

embedded image

155
B

embedded image

156
A

embedded image

157
A

embedded image

158
A

embedded image

159
A

embedded image

160
B

embedded image

161
B

embedded image

162
A

embedded image

163
A

embedded image

164
A

embedded image

165
A

embedded image

166
A

embedded image

167
A

embedded image

168
A

embedded image

169
A

embedded image

170
B

embedded image

171
C

embedded image

172
B

embedded image

173
A

embedded image

174
A

embedded image

175
A

embedded image

176
A

embedded image

177
B

embedded image

178
A

embedded image

179
A

embedded image

180
B

embedded image

181
A

embedded image

182
B

embedded image

183
A

embedded image

184
B

embedded image

185
B

embedded image

186
A

embedded image

187
B

embedded image

188
B

embedded image

189
B

embedded image

190
A

embedded image

191
A

embedded image

192
B

embedded image

193
B

embedded image

194
B

embedded image

195
B

embedded image

196
C

embedded image

197
A

embedded image

198
B

embedded image

199
A

embedded image

200
B

embedded image

201
C

embedded image

202
B

embedded image

203
A

embedded image

204
B

embedded image

205
A

embedded image

206
B

embedded image

207
A

embedded image

208
B

embedded image

209
A

embedded image

210
B

embedded image

211
B

embedded image

212
D

embedded image

213
B

embedded image

214
D

embedded image

215
B

embedded image

216
A

embedded image

217
A

embedded image

218
D

embedded image

219
D

embedded image

220
B

embedded image

221
A

embedded image

222
A

embedded image

223
A

embedded image

224
B

embedded image

225
A

embedded image

226
D

embedded image

227
C

embedded image

228
B

embedded image

229
E

embedded image

230
B

embedded image

231
A

embedded image

232
C

embedded image

233
C

embedded image

234
B

embedded image

235
B

embedded image

236
A

embedded image

237
A

embedded image

238
A

embedded image

239
D

embedded image

240
C

embedded image

241
A

embedded image

291
C

embedded image

292
C

embedded image

293
B

embedded image

294
B

embedded image

295
A

embedded image

296
B

embedded image

297
C

embedded image

298
B

embedded image

299
A

embedded image

300
A

embedded image

301
A

embedded image

302
A

embedded image

303
A

embedded image

304
A

embedded image

305
A

embedded image

306
B

embedded image

307
A

embedded image

308
A

embedded image

TABLE 2

IC 50 Values from GM3 Elisa Assay

Structure
Compound
IC50_uM_Mean

embedded image

242
D

embedded image

243
A

embedded image

244
A

embedded image

245
D

embedded image

246
C

embedded image

247
A

embedded image

248
B

embedded image

249
C

embedded image

250
B

embedded image

251
B

embedded image

252
B

embedded image

253
B

embedded image

254
B

embedded image

255
C

embedded image

256
B

embedded image

257
D

embedded image

258
D

embedded image

259
A

embedded image

260
A

embedded image

261
B

embedded image

262
A

embedded image

263
B

embedded image

264
A

embedded image

265
A

embedded image

266
A

embedded image

267
A

embedded image

268
A

embedded image

269
A

embedded image

270
A

embedded image

271
A

embedded image

272
A

embedded image

273
B

embedded image

274
C

embedded image

275
A

embedded image

276
B

embedded image

277
D

embedded image

278
E

embedded image

279
C

embedded image

282
C

embedded image

283
A

embedded image

284
A

embedded image

285
A

embedded image

286
D

embedded image

287
C

embedded image

289
B

embedded image

309
A

embedded image

310
C

embedded image

311
C

embedded image

312
B

embedded image

313
A

embedded image

314
C

embedded image

315
B

embedded image

316
D

embedded image

317
B

embedded image

318
B

embedded image

319
B

embedded image

320
A

embedded image

321
C

embedded image

322
B

TABLE 3

IC 50 Values

Structure
IC50_uM_Mean
Compound

embedded image

B
340

embedded image

A
341

embedded image

B
342

embedded image

B
343

embedded image

A
344

embedded image

A
345

embedded image

B
346

embedded image

B
347

embedded image

B
348

embedded image

B
349

embedded image

A
350

embedded image

B
351

embedded image

D
352

embedded image

B
353

embedded image

B
354

embedded image

C
355

embedded image

C
356

embedded image

B
357

embedded image

A
358

embedded image

B
359

embedded image

B
360

embedded image

D
361

embedded image

D
362

embedded image

B
363

embedded image

A
364

embedded image

A
365

embedded image

A
366

embedded image

A
367

embedded image

A
368

embedded image

A
369

embedded image

A
370

embedded image

A
371

embedded image

A
372

embedded image

A
373

embedded image

A
374

embedded image

B
375

embedded image

A
376

embedded image

A
377

embedded image

A
378

embedded image

B
379

embedded image

A
380

embedded image

C
381

embedded image

B
382

embedded image

B
383

embedded image

B
384

embedded image

C
385

embedded image

B
386

embedded image

B
387

embedded image

A
388

embedded image

A
389

embedded image

A
390

embedded image

B
391

embedded image

D
392

embedded image

D
393

embedded image

C
394

embedded image

D
395

embedded image

D
396

embedded image

D
397

embedded image

D
398

embedded image

C
399

embedded image

D
400

embedded image

B
401

embedded image

D
402

embedded image

C
403

embedded image

D
404

embedded image

C
405

embedded image

D
406

embedded image

C
407

embedded image

C
408

embedded image

B
409

embedded image

D
410

embedded image

D
411

embedded image

A
412

embedded image

A
413

embedded image

B
414

embedded image

B
415

embedded image

A
416

embedded image

A
417

embedded image

A
418

embedded image

A
419

embedded image

A
420

embedded image

A
421

embedded image

D
422

embedded image

C
423

embedded image

D
424

embedded image

D
425

embedded image

D
426

embedded image

D
427

embedded image

D
428

embedded image

D
429

embedded image

A
430

embedded image

A
431

embedded image

A
432

embedded image

A
433

embedded image

A
434

embedded image

A
435

embedded image

A
436

embedded image

A
437

embedded image

A
438

embedded image

B
439

embedded image

A
440

embedded image

A
441

embedded image

A
442

embedded image

A
443

embedded image

B
444

embedded image

B
445

embedded image

A
446

embedded image

A
447

embedded image

B
448

embedded image

A
449

embedded image

A
450

embedded image

B
451

embedded image

B
452

embedded image

A
453

embedded image

A
454

embedded image

A
455

embedded image

A
456

embedded image

A
457

embedded image

D
458

embedded image

D
459

embedded image

C
460

embedded image

B
461

embedded image

C
462

embedded image

B
463

embedded image

D
464

embedded image

B
465

embedded image

D
466

embedded image

B
467

embedded image

A
468

embedded image

B
469

embedded image

B
470

embedded image

C
471

embedded image

B
472

embedded image

A
473

embedded image

B
474

embedded image

A
475

embedded image

B
476

embedded image

D
477

embedded image

B
478

embedded image

A
479

embedded image

C
480

embedded image

D
481

embedded image

D
482

embedded image

D
483

embedded image

C
484

embedded image

D
485

embedded image

C
486

embedded image

D
487

embedded image

C
488

embedded image

D
489

embedded image

D
490

embedded image

C
491

embedded image

D
492

embedded image

C
493

embedded image

B
494

embedded image

A
495

embedded image

A
496

embedded image

A
497

embedded image

A
498

embedded image

A
499

embedded image

A
500

embedded image

A
501

embedded image

A
502

embedded image

A
503

embedded image

B
504

embedded image

D
505

embedded image

D
506

embedded image

B
507

embedded image

D
508

embedded image

B
509

embedded image

D
510

embedded image

D
511

embedded image

C
512

embedded image

D
513

embedded image

B
514

embedded image

A
515

embedded image

B
516

embedded image

B
517

embedded image

B
518

embedded image

D
519

embedded image

C
520

embedded image

D
521

embedded image

A
522

embedded image

B
523

embedded image

B
524

embedded image

A
525

embedded image

B
526

embedded image

C
527

embedded image

C
528

embedded image

A
529

embedded image

D
530

embedded image

A
531

embedded image

A
532

embedded image

B
533

embedded image

D
534

embedded image

D
535

embedded image

D
536

embedded image

A
537

embedded image

D
538

embedded image

D
539

embedded image

D
540

embedded image

D
541

embedded image

D
542

embedded image

D
543

embedded image

B
544

embedded image

B
545

embedded image

D
546

embedded image

A
547

embedded image

C
548

embedded image

D
549

embedded image

D
550

embedded image

D
551

embedded image

C
552

embedded image

D
553

embedded image

D
554

embedded image

B
555

embedded image

D
556

embedded image

D
557

embedded image

C
558

embedded image

B
559

embedded image

B
560

embedded image

D
561

embedded image

B
562

embedded image

D
563

embedded image

B
564

embedded image

A
565

embedded image

A
566

embedded image

B
567

embedded image

B
568

embedded image

D
569

embedded image

D
570

embedded image

D
571

embedded image

B
572

embedded image

B
573

embedded image

B
574

embedded image

B
575

embedded image

B
576

embedded image

B
577

embedded image

A
578

embedded image

D
579

embedded image

D
580

embedded image

B
581

embedded image

D
582

embedded image

D
583

embedded image

B
584

embedded image

B
585

embedded image

A
586

embedded image

B
587

embedded image

D
588

embedded image

C
589

embedded image

D
590

embedded image

D
591

embedded image

A
592

embedded image

B
593

embedded image

C
594

embedded image

D
595

embedded image

D
596

embedded image

D
597

embedded image

D
598

embedded image

C
599

embedded image

C
600

embedded image

D
601

embedded image

D
602

embedded image

B
603

embedded image

D
604

embedded image

D
605

embedded image

D
606

embedded image

C
607

embedded image

D
608

embedded image

B
609

embedded image

D
610

embedded image

D
611

embedded image

D
612

embedded image

D
613

embedded image

D
614

embedded image

B
615

embedded image

D
616

embedded image

C
617

embedded image

D
618

embedded image

C
619

embedded image

B
620

embedded image

C
621

embedded image

D
622

embedded image

D
623

embedded image

D
624

embedded image

D
625

embedded image

B
626

embedded image

D
627

embedded image

A
628

embedded image

B
629

embedded image

B
630

embedded image

D
631

embedded image

D
632

embedded image

B
633

embedded image

B
634

embedded image

D
635

embedded image

D
636

embedded image

B
637

embedded image

D
638

embedded image

B
639

embedded image

B
640

embedded image

A
641

embedded image

B
642

embedded image

C
643

embedded image

C
644

embedded image

D
645

embedded image

D
646

embedded image

B
647

embedded image

648

649

B
650

embedded image

C
651

embedded image

D
652

embedded image

A
653

embedded image

C
654

embedded image

B
655

embedded image

A
656

embedded image

B
657

embedded image

B
658

embedded image

B
659

embedded image

B
660

embedded image

C
661

embedded image

B
662

embedded image

B
663

embedded image

C
664

embedded image

D
665

embedded image

B
666

embedded image

B
667

embedded image

C
668

embedded image

D
669

embedded image

D
670

embedded image

D
671

embedded image

D
672

embedded image

D
673

embedded image

D
674

embedded image

D
675

embedded image

D
676

embedded image

D
677

embedded image

D
678

embedded image

D
679

embedded image

A
680

embedded image

C
681

embedded image

D
682

embedded image

D
683

embedded image

B
684

embedded image

D
685

embedded image

D
686

embedded image

D
687

embedded image

D
688

embedded image

D
689

embedded image

A
690

embedded image

D
691

embedded image

B
692

embedded image

A
693

embedded image

B
694

embedded image

B
695

embedded image

C
696

embedded image

B
697

embedded image

B
698

embedded image

A
699

embedded image

B
700

embedded image

C
701

embedded image

A
702

embedded image

A
703

embedded image

A
704

embedded image

A
705

embedded image

A
706

embedded image

A
707

embedded image

A
708

embedded image

A
709

embedded image

A
710

embedded image

A
711

embedded image

B
712

embedded image

B
713

embedded image

D
714

embedded image

D
715

embedded image

D
716

embedded image

D
717

embedded image

D
718

embedded image

D
719

embedded image

D
720

embedded image

D
721

embedded image

A
722

embedded image

A
723

embedded image

B
724

embedded image

B
725

embedded image

B
726

embedded image

A
727

embedded image

A
728

embedded image

A
729

embedded image

A
730

embedded image

A
731

embedded image

B
732

embedded image

A
733

embedded image

A
734

embedded image

A
735

embedded image

A
736

embedded image

B
737

embedded image

A
738

embedded image

A
739

embedded image

A
740

embedded image

A
741

EXAMPLE 4:
Compound A (N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)nonanamide) Effectively Inhibited PKD in a Mouse Model

embedded image

Design:

jck mice was administered Compound A ad libitum in feed (0.225% Compound A mixed with a standard diet chow in powdered format) from 26-64 days of age. Control jck mice were fed a control powdered diet from 26-64 days of age. At 63 days of age, animals were transferred to metabolic cages for 24 hour urine collection. At 64 days of age, animals were sacrificed by CO₂administration. Blood was collected by heart puncture for serum isolation. Kidneys were isolated and bisected; half of each kidney was fixed in 4% paraformaldehyde in PBS overnight for paraffin embedding and H&E staining.

Results:

Results are summarized in table 4 and discussed below.

TABLE 4

Summary of results, 0.225% Compound A in feed, 26-64 days of age

No of

Dose
Body weight
K/BW ratio
Cystic volume

animals
Gender
(mg/kg)
(g)
(%)
(% BW)
BUN (mg/dL)

9
M
Vehicle
22.03 ± 1.58
7.55 ± 1.65
2.86 ± 1.04
90.11 ± 10.02

9
M
Treated
18.43 ± 1.82*
4.46 ± 0.46*
0.88 ± 0.23*
39.25 ± 10.70*

10
F
Vehicle
19.20 ± 1.80
4.94 ± 0.73
1.22 ± 0.41
50.50 ± 14.32

10
F
Treated
15.93 ± 1.65*
3.57 ± 0.58*
0.58 ± 0.29*
34.67 ± 9.41*

*p < 0.05% compared to control (2-tailed t-test)

Kidney and Body Weights

Total body weight and kidney weight were determined at sacrifice. A statistically significant decrease in total body weight was noted (p-value<0.05, two-tailed t-test). A significant difference in kidney weight/body weight ratio was also observed (p-value<0.05, two-tailed t-test) for the treated animals, suggesting efficacy of the drug.

Cyst Volume:

Cyst volume was measured by quantitating the percentage of cystic area in histological sections of kidneys from the treated and control animals, multiplied by the kidney/body weight ratio. A significant decrease in cyst volume was observed (p-value<0.05, two-tailed t-test) for the treated animals.

Kidney Function:

Blood urea nitrogen (BUN) levels were determined in serum samples derived from animals at sacrifice. BUN levels were elevated in the untreated controls, while the treated animals demonstrated a significant reduction of BUN levels (p-value<0.05, two-tailed t-test).

CONCLUSION

Administration of Compound A in feed at 0.225% resulted in a statistically significant reduction of cystic disease, as measured by kidney/body weight ratio and cyst volume. This was accompanied by improved renal function in treated animals relative to controls. These improvements were observed in both males and females. Therefore, these results demonstrate that glucosylceramide synthase inhibition is an effective strategy to treat polycystic kidney disease.

Claims

1. A method of treating polycystic kidney disease in a subject, the method comprising administering to the subject an effective amount of a compound represented by the following structural formula:
2. The method of claim 1, wherein: Y is —H, —C(O)R, —C(O)OR or —C(O)NRR′; andR and R′ are each independently —H; a lower aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —CN, —NCS, —NO2, —NH2, lower alkoxy, lower haloalkoxy and aryl; or an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —CN, —NCS, —NO2, —NH2, lower alkoxy, lower haloalkoxy, lower aliphatic group and lower haloaliphatic group; orR and R′ taken together with the nitrogen atom of NRR′ form a non-aromatic heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of: halogen; —OH; —CN; —NCS; —NO2; —NH2; lower alkoxy; lower haloalkoxy; lower aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —CN, —NCS, —NO2, —NH2, lower alkoxy, lower haloalkoxy and aryl; and aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —CN, —NCS, —NO2, —NH2, lower alkoxy, lower haloalkoxy, lower aliphatic group and lower haloaliphatic group.
3. The method of claim 2, wherein: —N(R2R3) is a 5- or 6- membered non- aromatic nitrogen-containing heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl,haloalkyl, —OR40, —O(haloalkyl), —SR40, —NO2, —CN, —N(R41)2, —NR41C(O)R40, —NR41C(O) OR42, —N(R41)C(O)N(R41)2, —C(O)R40, —C(S)R40, —C(O)OR40, —OC(O)R40, —C(O)N(R41)2, —S(O)2R40, —SO2N(R41)2, —S(O)R42, —SO3R40, Ar2,V2—Ar2, —V2—OR40, —V2—O(haloalkyl), —V2—SR40, —V2—NO2, —V2—CN, —V2—N(R41)2, —V2—NR41C(O)R40, —V2—NR41CO2R42, —V2—N(R41)C(O)N(R41)2, —V2—C(O)R40, —V2—C(S)R40, —V2—CO2R40, —V2—OC(O)R40, —V2—C(O)N(R41)2—, —V2—S(O)2R40, —V2—SO2N(R41)2, —V2—S(O)R42, —V2—SO3R40, —O—V2—Ar2 and —S—V2—Ar2;each V2 is independently a C1-C4 alkylene group;Ar2 is an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; and each R40 is independentlyi) hydrogen;ii) an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; oriii) an C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; andeach R41 is independently R40, —CO2R40, —SO2R40 or —C(O)R40; or—N(R41)2 taken together is an optionally substituted non-aromatic heterocyclic group; and each R42 is independently: i) an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl; orii) an C1-C10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, nitro, cyano, hydroxy, C1-C6 haloalkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl and C1-C6 haloalkyl.
4. The method of claim 3, wherein R5 and R6 are each independently —H; —OH; a halogen; or a lower alkoxy or lower alkyl group.
5. The method of claim 4, wherein Y is —H.
6. he method of claim 5, wherein: R4 is an aliphatic or aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, Ar3, Ar3—Ar3, —OR50, —O(haloalkyl), —SR50, —NO2, —CN, —NCS, —N(R51)2, —NR51C(O)R50, —NR51C(O)OR52, —N(R51)C(O)N(R51)2, —C(O)R50, —C(S)R50, —C(O)OR50, —OC(O)R50, —C(O)N(R51)2, —S(O)2R50, —SO2N(R51)2, —S(O)R52, —SO3R50, —NR51SO2N(R51)2, —NR51SO2R52, —V4—Ar3, —V—OR50, —V4—O(haloalkyl), —V4—SR50, —V4—NO2, —V4—CN, —V4—N(R51)2, —V4—NR51C(O)R50, —V4—NR51CO2R52, —V4—N(R51)C(O)N(R51)2, —V4—C(O)R50,—V4—C(S)R50, —V4—CO2R50, —V4—OC(O)R50, —V4—C(O)N(R51)2—, —V4—S(O)2R50, —V4—SO2N(R51)2, —V4—S(O)R52, —V4—SO3R50, —V4—NR51SO2N(R51)2, —V4—NR51SO2R52, —O—V4—Ar3, —O—V5—N(R51)2, —S—V4—Ar3, —S—V5—N(R51)2, —N(R51)—V4—Ar3, —N(R51)—V5—N(R51)2, —NR51C(O)—V4—N(R51)2, —NR51C(O)—V4—Ar3, —C(O)—V4—N(R51)2, —C(O)—V4—Ar3, —C(S)—V4—N(R51)2, —C(S)—V4—Ar3, —C(O)O—V5—N(R51)2, —C(O)O—V4—Ar3, —O—C(O)—V5—N(R51)2, —O—C(O)—V4—Ar3, —C(O)N(R51)—V5—N(R51)2, —C(O)N(R51)—V4—Ar3, —S(O)2—V4—N(R51)2, —S(O)2—V4—Ar3, —SO2N(R51)—V5—N(R51)2, —SO2N(R51)—V4—Ar3, —S(O)—V4—N(R51)2, —S(O)—V4—Ar3, —S(O)2—O—V5N(R51)2, —S(O)2—O—V4—Ar3, —NR51SO2—V4—N(R51)2, —NR51SO2—V4—Ar3, —O—[CH2]p′—O—, —S—[CH2]p′—S—, and —[CH2]q′—;each V4 is independently a C1-C10 alkylene group;each V5 is independently a C2-C10 alkylene group;each Ar3 is independently an aryl group each optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy and haloalkyl; and each R50 is independentlyi) hydrogen;ii) an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; oriii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; andeach R51 is independently R50 , —CO2R50, —SO2R50 or —C(O)R50, or—N(R51)2 taken together is an optionally substituted non-aromatic heterocyclic group; and each R52 is independently: i) an aryl group optionally substituted with one or two substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; orii) an alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, amino, alkylamino, dialkylamino, alkoxy, nitro, cyano, hydroxy, haloalkoxy, alkoxycarbonyl, alkylcarbonyl and haloalkyl; andeach p′ is 1, 2, 3 or 4; andeach q′ is 3, 4, 5 or 6.
7. The method of claim 1, wherein the compound is represented by the following structural formula:
8. The method of claim 7, wherein R4 is an optionally substituted aryl group.
9. The method of claim 8, wherein R4 is selected from the group consisting of:
10. The method of claim 1, wherein r is 1 or 2.
11. The method of claim 1, wherein the compound is a (1R, 2R) stereoisomer.
12. The method of claim 1, wherein the compound is represented by the following structural formula:
13. The method of claim 1, wherein the compound is represented by the following structural formula:
14. The method of claim 1, wherein the compound is represented by the following structural formula:

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No. 13/595,251, filed Aug. 27, 2012, now U.S. Pat. No. 9,272,996, which is a continuation of U.S. application Ser. No. 13/122,135 filed on Mar. 31, 2011 now U.S. Pat. No. 8,309,593, which is the U.S. National Stage of International Application No. PCT/US2009/005435, filed Oct. 2, 2009, which designates the U.S., published in English, and claims the benefit of U.S. Provisional Application No. 61/102,541, filed Oct. 3, 2008. The entire teachings of the above applications are incorporated herein by reference.

US Referenced Citations (86)

Number	Name	Date	Kind
4065562	Ohata et al.	Dec 1977	A
4182767	Murai et al.	Jan 1980	A
4533668	Matsumura et al.	Aug 1985	A
4639436	Junge et al.	Jan 1987	A
5041441	Radin et al.	Aug 1991	A
5302609	Shayman et al.	Apr 1994	A
5472969	Platt et al.	Dec 1995	A
5525616	Platt et al.	Jun 1996	A
5631394	Wei et al.	May 1997	A
5707649	Inokuchi et al.	Jan 1998	A
5763438	Inokuchi et al.	Jun 1998	A
5849326	Inokuchi et al.	Dec 1998	A
5907039	Jinbo et al.	May 1999	A
5916911	Shayman et al.	Jun 1999	A
5945442	Shayman et al.	Aug 1999	A
5952370	Shayman et al.	Sep 1999	A
5972928	Chatterjee	Oct 1999	A
6030995	Shayman et al.	Feb 2000	A
6040332	Shayman et al.	Mar 2000	A
6051598	Shayman et al.	Apr 2000	A
6228889	Chatterjee	May 2001	B1
6255336	Shayman et al.	Jul 2001	B1
6335444	Jimbo et al.	Jan 2002	B1
6407064	Masuda et al.	Jun 2002	B2
6511979	Chatterjee	Jan 2003	B1
6569889	Shayman et al.	May 2003	B2
6610703	Jacob et al.	Aug 2003	B1
6660749	Butters et al.	Dec 2003	B2
6835831	Hirth	Dec 2004	B2
6855830	Hirth et al.	Feb 2005	B2
6890949	Shayman et al.	May 2005	B1
6916802	Shayman et al.	Jul 2005	B2
7148251	Shayman	Dec 2006	B2
7196205	Siegel et al.	Mar 2007	B2
7253185	Shayman et al.	Aug 2007	B2
7265228	Hirth et al.	Sep 2007	B2
7335681	Shayman et al.	Feb 2008	B2
7615573	Siegel et al.	Nov 2009	B2
7763738	Hirth et al.	Jul 2010	B2
8003617	Cheng et al.	Aug 2011	B2
8304447	Siegel et al.	Nov 2012	B2
8309593	Siegel et al.	Nov 2012	B2
8389517	Ibraghimov-Beskrovnaya et al.	Mar 2013	B2
8716327	Zhao et al.	May 2014	B2
8729075	Ibraghimov-Beskrovnaya et al.	May 2014	B2
8912177	Ibraghimov-Beskrovnaya et al.	Dec 2014	B2
8940776	Siegel et al.	Jan 2015	B2
9272996	Siegel et al.	Mar 2016	B2
9481671	Ibraghimov-Beskrovnaya	Nov 2016	B2
9532976	Cheng et al.	Jan 2017	B2
9556155	Zhao et al.	Jan 2017	B2
20010003741	Masuda et al.	Jun 2001	A1
20020156107	Shayman et al.	Oct 2002	A1
20020198240	Shayman et al.	Dec 2002	A1
20030050299	Hirth et al.	Mar 2003	A1
20030073680	Shayman et al.	Apr 2003	A1
20040260099	Shayman	Dec 2004	A1
20050009872	Hirth et al.	Jan 2005	A1
20050049235	Shayman et al.	Mar 2005	A1
20050222244	Siegel et al.	Oct 2005	A1
20050239862	Shayman et al.	Oct 2005	A1
20050267094	Shayman et al.	Dec 2005	A1
20060058349	Ali et al.	Mar 2006	A1
20060074107	Butters et al.	Apr 2006	A1
20060217560	Shayman	Sep 2006	A1
20070025965	Lobb	Feb 2007	A1
20070066581	Aerts	Mar 2007	A1
20070072916	Shayman	Mar 2007	A1
20070112028	Orchard	May 2007	A1
20070203223	Siegel et al.	Aug 2007	A1
20080146533	Shayman et al.	Jun 2008	A1
20080171874	Berger et al.	Jul 2008	A1
20090312392	Shayman et al.	Dec 2009	A1
20100256216	Siegel et al.	Oct 2010	A1
20100298317	Natoli et al.	Nov 2010	A1
20110166134	Ibraghimov-Beskrovnaya et al.	Jul 2011	A1
20110184021	Siegel et al.	Jul 2011	A1
20120022126	Cheng et al.	Jan 2012	A1
20120322786	Siegel et al.	Dec 2012	A1
20120322787	Siegel et al.	Dec 2012	A1
20130225573	Ibraghimov-Beskrovnaya et al.	Aug 2013	A1
20140336174	Ibraghimov-Beskrovnaya et al.	Nov 2014	A1
20150051261	Zhao et al.	Feb 2015	A1
20150190373	Cheng et al.	Jul 2015	A1
20150216872	Natoli et al.	Aug 2015	A1
20150225393	Siegel et al.	Aug 2015	A1

Foreign Referenced Citations (55)

Number	Date	Country
007395	Oct 2006	EA
126974	Dec 1984	EP
0 144 290	Jun 1985	EP
0765865	Apr 1997	EP
1 384 719	Jan 2004	EP
1 528056	May 2005	EP
1 576 894	Sep 2005	EP
2054371	Feb 1981	GB
35-5798	May 1960	JP
S60136595	Jul 1985	JP
9-169664	Jun 1997	JP
4140984	Jun 1997	JP
9216856	Aug 1997	JP
10-324671	Dec 1998	JP
10338636	Dec 1998	JP
2001-226362	Aug 2001	JP
2003-238410	Aug 2003	JP
WO 9710817	Mar 1997	WO
WO 9852553	Nov 1998	WO
WO 0104108	Jan 2001	WO
WO 0154654	Aug 2001	WO
WO 0180852	Nov 2001	WO
WO 0250019	Jun 2002	WO
WO 02055498	Jul 2002	WO
WO 02062777	Aug 2002	WO
WO 03008399	Jan 2003	WO
WO 03057874	Jul 2003	WO
WO 03068255	Aug 2003	WO
WO 2004007453	Jan 2004	WO
WO 2004056748	Jul 2004	WO
WO 2004078193	Sep 2004	WO
WO 2005039578	May 2005	WO
WO 2005040118	May 2005	WO
WO 2005063275	Jul 2005	WO
WO 2005068426	Jul 2005	WO
WO 2005087023	Sep 2005	WO
WO 2005108600	Nov 2005	WO
WO 2005123055	Dec 2005	WO
WO 2006023827	Mar 2006	WO
WO 2006053043	May 2006	WO
WO 2006053043	May 2006	WO
WO 2006081276	Aug 2006	WO
WO 2007022518	Feb 2007	WO
WO 2007134086	Nov 2007	WO
WO 2007134086	Nov 2007	WO
WO 2008011478	Jan 2008	WO
WO 2008011487	Jan 2008	WO
WO 2008012555	Jan 2008	WO
WO 2008024337	Feb 2008	WO
WO 2008097673	Aug 2008	WO
WO 2008150486	Dec 2008	WO
WO 2009045503	Apr 2009	WO
WO 2009117150	Sep 2009	WO
WO 2010014554	Apr 2010	WO
WO 2010039256	Apr 2010	WO

Non-Patent Literature Citations (175)

Entry
Abe, A., et al., “Reduction of Globotriasylceramide in Fabry Disease mice by substrate deprivation”, J. Clin Invest. 105(11): 1563-1571, Jun. 2000.
Abe, A., et al., “Improved Inhibitors of Glucosylceramide Synthase1,” J. Biochem., 111: 191-196 (1992).
Abe, A., et al., “Induction of glucosylceramide synthase by synthase inhibitors and ceramide,” Biochimics Biophysica Acta, 1299: 333-341 (1996).
Abe, A., et al., “Metabolic effects of short-chain ceramide and glucosylceramide on sphingolipids and protein kinase C,” Eur. J. Biochem, 210: 765-773 (1992).
Abe, A., et al., “Structural and stereochemical studies of potent inhibitors of glucosylceramide synthase and tumor cell growth,” J. Lipid Research, 36: 611-621 (1995).
Abe, A., et al., “Use of Sulfobutyl Ether β-Cyclodextrin as a Vehicle for d-threo-1-Phenyl-2-decanoylamino-3-morpholinopropanol-Related Glucosylceramide Synthase Inhibitors”, Analytical Biochemistry, vol. 287, pp. 344-347 (2000).
Abdel-Magid, A., et al., “Metal-Assisted Aldol Condensation of Chiral a-Halogenated Imide Enolates: A Stereocontrolled Chiral Epoxide Synthesis,” J. Am. Chem Soc., 108: 4595-4602 (1986).
Adams, L.A., et al. “Nonalcoholic fatty liver disease”, CMAJ, 172(7):899-905 (2005).
Alberti, C., et al., “Chloramphenicol. XII and XIII. Chloramphenicol analogs. p-Nitrophenyl diaminopropanols”, Chemical Abstracts Service, XP002495477 retrieved from CAPLUS Database accession No. 1957:17088 (abstract).
Alker, D., et al., “Application of Enantiopure Templated Azomethine Ylids to β-Hydroxy-a-amino Acid Synthesis,” Tetrahedron: Asymmetry, 54: 6089-6098 (1998).
Alon, R., et al., “Glycolipid Ligands for Selectins Support Leukocyte Tethering and Rolling Under Physiologic Flow Conditions,” J. Immunol., 154: 5356-5366 (1995).
Ames, Bruce N., “Assay of Inorganic Phosphate, Total Phosphate and Phosphatases,” Methods Enzymol., 8: 115-118 (1996).
Asano, N., “Glycosidase Inhibitors: update and perspectives on practical use”, Glycobiology, 13(10):93R-104R (2003).
Bielawska, A., et al.., “Ceramide-mediated Biology: Determination of Structural and Stereospecific Requirements Through the Use of N-Acyl-Phenylaminoalcohol Analogs,” J. Biol. Chem., 267: 18493-18497 (1992).
Bielawska, et al., “Modulation of cell growth and differentiation by ceramide,” FEBS Letters, 307(2): 211-214 (1992).
Blobe, G.C., et al., “Regulation of protein kinase C and its role in cancer biology,” Cancer Metastasis Rev., 13: 411-431 (1994).
Brenkert, A., et al.,“Synthesis of Galactosyl Ceramide and Glucosyl Ceramide by Rat Brain: Assay Procedures and Changes with Age,” Brain Res., 36: 183-193 (1972).
CAPLUS Listing of Accession No: 1985:221199, Keith McCullagh, et al., “Carboxyalkyl peptide derivatives.”.
Carson, K.G., et al., “Studies on Morpholinosphingolipids: Potent Inhibitors of Glucosylceramide Synthase,” Tetrahedron Letters, 35(17): 2659-2662 (1994).
Chatterjee, S., et al.,“Role of lactosylceramide and MAP kinase in the proliferation of proximal tubular cells in human polycystic kidney disease”, Journal of Lipid Research, 37(6): 1334-1344 (1996).
Chatterjee, S., et al.,“Oxidized low density lipoprotein stimulates aortic smooth muscle cell proliferation”, Glycobiology, 6(3): 303-311, 1996.
Clark, J.M., et al., “Nonalcoholic Fatty Liver Disease: An Underrecognized Cause of Cryptogenic Cirrhosis”, JAMA 289(22): 3000-3004 (2003).
Comuzzie, A.G., et al., “The Baboon as a Nonhuman Primate Model for the Study of the Genetics of Obesity”, Obesity Research, 11(1):75-80 (2003).
Dellaria, Jr., J.F., et al., “Enantioselective Synthesis of a-Amino Acid Derivatives via the Stereoselective Alkylation of a Homochiral Glycine Enolate Synthon1,” J. Org. Chem., 54:3916-3926 (1989).
Dickie, P., et al., “HIV-Associated Nephropathy in Transgenic Mice Expressing HIV-1 Genes,” Virology, 185:109-119, 1991.
Dittert, L.W., et al., “Acetaminophen Prodrugs I-Synthesis, Physicochemical Properties and Analgesic Activity”, J. Pharm. Sci. 57(5), pp. 774-780 (1968).
Deshmukh, G.D., et al., “Abnormalities of glycosphingolipid, sulfatide, and ceramide in the Polycystic (cpk/cpk)mouse”, Journal of Lipid Research, 35: 1611-1618 1994).
Elbein, A.D., “Glycosidase inhibitors: inhibitors of N-linked oligosaccharide processing” The FASEB Journal, 5: 3055-3063 (1991).
Evans, D.A., et al., “Stereoselective Aldol Condensations Via Boron Enolates1,” J. Am. Chem. Soc., 103: 3099-3111 (1981).
Fan, J-G., et al., “Preventie Effects of Metformin on Rats with nonalcoholic steatohepatitis”, Hepatology, 34(4)(1), p. 501A (2003).
Felding-Habermann, B., et al., “A Ceramide Analog Inhibits T Cell Proliferative Response Through Inhibition of Glycosphingolipid Synthesis and Enhancement of N,N-Dimethylsphingosins Synthesis,” Biochemistry, 29: 6314-6322 (1990).
Folch, J., et al., “A Simple Method for the Isolation and Purification of Total Lipides from Animal Tissues”, J. Biol. Chem., 226:497-509, 1956.
Freireich, E., et al.,“Quantitative Comparison of Toxicity of Anticancer Agents in Mouse, Rat, Hampster, Dog, Monkey, and Man”, Cancer Chemother. Reports 50(4):219 (1996).
Grcevska, L., et al., “Treatment with Steroids and Cyclophoshamide in Collapsing Glomerulopathy and Focal Segmental Glomerulosclerosis-Comparative Study”Nephrology Dialysis Transplantation, Oxford University Press, GB, 15(9): A89, XP008047905, ISSN: 0931-0509.
Hammett, L.P. Physical Organic Chemistry, (NY: McGraw), (1940).
Harwood, L.M., et al., “Double diastereocontrol in the synthesis of enantiomerically pure polyoxamic acid,” Chem. Commun., 2641-2642 (1998).
Harwood, L.M., et al., “Asymmetric Cycloadditions of Aldehydes to Stabilised Azomethine Ylids: Enantiocontrolled Construction of β-Hydroxy-a-amino acid Derivitives,” Tetrahedron: Asymmetry, 3(9): 1127-1130 (1992).
Högberg, T., et al., “Theoretical and Experimental Methods in Drug Design Applied on Antipsychotic Dopamine Antagonists.” In Textbook of Drug Design and Development, pp. 55-91 (1991).
Hospattankar, A.V., et al.,“Changes in Liver Lipids After Administration of 2- Decanoylamino-3-Morpholinopropiophenone and Chlorpromazine,” Lipids, 17(8): 538-543 (1982).
Husain, A., and Ganem, B., “syn-Selective additions to Garner aldehyde: synthesis of a potent glucosylceramide synthase inhibitor”, Tetrahedron Letters, 43: 8621-8623 (2002).
Huynh-Do, U., “Membranuous nephropathy: Pathogenesis, diagnostics and current treatment”, Der Nephrologe; Zeitschrift Für Nephrologie Und Hypertensiologie, Springer, Berlin, De, 2(1): 20-26 (Jan. 1, 2007).
Inokuchi, et al.,“Amino Alcohol Esters as Ceramide Analogs and Pharmaceuticals Containing Them for Treatment of Nerve Diseases,” Abstract of CAPLUS Accession No. 1998: 786189, JP 10324671 (1998).
Inokuchi, et al., “Aminoalcohol derivatives for treatment of abnormal proliferative diseases”, Chemical Abstracts Service, XP002495476 retrieved from CAPLUS Database accession No. 1998:816280 (abstract).
Inokuchi, J. et al., “Antitumor Activity via Inhibition of Glycosphingolipid Biosynthesis,” Cancer Lett., 38:23-30(1987).
Inokuchi, J., et al., “Preparation of the Active Isomer of 1-phenyl-2-decanoylamino-3-morpholino-1-propanol, Inhibitor of Murine Clucocerebroside Synthetase,” Journal of Lipid Research, 28: 565-571 (1987).
Inokuchi, J., et al .,“Inhibition of Experimental Metastasis of Murine Lewis Lung Carcinoma by an Inhibitor of Glucosylceramide Synthase and Its Possible Mechanism of Actions1”, Cancer Research, 50: 6731-6737 (Oct. 15, 1990).
Inokuchi, et al., (1996): SNT International HCAPLUS database, Columbus (OH), accession No. 1996: 214749.
Jaffrézou, Jr., et al., “Inhibition of lysosomal acid sphingomyelinase by agents which reverse multidrug resistance,” Biochim. Biophys. Acta, 1266: 1-8 (1995).
Jankowski, K., “Microdetermination of phosphorus in organic materials from polymer industry by microwave-induced plasma atomic emission spectrometry after microwave digestion”, Microchem. J., 70:41-49, 2001.
Jimbo, M., et al., “Development of a New Inhibitor of Glucosylceramide Synthase”, J. Biochem, 127: 485-491 (2000).
Kabayama, K., et al., “TNFa-induced insulin resistance in adipocytes as a membrane microdomain disorder: involvement in ganglioside GM3”, Glycobiology, 15(1): 21-29 (2005).
Kalén, A., et al., “Elevated Ceramide Levels in GH4C1 Cells Treated with Retinoic Acid,” Biochimica et Biophysica Acta, 1125: 90-96 (1992).
Kharkevich, D.A., “Pharmacology”, M., Medicament, 47-48 (1987).
Klein, M., et al., “Cyclosporine Treatment of Glomerular Diseases”, Annu. Rev. Med, 17 pgs. (Feb. 1, 1999).
Koga, K., and Yamada, S., “Stereochemical Studies. X. Effects of Neighboring Functional Groups on 1,2-Asymmetric Induction in the Reduction of Propiophenone Derivatives with Sodium Borohydride”, Chemical and Pharmaceutical Bulletin, 20(3): 526-538 (1972).
Kopaczyk, K., C., et al., “In Vivo Conversions of Cerebroside and Ceramide in Rat Brain,” J. Lipid Res., 6: 140-145 (1965).
Kurosawa, M., et al., “C-Labeling of novel Atypical β-Adrenoceptor Agonist, SM-11044,” Journal of Labelled Compounds and Radiopharmaceuticals, 38(3): 285-297 (1996).
Lee, L., et al. “Improved inhibitors of glucosylceramide synthase”, J. Bio Chem., 274(21): 14662-14669, 1999.
Levery, S.B., et al., “Disruption of the glucosylceramide biosynthetic pathway in Aspergillus nidulans and Aspergillus fumigatus by inhibitors of UDP-Glc:ceramide glucosyltransferase strongly affects spore germination, cell cycle, and hyphal growth”, FEBS Letters, vol. 525, pp. 59-64 (2002).
Masson, E., et al. “a-Series Gangliosides Mediate the Effects of Advanced Glycation End Products on Pericyte and Mesangial Cell Proliferation: A Common Mediator for Retinol and Renal Microangiopathy?” Diabetes, 54: 220-227 (2005).
Mitchell, S., et al., “Glycosyltransferase Inhibitors: Synthesis of D-threo-PDMP, L-threo-PDMP, and Other Brain Glucosylceramide Synthase Inhibitors from D- or L-Serine,” J. Org. Chem., 63: 8837-8842 (1998).
Miura, T., et al., “Synthesis and Evaluation of Morpholino and Pyrrolidinosphingolipids as Inhibitors of Glucosylceramide Synthase”, Bioorganic and Medicinal Chemistry, (6) 1481-1489 (1998).
Mok, C., et al., “Long-term Outcome of Diffuse Proliferative Lupus Glomerulonephritis Treated with Cyclophosphamide”, American Journal of Medicine, 119(4):355e.25-355e33 (Apr. 1, 2006).
Nakamura, K., et al., “Coomassie Brilliant Blue Staining of Lipids on Thin-Layer Plates,” Anal. Biochem., 142: 406-410 (1984).
Natoli, T.A., et al., “Inhibition of glucosylceramide accumulation results in effective blockade of polysystic kidney disease in mouse models” and supplemental information, Nature Medicine, 16(7): 788-792 (Jul. 2010).
Nicolaou, K., et al., “A Practical and Enantioselective Synthesis of Glycosphingolipids and Related Compounds. Total Synthesis of Globotriasylceramide (Gb3),” J. Am. Chem., Soc., 110: 7910-7912 (1988).
Nicolaus, B.J.R., “Symbiotic Approach to Drug Design”, Decision Making in Drug Research, XP-001111439, p. 1-14 (1983).
Nishida, A., et al ., “Practical Synthesis of threo-(1S, 2S)- and erythro-(1R, 2S)-1-Phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP) from L-Serine,” Synlett, 389-390(1998).
Nojiri, H., et al., “Ganglioside GM3: An acidic membrane component that increases during macrophage-like cell differentiation can induce monocytic differentiation of human myeloid and monoctyoid leukemic cell lines HL-60 and U937”, Proc. Natl. Acad. Sci., 83: 782-786 (1986).
Non-Final Office Action for U.S. Appl. No. 12/227,076 mailed on Nov. 23, 2011.
Notice of Allowance and Fee(s) Due for U.S. Appl. No. 12/601,871; “2-Acylaminopropoanol-Type Glucosylceramide Synthase Inhibitors” Date Mailed: Aug. 9, 2012.
Notice of Allowance and Fee(s) Due for U.S. Appl. No. 13/122,135; “2-Acylaminopropoanol-Type Glucosylceramide Synthase Inhibitors” Date Mailed: Aug. 1, 2012.
Office Action dated Mar. 29, 2012 for U.S. Appl. No. 12/601,871.
Ogawa, S., et al., “Synthesis and Biological Evaluation of Four Stereoisomers of PDMP-Analogue, N-(2-Decylamino-3-Hydroxy-3-Phenylprop-1-YL)-β-Valienamine, and Related Compounds,” Bioorganic & Medicinal Chemistry Letters, 7(14): 1915-1920 (1997).
Ong, et al., “Nonalcoholic Fatty Liver Disease and the epidemic of Obesity”, Cleveland Clinic Journal of Medicine, 71(8): 657-664 (Aug. 2004).
Overkleeft, H.S., et al., “Generation of Specific Deoxynojirimycin-type Inhibitors of the Non-lysosomal Glucosylceramidase,” The Journal of Biological Chemistry, 273(41):26522-26527 (1998).
Preiss, J., et al.,“Quantitative Measurement of sn-1,2-Diacylglycerols Present in Platelets, Hepatocytes, and ras-and sis-Transformed Normal Rat Kidney Cells,” J. Biol.Chem., 261(19): 8597-8600 (1986).
Qian, Q., et al., “Treatment prospects for autosomal-dominant polysystic kidney disease”, Kidney International, vol. 59, pp. 2005-2022 (2001).
Radin, N.S., “Killing Cancer Cells by Poly-drug elevation of ceramide levels, a hypothesis whose time has come?,” Eur. J. Biochem. (268(2): 193-204 (2001).
Radin, N.S., et al., “Metabolic Effects of Inhibiting Glucosylceramide Synthesis with PDMP and Other Substances.” Advances in Lipid Research: Sphingolipids, Part B., R.M. Bell et al., Eds. (San Diego: Academic Press), 26: 183-213 (1993).
Radin, N.S., et al., “Ultrasonic Baths as Substitutes for Shaking Incubator Baths,” Enzyme, 45: 567-70(1991).
Radin, N.S., et al., “Use of an Inhibitor of Glucosylceramide Synthesis, D-1-Phenyl-2-decanoylamino-3-morpholino-1-propanol,” In NeuroProtocols: A Companion to Methods in Neurosciences, S.K. Fisher, et al., Eds., (San Diego: Academic Press) 3: 145-155 (1993).
Rosenwald, A.G., et al., “Effects of the glucosphingolipid synthesis inhibitor, PDMP, on lysosomes in cultured cells,” J. Lipid Res., 35: 1232-1240 (1994).
Rosenwald, A.G., et al., “Effects of a Sphingolipid Synthesis Inhibitor on Membrane Transport Through the Secretory Pathway,” Biochemistry, 31: 3581-3590 (1992).
Rubino, MD., F., et al., “Letter to the Editor”, Annals of Surgery, 240(2):389-390 (2004).
Sandhoff, K., et al., “Biosynthesis and degradation of mammalian glycosphingolipids” Phil. Trans. R. Soc. Lond, B 358 :847-861 (2003).
Sasaki, A., et al., “Overexpression of Plasma Membrane-associated Sialidase Attentuates Insulin Signaling in Transgenic Mice”, The Journal of Biological Chemistry, 278(30):27896-27902 (2003).
Schwimmer, J.B., et al., “Obesity, Insulin Resistance, and and Other Clinicopathological Correlates of Pediatric Nonalcoholic Fatty Liver Disease”, Journal of Pediatrics, 143(4): 500-505 (2003).
Shayman, J.A., et al., “Glucosphingolipid Dependence of Hormone-Stimulated Inositol Trisphophate Formation,” J. Biol. Chem., 265(21): 12135-12138 (1990).
Shayman, J.A., et al., “Modulation of Renal Epithelial Cell Growth by Glucosylceramide,” The Journal of Biological Chemistry, 266(34):22968-22974 (1991).
Shukla, A., et al., “Metabolism of D-[3H]threo-1-phenyl-2-decanoylamino-3-morpholino-propanol, an inhibitor of glucosylceramide synthesis and the synergistic action of an inhibitor of microsomal monooxygenase,” J. of Lipid Research, 32: 713-722 (1991).
Shukla, G.S., et al., “Glucosylceramide Synthase of Mouse Kidney: Further Characterization with an Improved Assay Method1,” Arch. Biochem. Biophys., 283(2): 372-378 (1990).
Shukla, G., et al., “Rapid kidney changes resulting from glycosphingolipid depletion by treatment with a glucosyltransferase inhibitor,” Biochimica et Biophysica Acta, 1083: 101-108 (1991).
Skehan, P., et al., “New Colorimetric Cytotoxicity Assay for Anticancer-Drug Screening,” J. Natl. Cancer Inst., 82(13): 1107-1112 (1990).
Strum, J.C., et al.,“1-β-D-Arabinofuranosylcytosine Stimulates Ceramide and Diglyceride Formation in HL-60- Cells,” J. Biol. Chem., 269(22): 15493-15497 (1994).
Svensson, M., et al., “Epithelial Glucosphingolipid Express as a Determinant of Bacterial Adherence and Cytokine Production”, Infection and Immunity, 62(10): 4404-4410 (1994).
Tagami, S., et al., “Ganglioside GM3 Participates in the Pathological Conditions of Insulin Resistance”, The Journal of Biological Chemistry, 227(5): 3085-3092 (2002).
Tang, W., et al., “Phorbol Ester Inhibits 13-Cis-Retinoic Acid-Induced Hydrolysis of Phosphatidylinositol 4,5-Biophosphate in Cultured Murine Keratinocytes: A Possible Negative Feedback via Protein Kinase C-Activation,”Cell Bioch. Funct., 9: 183-191 (1991).
Tay-Sachs, URL: http://www.ninds.nih.gov/disorders/taysachs/taysachs.htm. National Institute of Health of Neurological Disorders and Stroke. Accessed online Sep. 9, 2011.
Yamashita, T., et al., “Enhanced insulin sensitivity in mice lacking ganglioside GM3”, Proc. Natl. Acad. Scl, 100(6): 3445-3449 (2003).
Uemura, K., et al., “Effect of an Inhibitor of Glucosylceramide Synthesis on Cultured Rabbit Skin Fibroblasts,” J. Biochem., (Tokyo) 108(4): 525-530 (1990).
Vunnum, R.,R., et al., “Analogs of Ceramide That Inhibit Glucocerebroside Synthetase in Mouse Brain,” Chemistry and Physics of Lipids, LD. Bergelson, et al., Eds. (Elsevier/North-Holland Scientific Publishers Ltd.), 26: 265-278 (1980).
Wermuth, C.G., et al.., “Designing Prodrug and Bioprecursors I: Carrier Prodrug”, The Practice of Medicinal Chemistry, C.G., Wermuth, Ed.(CA: Academic Press Limited), pp. 671-696 (1996).
Wong, C-H., et al.,“Synthesis and Evaluation of Homoazasugars as Glycosidase Inhibitors,” J. Org. Chem., 60: 1492-1501, (1995).
Yew, N. S., et al., “Increased Hepatic Insulin Action in Diet-Induced Obese Mice Following Inhibition of Glucosylceramide Synthase” PLoS one, 5(6): 1-9 (Jun. 2010).
Zador, I., et al. “A Role for Glycosphingolipid Accumulation in the Renal Hypertrophy of Streptozotocin-induced Diabetes Mellitus”, J. Clin. Invest., 91: 797-803 (1993).
Zhao, H., et al., “Inhibiting Glycosphingolipid Synthesis Ameliorates Hepatic Steatosis in Obese Mice” Hepatology, pp. 85-93 (Jul. 2009)).
Zhao, H., et al., “Inhibiting glycosphingolipid synthesis improves glycemic control and insulin sensitivity in animal models of type 2 diabetes.” Diabetes, 56(5): 1210-1218 (2007).
Ziche, M. et al., “Angiogenesis Can Be Stimulated or Repressed In Vivo by a Change in GM3 :GD3 Ganglioside Ratio,” Lab. Invest., 67:711-715 (1992).
International Preliminary Report on Patentability, issued in International Application PCT/US2005/040596, “Methods of Treating Diabetes Mellitus” dated May 15, 2007 (14 pages).
International Preliminary Report on Patentability for International Application No. PCT/US2008/006906, “2-Acylaminopropoanol-Type Glucosylceramide Synthase Inhibitors”, dated Dec. 10, 2009.
Notification of Transmittal of the International Search Report and Written Opinion of the International Searching Authority from counterpart International Application No. PCT/US2008/006906, “2-Acylaminopropoanol-Type Glucosylceramide Synthase Inhibitors”, dated Dec. 4, 2008.
Notification of Transmittal of the International Search Report and the Written Opinion of the International Searching Authority, or the Declaration of International Application No. PCT/US2008/011450, “Method of Treating Polycystic Kidney Diseases With Ceramide Derivatives”, dated Jan. 21, 2009.
Notification of Transmittal of the International Search Report and Written Opinion of the International Searching Authority, or the Declaration from counterpart International Application No. PCT/US2009/001773, “Method of Treating Lupus With Ceramide Derivatives”, dated Nov. 11, 2009.
Notification of Transmittal of the International Search Report and Written Opinion of the International Searching Authority, or the Declaration from counterpart International Application No. PCT/US2009/051864, “Glucosylceramide Synthase Inhibition for the Treatment of Collapsing Glomerulopathy and Other Glomerular Diseases”, dated Nov. 3, 2009.
Notification of Transmittal of the International Search Report and Written Opinion of the International Searching Authority, or the Declaration from counterpart International Application No. PCT/US2009/005435, “2-Acylaminopropoanol-Type Glucosylceramide Synthase Inhibitors”, dated Feb. 12, 2010.
International Search Report for PCT/US2002/00808, “Amino Ceramide-Like Compounds and Therapeutic Methods of Use” dated Oct. 1, 2002.
International Preliminary Report on Patentability, issued in International Application PCT/US2002/00808, “Amino Ceramide-Like Compounds and Therapeutic Methods of Use” dated Jan. 10, 2003.
International Preliminary Examination Report on Patentability, issue in International Application PCT/US2000/18935, “Amino Ceramide-Like Compounds and Therapeutic Methods of Use” (WO 01/04108) dated Jul. 20, 2001.
European Search Report, European Application No. 09003291.3, “Synthesis of UDP-Glucose: N-Acylsphingosine Glucosyl-Transferase Inhibitors” Apr. 29, 2009 (2478.2001-016).
International Preliminary Report on Patentability for International Application No. PCT/US2002/022659, “Synthesis of UDP-Glucose: N-Acylsphingosine Glucosyltransferase Inhibitors” dated Jul. 24, 2003.
International Search Report for PCT/US2002/022659, “Synthesis of UDP-Glucose: N-Acylsphingosine Glucosyltransferase Inhibitors” dated Nov. 5, 2002.
European Search Report for EP Patent Application No. 12007327.5, “Method of Treating Polycystic Kidney Diseases With Ceramide Derivatives” dated Apr. 11, 2013.
Notification of Transmittal of the International Search Report and the Written Opinion of the International Searching Authority, or the Declaration for International Application No. PCT/US2007/068521, “Methods of Treating Fatty Liver Disease” dated Nov. 21, 2007.
International Preliminary Report on Patentability for International Application No. PCT//US2007/068521, “Methods of Treating Fatty Liver Disease” dated Nov. 11, 2008.
International Search Report for International Application No. PCT/US2000/18935, “Amino Ceramide-Like Compounds and Therapeutic Methods of Use” dated Nov. 28, 2000.
International Preliminary Examination Report for International Application No. PCT/US2002/022659, “Synthesis of UDP-Glucose: N-Acylsphingosine Glucosyltransferase Inhibitors” dated Jul. 24, 2003.
International Report on Patentability for International Application PCT/US2007/068521, “Methods of Treating Fatty Liver Disease” dated Nov. 11, 2008 with Written Opinion.
International Preliminary Report on Patentability for International Application No. PCT/US2008/011450, “Method of Treating Polycystic Kidney Diseases With Ceramide Derivatives” dated Apr. 7, 2010.
International Preliminary Report on Patentability for International Application No. PCT/US2009/001773, “Method of Treating Lupus With Ceramide Derivatives” dated Sep. 21, 2010.
International Preliminary Report on Patentability for International Application No. PCT/US2009/051864, “Glucosylceramide Synthase Inhibition for the Treatment of Collapsing Glomerulopathy and Other Glomerular Diseases” dated Feb. 1, 2011.
Notification Concerning Transmittal of International Preliminary Report on Patentability for International Application No. PCT/US2009/005435, “2-Acylaminopropoanol-Type Glucosylceramide Synthase Inhibitors” dated Apr. 14, 2011.
Notice of Allowance and Fee(s) Due for U.S. Appl. No. 11/667,224; Date Mailed: Apr. 22, 2011.
Office Action for U.S. Appl. No. 12/601,871 dated Sep. 21, 2011.
Final Office Action for U.S. Appl. No. 12/227,076 dated Mar. 20, 2012.
Non-Final Office Action for U.S. Appl. No. 13/122,135, titled “2-Acylaminopropoanol-Type Glucosylceramide Synthase Inhibitors” mailed on Apr. 27, 2012.
Non-Final Office Action for U.S. Appl. No. 12/681,291 dated Dec. 10, 2012, “Method of Treating Polycystic Kidney Diseases with Ceramide Derivatives”.
Notice of Allowance and Fee(s) Due for U.S. Appl. No. 12/227,076; titled: “Methods of Treating Fatty Liver Disease” Date Mailed: Oct. 9, 2012.
Notice of Allowance and Fee(s) Due for U.S. Appl. No. 13/055,036; titled: “Glucosylceramide Synthase Inhibition for the Treatment of Collapsing Glomerulopathy and Other Glomerular Disease” Date Mailed: Oct. 31, 2012.
Office Action dated May 28, 2013 for U.S. Appl. No. 13/762,102; titled: “Glucosylceramide Synthase Inhibition for the Treatment of Collapsing Glomerulopathy and Other Glomerular Disease”.
International Search Report and Written Opinion for PCT/US2005/0405967, mailed Jun. 27, 2006 from the International Searching Authority of the European Patent Office.
Seibutsu Yuki Kagaku Kenkyusho KK, Database Accession No. XP-002372073, Derwent Publications Ltd., Class B03, Aug. 27, 2003.
Belikov., V.G., “Pharmaceutical Chemistry, Moscow”, Vysshaya Shkola Publishers, pp. 43-47 (1993).
Notice of Allowance and Fee(s) Due for U.S. Appl. No. 12/227,076; titled: “Methods of Treating Fatty Liver Disease” Date Mailed: Jun. 4, 2013.
European Search Report, European Application No. 13154970.1, “2-Acylaminopropoanol-Type Glucosylceramide Synthesis Inhibitors” dated Jul. 10, 2013.
European Search Report, European Application No. 13154967.7, “2-Acylaminopropoanol-Type Glucosylceramide Synthase Inhibitors” dated Jul. 18, 2013.
European Search Report, European Application No. 13154949.5, “2-Acylaminopropoanol-Type Glucosylceramide Synthase Inhibitors” dated Jul. 12, 2013.
European Search Report, European Application No. 13154955.2, “2-Acylaminopropoanol-Type Glucosylceramide Synthase Inhibitors” dated Jul. 10, 2013.
Non-Final Office for U.S. Appl. No. 12/681,291, titled “Method of Treating Polycystic Kidney Diseases with Ceramide Derivatives”, dated: Oct. 18, 2013.
Non-Final Office for U.S. Appl. No. 13/595,349, titled “2-Acylaminopropoanol-Type Glucosylceramide Synthase Inhibitors”, dated: Dec. 19, 2013.
Notice of Allowance and Fee(s) Due for U.S. Appl. No. 12/227,076; titled: “Methods of Treating Fatty Liver Disease” Date Mailed: Dec. 23, 2013.
Notice of Allowance and Fee(s) Due for U.S. Appl. No. 13/762,102; titled: “Glucosylceramide Synthase Inhibition for the Treatment of Collapsing Glomerulopathy and Other Glomerular Disease” Date Mailed: Jan. 9, 2014.
Non-Final Office for U.S. Appl. No. 13/193,990, titled “Method of Treating Diabetes Mellitus”, dated: Feb. 20, 2014.
Notice of Allowance and Fee(s) Due for U.S. Appl. No. 12/681,291; titled: “Method of Treating Polycystic Kidney Diseases With Ceramide Derivatives” Date Mailed: Aug. 4, 2014.
Notice of Allowance and Fee(s) Due for U.S. Appl. No. 13/595,349; titled: 2-Acylaminopropoanol-Type Glucosylceramide Synthase Inhibitors Date Mailed: Sep. 10, 2014.
Non-Final Office Action for U.S. Appl. No. 13/595,251, titled: “2-Acylaminopropoanol-Type Glucosylceramide Synthase Inhibitors” Date Mailed: Nov. 19, 2014.
Final Office Action for U.S. Appl. No. 14/595,251, titled: “2-Acylaminopropoanol-Type Glucosylceramide Synthase Inhibitors” Datd Mailed: May 5, 2015.
Extended European Search Report for European Application No. EP 15 16 2842, “Methods of Treating Fatty Liver Disease”, Date of completion: Jul. 24, 2015.
Non-Final Office Action for U.S. Appl. No. 14/255,634, titled: “Glucosylceramide Synthase Inhibition for the Treatment of Collapsing Glomerulopathy and Other Glomerular Disease” Date Mailed: Aug. 11, 2015.
Non-Final Office Action for U.S. Appl. No. 14/464,432, titled: “Method of Treating Diabetes Mellitus” Date Mailed: Sep. 9, 2015.
Notice of Allowance and Fee(s) Due for U.S. Appl. No. 13/595,251; titled: “2-Acylaminopropoanol-Type Glucosylceramide Synthase Inhibitors” Date Mailed: Oct. 21, 2015.
Non-Final Office Action for U.S. Appl. No. 14/247,732, titled: “Methods of Treating Fatty Liver Disease” Date Mailed: Jan. 25, 2016.
Non-Final Office Action for U.S. Appl. No. 14/532,432, titled: “Method of Treating Polycystic Kidney Diseases With Ceramide Derivatives” Date Mailed: Jan. 5, 2016.
Notice of Allowance and Fee(s) Due for U.S. Appl. No. 14/255,634; titled: “Glucosylceramide Synthase Inhibition for the Treatment of Collapsing Glomerulopathy and Other Glomerular Disease” Date Mailed: Mar. 1, 2016.
Notice of Allowance and Fee(s) Due for U.S. Appl. No. 14/255,634; titled: “Glucosylceramide Synthase Inhibition for the Treatment of Collapsing Glomerulopathy and Other Glomerular Disease” Date Mailed: Jun. 7, 2016.
Notice of Allowance for U.S. Appl. No. 14/464,432, “Method of Lowering Blood Glucose”, dated May 16, 2016.
Cellitti, Susan E., et al., “In vivo incorporation of Unnatural Amino Acids to Probe Structure, Dynamics, and Ligand Binding in a Large Protein by Nuclear Magnetic Resonance Spectroscopy”, J. Am. Chem. 130: 9266-9281 (2008).
Gennaro, et al., Remington, The Science and Practice of Pharmacy, Chapter 38, 20th Edition, 2000, pp. 703-712.
Nilsson, O., et al., “The Occurrence of Psychosing and Other Glycolipids in Spleen and Liver From the Three Major Types of Gaucher's Disease”, Biochimica et Biophysica Acta, 712 (1982) 453-463.
van Meer, G., et al., “The fate and function of glycosphingolipid glucosylceramide”, Phil. Trans. R. Soc. Lond. B (2003) 358, 869-873.
Yatsu, F..M., “Sphingolipidoses”, California Medicine, the Western Journal of Medicine, pp. 1-6 (Apr. 1971).
EP Search Report for EP Application No. EP 16 16 2074; “2-Acylaminopropoanol-Type Glucosylceramide Synthase Inhibitors”, Date of Mailing: Sep. 12, 2016.
Non-Final Office Action for U.S. Appl. No. 14/571,922, titled: “2-Acylaminopropoanol-Type Glucosylceramide Synthase Inhibitors” Date Mailed: Sep. 20, 2016.
Notice of Allowance and Fee(s) Due for U.S. Appl. No. 14/247,732; titled: “Methods of Treating Fatty Liver Disease” Date Mailed: Sep. 20, 2016.
Notice of Allowance and Fee(s) Due for U.S. Appl. No. 14/532,432; titled: “Method of Treating Polycystic Kidney Diseases with Ceramide Derivatives” Date Mailed: Oct. 25, 2016.

Related Publications (1)

	Number	Date	Country
	20160338996 A1	Nov 2016	US

Provisional Applications (1)

	Number	Date	Country
	61102541	Oct 2008	US

Continuations (2)

	Number	Date	Country
Parent	13595251	Aug 2012	US
Child	15003207		US
Parent	13122135		US
Child	13595251		US

2-acylaminopropoanol-type glucosylceramide synthase inhibitors

Information

Patent Number

Date Filed

Date Issued

Inventors

Original Assignees

Examiners

Agents

CPC

Field of Search

US

International Classifications

Disclaimer

Abstract

Description

Claims

RELATED APPLICATIONS

US Referenced Citations (86)

Foreign Referenced Citations (55)

Non-Patent Literature Citations (175)

Related Publications (1)

Provisional Applications (1)

Continuations (2)