WO2006065842A2 - 5,6,7,8-tetrahydroquinolines and related compounds and uses thereof - Google Patents
5,6,7,8-tetrahydroquinolines and related compounds and uses thereof Download PDFInfo
- Publication number
- WO2006065842A2 WO2006065842A2 PCT/US2005/045136 US2005045136W WO2006065842A2 WO 2006065842 A2 WO2006065842 A2 WO 2006065842A2 US 2005045136 W US2005045136 W US 2005045136W WO 2006065842 A2 WO2006065842 A2 WO 2006065842A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- optionally substituted
- unsubstituted
- substituted
- independently
- alkyl
- Prior art date
Links
- 0 *C(*)(*C(*)(*)*1)*C(I=C(*)C(*)=C2*)=C2C1=* Chemical compound *C(*)(*C(*)(*)*1)*C(I=C(*)C(*)=C2*)=C2C1=* 0.000 description 6
- BADXJIPKFRBFOT-UHFFFAOYSA-N CC(C)(CC(C1)=O)CC1=O Chemical compound CC(C)(CC(C1)=O)CC1=O BADXJIPKFRBFOT-UHFFFAOYSA-N 0.000 description 2
- ZSXQGMRTYANJKK-UHFFFAOYSA-N CC(C)(CC1O)CC2=C1C(C1CC1)C(C(CC(C)(C)C1)=O)=C1N2 Chemical compound CC(C)(CC1O)CC2=C1C(C1CC1)C(C(CC(C)(C)C1)=O)=C1N2 ZSXQGMRTYANJKK-UHFFFAOYSA-N 0.000 description 1
- YSDBJKNOEWSFGA-UHFFFAOYSA-N CC(N1CCN(C)CC1)=O Chemical compound CC(N1CCN(C)CC1)=O YSDBJKNOEWSFGA-UHFFFAOYSA-N 0.000 description 1
- RABKMJGKDCEXJS-UHFFFAOYSA-N CCC(C(C1C2CC2)=C(CC)NC(CC(C)(C)C2)=C1C2=O)=O Chemical compound CCC(C(C1C2CC2)=C(CC)NC(CC(C)(C)C2)=C1C2=O)=O RABKMJGKDCEXJS-UHFFFAOYSA-N 0.000 description 1
- UTBWDHODGXNUGU-UHFFFAOYSA-N CCNC(C1)C1=C Chemical compound CCNC(C1)C1=C UTBWDHODGXNUGU-UHFFFAOYSA-N 0.000 description 1
- FJRLXMTVYCGUFW-UHFFFAOYSA-N CCNC([I](C)C)=O Chemical compound CCNC([I](C)C)=O FJRLXMTVYCGUFW-UHFFFAOYSA-N 0.000 description 1
- DFWADNXPAGGDKQ-UHFFFAOYSA-N CCOC(CC(CN)=O)=O Chemical compound CCOC(CC(CN)=O)=O DFWADNXPAGGDKQ-UHFFFAOYSA-N 0.000 description 1
- DZCKFKMDEJDLLP-UHFFFAOYSA-N C[I](C(N1CCOCC1)=O)I Chemical compound C[I](C(N1CCOCC1)=O)I DZCKFKMDEJDLLP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
- C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
- C07D219/06—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/20—Spiro-condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
This invention relates to substituted 5,6,7,8-tetrahydroquinoline compounds, substituted dihydropyridine compounds, and substituted tricyclic compounds. The invention also relates to methods of preventing or treating metabolic disorders, such as diabetes mellitus, and conditions and complications associated with diabetes mellitus, comprising administering to a subject in need thereof a compound of the invention or a composition comprising such a compound. The invention further relates to methods of treating inflammatory bowel disease, comprising administering to a subject in need thereof a compound of the invention or a composition comprising such a compound.
Description
5,6,7,8-TETRAHYDROQUINOLINES AND RELATED COMPOUNDS AND USES THEREOF
RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No. 60/635,673, filed December 13, 2004 and U.S. Provisional Application No. 60/660,246, filed March 10, 2005. The entire teachings of the above applications are incorporated herein by reference. FIELD OF THE INVENTION
The present invention relates to substituted 5,6,7,8-tetrahydroquinoline compounds and substituted tricyclic compounds and compositions comprising substituted 5,6,7,8- tetrahydroquinoline compounds and substituted tricyclic compounds. The invention further relates to methods for preventing or treating metabolic disorders, such as diabetes mellitus, and conditions and complications associated with diabetes mellitus, comprising administering to a subject in need thereof a compound of the invention, or a composition comprising such a compound. The invention also relates to methods for treating inflammatory bowel disease, comprising administering to a subject in need thereof a substituted 5,6,7,8-tetrahydroquinoline compound, a substituted tricyclic compound, or a dihydropyridine compound. The invention still further relates to kits comprising a compound of the invention.
BACKGROUND OF THE INVENTION
Metabolic disorders are conditions characterized by defective metabolism of sources used to store or use energy to produce the proteins, fats, and sugars needed by the body. For example, diabetes mellitus is a chronic, systemic disease characterized by abnormalities in the metabolism of carbohydrates, proteins, fats and insulin. The disease is generally characterized by hyperglycemia resulting from the body's inability to properly metabolize blood glucose. In a non-diabetic subject, the pancreas appropriately increases production of insulin to reduce glucose levels. Insulin is a hormone that induces the liver to metabolize glucose to glycogen. Diabetics, however, produce too little insulin, entirely cease producing insulin or progressively become resistant to the action of insulin. As a result, circulating levels of glucose remain dangerously high and in some cases, blood levels of insulin and lipids are also abnormal.
Approximately 17 million people in the United States, or 6% of the population, have diabetes. An estimated 11 million have been diagnosed, with another 6 million people unaware that they have the disease. Type I diabetes comprises 7 to 10 percent of all cases. Type I diabetes is typically an early onset disease characterized by the inability of the body to produce insulin. This is believed to be a result of an autoimmune response against the insulin-producing β-cells (or islet cells) of the pancreas. Because the β-cells are destroyed, sufferers of Type I diabetes do not produce insulin and must be treated with exogenous insulin for life.
Type π diabetes is a gradual onset disease that usually presents in middle age. The majority of Type II diabetics are obese, with most suffering from visceral obesity. These individuals tend to have high levels of circulating lipids (including cholesterol), which contributes to development of vascular complications. Type II diabetics usually present with a combination of insulin resistance (i.e., an impairment in the body's ability to respond to insulin) and reduced insulin production by the pancreas (β-cell exhaustion). Secondary complications of diabetes have serious clinical implications. Approximately 25 percent of all new cases of end-stage renal failure occur in patients with diabetes. About 20,000 amputations are carried out in patients with diabetes each year, representing approximately half of the non-traumatic amputations performed in the United States. Furthermore, diabetes is the leading cause of new cases of blindness, with approximately 5000 new cases occurring annually.
In Type II diabetics, dietary and other lifestyle modifications are the starting point for disease management. Oral hypoglycemic agents may also be used with the goal of trying to control blood glucose at normal or close to normal limits. The most common agents fall into five general categories: biguanides (such as metfoπnin (Glucophage, Bristol Myers Squibb)), Peroxisomes Proliferator Activated Receptor γ (PP ARγ) agonists (including thiazolidinediones such as pioglitazone (Actos, Lilly) and rosiglitazone (Avandia, GlaxoSmithKline)), insulinotropic agents (including secretagogues such as repaglinide (Prandin, Novo Nordisk)), sulphonylureas (such as glimepiride (Amaryl, Aventis) and glipizide (Glucotrol XL, Pfizer)) and α-glucosidase inhibitors (such as acarbose (Glucobay, Bayer)). Patients who do not respond fully to monotherapy may experience improved responses when combination therapy selected from two or more different categories is employed. Combination drugs include Avandaryl (PPAR gamma agonist (Avandia) and sulphonylurea (Amaryl), GSK/Aventis), Avandamet (PPAR gamma agonist (Avandia) and metformin, GSK), Glucovance (sulphonylurea and metformin, BMS), and Metaglip (glipizide
and metformin, BMS). New drugs in development fall into additional categories, including PPAR α/γ agonists such as tesaglitazar (Galida, AstraZeneca), PPAR α/γ/δ agonists such as 677954 (Glaxo SmithKline), GLP-I (such as exenatide, Lilly/ Amylin) and dipeptidyl peptidase IV inhibitors (such as LAF 237, Novartis and MK-0431, Merck), glycogen phosphorylase inhibitors, tyrosine phophatase inhibitors, GLUT 4 mediated glucose transport modulators, immunoregulatory vaccines and β3 adrenergic agonists.
Despite these and other recent advances, there remains a need for additional agents that can reduce glucose levels, improve other abnormal parameters characterizing metabolic diseases (such as, for example, elevated lipid and insulin levels or reduced insulin sensitivity), prevent or delay the onset or progression of metabolic diseases, and/or reduce side effects associated with conventional metabolic disease therapy. A need also remains for agents with new mechanisms of action that can be used alone or in combination with conventional other active agents.
Inflammatory bowel disease describes a group of diseases and disorders that cause inflammation to the gastrointestinal tissue (e.g. ulcerative colitis and Crohn's Disease). It is estimated that as many as 2 million Americans suffer from some form of inflammatory bowel disease. The primary goal of current treatments is reducing the inflammation and contolling the symptoms. Current treatments include aminosalicylates, antibiotics, corticosteroids, immune modifiers, and surgery. These treatments are not successful in all patients and the treatments may also cause undesirable side-effects. Therefore, there is a continuing need for safe and effective treatments for inflammatory bowel disease.
Citation of any reference in this section is not to be construed as an admission that such reference is prior art to the present application.
SUMMARY OF THE INVENTION
The present invention provides novel compounds and uses of those compounds in the prevention, treatment or management of a metabolic disorder, a symptom or complication thereof. In particular, the invention provides methods for preventing, managing or treating metabolic disorders, such as diabetes mellitus, and conditions and complications associated with diabetes mellitus. The invention also provides methods for treating inflammatory bowel disease.
The present invention provides compounds represented by structural formula (I):
or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. In structural formula (I): n is 0, 1, or 2;
A is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl or an optionally substituted heteroaryl;
X2 is O, S, NRn, or ^R5R5; X3 is O, S, or NRn;
R1 Is CN, -C(O)Rn, -C(O)OR11, -C(O)SRn, -C(O)NR12R13, -C(NR14)Rn, -C(NR14)OR11, -C(NR14)SR11, -C(NR14)NR12R13, -C(S)R11, -C(S)OR11, -C(S)SR11,
-C(S)NR12R13, -OC(O)R11, -OC(O)OR11, -OC(O)SR11, -OC(O)NR12R13, -NR11C(O)Rn, -NRnC(O)OR115 -NRnC(O)SR11, -NR11C(O)NR12R13, -SC(O)Rn, -SC(O)OR11, -SC(O)SR11, -SC(O)NR12R13, -OC(NR14)Rn, -OC(NR14)OR11, -OC(NR14)SRn, -OC(NR14)NR12R13, -NRnC(NR14)Rn, -NRnC(NR14)OR115 -NRnC(NR14)SR11, -NRnC(NR14)NRi2R13, -SC(NR14)Rn, -SC(NR14)ORn, -SC(NR14)SRn,
-SC(NR14)NR12R13, -OC(S)Rn, -OC(S)ORn, -OC(S)SR11, -OC(S)NRi2Ri3, -NRnC(S)Rn, -NRnC(S)OR119 -NRnC(S)SRn, -NR11C(S)NR12R13, -SC(S)R11, -SC(S)OR115 -SC(S)SR11, -SC(S)NR12R13, -P(O)(ORn)2, -P(O)(OR11)(R11), -P(O)(Rn)2,
-P(S)(ORn)25 -P(S)(ORn)(R11), -P(S)(Rn)2, -P(O)(SRn)2, -P(O)(SR11)(R11), -P(O)(SRn)2, -P(O)(SR11)(Rn), -P(O)(ORn)(SRn), -P(S)(SR102, -P(S)(SR11)(R11), -P(S)(ORn)(SRn), -S(O)2R11, -NRnS(O)2Rn, -S(O)2NR12R13, -S(O)2ORn, or a bioisostere of an ester, amide or carboxylic acid;
R2, R-5, R.6 R9 and Rio, for each occurrence are, independently, -H or a substituent; or R9 and Rio, for each occurrence, taken together are 131CR27R2S, =O, =S, or =NR27;
R7 and R8 are each, independently, -H or a substituent; or R7 and Rg, together with the carbon to which they are attached, form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl; or R7 and R8 together form =CR27R28;
R11, for each occurrence, is, independently, -H, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R12 and R13, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri2 and Ri3, taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;
RH is -H, halo, -OH, -NHR15, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Ri 5 is H, alkyl, aryl or acetyl; and R27 and R28, for each occurrence, are independently, H or a lower alkyl.
In one embodiment, in compounds represented by formula (I), there applies one or more (including all) of the following provisos: a) when R2 is -OH, Ri is not -C(S)NH2; b) A is not methyl, when R2 is ethoxy; c) R2 is not -NHRn, -SRn, or -SS-heteroaryl; d) when R2 is cyclopentyl or isopropy, Ri is not j^-trifluorobenzoyl; e) when R2 is n-propyl, isopropyl or cyclopentyl, A is not ^-fluorophenyl or 3,4- difiuorophenyl; f) when R2 is methyl, A is not an unsubstituted phenyl or a nitrophenyl;
when R] is -C(O)ORi 6 and R2 is methyl, A is not mono-or di-chlorophenyl, mono-or di-bromophenyl, or mono- or di-methoxyphenyl, wherein R1O is a lower alkyl group; h) when A, R2, R7 and R8 are all methyl, Ri is not -CN or -C(O)OCH2CH3; and i) when A is methyl or ethyl and R] is -CN, R2 is not -SRn, -OH or -Cl.
The present invention also provides compounds represented by structural formula
(H):
or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. In structural formula (II), n, A, Xi, X2, X3, R2, R9 and Rio are defined as above;
R30 is -C(O)NR12R13, -OC(O)NR12R13, -NR11C(O)Rn, -NRnC(O)ORn, -NRnC(O)NRi2R13, -NRnC(NR14)NRi2Ri3, -P(O)(ORπ)2, -S(O)2Rn, -S(O)2NRi2Ri3, - S(O)2ORn, or a bioisostere of an ester, amide or carboxylic acid, wherein Rn, R]2, Ri3, and Ri4 are defined as above; and "
R31, and R32 are each, independently, a lower alkyl or a lower alkenyl; or R3] and R32, together with the carbon to which they are attached, form an optionally substituted cycloalkyl; or R31 and R32 are =CR27R2s, wherein R27 and R2s are defined as above.
The present invention also provides compounds represented by structural formula Oil):
or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. In structural formula (EH), n, Xi, X2, X3, R1, R2, R7, Rs, R9> and Rio are defined as above; and Ai is an optionally substituted aryl or an optionally substituted heteroaryl. In one embodiment, in compounds represented by formula (III), there applies one or more (including all) of the following provisos: a) when R2 is -OH, Rj is not -C(S)NH2; b) R2 is not -NHRn, -SRn, or -SS-heteroaryl; c) when R2 is cyclopentyl or isopropy, Ri is not j9-trifluorobenzoyl; d) when R2 is n-propyl, isopropyl or cyclopentyl, Ai is not/?-fluorophenyl or 3 ,4-difluorophenyl; e) when R2 is methyl, Ai is not an unsubstituted phenyl or a nitrophenyl; and f) when Ri is -C(O)ORi6 and R2 is methyl, Ai is not mono-or di-chlorophenyl, mono-or di-bromophenyl, or mono- or di-methoxyphenyl, wherein Ri 6 is a lower alkyl group.
The present invention also provides compounds represented by structural formula (IV):
R33 Is -C(O)Rn, -C(O)OR11, -C(O)SR11, -C(O)NR12R13, -C(NR14)R11, -C(NR14)OR11, -C(NR14)SR11, -C(NR14)NR12R13, -C(S)R11, -C(S)OR11, -C(S)SR11, -C(S)NRnR13, -OC(O)R11, -OC(O)OR115 -OC(O)SR11, -OC(O)NR12Ri3, -NRnC(O)R11, -NR11C(O)ORn5 -NRnC(O)SR11, -NR11C(O)NR12Ri3, -SC(O)R11, -SC(O)OR11, -SC(O)SRn, -SC(O)NR)2Ri3, -OC(NRi4)Rn, -OC(NRi4)ORn5 -OC(NRi4)SRn, -OC(NRi4)NRi2Ri3, -NRn C(NRi4)Rn, -NRnC(NR14)OR1I5 -NRnC(NRi4)SRiI, -NR11C(NRi4)NRi2Ri3, -SC(NRi4)Rn, -SC(NR14)ORu, -SC(NR14)SRπ, -SC(NR14)NR12R13, -OC(S)Rn, -OC(S)ORn, -OC(S)SRn, -OC(S)NR12R13, -NR11C(S)R11, -NRnC(S)OR115 -NR11C(S)SRn, -NR11C(S)NR12R13, -SC(S)R11, -SC(S)ORn5 -SC(S)SRn, -SC(S)NR12Rj3, -P(O)(ORn)2, -P(O)(OR1 1)(R11), -P(O)(Rn)2, -P(S)(ORn)2, -P(S)(OR11)(Rn)5 -P(S)(Rn)2, -P(O)(SRn)2, -P(O)(SRn)(Rn), -P(O)(SRn)2, -P(O)(SRn)(R11), -P(O)(OR11)(SR11), -P(S)(SRn)2, -P(S)(SR11)(R11), -P(SXORn)(SRn), -S(O)2Rn, -NRnS(O)2Rn, -S(O)2NR12R13, -S(O)2ORn, or a bioisostere of an ester, amide or carboxylic acid, wherein Rn, R12, R13, and R14 are defined as above.
The present invention also provides compounds represented by structural formula
(V):
A2 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloakenyl, or an optionally substituted heterocyclyl.
In one embodiment, in compounds represented by formula (V), there applies one or more (including all) of the following provisos: a) the compound is not 2,4,7, 7-tetramethyl-5-oxo-5,6,7,8-tetrahydroquinoline-3- carboxylic acid ethyl ester or 8,8-difluoro-4-isobutyl-7,7-dimethyl-5-oxo-2- trifiuoromethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carboxylic acid methyl ester; and b) RT is not -SR29, wherein R29 is a substituted alkyl.
The present invention also provides compounds represented by structural formula (VI):
In another embodiment, the present invention provides compounds represented by structural formula (VII):
CVH) or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein: Xi is N or N→O; X6 and X7 are each, independently, =0, =S, or
X4 is CR87R8S, NR95, O, or S;
NR95;
B is an optionally substituted C2-C10 alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl; an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted bicyclic aryl group, an optionally substituted tricyclic aryl group, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or a phenyl group which is substituted with: i) one substituent selected from the group consisting of an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, a haloalkoxy, -OR9 u -SR95, cyano, -C(O)R95, -C(O)OR95, -C(O)SR95, -C(O)NR93R94, -C(S)R95, -C(S)OR95, -C(S)SR95,
-C(S)NR93R94, -C(NR86)R95, -C(NR86)OR95, -C(NR86)SR95, -C(NR86)NR93R94, -OC(O)R95, -OC(O)OR95, -OC(O)SR95, -OC(O)NR93R94, -OC(S)R95, -OC(S)OR95, -OC(S)SR95, -OC(S)NR93R94, -OC(NR86)R95, -OC(NR86)OR95, -OC(NR86)SR95, -OC(NR86)NR93R94, -NR95C(O)R95, -NR95C(O)OR95, -NR95C(O)SR95, -NR95C(O)NR93R94,
-NR95C(S)R95, -NR95C(S)OR95, -NR95C(S)SR95, -NR95C(S)NR93R94, -NR95C(NR86)R95, -NR95C(NR86)OR95, -NR95C(NR86)SR95, -NR95C(NR86)NR93R94, -S(O)PR95, or -S(O)PNR93R94;
ii) two, four, five or six substituents, independently, selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a halo, nitro, a haloalkyl, a haloalkoxy, -OR95, -NR93R94, -SR95, cyano, -C(O)R95, -C(O)OR95; -C(O)SR95, -C(O)NR93R94, -C(S)R95, -C(S)OR95, -C(S)SR95, -C(S)NR93R94, -C(NR86)R95, -C(NR86)OR95, -C(NR86)SR95, -C(NR86)NR93R94, -OC(O)R95, -OC(O)OR95, -OC(O)SR95,
-OC(O)NR93R94, -OC(S)R95, -OC(S)OR95, -OC(S)SR95, -OC(S)NR93R94, -OC(NR86)R95, -OC(NR86)OR95, -OC(NR86)SR95, -OC(NR86)NR93R94, -NR95C(O)R95, -NR95C(O)OR95, -NR95C(O)SR95, -NR95C(O)NR93R94, -NR95C(S)R95, -NR95C(S)OR95, -NR95C(S)SR95, -NR95C(S)NR93R94, -NR95C(NR86)R95, -NR95C(NR86)OR95, -NR95C(NR86)SR95,
-NR95C(NR86)NR93R94, -S(O)PR95, or -S(O)PNR93R94; or iii) three substituents, independently, selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a halo, nitro, a haloalkyl, a haloalkoxy, -OR92, -NR93R94, -SR95, cyano, -C(O)R95, -C(O)OR95, -C(O)SR95, -C(O)NR93R94, -C(S)R95, -C(S)OR95, -C(S)SR95, -C(S)NR93R94, -C(NR86)R95, -C(NR86)OR95, -C(NR86)SR95,
-C(NR86)NR93R94, -OC(O)R95, -OC(O)OR95, -OC(O)SR95, -OC(O)NR93R94, -OC(S)R95, -OC(S)OR95, -OC(S)SR95, -OC(S)NR93R94, -OC(NR86)R95, -OC(NR86)OR95, -OC(NR86)SR95, -OC(NR86)NR93R94, -NR95C(O)R95, -NR95C(O)OR95, -NR95C(O)SR95, -NR95C(O)NR93R94, -NR95C(S)R95, -NR95C(S)OR95, -NR95C(S)SR95, -NR95C(S)NR93R94,
-NR95C(NR86)R95, -NR95C(NR86)OR95, -NR95C(NR86)SR95, -NR95C(NR86)NR93R94, -S(O)PR95, or -S(O)PNR93R94;
R78, R79, Rδ2, R83, Rs4, Rs5, Rs7, Res, Rδ9, and R9o are each, independently, H or a substituent;
Rg0 and Rg j are each, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl; or Rso and Rg i taken together are =CR95R95; or Rso and Rg1, together with the carbon to which they are attached form a cycloalkyl or a cycloalkenyl, provided that at least one of R8o and R81 is not H;
Rδδ, for each occurrence, is independently -H, a halo, an alkyl, -OR95, -NR93R94, -C(O)R95, -C(O)OR95, or -C(O)NR93R94;
R91, for each occurrence, is independently, -H, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R92, for each occurrence, is independently, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R93 and R94, for each occurrence are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R93 and R94 taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl; Rg5, for each occurrence, is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; q and r are each, independently, 0 or 1; and p is 1 or 2.
The present invention also provides compounds represented by structural formula (VIE):
(VEl) or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: X1, X6, X7, XA, XS, R-78, R79, Rso, Rsi, Rs2, Rss, Rg4, Rss, q and r are defined as for formula (VII); and
B] is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl.
The present invention also provides compounds represented by structural formula
(IX):
B2 is an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, an optionally substituted cycloheptyl, an optionally substituted cyclooctyl, an optionally substituted cycloalkenyl, or an optionally substituted heterocyclyl;
R97 is -H, an alkyl, -C(O)R98;
R9S is -H, -R99, -OR99 or -NR99R99; and
R99, for each occurrence, is independently, -H, a lower alkyl, an aryl, or an aralkyl.
The present invention also provides compounds represented by structural formula
(X):
(X) or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: Xe, X7, X4, Xs, R7S, R?9> Rδo, Rsb Rs2, R83, Rδ4; Rs5, q and r are defined as for formula (I);
Bi is defined as for formula (VIII); and R97 is defined as for formula (IX).
In another embodiment, the present invention provides compounds having the formula (XI):
(XI) or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein Do, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, and s are defined below.
The present invention also provides compounds having the formula (XII):
(xπ) or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein D2, Y, X9, R45, R46, R47, R52, R53, R54, R55, and s are defined below. The present invention also provides compounds having the formula (XIII)
(XIV)
or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph or prodrugs thereof wherein Ar, Q, X, Y, R34, R35, R36, R37 and s are as defined below. The invention also provides compounds having the formula (XV):
or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph or prodrug thereof, wherein Ar, X, Y, Z, V, R34, R35, R36, R37, s and t are as defined below. The invention also provides compounds having the formula (XVI):
(XVI)
or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph or prodrug thereof, wherein Ar', V, R1', R2', R3', R4' and t are as defined below.
The invention also provides compounds having the formula (XVII):
(xvπ) or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein Di, Xg, R45, R46, R47, R48, R49, Rs2, R-53> Rs4, R55, and s are defined below.
The compounds of formulas (I), (R), (UT), (TV), (V), (VI), (VE), (VHI), (IX), (X), and Table 1, and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof are particularly useful for preventing, treating, managing or ameliorating
metabolic disorders (including, but not limited to diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof) or a symptom thereof. In a specific embodiment, the compounds of formulas (I), (H), (IH), (IV), (V), (VI), (VU), (VIII), (IX), (X), (XI), (XU), (Xπi), (XIV), (XV), (XVI), (XVπ), and Table 1, and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof are used for preventing, treating, managing or ameliorating diabetes mellitus type I and/or type II, and conditions and complications associated therewith. In one embodiment, the compounds of formulas (I), (II), (in), (IV), (V), (VI), (VH), (VIII), (IX), (X), (XI), (XE), (XHI), (XIV), (XV), (XVI), (XVII), and Table 1, and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof are particularly useful for preventing, treating, or managing type II diabetes mellitus.
The present invention provides pharmaceutical compositions comprising an effective amount of one or more compound of formula (I), (II), (EQ), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XIT), (Xπi), (XIV), (XV), (XVI), (XVπ), or Table 1, or pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof, and a pharmaceutically acceptable carrier or vehicle. These compositions may further comprise additional agents. These compositions are useful for treating or preventing metabolic disorders, such as diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof. The present invention provides also methods for treating, preventing or managing a metabolic disorder, said methods comprising administering to a subject in need thereof a compound of formula (I), (H), (III), (IV), (V), (VI), (YU), (VDI)9 (IX), (X), (XI), (XU), (XIII), (XIV), (XV), (XVI), (XVπ), or Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, or a pharmaceutical composition comprising a compound of formula (I), (H), (HI), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XEQ), (XIV), (XV), (XVI), (XVπ), or Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. These methods may also comprise administering to the subject an additional agent separately or in a combination composition with the compound of formula (I), (II), (EI), (TV), (V), (VI), (VII), (VIII), QX), (X), (XI), (XII), (Xiπ), (XIV), (XV), (XVI), (XVII), or Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.
In a specific embodiment, the invention provides a method for reducing blood glucose levels, said method comprising administering to a subject in need thereof an effective amount of a compound of formula (I), (II), (IH), (IV), (V), (VI), (VH), (VHI), (IX),
(X), (XI), (Xn), (Xπi), (XIV), (XV), (XVI), (XVπ), or Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof or a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (Xn), (Xiπ), (XIV), (XV), (XVI), (XVII), or Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.
In another embodiment, the invention provides a method of improving blood lipid levels in a subject in need thereof, said method comprising administering to a subject in need thereof an effective amount of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIE), (IX), (X), (XI), (XH), (XIH), (XIV), (XV), (XVI), (XVH), or Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof or a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II), (TlI), (IV), (V), (VI), (VII), (VIIT), (IX), (X), (XI), (XII), (Xπi), (XIV), (XV), (XVI), (XVH), or Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. In accordance with these embodiments, a compound of formula (I), (H), (ffi), (IV), (V), (VI), (Vn), (Vπi), (IX), (X), (XI), (XII), (XHI), (XIV), (XV), (XVI), (XVH), or Table 1, may be administered in combination with other therapies (e.g., prophylactic or therapeutic agents). Examples of such therapies include, but are not limited to, dietary therapy, anti-diabetic agents, anti- obesity agents and lipid lowering agents.
In another embodiment, the invention provides a method of improving blood insulin levels, said method comprising administering to a subject in need thereof an effective amount of a compound of formula (I), (II), (in), (TV), (V), (VI), (VH), (VHI), (IX), (X), (XI), (XII), (XHI), (XIV), (XV), (XVI), (XVII), or Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof or a pharmaceutical composition comprising an effective amount of a compound of formula (I), (π), (IH), (IV), (V), (VI), (VII), (VHI), (IX), (X), (XI), (XII), (Xπi), (XIV), (XV), (XVI), (XVII), or Table 1 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.
In another embodiment, the invention provides a method of improving insulin sensitivity, said method comprising administering to a subject in need thereof an effective amount of a compound of formula (I), (H), (in), (IV), (V), (VI), (VH), (VHI), (LX), (X), (XI), (XH), (XIH), (XTV), (XV), (XVTj, (XVH), or Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof or a pharmaceutical composition comprising an effective amount of a compound of formula (I)5 (H), (IH), (IV), (V), (VI), (VTI), (VIH), (IX), (X), (XI), (Xn), (XHI), (XTV), (XV), (XVI), (XVπ), or Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. In accordance with these
embodiments, a compound of formula (I), (H), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (Xπi), (XIV), (XV), (XVI), (XVn), or Table 1 can be administered in combination with other therapies (e.g., prophylactic or therapeutic agents).
In another embodiment, the invention provides a method of achieving two or more of the following: (i) reducing blood glucose levels, (ii) improving blood lipid levels, (iii) improving blood insulin levels, and (iv) improving insulin sensitivity, said method comprising administering to a subject in need thereof an effective amount of a compound of formula (I), (II), (IE), (IV), (V), (VI), (VII), (VHI), (IX), (X), (XI), (XH), (Xffl), (XIV), (XV), (XVI), (XVII),or Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof or a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II), (IH), (IV), (V), (VI), (VII), (VHI), (IX), (X), (XI), (XII), (XHI), (XIV), (XV), (XVI), (XVn), or Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. In accordance with these embodiments, a compound of formula (I), (II),
(πi), (iv), (V), (VI), evil), (vm), (ix), (X), (xi), (XH), (XIΠ), (XIV), (XV), (xvi), (xvii), or Table 1 may be administered in combination with other therapies (e.g., prophylactic or therapeutic agents).
In certain embodiments, the present invention encompasses prophylactic and/or therapeutic protocols that provide better prophylactic or therapeutic profiles than current single agent therapies or combination therapies for metabolic disorders, such as diabetes mellitus, and conditions associated and complications associated with diabetes mellitus. The present invention provides kits comprising, in one or more containers, one or more compounds of formula (I), (H), (HI), (TV), (V), (VI), (VII), (VIH), (IX), (X), (XI), (XH), (XIH), (XIV), (XV), (XVI), (XVn), or Table 1.
The present invention also provides methods for treating inflammatory bowel disease, said methods comprising administering to a subject in need thereof a compound of formula (I)5 (II), (HI), (IV), (V), (VI), (VR), (VHI)5 (IX), (X), (XI), (XH), (XHI), (XIV), (XV)5 (XVI), (XVn), or Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, or a pharmaceutical composition comprising a compound of formula (I), (π), (IH), (IV)5 (V)5 (VI), (VH), (VET), (IX), (X)5 (XI)5 (XH)5 (XHI), (XIV)5 (XV)5 (XVI), (XVH), or Table I5 or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. In one aspect, the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows the results of a 7 day baseline glucose (7DBG) study to determine the effects of orally dosing test compounds daily for seven days on glucose levels in fed db/db mice. Figure 2 shows the results of a study examining the effects of Compounds 52 and
276 on disease severity in the rat DNBS-induced model of inflammatory bowel disease. On days 1-7, animals were orally dosed once per day with vehicle or test articles by oral gavage (doses were chosen to be less than the maximum tolerated dose for each compound in rats), and DNBS was administered intra-rectally on day 2 to induce colitis. Colons were excised and the colon-to-body weight ratios determined on day 8. Treatment with both Compound 52 and 276 resulted in a decrease in the colon-to-body weight ratio relative to vehicle-treated animals, indicative of reduced colon inflammation. Similar results were also observed by examining the absolute colon weights.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds and uses of said compounds. The present invention encompasses the use of the compounds of the invention for the prevention, treatment, management and/or amelioration of a metabolic disorder or a symptom thereof. In particular, the present invention encompasses the use of compounds of the invention to reduce blood glucose levels (preferably, normalize blood glucose levels), improve abnormal blood insulin levels (preferably, normalize blood insulin levels), improve lipid metabolism, reduce cholesterol, and/or improve insulin sensitivity (preferably, noπnalize insulin sensitivity). In certain embodiments, the present invention encompasses the use of compounds of the invention to treat inflammatory bowel disease. In one aspect, the present invention encompasses the use of compounds of the invention to treat ulcerative colitis or Crohn's disease.
In certain embodiments, the present invention encompasses treatment protocols that provide better prophylactic or therapeutic profiles than current single agent therapies or combination therapies for a metabolic disorder or one or more symptoms thereof. In particular, the invention provides prophylactic and therapeutic protocols for the prevention, treatment, management, and/or amelioration of a metabolic disorder or a symptom thereof, comprising administering to a subject in need thereof an effective amount of one or more
compounds of the invention alone or in combination with an effective amount of at least one other therapy other than a compound of the invention.
The present invention provides for pharmaceutical compositions and kits comprising one or more compounds of the invention for use in the prevention, treatment, management or amelioration of a metabolic disorder or a symptom thereof. The present invention also provides for phaπnaceutical compositions and kits comprising one or more compounds of the invention and one or more additional agents for use in the prevention, treatment, management, or amelioration of a metabolic disorder or a symptom thereof.
Terminology Unless otherwise specified, the below terms used herein are defined as follows:
As used herein, the term an "aromatic ring" or "aryl" means a monocyclic or polycyclic-aromatic radical comprising carbon and hydrogen atoms. Examples of suitable aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8- tetrahydronaphthyl. An aryl group can be unsubstituted or substituted with one or more aryl substituents (including without limitation alkyl (preferably, lower alkyl), haloalkyl (preferably lower haloalkyl) hydroxy, alkoxy (preferably, lower alkoxy), haloalkoxy (preferably lower haloalkoxy), alkyl sulfanyl, cyano, halo, amino, alkylamino (preferably lower alkylamino), dialkylamino (preferably lower dialkylamino), and nitro). In one embodiment, the aryl group is substituted with deuterium (e.g., one or more hydrogen atoms are replaced with a deuterium atom). Preferably, the aryl group is a monocyclic ring, wherein the ring comprises 6 carbon atoms, referred to herein as "(C6)aryl."
As used herein, the term "alkyl" means a saturated straight chain or branched non- cyclic hydrocarbon having from 1 to 10 carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n- nonyl and n-decyl; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, te/-/-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methyIpentyl, 4- methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3- dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4- dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3- dimtheylpentyl, 3, 3 -dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2- ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2 -methyl -2-ethylpentyl, 2-methyl-3-ethylpentyI, 2- methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl,
2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl and the like. The term "(Ci-C6)alkyl" means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms. Representative (Ci-Ce)alkyl groups are those shown above having from 1 to 6 carbon atoms. Alkyl groups included in compounds of this invention may be optionally substituted with one or more conventionally used alkyl substituents, such as -NH2, -NH-(CrC6)alkyl, -N[(CrC6)alkyl]2, -O-CCrCejalkyl, -S-(Ci-C6)alkyl, haloalkyl, haloalkoxy, oxo, halo, acyl, nitro, hydroxyl, cyano, aryl, -(C]-C6)alkyl-aryl, -O-aryl, -S-aryl, -NH-aryl, -N(aryl)2 -(C3-Ci0)cycloalkyl, -O-(C3-Ci0)cycloalkyl, -S-(C3-Ci0)cycloalkyl, -NH- (C3-C10)cycloalkyl, -N-[(C3-Ci0)cycloalkyl]2, 3-7 membered monocyclic heterocycle, -O-(3- 7 membered monocyclic heterocycle), -NH-(3-7 membered monocyclic heterocycle), -N-[(3- 7 membered monocyclic heterocycle)]2, -S-(3-7 membered monocyclic heterocycle), and the like. In addition, any carbon in the alkyl segment may be substituted with carbonyl (=0) or thiocarbonyl (=S).
The term alkylene refers to an alkyl or cycloalkyl group that has at least two points of attachment to at least two moieties (e.g., {-CH2-}, -{CH2CH2-},
An aralkyl group refers to an aryl group that is attached to another moiety via an alkylene linker. Aralkyl groups can be optionally substituted with one or more substituents.
The teπn "alkoxy," as used herein, refers to an alkyl or a cycloalkyl group which is linked to another moiety though an oxygen atom. Alkoxy groups can be optionally substituted with one or more substituents.
The term "heteroalkyl" refers to an alkyl group in which one or more methylenes in the alkyl chain are replaced by a heteroatom such as -O-, -S-, and -NR.26-- R26 is a hydrogen, alkyl, aryl, arylalkyl, alkenyl, alkynyl, heteroaryl, heteroarylalkyl, or heterocyclyl. Heteroalkyl groups can be substituted or unsubstituted.
The term "haloalkyl" refers to an alkyl group in which one or moreof the hydrogen atom is replaced by a halo group (e.g., -F, -Cl, -Br, and -I). Examples of haloalkyl groups
include trifluoromethyl, dichloromethyl, 2,2-dichloroethyl, 1,2-dichloroethyl, l-bromo-2- chloroethyl, 3-iodobutyl, and the like. Haloalkyl groups can be optionally substituted with one or more substituents by replacing a hydrogen with the substituent.
The term "haloalkoxy," as used herein, refers to a haloalkyl which is linked to another moiety though an oxygen atom. Haloalkoxy groups can be optionally substituted with one or more substituents.
As used herein, the term "alkenyl" means a straight chain or branched hydrocarbon radical having from 2 to 10 carbon atoms and having at least one carbon-carbon double bond. Representative straight chain and branched alkenyls include vinyl, allyl, 1-butenyl, 2- butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl- 1-butenyl, 2-methyl-2-butenyl, 2,3- dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1- octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl, 3- decenyl and the like. Alkenyl groups may be optionally substituted with one or more substituents. As used herein, the term "alkynyl" means a straight chain or branched hydrocarbon radical having from 2 to 10 carbon atoms and having at least one carbon-carbon triple bond. Representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl- 1-butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5- hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2- nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, 9-decynyl and the like. Alkynyl groups may be optionally substituted with one or more substituents.
As used herein, the term "cycloalkyl" means a saturated mono- or poly-cyclic alkyl radical having from 3 to 10 carbon atoms. Representative cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, decahydronapthylene, adamantyl, and the like. Cycloalkyl groups may be optionally substituted with one or more substituents.
As used herein, the term "cycloalkenyl" means a mono- or poly-cyclic non-aromatic hydrocarbon radical having at least one carbon-carbon double bond in the cyclic system and from 5 to 14 carbon atoms. Representative cycloalkenyls include cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl, cyclooctatetraenyl, cyclononenyl, cyclononadienyl, cyclodecenyl, cyclodecadienyl, l,3a,6,6a-tetrahydro- pentalene and the like. Cycloalkenyl groups may be substituted or unsubstituted.
As used herein, the term "heterocycle" or "heterocyclyl" means a mono- or poly- cyclic heterocyclic ring (typically having 3- to 14-members) which is either a saturated ring or a unsaturated non-aromatic ring. A 3-membered heterocycle can contain up to 3 heteroatoms, and a 4- to 14-membered heterocycle can contain up to 4 heteroatoms per each ring. Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The heterocycle may be attached via any heteroatom or carbon atom. Representative heterocycles include morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, benzo[l,3]dioxolyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. A heteroatom may be substituted with a protecting group known to those of ordinary skill in the art, for example, the hydrogen on a nitrogen may be substituted with a tert-butoxycarbonyl group. Furthermore, the heterocyclyl may be optionally substituted with one or more substituents (including without limitation a halogen atom, an alkyl radical, or aryl radical). Only stable isomers of such substituted heterocyclic groups are contemplated in this definition. Heterocyclyl groups can be optionally substituted with one or more substituents.
As used herein, the term "heteroaromatic" or "heteroaryl" means a monocyclic or polycyclic heteroaromatic ring (or radical thereof) having from 5 to 14 ring members comprising carbon atom ring members and one or more heteroatom ring members (such as, for example, oxygen, sulfur or nitrogen), wherein each ring in the heteroaryl ring system can have up to 4 heteroatoms. In one embodiment, the heteroaromatic ring is selected from 5-8 membered heteroaryl rings. In another embodiment, the heteroaromatic ring is a 5 or 6 membered ring. Representative heteroaryls include pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, indolizinyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, pyridinyl, thiadiazolyl, pyrazinyl, quinolyl, isoquniolyl, indazolyl, benzoxazolyl, benzofuryl, benzothiazolyl, indolizinyl, imidazopyridinyl, isothiazolyl, tetrazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, qunizaolinyl, purinyl, pyrrolo[2,3]pyrimidyl, pyrazolo[3,4]pyrimidyl or benzo(b)thienyl and the like. These heteroaryl groups (including indolizinyl when mentioned alone) may be optionally substituted with one or more substituents including (but not limited to amino, alkylamino, alkoxy, alkylthio, oxo, halo, acyl, nitro, hydroxyl, cyano, aryl, alkylaryl, aryloxy, arylthio, arylamino, carbocyclyl, carbocyclyloxy, carbocyclylthio, carbocyclylamino,
heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylthio, and the like. Particular heteroaryl substituents include halo and lower alkyl optionally substituted with one or more halo.
An heteroaralkyl group refers to a heteroaryl group that is attached to another moiety via an alkylene linker. Heteroaralkyl groups can be optionally substituted with one or more substituents.
As used herein, the term "heteroaromatic", "heteroaryl" or like terms means a monocyclic or polycyclic heteroaromatic ring comprising carbon atom ring members and one or more heteroatom ring members (such as, for example, oxygen, sulfur or nitrogen), for example, 1 to 5 heteroatoms. A heteroaryl may be fused to one or two rings, such as a cycloalkyl, a heterocyclyl, an aryl, or a heteroaryl. The point of attachment of a heteroaryl to a molecule may be on the heteroaryl, cycloalkyl, heterocyclyl or aryl ring, and the heteroaryl group may be attached to a groups, such as the 5,6,7, 8-tetrahydroquinoline core structure, through carbon or a heteroatom. In one embodiment, the heteroaromatic ring is selected from 5-8 membered heteroaryl rings. Examples of heteroaryl groups include pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, indolizinyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, triazinyl, thiadiazolyl, quinolyl, isoquniolyl, indazolyl, benzoxazolyl, benzofuryl, benzothiazolyl, imidazopyridinyl, isothiazolyl, tetrazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, qunizaolinyl, purinyl, pyrrolo[2,3]pyrimidyl, pyrazolo[3,4]pyrimidyl, [l,2,4]oxadiazolyl, and benzo(b)thienyl. Heteroaryl groups may be optionally substituted with one or more substituents.
As used herein, the term "(C5)heteroaryl" means an aromatic heteroaryl ring of 5 members, wherein at least one carbon atom of the ring is replaced with a heteroatom such as, for example, oxygen, sulfur or nitrogen. Representative (C5)heteroaryls include furyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyrazinyl, triazolyl, thiadiazolyl, [l,2,4]oxadiazolyl and the like.
As used herein, the teπn "(C6)heteroaryl" means an aromatic heteroaryl ring of 6 members, wherein at least one carbon atom of the ring is replaced with a heteroatom such as, for example, oxygen, nitrogen or sulfur. One of the (CO)II eteroaryl rings contains at least one carbon atom. Representative (C6)heteroaryls include pyridyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl and the like.
As used herein, the term "halogen" or "halo" means -F, -Cl, -Br or -I.
The term "substituent" or "substituted" refers to any desired substituent or substituents that do not have a substantially adverse affect on the stability of the compound. Examples of preferred substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as, an alkyl, an alkenyl, an alkynyl, an cycloalkyl, an cycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl, a heteraralkyl, a haloalkyl, -C(O)NRi8Ri9, -NR20C(O)R2I, a halo, -OR20, cyano, nitro, a haloalkoxy, -C(O)R20, -NRi8Ri9, -SR20, -C(O)OR20, -OC(O)R20, -NR20C(O)NRi8Ri9, -OC(O)NR18R19, -NR20C(O)OR21, -NR20C(NR14)NR18R19, -S(O)pR20, -S(O)pOR20, -S(O)pNRi8R19, -NR20S(O)pR2i, -P(O)(OR20)2, and -OP(O)(OR20)2. Ri8 and R19, for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri8 and R19 taken together with the nitrogen to which they are attached is optionally substituted heterocyclyl or optionally substituted heteroaryl. R20 and R21 for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl. Preferred substituents include halo (chloro, iodo, bromo, or fluoro); Ci-e alkyl; C2-6 alkenyl; C2-6 alkynyl; hydroxyl; Q.6 alkoxyl; amino; alkylamino; dialkylamino; nitro; thiol; alkylsulfanyl; imine; cyano; amido; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxo (=0); haloalkyl (e.g., trifluoromethyl); carbocyclic cycloalkyl, which may be monocyclic or fused or non-fused polycyclic {e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclyl, which may be monocyclic or fused or non-fused polycyclic {e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl); carbocyclic or heterocyclic, monocyclic or fused or non-flxsed polycyclic aryl {e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); amino (primary, secondary, or tertiary); -0-lower alkyl; -O-aryl, aryl; aryl-lower alkyl; CO2CH3; CONH2; OCH2CONH2; NH2; SO2NH2; OCHF2; CF3; OCF3; and such moieties may also be optionally substituted by a
fused-ring structure or bridge, for example -OCH2O-. These substituents may optionally be further substituted with a substituent selected from the above preferred substituents.
The terms "bioisostere" and "bioisosteric replacement" have the same meanings as those generally recognized in the art. Bioisosteres are atoms, ions, or molecules in which the peripheral layers of electrons can be considered identical. The term bioisostere is usually used to mean a portion of an overall molecule, as opposed to the entire molecule itself. Bioisosteric replacement involves using one bioisostere to replace another with the expectation of maintaining or slightly modifying the biological activity of the first bioisostere. The bioisosteres in this case are thus atoms or groups of atoms having similar size, shape and electron density. Preferred bioisosteres of esters, amides or carboxylic acids are compounds containing two sites for hydrogen bond acceptance. In one embodiment, the ester, amide or carboxylic acid bioisostere is a 5-membered monocyclic heteroaryl ring, such as an optionally substituted imidazolyl, an optionally substituted oxazolyl, or an optionally substituted [l,2,4]oxadiazolyl. As used herein, the terms "subject", "patient" and "animal" are used interchangeably.
The terms "subject" and "patient" refer to an animal {e.g., a bird such as a chicken, quail or turkey, or a mammal), preferably a mammal including a non-primate (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate (e.g., a monkey, chimpanzee and a human), and more preferably a human. In one embodiment, the subject is a non-human animal such as a faπn animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat, guinea pig or rabbit). In a preferred embodiment, the subject is a human. In another embodiment, the subject is refractory or non-responsive to current therapies for a metabolic disorder (e.g., diabetes mellitus type I and/or diabetes mellitus type II).
As used herein, the term "lower" refers to a group having up to four atoms. For example, a "lower alkyl" refers to an alkyl radical having from 1 to 4 carbon atoms, "lower alkoxy" refers to "-0-(C i-C4)alkyl and a "lower alkenyl" or "lower alkynyl" refers to an alkenyl or alkynyl radical having from 2 to 4 carbon atoms, respectively.
Unless indicated otherwise, the compounds of the invention containing reactive functional groups (such as (without limitation) carboxy, hydroxy, and amino moieties) also include protected derivatives thereof. "Protected derivatives" are those compounds in which a reactive site or sites are blocked with one ore more protecting groups. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like. Suitable protecting groups for amino and amido groups include acetyl, tert-butoxy-C(O)-,benzyloxy-C(O)-,and the like. Suitable protecting groups for hydroxy include benzyl, methoxymethyl,
trimethylsilyl, terf-butyl-dimethylsilyl, and the like. Other suitable protecting groups are well known to those of ordinary skill in the art and include those found in T. W. Greene, "Protecting Groups in Organic Synthesis," John Wiley & Sons, Inc. (1981).
As used herein, the term "compound(s) of this invention" and similar terms refers to a compound of formula (I), (II), (ED-), (IV), (V), (VI), (VH), (VHI), (IX), (X), (XI), (XU), (Xffl), (XTV), (XV), (XVI), (XVE), or Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph or prodrug thereof and also include protected derivatives thereof. In another embodiment, a "compound of the invention" is characterized by an ability to reduce elevated blood glucose levels without a significant cardiovascular effect. In another embodiment, a "compound of the invention" is characterized by an ability to reduce elevated blood glucose levels without significant acute toxicity. In another embodiment, a "compound of the invention" is characterized by an ability to treat inflammatory bowel disease. The compounds of the invention may contain one or more chiral centers and/or double bonds and, therefore, may exist as stereoisomers, such as cis or trans double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. According to this invention, the chemical structures depicted herein, including the compounds of this invention, encompass all of the corresponding compounds' geometric isomers, enantiomers and stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and geometric isomeric mixtures, enantiomeric mixtures and stereoisomeric mixtures. In some cases, one geometric isomer, enantiomer or stereoisomer will possess superior activity or an improved toxicity or kinetic profile compared to others. In those cases, such geometric isomers, enantiomers and stereoisomers of compounds of this invention are preferred.
As used herein, the term "polymorph" means solid crystalline forms of a compound of the present invention or complex thereof. Different polymorphs of the same compound can exhibit different physical, chemical and/or spectroscopic properties. Different physical properties include, but are not limited to stability (e.g., to heat or light), compressibility and density (important in formulation and product manufacturing), and dissolution rates (which can affect bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical characteristics (e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity). Different physical properties of
polymorphs can affect their processing. For example, one polymorph might be more likely to form solvates or might be more difficult to filter or wash free of impurities than another due to, for example, the shape or size distribution of particles of it.
As used herein, the term "hydrate" means a compound of the present invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
As used herein, the term "clathrate" means a compound of the present invention or a salt thereof in the form of a crystal lattice that contains spaces (e.g., channels) that have a guest molecule (e.g., a solvent or water) trapped within. As used herein and unless otherwise indicated, the term "prodrug" means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound of this invention. Prodrugs may only become active upon such reaction under biological conditions, or they may have activity in their unreacted forms. Examples of prodrugs contemplated in this invention include, but are not limited to, analogs or derivatives of compounds of formulas (I), (II), (ITl), (IV), (V), (VI), (VU), (VIH), (IX)5 (X), (XI), (XE), (XJE), (XTV), (XV), (XVI), (XVII), or compounds in Table 1 that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Other examples of prodrugs include derivatives of compounds of formula (T), (II), (HI), (IV), (V), (VI), (VII), (VIH), (IX), (X), (XI), (Xn), (XHI), (XTV), (XV), (XVI), (XVII), or compounds in Table 1 that comprise -NO, -NO2, -ONO, or -ONO2 moieties. Prodrugs can typically be prepared using well-known methods, such as those described by 1 BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed). As used herein and unless otherwise indicated, the terms "biohydrolyzable amide",
"biohydrolyzable ester", "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureide" and "biohydrolyzable phosphate analogue" mean 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 uptake, duration of action, or onset of action; or 2) is itself biologically inactive but is converted in vivo to a biologically active compound. Examples of biohydrolyzable 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, heterocyclyl and heteroaromatic amines, and polyether amines. As used herein, the terms "metabolic disease" and "metabolic disorder" are used interchangeably to refer to diseases and disorders associated with abnormal anabolism or assimilation and/or catabolism, including, without limitation diseases and disorders associated with abnormal carbohydrate metabolism, fat metabolism, and protein metabolism. Non-limiting examples of metabolic disorders include metabolic syndrome X diseases (including diabetes mellitus, obesity, hypertension, dyslipidemias and heart disease), Tangier disease, Wilson's disease (hepatolenticular degeneration), acromegaly, Addison's disease, Cushing's syndrome, Creutzfeldt-Jakob disease, hyperparathyroidism, multiple endocrine neoplasia Type 1, prolactinoma, galactosemia, glycogen storage diseases (e.g., Type O Liver, von Gierke's disease (Type IA), Type IB, Pompe's disease (Type II), Forbes' disease (Type III), Andersen's disease (Type IV), McArdle's disease (Type V), Hers' disease (Type VI), and Tarui's disease (Type VII)), hypoglycemia, Gaucher' s disease, Fabry's disease, Mucopolysaccharidoses, Sandhoff Disease, Niemann-Pick Disease, aspartylglusomarinuria, biotinidase deficiency, carbohydrate deficient glycoprotein syndrome (CDGS), Crigler- Najjar syndrome, cystinosis, diabetes insipidus, glutaric aciduria, Hurler, lactic acidosis, long chain 3 hydroxyacyl CoA dehydrogenase deficiency (LCHAD) and also includes without limitation diseases and conditions associated with diabetes mellitus (diabetes mellitus type I and/or type II).
As used herein, the term "diabetes mellitus" refer to diabetes mellitus type I and/or type II. In certain embodiment, the term "diabetes mellitus" refers to diabetes mellitus type I. In other embodiments, the term "diabetes mellitus" refers to diabetes mellitus type II. In yet other embodiments, the term "diabetes mellitus" refers to diabetes mellitus type I and type II.
As used herein, the term "diseases and conditions associated with diabetes mellitus" and similar terms, refer to conditions associated with diabetes mellitus type I and/or type II, including, without limitation, hyperglycemia, hyperinsulinaemia, dyslipidemia (e.g., hyperlipidaemia), insulin resistance, impaired glucose metabolism, obesity, diabetic retinopathy, chronic microvascular complications, macular degeneration, cataracts, diabetic nephropathy, glomerulosclerosis, diabetic neuropathy, erectile dysfunction, premenstrual syndrome, vascular restenosis, and ulcerative colitis. Furthermore, "complications of
diabetes mellitus" comprise, but are not restricted to: coronary heart disease, hypertension, angina pectoris, pain, numbness, muscle weakness, incontinence, myocardial infarction, arteriosclerosis, stroke, skin and connective tissue disorders, foot ulcerations, polyneuropathy, kidney disease, renal failure, metabolic acidosis, arthritis, osteoporosis and conditions of impaired glucose tolerance.
As used herein, the term "inflammatory bowel disease" refers to all forms of inflammatory processes in the gastrointestinal tissue, including but not limited to, pseudomembranous colitis, hemorrhagic colitis, hemolytic-uremic syndrome colitis, collagenous colitis, ischemic colitis, radiation colitis, drug and chemically induced colitis, diversion colitis, ulcerative colitis, irritable bowel syndrome, irritable colon syndrome, ileitis, Barrett's syndrome, and Crohn's disease; and within Crohn's disease all the subtypes including active, refractory, and fistulizing and Crohn's disease.
As used herein, the term "pharmaceutically acceptable salt," is a salt formed from, for example, an acid and a basic group of one of the compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VHI), (IX), (X), (XI), (XH), (XDI), (XIV), (XV), (XVI), (XVII), or Table 1. Illustrative salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, besylate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate,/>- toluenesulfonate, and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term "pharmaceutically acceptable salt" also refers to a salt prepared from a compound of formula (I), (II), (HI), (IV), (V), (VI), (VII), (VIH), (IX), (X), (XI), (XH), (XDJ), (XIV), (XV), (XVI), (XVII), or Table 1 having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N, N,-di-lower alkyl-N- (hydroxy lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2- hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and
the like. The term "pharmaceutically acceptable salt" also refers to a salt prepared from a compound of formula (I), (II), (EOT), (IV), (V), (VI), (VII), (VDI), (IX), (X), (XI), (XE), (XDI), (XIV), (XV), (XVI), (XVII), or Table 1 having a basic functional group, such as an amino functional group, and a pharmaceutically acceptable inorganic or organic acid. Suitable acids include, but are not limited to, hydrogen sulfate, citric acid, acetic acid, oxalic acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,and/>-toluenesulfonic acid.
As used herein, the term "pharmaceutically acceptable solvate," is a solvate formed from the association of one or more solvent molecules to one of the compounds of formula (I), (II), (HI), (IV), (V), (VI), (VII), (VIE), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), or Table 1. The term solvate includes hydrates (e.g., hemi-hydrate, mono-hydrate, dihydrate, trihydrate, tetrahydrate, and the like).
As used herein, the term "effective amount" refers to an amount of a compound of this invention which is sufficient to reduce or ameliorate the severity, duration, progression, or onset of a metabolic disorder, prevent the advancement of a metabolic disorder, cause the regression of a metabolic disorder, prevent the recurrence, development, onset or progression of a symptom associated with a metabolic disorder, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy. In a specific embodiment, an "effective amount" refers to an amount of a compound which is sufficient to reduce blood glucose levels (preferably, normalize glucose levels), improve abnormal blood levels of insulin (preferably, normalize blood insulin levels), improve lipid metabolism, improve cholesterol levels and/or improve insulin sensitivity in a subject in need thereof or in an animal model of a particular metabolic disorder characterized by abnormal glucose levels, insulin levels, lipid metabolism or insulin sensitivity.
As used herein, the terms "improve" or "improving" mean to return to a normal level (e.g., to return glucose, insulin or lipid levels in the blood to a normal level). In one embodiment, "improve" or "improving" mean to lower the level. In one embodiment, "improve" or "improving" mean to increase the level.
Non-limiting examples of an effective amount of a compound of the invention are provided herein below. An effective amount of the compound when administered orally will typically range from about 0.1 mg/day to about 5000 mg/day (and preferably, about 1
mg/day to about 1000 mg/day and more preferably, about 10 to about 500 mg/day). These amounts may be administered in a single dosage form or may be administered in several (e.g., two to six, preferably two to four and more preferably, two or three) doses per day. Effective amounts will also vary, as recognized by those skilled in the art, depending on the diseases treated, route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatments such as use of other agents.
As used herein, the terms "treat", "treatment" and "treating" refer to the reduction or amelioration of the progression, severity and/or duration of a metabolic disorder, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of a metabolic disorder resulting from the administration of one or more therapies (e.g., one or more therapeutic agents such as a compound of the invention). In specific embodiments, the terms "treat", "treatment" and "treating" refer to the amelioration of at least one measurable physical parameter of a metabolic disorder, not necessarily discernible by the patient. In other embodiments the terms "treat", "treatment" and "treating" refer to the inhibition of the progression of a metabolic disorder, either physically by, e.g. , stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both. In other embodiments the terms "treat", "treatment" and "treating" refer to the reduction in blood glucose levels (preferably, the normalization of blood glucose levels), the improvement in blood insulin levels (preferably, the normalization of blood insulin levels), the improvement in lipid metabolism, the reduction in cholesterol levels, the improvement in insulin sensitivity (preferably, the normalization of insulin sensitivity) and/or the inhibition or reduction in the onset, development or progression of one or more symptoms associated with a metabolic disorder. In yet other embodiments, the terms "treat", "treatment" and "treating" refer to an improvement in the score in a diabetes assessment test, such as the Audit of Diabetes-Dependent Quality of Life, Appraisal of Diabetes Scale, Diabetes Care Profile, Diabetes Impact Measurement Scales, Diabetes Quality of Life Measure, Diabetes- Specific Quality-of-Life Scale, and Well-being Enquiry for Diabetics.
As used herein, the terms "prevent", "prevention" and "preventing" refer to the reduction in the risk of acquiring or developing a given metabolic disorder, or the reduction or inhibition of the recurrence, onset or development of one or more symptoms of a given metabolic disorder. In a preferred embodiment, a compound of the invention is administered as a preventative measure to a patient, preferably a human, having a genetic predisposition to any of the disorders described herein.
As used herein, the terms "prophylactic agent" and "prophylactic agents" as used refer to any agent(s) which can be used in the prevention of a metabolic disorder or one or more symptoms thereof. In certain embodiments, the term "prophylactic agent" refers to a compound of the invention. In certain other embodiments, the term "prophylactic agent" does not refer a compound of the invention. Preferably, a prophylactic agent is an agent which is known to be useful for, or has been or is currently being used to prevent or impede the onset, development, progression and/or severity of a metabolic disorder.
As used herein, the terms "therapeutic agent" and "therapeutic agents" refer to any agent(s) which can be used in the treatment, management, or amelioration of a metabolic disorder or one or more symptoms thereof. In certain embodiments, the term "therapeutic agent" refers to a compound of the invention. In certain other embodiments, the term "therapeutic agent" does not refer to a compound of the invention. When the term "therapeutic agent" does not refer to a compound of the invention, preferably, it is an agent which is known to be useful for, or has been or is currently being used for the treatment, management, prevention, or amelioration a metabolic disorder or one or more symptoms thereof.
As used herein, the term "synergistic" refers to a combination of a compound of the invention and another therapy (e.g., a prophylactic or therapeutic agent), which is more effective than the additive effects of the therapies. A synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) permits the use of lower dosages of one or more of the therapies and/or less frequent administration of said therapies to a subject with a metabolic disorder. The ability to utilize lower dosages of a therapy (e.g., a prophylactic or therapeutic agent) and/or to administer said therapy less frequently reduces the toxicity associated with the administration of said therapy to a subject without reducing the efficacy of said therapy in the prevention, management or treatment of a metabolic disorder. In addition, a synergistic effect can result in improved efficacy of agents in the prevention, management or treatment of a metabolic disorder. Finally, a synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) may avoid or reduce adverse or unwanted side effects associated with the use of either therapy alone.
As used herein, the phrase "side effects" encompasses unwanted and adverse effects of a therapy (e.g., a prophylactic or therapeutic agent). Side effects are always unwanted, but unwanted effects are not necessarily adverse. An adverse effect from a therapy (e.g., prophylactic or therapeutic agent) might be harmful or uncomfortable or risky. Side effects
include, but are not limited to fever, chills, lethargy, gastrointestinal toxicities (including gastric and intestinal ulcerations and erosions), nausea, vomiting, neurotoxicities, nephrotoxicities, renal toxicities (including such conditions as papillary necrosis and chronic interstitial nephritis), hepatic toxicities (including elevated serum liver enzyme levels), myelotoxicities (including leukopenia, myelosuppression, thrombocytopenia and anemia), dry mouth, metallic taste, prolongation of gestation, weakness, somnolence, pain (including muscle pain, bone pain and headache), hair loss, asthenia, dizziness, extra-pyramidal symptoms, akathisia, cardiovascular disturbances and sexual dysfunction.
As used herein, the term "in combination" refers to the use of more than one therapies (e.g., one or more prophylactic and/or therapeutic agents). The use of the term "in combination" does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject with a metabolic disorder. A first therapy (e.g., a prophylactic or therapeutic agent such as a compound of the invention) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent such as an anti-diabetic agent) to a subject with a metabolic disorder.
As used herein, the terms "therapies" and "therapy" can refer to any protocol(s), method(s), and/or agent(s) that can be used in the prevention, treatment, management, or amelioration of a metabolic disorder or one or more symptoms thereof. In certain embodiments, the terms "therapy" and "therapies" refer to hormonal therapy, biological therapy, and/or other therapies useful in the prevention, management, treatment or amelioration of a metabolic disorder or one or more symptoms thereof known to one of skill in the area (e.g., skilled medical personnel).
A used herein, a- "protocol" includes dosing schedules and dosing regimens. The protocols herein are methods of use and include prophylactic and therapeutic protocols. As used herein, the terms "manage," "managing," and "management" refer to the beneficial effects that a subject derives from a therapy (e.g., a prophylactic or therapeutic agent), which does not result in a cure of the disease. In certain embodiments, a subject is
administered one or more therapies (e.g., one or more prophylactic or therapeutic agents) to
"manage" a disease so as to prevent the progression or worsening of the disease.
As used herein, the teπns "non-responsive" and "refractory" describe patients treated with a currently available therapy (e.g., a prophylactic or therapeutic agent) for a metabolic disorder, which is not clinically adequate to relieve one or more symptoms associated with such disorder. Typically, such patients suffer from severe, persistently active disease and require additional therapy to ameliorate the symptoms associated with their metabolic disorder.
As used herein, a composition that "substantially" comprises a compound means that the composition contains more than about 80% by weight, more preferably more than about
90% by weight, even more preferably more than about 95% by weight, and most preferably more than about 97% by weight of the compound.
As used herein, a reaction that is "substantially complete" means that the reaction contains more than about 80% by weight of the desired product, more preferably more than about 90% by weight of the desired product, even more preferably more than about 95% by weight of the desired product, and most preferably more than about 97% by weight of the desired product.
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.
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. The compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
When administered to a patient, e.g., to a non-human animal for veterinary use or for improvement of livestock, or to a human for clinical use, the compounds of the invention are administered in isolated form or as the isolated form in a pharmaceutical composition. As used herein, "isolated" means that the compounds of the invention are separated from other components of either (a) a natural source, such as a plant or cell, preferably bacterial culture, or (b) a synthetic organic chemical reaction mixture. Preferably, the compounds of the invention are purified using conventional techniques. As used herein, "purified" means that when isolated, the isolate contains at least 95%, preferably at least 98%, of a single compound of the invention by weight of the isolate. As used herein, a composition that is "substantially free" of a compound means that the composition contains less than about 20% by weight, more preferably less than about 10% by weight, even more preferably less than about 5% by weight, and most preferably less than about 3% by weight of the compound.
Only those choices and combinations of substituents that result in a stable structure are contemplated. Such choices and combinations will be apparent to those of ordinary skill in the art and may be determined without undue experimentation.
The invention can be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments of the invention.
The Compounds of the Invention
The present invention encompasses compounds having formulas (I), (II), (III), (IV), (V), (VI), (VII), (VUI)9 (IX), (X), (XI), (XII), (XIH), (XIV), (XV), (XVI), (XVII), and those set forth in Table 1 and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof. In one aspect, the invention provides compounds formula (I) as set forth below:
(I)
or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein n, A, X1, X2, X3, Ri, R2, R7, R-8, R9, and R10 are defined as above.
Compounds of formula (I) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for treating or preventing metabolic disorders, including diabetes mellitus, conditions associated with diabetes mellirus and certain complications thereof.
Compounds of formula (I) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for treating inflammatory bowel disease.
In one embodiment, in compounds represented by formula (I), there applies one or more (including all) of the following provisos: a) when R2 is -OH, R, is not -C(S)NH2; b) A is not methyl, when R2 is ethoxy; c) R2 is not -NHRn, -SRn, or -SS-heteroaryl; d) when R2 is cyclopentyl or isopropy, Ri is not/p-trifluorobenzoyl; e) when R2 is n-propyl, isopropyl or cyclopentyl, A is not ^-fluorophenyl or 3,4- difluorophenyl; f) when R2 is methyl, A is not an unsubstituted phenyl or a nitrophenyl; g) when Ri is -C(O)ORi6 and R2 is methyl, A is not mono-or di-chlorophenyl, mono-or di-bromophenyl, or mono- or di-methoxyphenyl, wherein R16 is a lower alkyl group; h) when A, R2, R7 and R8 are all methyl, R] is not -CN or -C(O)OCH2CH3; and i) when A is methyl or ethyl and Ri is -CN, R2 is not -SRn, -OH or -Cl. In one embodiment, in compounds represented by formula (I), there applies all of provisos a) through i).
In another embodiment, in compounds represented by formula (I), there applies provisos d) and e).
In another embodiment, in compounds represented by formula (I), no provisos apply. In another embodiment, in the compounds represented by formula (I), Xi is N, X2 is
>CR5R6, and X3 is O. Preferably, Xj is N, X2 is -CH2-, and X3 is O.
In another embodiment, in the compounds represented by formula (I), A is a substituted or unsubstituted aryl. Preferably, in this embodiment, A is^-chlorophenyl or^- methoxyphenyl.
In another embodiment, in the compounds represented by formula (I), X1 is N, X2 is -CHo-, X3 is O, and A is a substituted or unsubstituted aryl. Preferably, in this embodiment, A isjP-chlorophenyl or/7-methoxyphenyl.
In another embodiment, in the compounds represented by formula (I), R7 and R8 are each, independently, a lower alkyl. Preferably, in this embodiment, R7 and R8 are both methyl.
In another embodiment, in the compounds represented by formula (I), X] is N, X2 is -CH2-, X3 is O, A is a substituted or unsubstituted aryl, such as />-chlorophenyl orp- methoxyphenyl, and R7 and R8 are each, independently, a lower alkyl. Preferably, in this embodiment, R7 and R8 are both methyl.
In another embodiment, in the compounds represented by formula (I), Ri is -C(O)ORn, -C(O)NRi2Ri3 or cyano. Preferably, in this embodiment, Ri is -C(O)NR12Ri3; more preferably, Ri is selected from the following structures:
-CHo-, X3 is O, A is a substituted or unsubstituted aryl, such as />-chlorophenyl or p- methoxyphenyl, and R] is -C(O)ORn, -C(O)NRi2Ri3 or cyano. Preferably, in this embodiment, Ri is -C(O)NRnRi3; more preferably, Ri is selected from the following structures:
In another embodiment, in the compounds represented by formula (I), R2 is a lower alkyl or a heteroalkyl.
In another embodiment, in the compounds represented by formula (I), Xi is N, X2 is -CH2-, X3 is O, A is a substituted or unsubstituted aryl, such as />-chlorophenyl or p- methoxyphenyl, and R2 is a lower alkyl or a heteroalkyl.
In another embodiment, in the compounds represented by formula (I), A is a substituted or unsubstituted heteroaryl. Preferably, in this embodiment, A is pyrid-3-yl, A- methoxypyrid-3-yl, 6-hydroxypyrid-3-yl, or 5-methylfuran-2-yl; more preferably, A is pyrid- 3-yl. In another embodiment, in the compounds represented by formula (I), X] is N, X2 is
-CH2-, X3 is O, and A is a substituted or unsubstituted heteroaryl, such as pyrid-3-yl, A- methoxypyrid-3-yl, 6-hydroxypyrid-3-yl, or 5-methylfuran-2-yl.
In another embodiment, in the compounds represented by formula (I), Xj is N, X2 is -CH2-, X3 is O, A is a substituted or unsubstituted heteroaryl, such as pyrid-3-yl, A- methoxypyrid-3-yl, 6-hydroxypyrid-3-yl, or 5-methylfuran-2-yl, and R7 and Rg are each, independently, a lower alkyl. Preferably, in this embodiment, R7 and Rs are both methyl.
In another embodiment, in the compounds represented by formula (I), Xi is N, X2 is -CH2-, X3 is O, A is a substituted or unsubstituted heteroaryl, such as pyrid-3-yl, A- methoxypyrid-3-yl, 6-hydroxypyrid-3-yl, or 5-methylfuran-2-yl, and Ri is -C(OjORn, -C(O)NRi2Ri3 or cyano. Preferably, in this embodiment, Ri is -C(O)NRi2Rn; more preferably, Ri is selected from the following structures:
In another embodiment, in the compounds represented by formula (I), Xi is N, X2 is -CH2-, X3 is O, A is a substituted or unsubstituted heteroaryl, such as pyrid-3-yl, A- methoxypyrid-3-yl, 6-hydroxypyrid-3-yl, or 5-methylfuran-2-yl, and R2 is a lower alkyl or a heteroalkyl.
In another embodiment, in the compounds represented by formula (I), A is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl. Preferably, in this embodiment, A is methyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, 1- methylcyclopropyl, or cyclopropylmethyl; more preferably, A is isopropyl or cyclopropyl.
In another embodiment, in the compounds represented by formula (I), Xj is N, X2 is -CH2-, X3 is O, and A is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl, such as methyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, 1- methylcyclopropyl, or cyclopropylmethyl.
In another embodiment, in the compounds represented by formula (I), Xi is N, X2 is -CH?-, X3 is O, A is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl, such as methyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, 1- methylcyclopropyl, or cyclopropylmethyl, and R7 and Rs are each, independently, a lower alkyl. Preferably, in this embodiment, R7 and Rg are both methyl.
In another embodiment, in the compounds represented by formula (I), Xi is N, X2 is -CH2-, X3 is O, A is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl, such as methyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, 1- methylcyclopropyl, or cyclopropylmethyl, and Ri is -C(O)ORn, -C(O)NRI2RB or cyano. Preferably, in this embodiment, Ri is -C(O)NR]2Rn; more preferably, R] is selected from the following structures:
In another embodiment, in the compounds represented by formula (I), Xj is N, X2 is -CH2-, X3 is O, A is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl, such as methyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, 1- methylcyclopropyl, or cyclopropylmethyl, and R2 is a lower alkyl or a heteroalkyl.
In another aspect, the invention provides compounds of foπnula (II) as set forth below:
or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. In structural formula (II), n, A, Xj, X2, X3, R2, R9, Rio, R30, R3i, and R32 are defined as above.
Compounds of formula (II) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for treating or preventing metabolic disorders, including diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof. Compounds of formula (II) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for treating inflammatory bowel disease.
In another embodiment, in the compounds represented by formula (II), Xj is N, XT is >CR5R6, and X3 is O, preferably, Xi is N, X2 is -CH2-, and X3 is O. In another embodiment, in the compounds represented by formula (II), A is a substituted or unsubstituted aryl. Preferably, in this embodiment, A is/j-chlorophenyl oxp- methoxyphenyl.
In another embodiment, in the compounds represented by formula (II), Xi is N, X2 is -CH2-, X3 is O, and A is a substituted or unsubstituted aryl. Preferably, in this embodiment, A is />-chlorophenyl or j9-methoxyphenyl.
In another embodiment, in the compounds represented by formula (II), R3o is -C(O)NRi2Ri3. Preferably, in this embodiment, Ri is -C(O)NRi2Ri3; more preferably, Ri is selected from the following structures:
-CH2-, X3 is O, A is a substituted or unsubstituted aryl, such as /?-chlorophenyl orp- methoxyphenyl, and R30 is -C(O)NRi2Ri3; preferably, R3o is selected from the following structures: •
In another embodiment, in the compounds represented by formula (IJ), A is a substituted or unsubstituted heteroaryl. Preferably, in this embodiment, A is pyrid-3-yl, 4- methoxypyrid-3-yl, 6-hydroxypyrid-3-yl, or 5-methylfuran-2-yl; more preferably, A is pyrid- 3-yl.
In another embodiment, in the compounds represented by formula (II), Xj is N, X2 is -CH2-, X3 is O, and A is a substituted or unsubstituted heteroaryl, such as pyrid-3-yl, 4- methoxypyrid-3-yl, 6-hydroxypyrid-3-yl, or 5-methylfuran-2-yl.
In another embodiment, in the compounds represented by formula (II), Xi is N, Xo is -CH2-, X3 is O, A is a substituted or unsubstituted heteroaryl, such as pyrid-3-yl, A- methoxypyrid-3-yl, 6-hydroxypyrid-3-yl, or 5-methylfuran-2-yl, and R30 is -C(O)NRi2Ru; R30 is selected from the following structures:
In another embodiment, in the compounds represented by formula (II), Xi is N, X2 is -CH2-, X3 is O, A is a substituted or unsubstituted heteroaryl, such as pyrid-3-yl, 4-methoxypyrid-3- yl, 6-hydroxypyrid-3-yl, or 5-methylfuran-2-yl, and R2 is a lower alkyl or a heteroalkyl.
In another embodiment, in the compounds represented by formula (II), A is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl. Preferably, in , this embodiment, A is methyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, 1- methylcyclopropyl, or cyclopropylmethyl; more preferably, A is isopropyl or cyclopropyl.
In another embodiment, in the compounds represented by formula (II), Xj is N, X2 is -CH2-, X3 is O, and A is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl, such as methyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, 1- methylcyclopropyl, or cyclopropylmethyl.
In another embodiment, in the compounds represented by formula (II), X] is N, X2 is -CHo-, X3 is O, A is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl, such as methyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, 1-
methylcyclopropyl, or cyclopropylmethyl, and R30 is -C(O)NRi2Ri3. Preferably, in this embodiment, R3o is selected from the following structures:
In another embodiment, in the compounds represented by formula (II), Xi is N, X2 is -CH?-, X3 is O, A is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl, such as methyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, 1- methylcyclopropyl, or cyclopropylmethyl, and R2 is a lower alkyl or a heteroalkyl.
In another aspect, the invention provides compounds of formula (III) as set forth below:
or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. In structural formula (III), n, Ai, Xi, X2, X3, Ri, R2, R7, Rg, R9, and Rio are defined as above.
Compounds of formula (III) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for treating or preventing metabolic disorders, including diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof. Compounds of formula (III) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for treating inflammatory bowel disease.
In one embodiment, in compounds represented by formula (III), there applies one or more (including all) of the following provisos:
a) when R2 is -OH, R, is not -C(S)NH2; b) R2 is not -NHRn, -SRn, or-SS-heteroaryl; c) when Ro is cyclopentyl or isopropy, R] is not/>trifluorobenzoyl; d) when R2 is n-propyl, isopropyl or cyclopentyl, Ai is not ^-fluorophenyl or 3,4-difluorophenyl; e) when R2 is methyl, Ai is not an unsubstituted phenyl or a nitrophenyl; and f) when Ri is -C(O)ORi 6 and R2 is methyl, Ai is not mono-or di-chlorophenyl, mono-or di-bromophenyl, or mono- or di-methoxyphenyl, wherein Ri6 is a lower alkyl group. In another embodiment, in compounds represented by formula (III), there applies provisos c) and d).
In another embodiment, in compounds represented by formula (III), no provisos apply.
In another embodiment, in the compounds represented by formula (III), X] is N, X2 is -CH2-, and X3 is O.
In another embodiment, in the compounds represented by formula (HI), Aj is selected from the group consisting of a substituted or unsubstituted phenyl, a substituted or unsubstituted pyridyl, a substituted or unsubstituted furanyl, a substituted or unsubstituted anthracenyl, a substituted or unsubstituted fluorenyl, a substituted or unsubstituted indenyl, a substituted or unsubstituted azulenyl, a substituted or unsubstituted naphthyl, a substituted or unsubstituted 5,6,7,8-tetrahydronaphthyl, a substituted or unsubstituted thienyl, a substituted or unsubstituted pyrrolyl, a substituted or unsubstituted oxazolyl, a substituted or unsubstituted imidazolyl, a substituted or unsubstituted indolizinyl, a substituted or unsubstituted thiazolyl, a substituted or unsubstituted isoxazolyl, a substituted or unsubstituted pyrazolyl, a substituted or unsubstituted isothiazolyl, a substituted or unsubstituted pyridazinyl, a substituted or unsubstituted pyrimidinyl, a substituted or unsubstituted pyrazinyl, a substituted or unsubstituted triazinyl, a substituted or unsubstituted triazolyl, a substituted or unsubstituted thiadiazolyl, a substituted or unsubstituted quinolyl, a substituted or unsubstituted isoquniolyl, a substituted or unsubstituted indazolyl, a substituted or unsubstituted benzoxazolyl, a substituted or unsubstituted benzofuryl, a substituted or unsubstituted benzothiazolyl, a substituted or unsubstituted indolizinyl, a substituted or unsubstituted imidazopyridinyl, a substituted or unsubstituted isothiazolyl, a substituted or unsubstituted tetrazolyl, a substituted or unsubstituted benzimidazolyl, a substituted or unsubstituted benzoxazolyl, a substituted or
unsubstituted benzothiazolyl, a substituted or unsubstituted benzothiadiazolyl, a substituted or unsubstituted benzoxadiazolyl, a substituted or unsubstituted indolyl, a substituted or unsubstituted tetrahydroindolyl, a substituted or unsubstituted azaindolyl, a substituted or unsubstituted imidazopyridyl, a substituted or unsubstituted qunizaolinyl, a substituted or unsubstituted purinyl, a substituted or unsubstituted pyrrolo[2,3]pyrimidyl, a substituted or unsubstituted pyrazolo[3,4]pyrimidyl or a substituted or unsubstituted benzo(b)thienyl. Preferably, in this embodiment, Xi is N, X2 is -CH2-, and X3 is O.
In another embodiment, Aj is unsubstituted. Preferably, in this embodiment, Xi is N, X2 is -CH2-, and X3 is O. In another embodiment, Ai is substituted with one or more substituents selected from the group consisting of an alkyl, an alkenyl, an alkynyl, an cycloalkyl, an cycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl, a heteraralkyl, a haloalkyl, -C(O)NRi gRi9, -NR20C(O)R2I, a halo, -OR20, cyano, nitro, a haloalkoxy, -C(O)R20, -NRi8Ri9, -SR20, -C(O)OR20, -OC(O)R20, -NR20C(O)NRi8Ri9, -OC(O)NRi8Ri9, -NR20C(O)OR5, -S(O)pR20, and -S(O)pNRi8Ri9, wherein Ri8, Ri9, R20 and R2] for each occurrence are independently defined as above. Preferably, in this embodiment, Xj is N, X2 is -CH2-, and X3 is O.
In another embodiment, A] is a substituted or unsubstituted phenyl, a substituted or unsubstituted pyridyl, or a substituted or unsubstituted furanyl. Preferably, in this embodiment, Xi is N, X2 is -CH2-, and X3 is O.
In another embodiment, Aj is a phenyl, a pyridyl, or a furanyl which is substituted' with one or more substitutents selected from the group consisting of a halo, an alkoxy, hydroxyl and an alkyl. Preferably, in this embodiment, Xi is N, X2 is -CH2-, and X3 is O.
In another embodiment, in the compounds represented by formula (III), R7 and R8 are each, independently, a lower alkyl. Preferably, in this embodiment, R7 and R8 are both methyl.
In another embodiment, in the compounds represented by formula (HI), X] is N, X2 is -CH2-, X3 is O, and R7 and R8 are each, independently, a lower alkyl. Preferably, in this embodiment, R7 and R8 are both methyl. In another embodiment, in the compounds represented by formula (III), Ri is
-C(O)ORn, -C(O)NRi2Ri3 or cyano. Preferably, in this embodiment, Rj is -C(O)NRi2Ri3; more preferably, Ri is selected from the following structures:
In another embodiment, in the compounds represented by formula (EI), Xi is N, X2 is -CH2-, X3 is O, and Ri is -C(O)ORn, -C(O)NR]2Ri3 or cyano. Preferably, in this embodiment, R1 is -C(O)NRi2Ri3; more preferably, Ri is selected from the following structures:
In another embodiment, in the compounds represented by formula (III), R2 is a lower alkyl or a heteroalkyl.
In another embodiment, in the compounds represented by formula (ITI), Xi is N, X2 is -CH2-, X3 is O, and R2 is a lower alkyl or a heteroalkyl.
In another aspect, the invention provides compounds of formula (IV) as set forth below:
(IV) or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. In structural formula (IV), n, ring A, X1, X2, X3, R2, R7, R8, R9, Rio and R33 are defined as above.
Compounds of formula (IV) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for treating or
preventing metabolic disorders, including diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
Compounds of formula (IV) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for treating inflammatory bowel disease.
In one embodiment, in compounds represented by formula (IV), Xi is N, X2 is >CR5R6, and X3 is O. Preferably, Xi is N, X2 is -CH2-, and X3 is O.
In another embodiment, in compounds represented by formula (FV), R7 and Rs are each, independently, a lower alkyl. In another embodiment, in compounds represented by formula (IV), Xi is N, X2 is
-CHo-, X3 is O, and R7 and Rg are each, independently, a lower alkyl.
In another embodiment, in compounds represented by formula (IV), R33 is -C(O)ORn or -C(O)NRi2R13. Preferably, in this embodiment, R33 is -C(O)NRi2Ri3; more preferably, R33 is selected from the following structures:
In another embodiment, in compounds represented by formula (IV), Xi is N, X2 is -CH2-, X3 is O, and R33 is -C(O)OR11 or -C(O)NRi2Ri3. Preferably, in this embodiment, R33 is -C(O)NRi2Ri3; more preferably, R33 is selected from the following structures:
In another embodiment, in compounds represented by formula (IV), R2 is a lower alkyl or a heteroalkyl.
In another embodiment, in compounds represented by formula (IV), Xi is N, X2 is -CH2-, X3 is O, and R2 is a lower alkyl or a heteroalkyl.
In another embodiment, in compounds represented by formula (TV), R33 is a bioisostere of an ester, amide or carboxylic acid. In this embodiment, R33 is preferably an
optionally substituted imidazolyl, an optionally substituted oxazolyl, or an optionally substituted [l,2,4]oxadiazolyl.
In another embodiment, in compounds represented by formula (IV), X] is N, X^ is -CH2-, X3 is O, and R33 is a bioisostere of an ester, amide or carboxylic acid. In this embodiment, R33 is preferably an optionally substituted imidazolyl, an optionally substituted oxazolyl, or an optionally substituted [l,2,4]oxadiazolyl.
In another aspect, the invention provides compounds of formula (V) as set forth below:
Compounds of formula (V) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for treating or preventing metabolic disorders, including diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
Compounds of formula (V) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for treating inflammatory bowel disease.
In one embodiment, in compounds represented by formula (V), there applies one or more (including all) of the following provisos: a) the compound is not 2,4,7,7-tetramethyl-5-oxo-5,6,7,8-tetrahydroquinoIine-3- carboxylic acid ethyl ester or 8,8-difluoro-4-isobutyl-7,7-dimethyl-5-oxo-2- trifluoromethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carboxylic acid methyl ester; and b) R2 is not -SR29, wherein R29 is a substituted alkyl.
In another embodiment, in compounds represented by formula (V), no provisos apply.
In another embodiment, in compounds represented by formula (V), Xi is N, XT is -CH2-, and X3 is O.
In another embodiment, in compounds represented by formula (V), A2 is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl. Preferably, in this embodiment, X] is N, X2 is -CH2-, and X3 is O.
In another embodiment, in compounds represented by formula (V), A2 is an unsubstituted alkyl or an unsubstituted cycloalkyl. Preferably, in this embodiment, Xi is N, X2 is -CH2-, and X3 is O.
In another embodiment, in compounds represented by formula (V), A2 is an alkyl or a cycloalkyl which is substituted with one or more substituents selected from the group consisting of an alkyl, an alkenyl, an alkynyl, an cycloalkyl, an cycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl, a heteraralkyl, a haloalkyl, -C(O)NR1SRi9, -NR2oC(0)R2i, a halo, -OR20, cyano, nitro, a haloalkoxy, -C(O)R20, -NRi8Ri9, -SR20, -C(O)OR20, -OC(O)R20, -NR20C(O)NR18Ri9, -OC(O)NR18Ri9, -NR20C(O)OR5, -S(O)pR20, -S(O)pNR]8Ri9, =0, =S, and =N-R20, wherein Ri8, R19, R20 and R2i for each occurrence are, independently, defined as above. Preferably, in this embodiment, Xj is N, X2 is -CH2-, and X3 is O.
In another embodiment, in compounds represented by foπnula (V), A2 is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n- octyl, n-nonyl, n-decyl, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methyIbutyl, 3- methylbutyl, 2-methylpentyl, 3-methylpenτyl, 4-methylpentyl, 2-methylhexyl, 3- methylhexyl, 4-methylhexyl, 5-methyIhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4- dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2- dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimtheylpentyl, 3,3-dimethylhexyl, 4,4- dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2- methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2- ethylhexyl, 2-methyl-3-ethylhexyI, 2-methyI-4-ethylhexyl, 2,2-diethylpentyl, 3,3- diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl, cyclopropyl, 1-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Preferably, in this embodiment, Xj is N, X2 is -CH2-, and X3 is O.
In another embodiment, in compounds represented by formula (V), A2 is methyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, 1-methylcyclopropyl, or cyclopropylmethyl. Preferably, in this embodiment, Xi is N, X2 is -CH2-, and X3 is O.
In another embodiment, in compounds represented by formula (V), R31 and R32 are each, independently, a lower alkyl. Preferably, in this embodiment, Xi is N, X2 is -CH2-, and X3 is O.
In another embodiment, in compounds represented by formula (V), R33 is -C(O)ORn or -C(O)NR12R13. Preferably, in this embodiment, R33 is -C(O)NRnRi3; more preferably, R33 is selected from the following structures:
In another embodiment, in compounds represented by formula (V), Xj is N, X2 is -CH2-, X3 is O. and R33 is -C(O)ORn or -C(O)NR12R]3. Preferably, in this embodiment, R33 I O is -C(O)NRi2Ri3; more preferably, R33 is selected from the following structures:
In another embodiment, in compounds represented by formula (V), R2 is a lower alkyl or a heteroalkyl. Preferably, in this embodiment, X1 is N, X2 is -CH2-, and X3 is O. 5 In another embodiment, in compounds represented by formula (V), R33 is a bioisostere of an ester, amide or carboxylic acid. In this embodiment, R33 is preferably an optionally substituted imidazolyl, an optionally substituted oxazolyl, or an optionally substituted [l,2,4]oxadiazolyl. Preferably, in this embodiment, Xi is N, X2 is -CH2-, and X3 is O. 0 In another aspect, the invention provides compounds of formula (VT) as set forth below:
or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. In structural formula (VI), n, A3, X1, X2, X3, R1, R2, R7, Rg, RΘ, and Rj0 are defined as above Compounds of formula (VI) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for treating or preventing metabolic disorders, including diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
Compounds of formula (VI) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for treating inflammatory bowel disease.
In one embodiment, in compounds represented by formula (VI), there applies one or more (including all) of the following provisos: a) when R2 is cyclopenryl or isopropy, Ri is not/»-trifluorobenzoyl; b) when R2 is n-propyl, isopropyl or cyclopentyl, A3 is not ^-fluorophenyl or
3,4-difluorophenyl; and c) when A3 is H and R2 is methyl, Ri is not -C(O)-guanidinyl. In another embodiment, in compounds represented by formula (VI), there applies all of the above provisos. In another embodiment, in compounds represented by formula (VI), there applies provisos a) and b).
In another embodiment, in compounds represented by formula (VI), there applies proviso c).
In another embodiment, in compounds represented by formula (VI), no provisos apply.
In another embodiment, in the compounds represented by formula (VI), Xi is N, X2 is >CR5R6, and X3 is O. Preferably, X, is N, X2 is -CH2-, and X3 is O.
In another embodiment, in the compounds represented by formula (VI), A3 is a substituted or unsubstituted aryl. Preferably, in this embodiment, A3 is/>-chlorophenyl or p- methoxyphenyl.
In another embodiment, in the compounds represented by formula (VI), Xi is N, X2 is -CH2-, X3 is O, and A3 is a substituted or unsubstituted aryl. Preferably, in this embodiment, A is />-chlorophenyl or /?-methoxyphenyl.
In another embodiment, in the compounds represented by formula (VI), R7 and Rz are each, independently, a lower alkyl. Preferably, in this embodiment, R7 and Rs are both methyl. In another embodiment, in the compounds represented by formula (VI), Xi is N, X2 is -CH2-, X3 is O, A3 is a substituted or unsubstituted aryl, such as ^-chlorophenyl orp- methoxyphenyl, and R7 and Rg are each, independently, a lower alkyl. Preferably, in this embodiment, R7 and Rg are both methyl.
In another embodiment, in the compounds represented by formula (VI), Ri is -C(O)ORn, -C(O)NRI2RB or cyano. Preferably, in this embodiment, Ri is -C(O)NR12Ri3; more preferably, Ri is selected from the following structures:
In another embodiment, in the compounds represented by formula (VI), Xi is N, X2 is -CH2-, X3 is O, A3 is a substituted or unsubstituted aryl, such as ^-chlorophenyl orp- methoxyphenyl, and Ri is -C(O)ORn, -C(O)NRi2Ri3 or cyano. Preferably, in this embodiment, Ri is -C(O)NRi2Ri3; more preferably, Ri is selected from the following structures:
In another embodiment, in the compounds represented by formula (VI), R2 is a lower alkyl or a heteroalkyl.
In another embodiment, in the compounds represented by formula (VI), Xi is N, X2 is -CH2-, X3 is O, A3 is a substituted or unsubstituted aryl, such as j9-chlorophenyl orp- methoxyphenyl, and R2 is a lower alkyl or a heteroalkyl.
In another embodiment, in the compounds represented by formula (VI), A3 is a substituted or unsubstituted heteroaryl. Preferably, in this embodiment, A3 is pyrid-3-yl, A- methoxypyrid-3-yl, 6-hydroxypyrid-3-yl, or 5-methylfuran-2-yl; more preferably, A3 is pyrid-3-yl.
In another embodiment, in the compounds represented by formula (VI), Xi is N, Xo is -CH2-, X3 is O, and A3 is a substituted or unsubstituted heteroaryl, such as pyrid-3-yl, A- methoxypyrid-3-yl, 6-hydroxypyrid-3-yl, or 5-methylfuran-2-yl.
In another embodiment, in the compounds represented by formula (VI), Xi is N, X2 is -CH2-, X3 is O, A3 is a substituted or unsubstituted heteroaryl, such as pyrid-3-yl, A- methoxypyrid-3-yl, 6-hydroxypyrid-3-yl, or 5-methylfuran-2-yl, and R7 and Rs are each, independently, a lower alkyl. Preferably, in this embodiment, R7 and R8 are both methyl. In another embodiment, in the compounds represented by formula (VI), Xi is N, X2 is -CH2-, X3 is O, A3 is a substituted or unsubstituted heteroaryl, such as pyrid-3-yl, A- methoxypyrid-3-yl, 6-hydroxypyrid-3-yl, or 5-methyIfuran-2-yl, and Ri is -C(O)ORn, -C(O)NR12Rj3 or cyano. Preferably, in this embodiment, Ri is -C(O)NRi2Ri3; more preferably, Ri is selected from the following structures:
In another embodiment, in the compounds represented by formula (VI), Xj is N, X2 is -CH2-, X3 is O, A3 is a substituted or unsubstituted heteroaryl, such as pyrid-3-yl, 4- methoxypyrid-3-yl, 6-hydroxypyrid-3-yl, or 5-methylfuran-2-yl, and R2 is a lower alkyl or a heteroalkyl. In another embodiment, in the compounds represented by formula (VI), A3 is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl. Preferably, in this embodiment, A3 is methyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, 1- methylcyclopropyl, or cyclopropylmethyl; more preferably, A3 is isopropyl or cyclopropyl. In another embodiment, in the compounds represented by formula (VI), Xi is N, X2 is -CH2-, X3 is O, and A3 is a substituted or unsubstituted alkyl or a substituted or
unsubstituted cycloalkyl, such as methyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, 1 - methylcyclopropyl, or cyclopropylmethyl.
In another embodiment, in the compounds represented by formula (VI), Xj is N, X2 is -CH2-, X3 is O, A3 is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl, such as methyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, 1- methylcyclopropyl, or cyclopropylmethyl, and R7 and Rg are each, independently, a lower alkyl. Preferably, in this embodiment, R7 and Rs are both methyl.
In another embodiment, in the compounds represented by formula (VI), Xi is N, X2 is -CH2-, X3 is O, A3 is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl, such as methyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, 1- methylcyclopropyl, or cyclopropylmethyl, and Ri is -C(O)ORn, -C(O)NR12Rn or cyano. Preferably, in this embodiment, Ri is -C(O)NRnRn; more preferably, Ri is selected from the following structures:
In another embodiment, in the compounds represented by formula (VI), Xi is N, X2 is -CH2-, X3 is O, A3 is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl, such as methyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, 1- methylcyclopropyl, or cyclopropylmethyl, and R2 is a lower alkyl or a heteroalkyl.
In one aspect, the invention provides compounds formula (VII) as set forth below:
(VTf) or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein X1, X6, X7, X4, X5, R7S, R79, Rso, Rsi, Rs2, Rs3, R-84, Rs5, B, q and r are defined as above.
Compounds of formula (VII) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for treating or preventing metabolic disorders, including diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
Compounds of formula (VII) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for inflammatory bowel disease.
In another aspect, the invention provides compounds formula (VET) as set forth below:
(vm) or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein X1, Xe, X7, X4, Xs, R78, R-79, Rso, Rs1, Rs2, Rs3, Rs4, Rg5, B1, q and r are defined as above.
Compounds of formula (VIII) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for treating or preventing metabolic disorders, including diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
Compounds of formula (VIII) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for treating inflammatory bowel disease.
In another aspect, the invention provides compounds formula (IX) as set forth below:
Compounds of formula (IX) and a pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for treating or preventing metabolic disorders, including diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
Compounds of formula (IX) and a pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for treating inflammatory bowel disease.
In another aspect, the invention provides compounds formula (X) as set forth below:
(X) or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein X6, X7, X4, Xs, R78, R79, R-80, R-81, R-82, Rg3, Rs4, Rss, R97, B2, q and r are defined as above.
Compounds of formula (X) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for treating or preventing metabolic disorders, including diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
Compounds of formula (X) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for treating inflammatory bowel disease.
In one embodiment, B in the compounds represented by formula (VII) is a substituted phenyl group.
In another embodiment, B in the compounds represented by formula (VII) is an optionally substitutedheteroaryl. In one aspect of this embodiment, B is pyrid-3-yl, A- methoxypyrid-3-yl, 6-hydroxypyrid-3-yl, or 5-methylfuran-2-yl.
In another embodiment, B in the compounds represented by formula (VII) is an optionally substituted C2-C10 alkyl. In one aspect of this embodiment, B is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -butyl, t-butyl, or cyclopropylm ethyl.
In another embodiment, B in the compounds represented by formula (VII) is an optionally substituted cycloalkyl. In one aspect of this embodiment, B is cyclopropyl, cyclopentyl, cyclohexyl, or 1-methylcyclopropyl.
In another embodiment, Bi in the compounds represented by formula (VET) or (X) is an optionally substituted aryl.
In another embodiment, Bi in the compounds represented by formula (VIII) or (X) is an optionally substitutedheteroaryl. In one aspect of this embodiment, Bi is pyrid-3-yl, 4-methoxypyrid-3-yl, 6-hydroxypyrid-3-yl, or 5-methylfuran-2-yl.
In another embodiment, Bj in the compounds represented by foπnula (VIII) or (X) is an optionally substituted C2-C10 alkyl. In one aspect of this embodiment, Bj is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, or cyclopropylmethyl. In another embodiment, Bj in the compounds represented by foπnula (VIII) or (X) is an optionally substituted cycloalkyl. In one aspect of this embodiment, Bi is cyclopropyl, cyclopentyl, cyclohexyl, or 1-methylcyclopropyl.
In another embodiment, B2 in the compounds represented by foπnula (IX) is an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, an optionally substituted cycloheptyl, an optionally substituted cyclooctyl. In one aspect of this embodiment, B2 is an optionally substituted cyclopropyl.
In another embodiment, Ba in the compounds represented by formula (IX) is an optionally substituted heterocycle. In another embodiment, B2 in the compounds represented by formula (IX) is an optionally substituted cycloalkenyl. In another embodiment, in the compounds represented by formula (VII), (VIII), (IX), or (X), X5 is CR89R90.
In another embodiment, in the compounds represented by foπnula (VII), (VIII), (IX), or (X), X5 is CR89Rw, and R78, R79, Rs2, Rs3, Rg4, Rss, Rs9 and R90 are H.
In another embodiment, in the compounds represented by formula (VII), (VIII), (IX), or (X), q is 1.
In another embodiment, in the compounds represented by formula (VII), (VIII), (IX), or (X), R80 and R81 are each, independently, a lower alkyl; or R80 and R81 taken together are =CR9δR96, or R80 and R81 taken together with the carbon to which they are attached are cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein R96, for each occurrence, is
independently, -H or a lower alkyl. In one aspect of this embodiment, Rgo and Rgj are each, independently, a lower alkyl. In another aspect of this embodiment, Rso and Rg i are each methyl. In another aspect of this embodiment, Rso and
taken to gether are
In another aspect of this embodiment, Rso and Rs i taken together with the carbon to which they are attached are cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
In another embodiment, in the compounds represented by formula (VII), (VIII), (IX), or (X), X6 and X7 are O.
In another embodiment, in the compounds represented by formula (VII), (VIII), (IX), or (X), r is 1. In another embodiment, in the compounds represented by formula (VII), (VIE), (IX), or (X), r is 1, and X4 is CH2.
In another embodiment, in the compounds represented by formula (VII), (VIII), (IX), or (X), r is 1, and X4 is NRp5, wherein R95 is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl. In one aspect of this embodiment, Rg5 is -H or a lower alkyl.
In another embodiment, in the compounds represented by formula (VII), (VIII), (IX), or (X), r is 1, and X4 is O.
In another embodiment, in the compounds represented by formula (VII), (VIE), (IX), or (X), r is O.
In another embodiment, in the compounds represented by formula (VII), (VIII), (IX), or (X), r is 0, and X4 is CH2. In another embodiment, in the compounds represented by formula (VII), (VIII), (IX), or (X), r is 0, and X4 is NR95, wherein R95 is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl. In one aspect of this embodiment, R95 is -H or a lower alkyl.
In another embodiment, in the compounds represented by formula (VII), (VIE), (IX), or (X), r is 0, and X4 is O.
In another embodiment, in the compounds represented by formula (VII), (VIII), (IX), or (X), X4 is NR95, X5 is O, q is 1 and r is 1. In one aspect of this embodiment, X4 is NR95, X5 is O, n is 1, r is 1, and R78, R79, R82, R83, R_4, and Rss are H. In another aspect of this embodiment, X4 is NR95; X5 is O; q is 1; r is 1; R78, R79, Rs2, Rs3, R84, and R85 are H; and Rso and R81 are each, independently, a lower alkyl; or R8o and R81 taken together are or R8O and R81 taken together with the carbon to which they are attached are cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein R96, for each occurrence, is independently, -H or a lower alkyl. In another aspect of this embodiment, X6 and X7 are O.
In another aspect, the invention provides compounds foπnula (XI) as set forth below:
(XI) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof, wherein: s is 0, 1, or 2;
D2 is an optionally substituted aiyl or an optionally substituted heteroaryl;
R45 is -H or an alkyl;
R46 is -C(O)OR56, -C(O)R56, -C(O)NR57R58, -CN, -CH(OR56)R56, -C(=NR56)R56, -C(S)R56, -C(S)OR56, -C(S)NR57R58, -CH(NR57R58)R56; or -CH(SR56)R56;
R47 is H or a substituent;
R48 and R49 are each, independently, -H, -OR56, or -NR57R58; or R48 and R49 taken together are
provided that at least one Of R48 or R49 is not -H;
R50 and R51 are each, independently, -H or a substituent;
R52 and R53 are each, independently, -H or a substituent; or R52 and R53, together with the carbon to which they are attached, form an optionally substituted cycloalkyl;
R54 and R55, for each occurrence, are, independently, -H or a substituent;
R56, for each occurrence, is, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R57 and R5S, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R57 and R58, taken together with the nitrogen to which they are attached are an optionally substituted heterocycloalkyl or optionally substituted heteroaryl;
R59 is -H, halo, -OROO, -NReoRβo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; and
Rόo is H, alkyl, aryl or acetyl.
Compounds of formula (XI) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for treating inflammatory bowel disease. In one embodiment, in compounds represented by formula (XI), there applies one or more (including all) of the following provisos:
1) R47 is not lower alkyl, cyclopentyl, phenyl, bromomethyl, trifluoromethyl, -NH2, nitro, -NHC(O)NH-phenyl, -SH, -SS-heterocycle, -S-(lower alkenyl), or -S-(cycloalkenyl); 2) when D2 is o-chlorophenyl, R47 is not a methyl substituted with a heteroaralkoxy;
3) when D2 is o-(trifluoromethyl)-phenyl, R47 is not -CH2-S(O)j-phenyl, -CH2-S(O)j-pyridyl, or -CH2(CH3)-S(O)j-phenyl, wherein j is 0, 1, or 2;
4) when.D2 is a chlorophenyl, R47 is not -SH, -SCH3, -SCH2CH3, -SCH(CH2)CH3, -SCH2C(O)NH2, or -SCH2C(O)NH-(bromophenyl); and
5) when R47 is -H, D2 is not thiazolyl.
In another embodiment, in the compounds of formula (XI), there applies one or more (including all) of the following provisos:
1) when R47 is methyl, D2 is not chlorophenyl, dichlorophenyl, /?-nitrophenyl, or 5 -chloro-benzo [ 1 ,3] dioxolyl;
2) when R47 is isopropyl or cyclopentyl, either R46 is notp- (trifluoromethyl)benzoyl or D2 is not ^-fluorophenyl; and
3) R47 is not -NH2.
In another embodiment, in the compounds of formula (XI), there applies one or more (including all) of the following provisos:
1) when R47 is methyl, D2 is not chlorophenyl or 5-chloro-benzo[l,3]dioxolyl; and
2) when R47 is cyclopentyl, R46 is not j9-(trifiuoromethyl)-benzoyl.
In another embodiment, R4S and R49 together are =O in compounds represented by formula (XI).
In another embodiment, s is 1 in compounds represented by formula (XI).
In another embodiment, in compounds represented by formula (XI), D2, s, R45, R46, R47, R4S, R49, R50, R51, R52, R53, R54, and R55 are selected from those included in specific exemplified compounds described herein.
In another aspect, the invention provides compounds of formula (XII) as set forth below:
Compounds of formula (XII) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for treating inflammatory bowel disease.
In one embodiment, in compounds represented by formula (XII), there applies one or more (including all) of the following provisos:
1) R47 is not a lower alkyl, a halomethyl, phenyl, cyano, or hydroxym ethyl;
2) when R47 is H or -NH2, D2 is not a substituted quinolinyl; and
3) when R47 is 2-(N,N-dimethylamino)-ethyl or methoxymethyl, D2 is not 0- chlorophenyl or o-(trifluoromethyl)-phenyl. In another embodiment, in compounds represented by formula (XII), there applies one or two of the following provisos:
1) when R47 is methyl, D2 is not chlorothienyl, methylthienyl, l-oxo-pyridin-3- yl, l-oxo-2-chloropyridin-3-yl, l-oxo-2-methylpyridin-3-yl, 2-phenyl-4-oxo-thiochromenyl, a substituted 4-oxo-benzopyranyl, or a substituted phenyl; 2) when R47 is methyl, D2 is not chlorothienyl, methylthienyl, 2-phenyl-4-oxo- thiochromenyl, a substituted 4-oxo-benzopyranyl, or a substituted phenyl;
3) when R47 is methyl, D2 is not l-oxo-pyridin-3-yl, l-oxo-2-chloropyridin-3-yl, or 1 -oxo-2 -methylpyridin-3-yl; and
4) when R47 is methoxymethyl or (CHs)2NCH2CH2-, D2 is not o-chlorophenyl. In another embodiment, Y is =0 in compounds represented by formula (XII).
In another embodiment, X9 is -O- in compounds represented by formula (XII).
In another embodiment, s is 1 in compounds represented by formula (XII).
In another embodiment, in compounds represented by formula (XII), D2, Y, s, R45, R46, R47, R52, R53, R54, and R55 are selected from those included in specific exemplified compounds described herein.
In another embodiment, in compounds represented by formula (XI) or (XII), D2 is selected from the group consisting of a substituted or unsubstituted phenyl, a substituted or unsubstituted pyridyl, a substituted or unsubstituted 1-oxo-pyridyl, a substituted or unsubstituted furanyl, a substituted or unsubstituted anthracenyl, a substituted or unsubstituted fluorenyl, a substituted or unsubstituted indenyl, a substituted or unsubstituted azulenyl, a substituted or unsubstituted naphthyl, a substituted or unsubstituted 5,6,7,8- tetrahydronaphthyl, a substituted or unsubstituted benzo[l,3]dioxolyl, a substituted or unsubstituted thienyl, a substituted or unsubstituted pyrrolyl, a substituted or unsubstituted oxazolyl, a substituted or unsubstituted imidazolyl, a substituted or unsubstituted thiazolyl, a substituted or unsubstituted isoxazolyl, a substituted or unsubstituted quinoliny, a substituted or unsubstituted pyrazolyl, a substituted or unsubstituted isothiazolyl, a substituted or unsubstituted pyridazinyl, a substituted or unsubstituted pyrimidinyl, a substituted or unsubstituted pyrazinyl, a substituted or unsubstituted triazinyl, a substituted or unsubstituted triazolyl, a substituted or unsubstituted thiadiazolyl, a substituted or
unsubstituted quinolyl, a substituted or unsubstituted isoquniolyl, a substituted or unsubstituted indazolyl, a substituted or unsubstituted benzoxazolyl, a substituted or unsubstituted benzofuryl, a substituted or unsubstituted benzothiazolyl, a substituted or unsubstituted indolizinyl, a substituted or unsubstituted imidazopyridyl, a substituted or unsubstituted isothiazolyl, a substituted or unsubstituted tetrazolyl, a substituted or unsubstituted benzimidazolyl, a substituted or unsubstituted benzoxazolyl, a substituted or unsubstituted benzothiazolyl, a substituted or unsubstituted benzothiadiazolyl, a substituted or unsubstituted benzoxadiazolyl, a substituted or unsubstituted indolyl, a substituted or unsubstituted tetrahydroindolyl, a substituted or unsubstituted azaindolyl, a substituted or unsubstituted imidazopyridyl, a substituted or unsubstituted qunizaolinyl, a substituted or unsubstituted purinyl, a substituted or unsubstituted pyrrolo[2,3]pyrimidyl, a substituted or unsubstituted pyrazolo[3,4]pyrimidyl, a substituted or unsubstituted imidazo[l,2-a]pyridyl, or a substituted or unsubstituted benzo(b)thienyl.
In another embodiment, in compounds represented by formula (XI) or (XII), D2 is substituted with one or more substituents selected from the group consisting of an alkyl, an alkenyl, an alkynyl, an cycloalkyl, an cycloalkenyl, a heterocycloalkyl, an aryl, a heteroaryl, an aralkyl, a heteraralkyl, a haloalkyl, -C(O)NR6IR62, -NR63C(O)R64, a halo, -OR63, cyano, nitro, a haloalkoxy, -C(O)R63, -NR61R62, -SR63, -C(O)OR63, -OC(O)R63, -NR63C(O)NR6IR62, -OC(O)NR6IR62, -NR63C(O)OR64, -S(O)jR63, and
wherein:
R6I and R62, for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an . optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R6] and R62 taken together with the nitrogen to which they are attached is optionally substituted heterocycloalkyl or optionally substituted heteroaryl; and
R63 and R64 for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl.
In another embodiment, in compounds represented by formula (XI), D2 is selected from the group consisting of a substituted or unsubstituted phenyl, a substituted or
unsubstituted benzo[l,3]dioxolyl, a substituted or unsubstituted pyridyl, a substituted or unsubstituted indolyl, a substituted or unsubstituted quinolinyl, a substituted or unsubstituted 1-oxo-pyridyl, a substituted or unsubstituted pyridazinyl, a substituted or unsubstituted pyrimidinyl, a substituted or unsubstituted pyrazinyl, a substituted or unsubstituted furanyl, a substituted or unsubstituted thienyl, a substituted or unsubstituted [l,3,5]triazinyl, a substituted or unsubstituted thiazolyl, a substituted or unsubstituted imidazolyl, a substituted or unsubstituted oxazolyl, a substituted or unsubstituted indolizinyl, a substituted or unsubstituted imidazo[l,2-a]pyridyl, a substituted or unsubstituted 2,3-dihydro- benzo[l,4]dioxinyl, and a substituted or unsubstituted naphthyl.
In another embodiment, in compounds represented by formula (XI) or (XII), D2 is substituted with one, two or three substituents selected from the group consisting of halo, nitro, -NR65R05, lower alkyl, lower alkoxy, lower alkyl sulfanyl, lower haloalkyl, phenyl, hydroxyl, cyano, and lower alkyl sulfonyl, wherein R^5, for each occurrence, is -H or a lower alkyl. In another embodiment, D2 is a phenyl or pyridyl ring substituted with one or more halo groups. In another embodiment, D2 is an unsubstituted pyridyl or 1-oxo-pyridyl. In another embodiment, D2 is a phenyl or pyridyl ring substituted with one or more -O-lower alkyl-NH-CH2-CH(OH)-CH2-O-phenyl groups. In another embodiment, D2 is a phenyl or pyridyl ring substituted with one or more methyl, phenyl, -NBw, -CN, -CF3, -OH, -OCH3, methanesulfonyl, methylsufanyl, or -N3 groups.
In another aspect, the invention provides compounds of formula (XIII) as set forth below:
(xm) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof wherein:
D and E are independently selected from -H, -halo, -NO2, -CN, -OH, -N(R38)(R38), -OR38, -C(O)R38, -OC(O)R38, -C(O)NHC(O)R38, substituted or unsubstituted -(Ci-C10)alkyl, substituted or unsubstituted -(C2-C 10)alkenyl, substituted or unsubstituted -(C2-Cio)alkynyl, substituted or unsubstituted -(C3-C io)cycloalkyl, substituted or unsubstituted -(Cs- Ci4)bicycloalkyl, substituted or unsubstituted -(C5-Cio)cycloalkenyl, substituted or unsubstituted 3-7 membered monocyclic heterocycle, substituted or unsubstituted 8-12 rnembered bicyclic heterocycle, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, -(C1-C6)alkyl-Z-(Ci-C1o)alkyl- R44, -(Ci-Cio)alkyl-R44, -(C1-CI0)alkyl-N(R38)(R38), -CO2R38, -C(O)OCH(R38)(R38), -NHC(O)R38, -NHC(O)NHR385 -C(O)NHR38, -OC(O)R38, -OC(O)OR38, -
S(O)N(R38)(R38), -SR38, -S(O)R38, -S(O)2R38 and a substituted or unsubstituted aromatic or heteroaromatic ring, wherein if the ring is substituted, the substituents are independently selected from the group consisting of substituted or unsubstituted lower alkyl, -halo, -CN, - N(R38)(R38), -OR39, -C(O)R38, -C(O)2R38, -OC(O)R38, -NO2, and -C(O)N(R38)(R38), or two adjacent carbon atoms on the ring are linked by the group -0-(CH2)g-0- to form a bicyclic ring system, wherein g is an integer selected from 1, 2, 3 or 4;
X is selected from the group consisting of O, S, -NR38, and -C(R38)(R38); Y is O or S; Z is at each occurrence independently-O-, -S-, -N(R38)-, -C(O)-, -OC(O)-,
-C(O)N(R38)C(O)-, substituted or unsubstituted -(Ci-Cio)alkyl-, substituted or unsubstituted -(C2-C io)alkenyl-, substituted or unsubstituted -(C2-Cio)alkynyl-, substituted or unsubstituted -(C3-Cio)cycloalkyl-, substituted or unsubstituted -(Cs-Ci4)bicycloalkyl-, substituted or unsubstituted -(C5-Cio)cycloalkenyl-, substituted or unsubstituted -(C3- C]o)heterocycle-, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, -C(O)O-, -C(O)OC(R38)(R38)-, -N(R38)C(O)-, -N(R38)C(O)NR38-, -C(O)NR38-, -OC(O)O-, -S(O)N(R38)-, -S(O)- or -S(O)2-;
R34 and R35 are at each occurrence independently selected from -H, -halo, -CN, -N3, -NO2, -CN, -OH, -N(R38)(R38), -OR38, -C(O)R38, -OC(O)R38, -C(O)NHC(O)R38, substituted or unsubstituted -(Cj-Cio)alkyl, substituted or unsubstituted -(C2-C io)alkenyl, substituted or unsubstituted -(C2-C io)alkynyl, substituted or unsubstituted -(C3-Cio)cycloalkyl, substituted or unsubstituted -(C8-Ci4)bicycloalkyl, substituted or unsubstituted -(C5-Cio)cycloalkenyl, substituted or unsubstituted 3-7 membered monocyclic heterocycle, substituted or
unsubstituted 8-12 membered bicyclic heterocycle, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, -CO2R3S, -C(O)OCH(R38)(R38), -NHC(O)R38 5 -NHC(O)NHR38, -C(O)NHR38, -OC(O)R38, -OC(O)OR38, -S(O)N(R38)(R38), -SR38, -S(O)R38, and -S(O)2R38; R36 is at each occurrence independently -H, -C(O)R38 or substituted or unsubstituted
-(C,-Cio)alkyl;
R37 is at each occurrence independently -H, -halo, -CN, -N3, -NO2, -CN, -OH, -N(R38)(R38), -OR38, -C(O)R38, -OC(O)R38, -C(O)NHC(O)R38, substituted or unsubstituted -(Ci-Cio)alkyl, substituted or unsubstituted -(C2-C io)alkenyl, substituted or unsubstituted -(C2-C io)alkynyl, substituted or unsubstituted -(C3-Cio)cycloalkyl, substituted or unsubstituted -(Cg-C H)bicyc]oalkyl, substituted or unsubstituted -(C5-C io)cycloalkenyl, substituted or unsubstituted 3-7 membered monocyclic heterocycle, substituted or unsubstituted 8-12 membered bicyclic heterocycle, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, -CO2R385 -C(O)OCH(R38)(R38), -NHC(O)R38 , -NHC(O)NHR38, -C(O)NHR38, -OC(O)OR38,
-S(O)N(R38)(R3S), -SR38, -S(O)R38, -S(O)2R38 or a substituted or unsubstituted bioisosteric replacement of an ester; each R38 is at each occurrence independently H or substituted or unsubstituted -(C1- Cio)alkyl; each R39 is at each occurrence independently H, substituted or unsubstituted -(C1-
Cio)alkyl or -(CH2)k-N(R38)-(Ci-C6)alkyl optionally substituted with one or more -OR38 or -O-aryl groups;
R44 is at each occurrence independently selected from -H5 -halo, -CN, -N3, -NO2, -CN, -OH, -N(R38)(R38), -OR38, -C(O)R38, -OC(O)R38, -C(O)NHC(O)R38, substituted or unsubstituted -(Ci-Cio)alkyl, substituted or unsubstituted -(C2-Ci o)alkenyl, substituted or unsubstituted -(C2-Cio)alkynyl, substituted or unsubstituted -(C3-Cio)cycloalkyl, substituted or unsubstituted -(C3-Ci4)bicycloalkyl, substituted or unsubstituted -(C5-Cio)cycloalkenyl, substituted or unsubstituted 3-7 membered monocyclic heterocycle, substituted or unsubstituted 8-12 membered bicyclic heterocycle, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, -CO2R3S, -C(O)OCH(R38)(R38), -NHC(O)R38 5 -NHC(O)NHR38, -C(O)NHR38, -OC(O)R38, -OC(O)OR38, -S(O)N(R38)(R38), -SR38, -S(O)R38, and -S(O)2R38; s is an integer selected from 0-2; and
k is an integer selected from 1-6.
Compounds of formula (XIII) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for treating inflammatory bowel disease. In one embodiment, in compounds represented by formula (XIII), R34 and R35 are both alkyl, preferably lower alkyl more preferably methyl.
In another embodiment, in compounds represented by formula (XIII), one of R34 and R35 is H and the other is alkyl, preferably lower alkyl more preferably isopropyl or methyl.
In another embodiment, in compounds represented by formula (XIII), R36 is H. In another embodiment, R36 is other than H, such as methyl or ethyl.
In another embodiment, in compounds represented by formula (XIII), Y is O.
In another embodiment, in compounds represented by formula (XIII), D is a phenyl or pyridyl ring substituted with one or more halo groups. In another embodiment, D is a phenyl or pyridyl ring substituted with one or more -O-lower alkyl-NH-CH2-CH(OH)-CH2- O-phenyl groups. In another embodiment, D is a phenyl or pyridyl ring substituted with one or more methyl, phenyl, -NH2, -CN, -CF3, -OH or -N3 groups. In another embodiment, D is quinoline, indole, pyridine oxide, pyradizine, pyrimidine, pyrazine, furan, thiophene, triazine, thiazole, imidazole, oxazole, indolizine, imidazo pyridine, naphthalene, dihydrobenzodioxine or benzo(l,3)dioxole. In another embodiment, in compounds represented by formula (XIII), E is -(Ci-
C6)alkyl-0-(Ci~Cio)alkyl-3-7 membered monocyclic heterocycle. In another embodiment, E is -(CH2)-O-(CH2)2-3-7 membered monocyclic heterocycle. In another embodiment, E is -(CH2)-O-(CH2)-3-7 membered monocyclic heterocycle. In another embodiment, E is -(Ci - Cδ)alkyl-0-(Ci-Cio)alkyl-NH2. In another embodiment, E is -(Ci-C6)alkyl-O-(CrCi0)alkyl- N3. In another embodiment, E is -(CEk)-O-(Ci-CjO)-NR38R3S. In another embodiment, E is -(CH2)-0-(C1-Cio)-NH-(C1-C6)alkyl. In another embodiment, E is -(CH2)-O-(d-Ci0)- N((CrC6)alkyl)2. In another embodiment, E is -(CBb)-O-(Ci-C]O)-NH2. In another embodiment, E is -(CH2)-O-(Ci-Ci0)-N3. In another embodiment, E is ~(CH2)-O-(CH2)2- NR38R38. In another embodiment, E is -(CH2)-O-(CH2)2- NH-(Ci-C6)alkyl. In another embodiment, E is -(CH2)-O-(CH2)2-N((Ci-C6)alkyl)2. In another embodiment, E is -(CH2)- O-(CH2)2-NH2. In another embodiment, E is -(CH2)-O-(CH2)2-N3.
In another embodiment, in compounds represented by formula (XIII), X is -CH2-.
In another embodiment, in compounds represented by formula (XIII), Z is O or S. In another embodiment, Z is -N(CHs)-. In another embodiment, Z is -CH2-.
In another embodiment, in compounds represented by formula (XIII), Z is O or S and R34 is a substituted or unsubstituted 3-7 membered monocyclic heterocycle or a substituted or unsubstituted 8-12 membered bicyclic heterocycle.
In another embodiment, in compounds represented by formula (XIII), R44 is amino or azido. In another embodiment, R44 is -NH-CH2-CH(OH)-CH2-O-phenyl. In another embodiment, R44 is -NH-C(O)-lower alkyl. In another embodiment, R44 is -C(O)-O-lower alkyl. In another embodiment, R44 is -NH-lower alkyl or -N-(lower alkyi)2, wherein lower alkyl is preferably methyl or ethyl. In another embodiment, R44 is an isoindole-l,3-dione. In another embodiment, R44 is piperazine or morpholine. In another embodiment, R44 is a 5 membered monocyclic heterocycle. In another embodiment, R44 is a nitrogen containing 5 membered monocyclic heterocycle, such as pyrrole, imidazole or triazole.
In another embodiment, in compounds represented by formula (XIII), R37 is -OC(O)R38, wherein R38 is substituted or unsubstituted -(Ci-Cio)alkyl. Preferably, R38 is methyl, ethyl or propyl.
In another embodiment, in compounds represented by formula (XIII), R37 is -C(O)OR38, wherein R38 is substituted or unsubstituted -(Cj-Cio)alkyl. Preferably, R38 is methyl, ethyl or propyl. In another embodiment, in compounds represented by formula (XIII), R37 is
-C(O)OCH2CH3. In another embodiment, R37 is -C(O)OH.
In another embodiment, in compounds represented by formula (XIII), R37 is -C(O)NHR38, where R38 is H, methyl, ethyl or propyl.
In another embodiment, in compounds represented by formula (XIII), R37 is a substituted or unsubstituted 5 membered monocyclic heterocycle, wherein the dihydropyridine core structure can be bound to either a carbon atom or a heteroatom of the 5 membered monocyclic heterocycle.
In another embodiment, in compounds represented by formula (XIII), R37 is a bioisosteric replacement of an ester including, but not limited to, oxazole and oxadiazole. In another embodiment, in compounds represented by formula (XIII), R3-7 is -CN.
In another embodiment, in compounds represented by formula (XIII), R3g is -(Cr Cio)alkyl substituted with a 3-7 membered monocyclic heterocycle, a 8-12 membered bicyclic heterocycle or -CN.
In another embodiment, in compounds represented by formula (XIII), g is an integer selected from 1 or 2.
In another embodiment, in compounds represented by formula (XIII), there applies a proviso that E is not substituted or unsubstituted -(CrC]0)alkyl, -(C3-C io)cycloalkyl, -S(O)R38, -S(O)2R38 or -C(O)NHR38.
In another embodiment, in compounds represented by formula (XIII), there applies a proviso that R44 is not a 3-7 membered monocyclic heterocycle or 8-12 membered bicyclic heterocycle.
In another embodiment, in compounds represented by formula (XIII), there applies a proviso that R34 and R35 are not both H.
In another embodiment, in compounds represented by formula (XIII), there applies a proviso that if X is CR2, R34 and R35 are not both H.
In another embodiment, in compounds represented by formula (XIII), there applies a proviso that if X is O, s is not O.
In another embodiment, in compounds represented by formula (XIII), there applies a proviso that if D is a bicyclic ring, R34 and R35 are not both H.
In another embodiment, in compounds represented by formula (XIII), there applies a proviso that if X is -(CH2)- or D is a bicyclic ring, R34 and R35 are not both H.
In another embodiment, in compounds represented by formula (XIII), there applies a proviso that if R3g is other than H, R34 and R35 are not both H.
In another embodiment, in compounds represented by formula (XIII), there applies a proviso that if X is O, s is not O and if R36 is other than H, R34 and R35 are not both H.
In another aspect, the invention provides compounds of formula (XIV) as set forth below:
(XIV)
and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof wherein:
Ar is a substituted or unsubstituted aromatic or heteroaromatic ring, wherein if the ring is substituted, the substituents are independently selected from the group consisting of substituted or unsubstituted lower alkyl, -halo, -CN, -N(R3S)(RsS), -OR39, -C(O)R38,
-C(O)2R3S, -OC(O)R38, -NO2, and -C(O)N(R38)(R3S), or two adjacent carbon atoms on the ring are linked by the group -0-(CHo)8-O- to form a bicyclic ring system, wherein g is an integer selected from 1, 2, 3 or 4;
Q is H, -halo, -NO2, -CN, -OH, -N(R38)(R38), -OR38, -C(O)R38, -OC(O)R38, -C(O)NHC(O)R38, substituted or unsubstituted -(C2-C 10)alkyl, substituted or unsubstituted -(C2-Cio)alkenyl, substituted or unsubstituted -(C2-C!0)alkynyl, substituted or unsubstituted -(C3-Cio)cycloalkyl, substituted or unsubstituted -(C8-Ci4)bicycloalkyl, substituted or unsubstituted -(C5-Cio)cycloalkenyl, substituted or unsubstituted 3-7 membered monocyclic heterocycle, substituted or unsubstituted 8-12 membered bicyclic heterocycle, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, -(Co-C6)alkyl-Z-(CrCio)alkyl-R44, -(C,-Cio)alkyl-R44, -CO2R38, -C(O)OCH(R38)(R38), -NHC(O)R38, -NHC(O)NHR38, -C(O)NHR38, -OC(O)R38, -OC(O)OR38, -S(O)N(R38)(R38), -SR38, -S(O)R38, -S(O)2R38 or a substituted or ■ unsubstituted aromatic or heteroaromatic ring, wherein if the ring is substituted, the substituents are independently selected from the group consisting of substituted or unsubstituted lower alkyl, -halo, -CN, -N(R38)(R38), -OR39, -C(O)R38, -C(O)2R38, -OC(O)R38, -NO2, and -C(O)N(R38)(R38);
X is selected from the group consisting of O, S, -NR38, and -C(R38)(R38); Y is O or S; Z is at each occurrence independently -0-, -S-, -N(R38)-, -C(O)-, -OC(O)-,
-C(O)N(R38)C(O)-, substituted or unsubstituted -(Ci-Cio)alkyl-, substituted or unsubstituted -(C2-Cio)alkenyl-, substituted or unsubstituted -(C2-C]0)alkynyl-, substituted or unsubstituted -(C3-Cio)cycloalkyl-, substituted or unsubstituted ~(C8-Ci4)bicycloalkyl-, substituted or unsubstituted -(C5-Cio)cycloalkenyl-, substituted or unsubstituted -(C3- Cio)heterocycle-, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, -C(O)O-, -C(O)OC(R38)(R3S)-, -N(R38)C(O)-, -N(R38)C(O)NR38-, -C(O)NR38-, -OC(O)O-, -S(O)N(R38)-, -S(O)-, or -S(O)2-;
R.34 and R35 are at each occurrence independently selected from -H, -halo, -CN, -N3, -NO2, -CN, -OH, -N(R38)(R38), -OR38, -C(O)R38, -OC(O)R38, -C(O)NHC(O)R38, substituted or unsubstituted -(Ci-Cio)alkyl, substituted or unsubstituted -(C2-C iO)alkenyl, substituted or unsubstituted -(C2-C]0)alkynyl, substituted or unsubstituted -(C3-C]0)cycloalkyl, substituted or unsubstituted -(C8-Ci4)bicycloalkyl, substituted or unsubstituted -(C5-Cio)cycloalkenyl, substituted or unsubstituted 3-7 membered monocyclic heterocycle, substituted or unsubstituted 8-12 membered bicyclic heterocycle, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, -CO2R38, -C(O)OCH(R38)(R38), -NHC(O)R38 5 -NHC(O)NHR38, -C(O)NHR38, -OC(O)R38, -OC(O)OR38, -S(O)N(R38)(R38), -SR38, -S(O)R38, and -S(O)2R38;
R36 is at each occurrence independently -H, -C(O)R38 or substituted or unsubstituted -(Ci-C10)alkyI;
R37 is at each occurrence independently -H, -halo, -CN, -N3, -NO2, -CN, -OH, -N(R38)(R38), -OR38, -C(O)R38, -OC(O)R38, -C(O)NHC(O)R38, substituted or unsubstituted -(Ci-Cio)alkyl, substituted or unsubstituted -(C2-Cio)alkenyl, substituted or unsubstituted -(C2-C io)alkynyl, substituted or unsubstituted -(C3-Cio)cycloalkyl, substituted or unsubstituted -(C8-C i4)bicycloalkyl, substituted or unsubstituted -(C5-C io)cycloalkenyl, substituted or unsubstituted 3-7 membered monocyclic heterocycle, substituted or unsubstituted 8-12 membered bicyclic heterocycle, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, -CO2R38, -C(O)OCH(R38)(R38), -NHC(O)R38 , -NHC(O)NHR38, -C(O)NHR38, -OC(O)OR38, -S(O)N(R38)(R3s), -SR38, -S(O)R38, -S(O)2R38 or a substituted or unsubstituted bioisosteric replacement of an ester; each R38 is at each occurrence independently H or substituted or unsubstituted -(Ci- C10)alkyl; each R39 is at each occurrence H, substituted or unsubstituted -(Ci-Cio)alkyl or -(CH2X-N(R38)-(Ci-C6)alkyl optionally substituted with one or more -OR38 or -O-aryl groups;
R44 is at each occurrence independently selected from -H, -halo, -CN, -N3, -NO2, -CN, -OH, -N(R38)(R38), -OR38, -C(O)R38, -OC(O)R38, -C(O)NHC(O)R38, substituted or unsubstituted -(Ci-Cio)alkyl, substituted or unsubstituted -(C2-C io)alkenyl, substituted or unsubstituted -(C2-C io)alkynyl, substituted or unsubstituted -(C3-Cio)cycloalkyl, substituted or unsubstituted -(C8-Ci4)bicycloalkyl, substituted or unsubstituted -(Cs-C10)cycloalkenyl,
substituted or unsubstituted 3-7 membered monocyclic heterocycle, substituted or unsubstituted 8-12 membered bicyclic heterocycle, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, -CO2R38, -C(O)OCH(R38)(R38), -NHC(O)R38 , -NHC(O)NHR38, -C(O)NHR38, -OC(O)R38, -OC(O)OR38, -S(O)N(R38)(R38), -SR38, -S(O)R38, and -S(O)2R38; s is an integer selected from 0-2; and k is an integer selected from 1-6.
Compounds of formula (XIV) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for treating inflammatory bowel disease.
In one embodiment, in compounds represented by formula (XIV), Ar is a phenyl or pyridyl ring which can be substituted with one or more halo (e.g., chloro or fluoro), methyl, phenyl, -NH2, -CN, -NO2, -CF3, OH, 0-lower alkyl, or O-R3<). In another embodiment, Ar is a phenyl or pyridyl ring substituted with one or more -O-lower alkyl-NH-CH2-CH(OH)- CH2-O-phenyl groups. In another embodiment, Ar is quinoline, indole, pyridine oxide, pyradizine, pyrimidine, pyrazine, furan, thiophene, triazine, thiazole, imidazole, oxazole, indolizine, imidazo pyridine, naphthalene, dihydrobenzodioxine or benzo(l,3)dioxole.
In another embodiment, in compounds represented by formula (XIV), R34 and R35 are independently selected from H and lower alkyl and R37 is CO2-lower alkyl (e.g., CO2CH2CH3 or CO2CH3).
In another embodiment, in compounds represented by formula (XIV), R34 and R35 are alkyl, preferably lower alkyl, more preferably methyl. In one embodiment, one of R34 and R35 is H and the other is alkyl, preferably lower alkyl more preferably isopropyl or methyl. In another embodiment, in compounds represented by formula (XIV), R36 is H or lower alkyl (e.g., methyl or ethyl).
In another embodiment, in compounds represented by formula (XIV), R38 is at each occurrence independently H or lower alkyl. In another embodiment, R38 is -(Ci-Cio)alkyl substituted with a 3-7 membered monocyclic heterocycle, a 8-12 membered bicyclic heterocycle or -CN.
In another embodiment, in compounds represented by formula (XIV), R39, when substituted, is substituted with -OCβHs.
In another embodiment, s is 1.
In another embodiment, in compounds represented by formula (XIV), k is an integer selected from 3 or 4.
In another embodiment, in compounds represented by formula (XIV), R37 is a substituted or unsubstituted 5 membered monocyclic heterocycle, wherein the dihydropyridine core structure can be bound to either a carbon atom or a heteroatom of the 5 membered monocyclic heterocycle. In another embodiment, R37 is a bioisosteric replacement of an ester including, but not limited to, oxazole and oxadiazole. In another embodiment, R37 is -CN.
In another embodiment, in compounds represented by formula (XIV), R37 is -OC(O)R38, wherein R38 is substituted or unsubstituted -(Ci-Cio)alkyl. Preferably, R38 is methyl, ethyl or propyl.
In another embodiment, in compounds represented by formula (XIV), R37 is -C(O)OR38, wherein R38 is substituted or unsubstituted -(C1-C1o)alkyl. Preferably, R38 is methyl, ethyl or propyl. In another embodiment, in compounds represented by formula (XIV), R37 is
-C(O)OH.
In another embodiment, in compounds represented by formula (XIV), R37 is -C(O)NHR38, where R38 is H, methyl, ethyl or propyl.
In another embodiment, in compounds represented by formula (XIV), X is -CH2-. In another embodiment, in compounds represented by formula (XIV), Z is O or S.
In another embodiment, Z is -N(CH3)-. In another embodiment, Z is -CH2-.
In another embodiment, in compounds represented by formula (XIV), Z is O or S and R34 is a substituted or unsubstituted 3-7 membered monocyclic heterocycle or a substituted or unsubstituted 8-12 membered bicyclic heterocycle. In another embodiment, in compounds represented by formula (XIV), Q is -(Cp
Cio)alkyl-3-7 membered monocyclic heterocycle. In another embodiment, Q is -O-(CH2)2- 3-7 membered monocyclic heterocycle. In another embodiment, Q is -O-(CH2)-3-7 membered monocyclic heterocycle. In another embodiment, Q is -0-(Ci~Cio)alkyl-NH2. In another embodiment, Q is -O-(Ci-Ci0)alkyl-N3. In another embodiment, Q is -0-(C1-C1O)- NR38R3S. In another embodiment, Q is -0-(Ci-Cio)-NH-(CrC6)alkyl. In another embodiment, Q is -O-(Ci-Ci0)-N((Ci-C6)alkyl)2. In another embodiment, Q is -0-(Ci-Ci0)- NH2. In another embodiment, Q is -0-(Ci-Cio)-N3. In another embodiment, Q is -O- (CH2^-NR38R38. In another embodiment, Q is -0-( CH2)2- NH-(d-C6)alkyl. In another
embodiment, Q is -O-(CH2)2-N((C1-C6)alkyl)2. In another embodiment, Q is -O-(CH2)2- NH2. In another embodiment, Q is -O-(CH2)2-N3. In another embodiment, Q is piperazine.
In another embodiment, in compounds represented by formula (XIV), R44 is -NH2 or -N3. In another embodiment, R44 is -NH-CH2-CH(OH)-CH2-O-phenyl. In another embodiment, R44 is -NH-C(O)-lower alkyl. In another embodiment, R44 is -NH-lower alkyl or -N-(lower alkyl)2, wherein lower alkyl is preferably methyl or ethyl. In another embodiment, R44 is -C(O)-O-lower alkyl. In another embodiment, R44 is an isoindole-1,3- dione. In another embodiment, R44 is piperazine or morpholine. In another embodiment, R44 is a 5 membered monocyclic heterocycle. In another embodiment, R44 is a nitrogen containing 5 membered monocyclic heterocycle, such as pyrrole, imidazole or triazole.
In another embodiment, in compounds represented by formula (XIV), g is an integer selected from 1 or 2.
In another embodiment, in compounds represented by formula (XIV), there applies a proviso that R34 and R35 are not both H. In another embodiment, in compounds represented by formula (XIV), there applies a proviso that if X is CH2, R34 and R35 are not both H.
In another embodiment, in compounds represented by formula (XIV), there applies a proviso that Q is not H.
In another embodiment, in compounds represented by formula (XIV), there applies a proviso that if X is O, s is not 0.
In another embodiment, in compounds represented by formula (XIV), there applies a proviso that if Ar is a bicyclic ring, R34 and R35 are not both H.
In another embodiment, in compounds represented by formula (XIV), there applies a proviso that if X is -(CH2)- or D is a bicyclic ring, R34 and R35 are not both H. In another embodiment, in compounds represented by formula (XIV), there applies a proviso that if R3β is other than H, R34 and R35 are not both H.
In another embodiment, in compounds represented by formula (XIV), Q is -halo, -NO2, -CN, -OH, -N(R38)(R38), -OR38, -C(O)R38, -OC(O)R38, -C(O)NHC(O)R38, substituted or unsubstituted -(C2-C10)alkyl, substituted or unsubstituted -(C2-Cio)alkenyl, substituted or unsubstituted -(C2-Cio)alkynyl, substituted or unsubstituted -(C3-Cio)cycloalkyl, substituted or unsubstituted -(C8-Ci4)bicycloalkyl, substituted or unsubstituted -(C5-C io)cycloalkenyl, substituted or unsubstituted 3-7 membered monocyclic heterocycle, substituted or unsubstituted 8-12 membered bicyclic heterocycle, substituted or unsubstituted phenyl,
substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, -(Co-Ce)alkyl-Z- (C1-Cio)alkyl-R34, -CO2R38, -C(O)OCH(R38)(R38), -NHC(O)R38, -NHC(O)NHR38, -C(O)NHR38, -OC(O)R38, -OC(O)OR38, -S(O)N(R38)(R38), -SR38, -S(O)R38, -S(O)2R38 or a substituted or unsubstituted aromatic or heteroaromatic ring, wherein if the ring is substituted, the substituents are independently selected from the group consisting of substituted or unsubstituted lower alkyl, -halo, -CN, -N(R38)(R38), -OR39, -C(O)R38, -C(O)2R38, -OC(O)R38, -NO2, and -C(O)N(R38)(R38).
In another embodiment, in compounds represented by formula (XIV), one or more of the substituents R34, R35, R36, R37, R38, R39, Ar, X, Y and s are selected from those included in the specific exemplified compounds described herein.
In another aspect, the invention provides compounds of formula (XV) as set forth below:
and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof wherein:
Ar is a mono- or poly-substituted or unsubstituted aromatic or heteroaromatic ring, wherein if the ring is substituted, the substituents are independently selected from the group consisting of substituted or unsubstituted lower alkyl, -halo, -CN, -N(R38)(R38), -OR39, -C(O)R38, -C(O)2R38, -OC(O)R38, -NO2, and -C(O)N(R38)(R38), or two adjacent carbon atoms on the ring are linked by the group -O-(CH2)g-O- to form a bicyclic ring system, wherein g is an integer selected from 1, 2, 3 or 4;
V is H, -halo, N3, -NO2, -CN, -OH, -N(R38)(R40), -OR38, -C(O)R38, -OC(O)R38, -C(O)NHC(O)R38, substituted or unsubstituted 3-7 membered monocyclic heterocycle or substituted or unsubstituted 8-12 membered bicyclic heterocycle;
X is selected from the group consisting of O, S, -NR38, and -C(R38)(R38);
Y is O or S;
Z is -O-, -S-, -N(R38)-, -C(O)-, -OC(O)-, -C(O)N(R38)C(O)-, substituted or unsubstituted -(Ci-Cio)alkyl-, substituted or unsubstituted -(C2-Cio)alkenyl-, substituted or unsubstituted -(C2-C io)alkynyl-, substituted or unsubstituted -(C3-Cio)cycloalkyl-, substituted or unsubstituted -(C8-Ci4)bicycloalkyl-, substituted or unsubstituted -(C5- Cjo)cycloalkenyl-, substituted or unsubstituted -(C3-Cio)heterocycle-, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, -C(O)O-, -C(O)OC(R38)(R38)-, -N(R38)C(O)-, -N(R38)C(O)NR38-, -C(O)NR38-, -OC(O)O-, -S(O)N(R38)-, -S(O)-, or -S(O)2-; R34 and R35 are at each occurrence independently selected from -H, -halo, -CN, -N3,
-NO2, -CN, -OH, -N(R38)(R38), -OR38, -C(O)R38, -OC(O)R38, -C(O)NHC(O)R38, substituted or unsubstituted -(Ci-Cio)alkyl, substituted or unsubstituted -(C2-C io)alkenyl, substituted or unsubstituted -(C2-Cio)alkynyl, substituted or unsubstituted -(C3-C ]0)cycloalkyl, substituted or unsubstituted -(C8-Ci4)bicycloalkyl, substituted or unsubstituted -(C5-C1 o)cycloalkenyl, substituted or unsubstituted 3-7 raembered monocyclic heterocycle, substituted or unsubstituted 8-12 membered bicyclic heterocycle, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, -CO2R38, -C(O)OCH(R38)(R38), -NHC(O)R38 5 -NHC(O)NHR38, -C(O)NHR38, -OC(O)R38, -OC(O)OR38, -S(O)N(R38)(R38), -SR38, -S(O)R38, and -S(O)2R38; R3(5 is at each occurrence independently -H, -C(O)R38 or substituted or unsubstituted
-(Ci-C,o)alkyl;
R37 is at each occurrence independently -H, -halo, -CN, -N3, -NO2, -CN, -OH, -N(R38)(R38), -OR38, -C(O)R38, -OC(O)R38, -C(O)NHC(O)R38, substituted or unsubstituted -(Ci-Cio)alkyl, substituted or unsubstituted -(C2-C1o)alkenyl, substituted or unsubstituted -(C2-C io)alkynyl, substituted or unsubstituted -(C3-Ci0)cycloalkyl, substituted or unsubstituted -(C8-Ci4)bicycloalkyl, substituted or unsubstituted -(C5-Cio)cycloalkenyl, substituted or unsubstituted 3-7 membered monocyclic heterocycle, substituted or unsubstituted 8-12 membered bicyclic heterocycle, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, -CO2R38, -C(O)OCH(R38)(R38), -NHC(O)R38 5 -NHC(O)NHR38, -C(O)NHR385 -OC(O)OR38,
-S(O)N(R38)(R38), -SR38, -S(O)R38, -S(O)2R38 or a substituted or unsubstituted bioisosteric replacement of an ester;
each R38 is at each occurrence independently H or substituted or unsubstituted -(Ci- Cio)alkyl; each R39 is at each occurrence independently H, substituted or unsubstituted -(Ci- Cio)alkyl or -(CH2)k-N(R38)-(Ci-C6)alkyl optionally substituted with one or more -OR38 or -O-aryl groups;
R40 is selected from the group consisting of H and substituted or unsubstituted -(Cr Cio)alkyl optionally substituted with one or more -OR38 or -O-aryl groups; t is an integer selected from 1-10; s is an integer selected from 0-2; and k is an integer selected from 1-6.
Compounds of fonnula (XV) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for treating inflammatory bowel disease.
In one embodiment, in compounds represented by formula (XV), Ar is a phenyl or pyridyl ring which can be substituted with one or more halo (e.g., chloro or fluoro), methyl, phenyl, -NH2, -CN, -NO2, OH, -CF3, O-lower alkyl, or O-R39. In another embodiment, Ar is a phenyl or pyridyl ring substituted with one or more -O-lower alkyl-NH-CH2-CH(OH)- CHo-O-phenyl groups. In another embodiment, Ar is quinoline, indole, pyridine oxide, pyradizine, pyrimidine, pyrazine, furan, thiophene, triazine, thiazole, imidazole, oxazole, indolizine, imidazo pyridine, naphthalene, dihydrobenzodioxine or benzo(l,3)dioxole.
In another embodiment, in compounds represented by fonnula (XV), V is-halo, N3, -NO2, -CN, -OH, -N(R38)(R40), -OR38, -C(O)R38, -OC(O)R38 or -C(O)NHC(O)R38. In another embodiment, V is NH2 or N3. In another embodiment, V is -NH-CH2-CH(OH)- CH2-0-phenyl. In another embodiment, V is -NH-C(O)-lower alkyl. In another embodiment, V is -NH-lower alkyl or -N-(lower alkyl)2, wherein lower alkyl is preferably methyl or ethyl. In another embodiment, V is -C(O)-O-lower alkyl In another embodiment,
V is an isoindole-l,3-dione. In another embodiment, V is piperazine or morpholine. In another embodiment, V is a 5 membered monocyclic heterocycle. In another embodiment,
V is a nitrogen containing 5 membered monocyclic heterocycle, such as pyrrole, imidazole or triazole.
In embodiments where V is a heterocycle in compounds represented by formula (XV), the -(CH2)- group can be bound to a carbon atom or a heteroatom of V.
In another embodiment, in compounds represented by formula (XV), X is O or CH2.
In another embodiment, in compounds represented by formula (XV), R34 and R35 are independently selected from H and lower alkyl and R37 is CO2-lower alkyl (e.g., CO2CH2CH3 or CO2CH3).
In another embodiment, in compounds represented by formula (XV), R34 and R35 are alkyl, preferably lower alkyl, more preferably methyl. In one embodiment, one Of R34 and R3S is H and the other is alkyl, preferably lower alkyl more preferably isopropyl or methyl.
In another embodiment, in compounds represented by formula (XV), R38 is -(Ci- Cio)alkyl substituted with a 3-7 membered monocyclic heterocycle, a 8-12 membered bicyclic heterocycle or -CN. In another embodiment, in compounds represented by formula (XV), R36 is H or lower alkyl (e.g., methyl or ethyl).
In another embodiment, in compounds represented by formula (XV), R37 is a substituted or unsubstituted 5 membered monocyclic heterocycle, wherein the dihydropyridine core structure can be bound to either a carbon atom or a heteroatom of the 5 membered monocyclic heterocycle. In another embodiment, R37 is a bioisosteric replacement of an ester including, but not limited to, oxazole and oxadiazole. In another embodiment, R37 is -CN.
In another embodiment, in compounds represented by formula (XV), R37 is -OC(O)R38, wherein R3g is substituted or unsubstituted -(C1-Ci0)SIlCyI. Preferably, R38 is methyl, ethyl or propyl.
In another embodiment, in compounds represented by formula (XV), R37 is -C(O)OR38, wherein R38 is substituted or unsubstituted -(Ci-Cio)alkyl. Preferably, R38 is methyl, ethyl or propyl.
In another embodiment, in compounds represented by formula (XV), R37 is -C(O)OH.
In another embodiment, in compounds represented by formula (XV), R37 is -C(O)NHR38, where R38 is H, methyl, ethyl or propyl.
In another embodiment, in compounds represented by formula (XV), X is -CH2-.
In another embodiment, in compounds represented by formula (XV), Z is O or S. In another embodiment, Z is -N(CH3)-. In another embodiment, Z is -CH2-.
In another embodiment, in compounds represented by formula (XV), Z is O or S and V is a substituted or unsubstituted 3-7 membered monocyclic heterocycle or a substituted or
unsubstituted 8-12 membered bicyclic heterocycle, wherein the -(CH2)r group can be bound to a carbon atom or a heteroatom of V.
In another embodiment, in compounds represented by formula (XV), R38 is at each occurrence independently H or lower alkyl. In another embodiment, in compounds represented by formula (XV), R39, when substituted, is substituted with -OCOH5.
In another embodiment, in compounds represented by formula (XV), t is an integer selected from 1, 2, 3, 4 or 5.
In another embodiment, in compounds represented by formula (XV), s is 1. In another embodiment, in compounds represented by formula (XV), k is an integer selected from 3 or 4.
In another embodiment, in compounds represented by formula (XV), g is an integer selected from 1 or 2.
In another embodiment, in compounds represented by formula (XV), there applies a proviso that R34 and R35 are not both H.
In another embodiment, in compounds represented by formula (XV), there applies a proviso that if Ar is a bicyclic ring, R34 and R35 are not both H.
In another embodiment, in compounds represented by formula (XV), there applies a proviso that if X is -(CH2)-, R34 and R35 are not both H. In another embodiment, in compounds represented by formula (XV), there applies a proviso that if X is -(CH2)- or D is a bicyclic ring, R34 and R35 are not both H.
In another embodiment, in compounds represented by formula (XV), there applies a proviso that when Z is substituted or unsubstituted -(Ci-Cio)alkyl or fluoroalkyl, then V is not H or halo. In another embodiment, in compounds represented by formula (XV), there applies a proviso that if R36 is other than H, R34 and R35 are not both H.
In another embodiment, in compounds represented by formula (XV), one or more of the substituents R34, R35, R36, R37, R38, R39, R40, V, X, Y5 1, s, and k are selected from those included in the specific exemplified compounds described herein. In another aspect, the invention provides compounds of formula (XVI) as set forth below:
(XVI)
and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof wherein: Ar' is phenyl or pyridyl, which may be unsubstituted or independently substituted with one or more substituted or unsubstituted lower alkyl, -halo, -CN, -N(R's)(R5 5), -OR'5, -C(O)IT5, -C(O)2R5 S, -OC(O)R'5, -NO2, or -C(O)N(R'5)(R'5) groups, or two adjacent carbon atoms on the phenyl or pyridyl are linked by the group -0-(CH2)g-0- to form a bicyclic ring system, wherein g is an integer selected from 1, 2, 3 or 4; V is H, N(R' 1 i)(R' 11), N3, substituted or unsubstituted 3-7 membered monocyclic heterocycle or substituted or unsubstituted 8-12 membered bicyclic heterocycle; each R'i and R'2 may be independently selected from H and substituted or unsubstituted lower alkyl;
R'3 is -C(O)R'5, -H, or substituted or unsubstituted lower alkyl; R'4 is -CN, -CO2-lower alkyl, -C(0)NHR'5 or a bioisosteric replacement of an ester; each R'5 is at each occurrence independently H or substituted or unsubstituted -(C1- C10) alkyl;
R'π is at each occurrence independently selected from -H, -OH, -N(TTs)(R5 S), -OR's, -C(0)R'5) -C(O)NHC(O)R'5, substituted or unsubstituted -(Ci-C10)alkyl, substituted or unsubstituted -(C2-Cio)alkenyl, substituted or unsubstituted -(C2-Cio)alkynyl, substituted or unsubstituted -(C3-Cio)cycloalkyl, substituted or unsubstituted
substituted or unsubstituted -(Cs-Cio)cycloalkenyl, substituted or unsubstituted 3-7 membered monocyclic heterocycle, substituted or unsubstituted 8-12 membered bicyclic heterocycle, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, -CO2R'5, -C(O)OCH(R'5)(R'5), -NHC(O)R'S ,
-NHC(O)NHR5S, -C(O)NHR5S, -S(O)N(R'5)(R5 5), -SR'5, -S(O)R5S, and -S(O)2R'5; and t is an integer selected from the group consisting of 1, 2, 3 and 4.
Compounds of formula (XVI) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for treating inflammatory bowel disease.
More specific compounds of formula (XVI) include those wherein: Ar' is an ortho-substituted or unsubstituted phenyl or pyridyl, wherein if the phenyl or pyridyl is substituted, the substituents are independently selected from the group consisting of lower alkyl, -halo, -CN, -N(R'5)(R'5), -OR'5, -C(O)R'5, -C(O)2R'5, - OC(0)R'5, -NO2, and -C(O)N(R'5)(R'5);
V is -NH2 or -N3; R'i and R'2 may be independently selected from -H and substituted or unsubstituted
-lower alkyl;
R^ 3 is -C(O)R'5, -H, or substituted or unsubstituted -lower alkyl;
R'4 is -CN or -CO2-lower alkyl; each R'5 is independently -H or substituted or unsubstituted -(C1-CiO) alkyl; and t is 2 or 3.
In another embodiment, in compounds represented by formula (XVI), Ar' is phenyl substituted with one or more -halo, methyl, phenyl, -NO2, -CF3, OH, lower alkoxy, -CN or -NHT groups. In another embodiment, Ar' is quinoline, indole, pyridine oxide, pyradizine, pyrimidine, pyrazine, furan, thiophene, triazine, thiazole, imidazole, oxazole, indolizine, imidazo pyridine, naphthalene, dihydrobenzodioxine or benzo(l,3)dioxole.
In another embodiment, in compounds represented by formula (XVI), t is 2 and V is -NH2.
In another embodiment, in compounds represented by formula (XVI), g is an integer selected from 1 or 2. In another embodiment, in compounds represented by formula (XVI), R'3 is H, methyl or ethyl.
In another embodiment, in compounds represented by formula (XVI), R'4 is -CN.
In another embodiment, in compounds represented by formula (XVI), R'4 is -C(0)0R!5, wherein R'5 is substituted or unsubstituted -(CrCi0)alkyl. Preferably, R'5 is methyl, ethyl or propyl.
In another embodiment, in compounds represented by formula (XVI), R'4 is -OC(O)OH.
In another embodiment, in compounds represented by formula (XVI), R'4 is a bioisosteric replacement of an ester including, but not limited to, oxazole and oxadiazole.
In another embodiment, in compounds represented by formula (XVI), R'4 is -C(O)NHRZ5, where R'5 is H, methyl, ethyl or propyl. In another embodiment, in compounds represented by formula (XVI), V is
N(R'i)(R'i) or N3. In another embodiment, V is NH2. In another embodiment, V is -NH- CH2-CH(OH)-CH2-O-phenyl. In another embodiment, V is -NH-C(O)-lower alkyl. In another embodiment, V is -C(0)-0-lower alkyl. In another embodiment, V is -NH-lower alkyl or -N-(lower alkyl)2, wherein lower alkyl is preferably methyl or ethyl. In another embodiment, V is an isoindole-l,3-dione. In another embodiment, V is piperazine or morpholine. In another embodiment, V is a 5 membered monocyclic heterocycle. In another embodiment, V is a nitrogen containing 5 membered monocyclic heterocycle, such as pyrrole, imidazole or triazole.
In embodiments where V is a heterocycle in compounds represented by formula (XVI), the -(CH2)- group can be bound to a carbon atom or a heteroatom of V.
In another embodiment, in compounds represented by formula (XVI), R'i and R'2 are alkyl, preferably lower alkyl more preferably methyl.
In another embodiment, in compounds represented by formula (XVI), one of R'i and R'2 is H and the other is alkyl, preferably lower alkyl more preferably isopropyl or methyl.
In another embodiment, in compounds represented by foπnula (XVI), there applies a proviso that R'i and R'2 are not both H.
In another embodiment, in compounds represented by formula (XVI), there applies a proviso that if Ar' is a bicyclic ring, R'i and R'2 are not both H. In another embodiment, in compounds represented by formula (XVI), there applies a proviso that if R'3 is other than H, R'i and R'2 are not both H.
In another aspect, the invention provides compounds represented by formula (XVII) as set forth below:
(xvπ) or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein s, R45, R46, R47, R48, R49, R-52, R53, R54, and R55 are defined above; Di is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, or an optionally substituted heterocycloalkyl; X8 is O, S, -NR56-, or >CR5oR5i; and R5o and R5] are each, independently, -H or a substituent.
Compounds of formula (XVII) and pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof are particularly useful for treating inflammatory bowel disease.
In one embodiment, in compounds represented by formula (XVII), there applies one or more (including all) of the following provisos:
1) when R47 is methyl, Di is not a lower alkyl or a lower alkenyl group, wherein the lower alkyl or the lower alkenyl group is substituted with phenyl, nitrophenyl, pyridyl, cyclohexyl, phenylmethoxy, or -S(O)jCH3, wherein j is 0, 1, or 2;
2) when R47 is isopropyl or cyclopentyl, R46 is notjs»-(trifluoromethyl)benzoyl;
3) when R46 is cyano, R47 is not -SR56;
4) when R46 is cyano, -C(O)OCHaCH3, benzoyl, or acetyl, all of Di, R47, R52, and R53 are not methyl; and
5) provided that the compound is not 2,7,7-trimethyl-4-(hex-l-yl)-5-oxo- l,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl ester, 2-amino-4-ethyl-5-oxo-7,7- dimethyl-l,4,5,6,7,8-hexahydroquinoline-3-carbonitrile, 2-amino-4-methyl-5-oxo- l,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl ester, 2-phenyl-4-(2-phenylethyn-l- yl)-5-oxo-l,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl ester, 2-methyl-4- tetrahydrothienyl-S-oxo-lASjβ^δ-hexahydro-quinoline-S-carboxylic acid ethyl ester, 2,7,7- ti-imethyl^-cyclohexyl-S-oxo-l^jSjβ^^-hexahydroquinoline-S-carbonitrile, 2,7,7- trimethyl^-isopropyl-S-oxo-l^^jβJjS-hexahydroquinoline-S-carboxylic acid ethyl ester,
2,7,7-trimethyl-4-cyclopentyl-5-oxo-l,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl ester, 2,4-dimethyl-5-oxo-l,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl ester, or 2,4-dimethyl-5-oxo-4,7-dihydro-lH-furo[3,4-b]pyridine-3-carboxylic acid methyl ester.
In another embodiment, in compounds represented by formula (XVII), R48 and R49 taken together are =0.
In another embodiment, in compounds represented by formula (XVII), s is 1.
In another embodiment, in compounds represented by formula (XVII), Xg is -0-. In another embodiment, X8 is >CR5oR-5i -
In another embodiment, in compounds represented by foπnula (XVII), D1, s, Xg, R45, R46, R47, R48, R49, R52, R53, R54, and R55 are selected from those included in specific exemplified compounds described herein.
In another embodiment, in compounds represented by formula (XVII), Di is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl.
In another embodiment, in compounds represented by formula (XVII), D] is substituted with one or more substituents selected from the group consisting of an alkyl, an alkenyl, an alkynyl, an cycloalkyl, an cycloalkenyl, a heterocycloalkyl, an aryl, a heteroaryl, an aralkyl, a heteraralkyl, a haloalkyl, -C(O)NR6]R62, -NR63C(O)RO4, a halo, -OR63, cyano, nitro, a haloalkoxy, -C(O)R63, -NR6iR62, -SR63, -C(O)OR63, -OC(O)R63, -NR63C(O)NR61R62, -OC(O)NR6IR62, -NR63C(O)OR64, -S(O)jR63, -S(O)jNR61R62, =0, =S, and
wherein R6], R62, R63 and R64 are defined above.
In another embodiment, in compounds represented by formula (XVlI), Dj is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n- octyl, n-nonyl, n-decyl, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3- methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3- methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4- dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2- dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimtheylpentyl, 3,3-dimethylhexyl, 4,4- dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2- methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2- ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3- diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl, cyclopropyl, 1-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.
In another embodiment, in compounds represented by formula (XVII) D] is methyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, 1-methylcyclopropyl, or cyclopropylmethyl.
In another embodiment, R5o and R51 are -H in compounds represented by formula (XI) or (XVπ). In another embodiment, R54 and R55, for each occurrence, are -H in compounds represented by formula (XI), (XII), or (XVII).
In another embodiment, in compounds represented by formula (XI), (XII), or (XVII), R52 and R53 are both alkyl, preferably lower alkyl more preferably methyl.
In another embodiment, in compounds represented by formula (XI), (XII), or (XVII), one of R52 and R53 is H and the other is alkyl, preferably lower alkyl more preferably isopropyl or methyl.
In another embodiment, in compounds represented by formula (XI), (XII), or (XVII), R5O and R53 together with the carbon to which they are attached form a (C3- C7)cycloalkyl, preferably a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In another embodiment, in compounds represented by formula (XI), (XII), or
(XVII), R45 is H.
In another embodiment, in compounds represented by formula (XI), (XII), or (XVII), R45 is a lower alkyl, such as methyl or ethyl.
In another embodiment, in compounds represented by formula (XI), (XII), or (XVII), R46 is -C(O)O-(lower alkyl), -C(O)OH, cyano, -C(O)NR65R65, -C(O)-(lower alkyl), wherein R65, for each occurrence, is -H or a lower alkyl. In another embodiment, R46 is -OC(O)R65, wherein R65 is H or a lower alkyl. Preferably, R65 is methyl, ethyl or propyl. In another embodiment, R46 is -C(O)OR65, wherein R65 is H or a lower alkyl. Preferably, R65 is methyl, ethyl or propyl. In another embodiment, R46 is -C(O)OCH2CH3. In another embodiment, R46 is -C(O)OH. In another embodiment, R46 is -C(O)NHR65, wherein R65 is H or a lower alkyl. Preferably, R65 is methyl, ethyl or propyl. In another embodiment, R46 is a substituted or unsubstituted 5 membered monocyclic heterocycle, wherein the dihydropyridine core structure can be bound to either a carbon atom or a heteroatom of the 5 membered monocyclic heterocycle. In another embodiment, R46 is a bioisosteric replacement of an ester including, but not limited to, oxazole and oxadiazole. In another embodiment, R46 is -CN.
In another embodiment, in compounds represented by formula (XI), (XII), or (XVII), R47 is -(Ci-C6)alkyl-0-(C]-Cio)alkyl-3-7 membered monocyclic heterocycle. In another embodiment, R47 is -(CH2)-O-(CH2)2-3-7 membered monocyclic heterocycle. In
another embodiment, R47 is -(CH2)-O-(CH2)-3-7 membered monocyclic heterocycle. In another embodiment, R47 is -(C]-C6)alkyl-0-(Ci-Cio)alkyl-NH2. In another embodiment, R47 is
-(Ci-C6)alkyl-0-(Ci-Cio)alkyl-N3. In another embodiment, R47 is -(CH2)-O-(Ci-C10)- NR6IR62- In another embodiment, R47 is -(CH2)-O-(C1-C10)-NH-(C1-C6)alkyl. In another embodiment, R47 is -(CH2)-0-(Ci-Cio)-N((Ci-C6)alkyl)2. In another embodiment, R47 is -(CH2)-0-(Ci-Cio)-NH2. In another embodiment, R47 is -(CH2)-0-(CrCio)-N3. In another embodiment, R47 is -(CH2)^-(CHa)2-NRe]Ro2. In another embodiment, R47 is -(CH2)-O- (CH2)2- NH-(C rC6)alkyl. In another embodiment, R47 is -(CH2)-O-(CH2)2-N((Cr C6)alkyl)2. In another embodiment, R47 is -(CH2)-O-(CH2)2-NH2. In another embodiment, R47 is -(CH2)-O-(CH2)2-N3.
In another embodiment, in compounds represented by formula (XI), (XII), or (XVII), R47 is cyclopropyl, ethoxymethyl, 2-amino-ethoxymethyl, 2-azido-ethoxymethyl, 2-(2- hydroxy-3-phenoxy-propylamino)-ethoxymethyl, propoxymethyl, isopropoxymethyl, N- mesyl-2-aminoethoxymethyl, N-acetyl-2-aminoethoxymethyl, N-ethyl-2- aminoethoxymethyl, N-methyl-2-aminoethoxymethyl, 2-(l,3-dioxo-l,3-dihydro-isoindol-2- yl)-ethoxymethyl, morpholin-4-yl-methyl, 2-morpholin-4-yl-ethoxymethyl, N5N- dimethylaminomethyl, carbethoxycarbonylmethoxymethyl, N-(2-hydroxyethyl)-N- methylaminomethyl, piperazin-1-yl-methyl, 2-hydroxyethoxymethyl, N,N-dimethylamino- ethoxymethyl, 4-aminobutyl, imidazol-5-yl-methoxymethyl, imidazol-4-yl-methoxymethyl, 2-imidazol-l-yl-ethoxymethyl, 3-imidazol-l-yl-propyl, 3-pyrazol-l-yl-propyl, propoxymethyl, isopropoxymethyl, methoxyethoxymethyl, pyrrol-3-yl-methoxymethyl, pyrrol-2-yl-methoxymethyl, [l,2,4]triazol-3-yl-methoxymethyl, 2H-pyrazol-3-yl- methoxymethyl, 3H-[l,2,3]triazol-4-yl-methoxymethyl, or 2-pyrrol-l-yl-ethoxymethyl. In another embodiment, in compounds represented by formula (XI), (XH), or (XVII),
R47 is -NR72R73 or -OR74, wherein R72 and R73 are each, independently, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl,
-C(O)R75, -C(O)OR75, -C(O)NR76R77, -S(O)2R75, or -S(O)R75; or R72 and R73, taken together with the nitrogen to which they are attached are an optionally substituted heterocycloalkyl or optionally substituted heteroaryl; R74 is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally
substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, -C(O)R7S, -C(O)OR75, -C(O)NR76R??, -S(O)2R75, or -S(O)R75; R75 is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; and R76 and R77 are each, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl, or R76 and R77 taken together with the nitrogen to which they are attached are an optionally substituted heterocycloalkyl or optionally substituted heteroaryl.
In a preferred embodiment, in compounds represented by formula (XI), (XII), or (XVII), R47 is cyclopropyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, N-mesyl-2- aminoethoxymethyl, N-acetyl-2-aminoethoxymethyl, 2-(l,3-dioxo-l,3-dihydro-isoindol-2- yl)-ethoxymethyl, carbethoxycarbonylmethoxymethyl, 2-hydroxyethoxymethyl, imidazol-5- yl-methoxymethyl, imidazol-4-yl-methoxymethyl, 2-imidazol-l-yl -ethoxymethyl, 3- imidazol-1-yl-propyl, 3-pyrazol-l-yl-propyl, isopropoxymethyl, methoxyethoxymethyl, pyrrol-3-yl-methoxymethyl, pyrrol-2 -yl-methoxymethyl, [l,2,4]triazol-3 -yl-methoxymethyl, 2H-pyrazol-3-yl-methoxymethyl, 3H-[l,2,3]triazol-4-yl-methoxymethyl, or 2-pyrrol-l-yl- ethoxymethyl. In another preferred embodiment, R47 is -halo, -NO2, -CN, -OH, -OR66, -C(O)RO7,
-OC(O)R67, -C(O)NHC(O)R66, -(C2-Ci0)alkenyl, -(C2-C 10)alkynyl, -(C3-Ci4)bicycloalkyl, -(C5-C10)cycloalkenyl, naphthyl, benzyl, -(Ci-C6)alkyl-Zi-(Ci-Ci0)alkyl-R72, -(CrC10)alkyl- R72, -(CrC10)alkyl-NHR71, -CO2R67, -NHC(O)R67, -NHC(O)NHR67, -C(O)NHR67, -OC(O)R67, -OC(O)OR67, or -S(O)N(R67)(R67), wherein R72, for each occurrence, is, independently, selected from -H, halo, -CN, -NO2, -CN, -OH, -OR67, -C(O)R57, -OC(O)R67, -C(O)NHC(O)R67, -(CrC10)alkyl, -(C2-C 10)alkenyl, -(C2-C io)alkynyl, -(C3-C10)cycloalkyl, -(C8-Ci4)bicycloalkyl, -(C5-C1o)cycloalkenyl, phenyl, naphthyl, benzyl, -CO2R67, -C(O)OCH(R67)(R67), -NHC(O)R67, -NHC(O)NHR67, -C(O)NHR67, -OC(O)R67, -OC(O)OR67, -NR67S(O)2R66, -S(O)N(R67)(R67), -SR67, -S(O)R67, and -S(O)2R67.
In another preferred embodiment, in compounds represented by formula (XI), (XII), or (XVπ), R47 is a lower alkyl, a lower haloalkyl, a cycloalkyl, a -(Ci-C6)alkyl-NHR7i, a -(Ci-C6)alkyl-O-(Ci-C6)alkyl-NHR7i, wherein R7i, for each occurrence, is -S(OMCi-C6)alkyl, -S (O)2-(C i-C6)alkyl, and -C(O)-(Ci -C6)alkyl. One or more embodiments of for the compounds represented by formulas (I), (II), cm), (IV), (V), (VI), (vπ), (vm), (K)5 (X), (XI), (xn), (XΠL), (xrv), (xv), (xvi), (xvπ), or one or more substituents of the exemplary compounds of the invention (see Table 1) may be combined to form additional compounds of the invention. All such combinations are expressly encompassed in this invention. In one embodiment, compounds of the invention are characterized by an ability to reduce elevated blood glucose levels without a significant cardiovascular effect. In this context, a "significant cardiovascular effect" is no more than 75% (preferably, no more than 60% and more preferably, no more than 50%) of the cardiovascular activity of amlodipine in a standard procedure measuring mean arterial blood pressure (MAP) in a suitable cardiovascular animal model. In another embodiment, preferred compounds of this invention have activity against metabolic disorders without having significant acute toxicity. In this context, "without having significant acute toxicity" means having an LD50 above about 250 mg/kg, above about 500 mg/kg, above about 750 mg/kg or above about 1000 mg/kg. Preferred substituted 5-oxo-5,6,7,8-tetrahydroquinoline compounds are those with a molecular weight of about 300 g/mol to about 500 g/mol, from about 350 g/mol to about 450 g/mol, or from about 400 g/mol to about 450 g/mol.
Compounds of the invention advantageously can possess one or more desired biological activities. Such activities include, but are not limited to, one or more of the following: the ability to reduce blood glucose levels, the ability to reduce cholesterol levels, the ability to normalize blood levels of lipids, the ability to normalize blood levels of insulin, and/or the ability to improve insulin sensitivity in a patient in need thereof.
In one embodiment, compounds of the invention are useful for reducing blood glucose levels, reducing cholesterol levels, normalizing blood levels of lipids, and normalizing blood levels of insulin and/or improving insulin sensitivity in a patient in need thereof.
Exemplary Compounds of the Invention
Exemplary compounds of the invention are depicted in Table 1 below, including pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof .
Table 1
acid
acid
-
acid
-
acid
acid
-
1 -
acid
1-5- acid
acid
ester
acid
acid
-
1-5- acid
acid
acid
acid
acid
1-
acid
acid
acid
acid
acid
acid
acid
, 8- acid
[4,3 -
acid
acid
acid
acid
acid
1 H- acid
acid
-
-
acid
acid
acid
-
acid
acid
1 H-
acid
acid
acid
acid
1 H-
1 H-
Methods for Making Compounds of the Invention
Compounds of the invention can be obtained via standard, well-known synthetic methodology, see e.g., March, J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992. In particular, compounds of the invention can be obtained by methods well-known in the art for preparing 1,4-dihydropyridine compounds or 1,4,5,6,7,8- hexahydro-quinoline (e.g., known Ca2+ ion-channel blockers), followed by an oxidation step to form the 5,6,7, 8-tetrahydroquinoline. Certain 1,4-dihydropyridine compounds can be obtained by the processes set forth in U.S. Provisional Application No. 60/561,246 entitled, "Methods for Synthesis of Dihydropyridine Compounds," filed April 9, 2004 and U.S. Application No. 10/939,252 entitled "Dihydropyridine Compund for Treating or Preventing Metabolic Disorder," filed Sept. 10, 2004 (the entire teachings of which are incorporated herein by reference). The 1,4-dihydropyridine compounds can then be oxidized to form a compound of the invention by the following procedure:
Oxidation Procedure:
To a solution of a 1,4-dihydropyridine compound in acetone (HPLC grade) at O0C is added 2.5 eq of ammonium cerium (IV) nitrate (CAN) and the reaction allowed to stir at O0C until complete (~2 hrs). The reaction is then quenched with saturated aqueous Na2SO3 and extracted with ethyl acetate (EtOAc). The organic layer is then washed 3 times with water and 1 time with brine, dried, filtered and concentrated. A short column is then run to remove any remaining metal to yield a 5,6,7,8-tetrahydroquinoline compound of the invention as a white solid.
Starting materials useful for preparing compounds of the invention and intermediates therefore, are commercially available or can be prepared from commercially available materials using known synthetic methods and reagents.
In addition, compounds of the invention can also be prepared as shown below in Schemes I, π, in, IV and Examples.
Scheme I
NaH (CH2)q
V- .OH /
\ Cl R V
(CH2)^ 1 THF, DMF -α R1
0 O Step i
q is an integer from one to 10.
V is H, halo, N3, NO2, CN, ORn, NR12R13, C(O)NHC(O)R11, an optionally substituted heterocyclyl or an optionally substituted heteroaryl.
Scheme HI
Z is -O-, -S-, -N(Rn)-, -C(O)-, -OC(O)-, -C(O)N(R11)C(O)-, substituted or unsubstituted -(Cl-ClO)alkyl-, substituted or unsubstituted -(C2-C1o)alkenyl-, substituted or unsubstituted (C2-C10)alkynyl-, substituted or unsubstituted -(C3-C]4)cycloalkyl-, substituted or unsubstituted -(C5-C10)cycloalkenyl-, substituted or unsubstituted -(C3-C14)heterocyclyl-, a substituted or unsubstituted -(C5-C14)heteroaryl-, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, -C(O)O-, - C(OPC(R11)(R11X -N(R11)C(O)-, N(Rn)C(O)NR11-, -C(O)NR11-, -OC(O)O-, -S(O)N(Rn)-, -S(O)-, or -S(O)2-.
In particular, tricyclic compounds of the invention can be obtained by methods well- known in the art for preparing 1,4-dihydropyridine compounds or 1,4,5,6,7,8-hexahydro- quinoline (e.g., known Ca2+ ion-channel blockers), followed by a cyclization step to form the
third ring as described herein in Example 3. In compounds of the invention that have an aromatic middle ring, an oxidation step is preformed, as above.
Uses of Compounds of the Invention
The present invention is directed to therapies which involve administering one of more compounds of the invention, and compositions comprising said compounds to a subject, preferably a human subject, for preventing, treating, managing, or ameliorating a metabolic disorder or one or more symptoms thereof.
In one embodiment, the invention provides a method of preventing, treating, managing, or ameliorating a metabolic disorder or one or more symptoms thereof, said method comprising administering to a subject in need thereof an effective amount of one or more compounds of the invention. In a specific embodiment, the invention provides a method of preventing, treating, managing, or ameliorating diabetes mellitus (type I and/or type II), and/or a symptom, condition and/or complication associated therewith, said method comprising administering to a subject in need thereof an effective amount of one or more compounds of the invention. In another embodiment, the invention provides a method of achieving one, two, three or more of the following: (i) reducing blood glucose levels, (ii) improving blood lipid levels, (iii) improving blood insulin levels, and (iv) improving insulin sensitivity, said method comprising administering to a subject in need thereof an effective amount of a compound of formula (I), (H), (IH), (IV), (V), (VI) ,(VII), (VHI), (IX), (X), or Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.
In one embodiment, the invention encompasses a method for preventing, treating, managing, or ameliorating a metabolic disorder (e.g., type I and/or type II diabetes mellitus) or one or more symptoms thereof, comprising administering an effective amount of one or more compounds of the invention or derivatives thereof, including pharmaceutically acceptable salts, solvates, clathrates, or prodrugs thereof, to a patient in need thereof.
In another embodiment, the invention encompasses a method for preventing, treating, managing, or ameliorating a metabolic disorder (e.g., type I and/or type II diabetes mellitus) or one or more symptoms thereof, comprising administering an effective amount of a 5,6,7,8-tetrahydroquinoline compound of the invention characterized by an ability to reduce elevated blood glucose levels without a significant cardiovascular effect.
In another embodiment, the invention encompasses a method for preventing, treating, managing, or ameliorating a metabolic disorder (e.g., type I and/or type II diabetes mellitus)
or one or more symptoms thereof, comprising administering an effective amount of a compound of the invention characterized by an ability to reduce elevated blood glucose levels without a significant cardiovascular effect.
In another embodiment, the invention encompasses a method for preventing, treating, managing, or ameliorating a metabolic disorder (e.g., type I and/or type II diabetes mellitus) or one or more symptoms thereof, comprising administering an effective amount of a compound of the invention which does not have significant toxicity.
In another embodiment, the invention encompasses a method for preventing, treating, managing, or ameliorating inflammatory bowel disease or one or more symptoms thereof, comprising administering an effective amount of one or more compounds of the invention or derivatives thereof, including pharmaceutically acceptable salts, solvates, clathrates, or prodrugs thereof, to a patient in need thereof. In another embodiment, the invention encompasses a method for preventing, treating, managing, or ameliorating ulcerative colitis or one or more symptoms thereof, comprising administering an effective amount of one or more compounds of the invention or derivatives thereof, including pharmaceutically acceptable salts, solvates, clathrates, or prodrugs thereof, to a patient in need thereof. In another embodiment, the invention encompasses a method for preventing, treating, managing, or ameliorating Crohn's disease or one or more symptoms thereof, comprising administering an effective amount of one or more compounds of the invention or derivatives thereof, including pharmaceutically acceptable salts, solvates, clathrates, or prodrugs thereof, to a patient in need thereof. hi another embodiment, the invention encompasses a method for preventing, treating, managing, or ameliorating a metabolic disorder (e.g., type I and/or type π diabetes mellitus) or one or more symptoms thereof, comprising administering an effective amount of a compound of formula (I):
or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein n, A5 Xi, X2, X3, Ri, R2, R7, Rs, R9, and R]0 are as defined above, to a patient in need thereof.
In another embodiment, the invention encompasses a method for preventing, treating, managing, or ameliorating a metabolic disorder (e.g., type I and/or type π diabetes mellitus) or one or more symptoms thereof, comprising administering an effective amount of a compound of formula (II):
or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein n, A, Xi, X2, X3, R2, R9, Rio, R30, R-31J and R32 are as defined above, to a patient in need thereof.
In another embodiment, the invention encompasses a method for preventing, treating, managing, or ameliorating a metabolic disorder (e.g., type I and/or type II diabetes mellitus) or one or more symptoms thereof, comprising administering an effective amount of a compound of formula (IH):
In another embodiment, the invention encompasses a method for preventing, treating, managing, or ameliorating a metabolic disorder (e.g., type I and/or type II diabetes mellitus) or one or more symptoms thereof, comprising administering an effective amount of a compound of formula (IV):
In another embodiment, the invention encompasses a method for preventing, treating, managing, or ameliorating a metabolic disorder (e.g., type I and/or type II diabetes mellitus) or one or more symptoms thereof, comprising administering an effective amount of a compound of formula (V):
In another embodiment, the invention encompasses a method for preventing, treating, managing, or ameliorating a metabolic disorder (e.g., type I and/or type II diabetes mellitus) or one or more symptoms thereof, comprising administering an effective amount of a compound of formula (VII):
(VII) or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein Xi, Xe, X7, X4, X5, R78, R79, Rβo, Rδi, Rδ2, Rδ3, Rδ4, Rs5, B, q and r are defined as above.
In another embodiment, the invention encompasses a method for preventing, treating, managing, or ameliorating a metabolic disorder (e.g., type I and/or type II diabetes mellitus) or one or more symptoms thereof, comprising administering an effective amount of a compound of formula (VIII):
(VHI) or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein X1, Xe, X7, X4, X5, R78, R79, Rso, Rs l, R82, Rs3, Rs4, Res, Bi, q and r are defined as above.
In another embodiment, the invention encompasses a method for preventing, treating, managing, or ameliorating a metabolic disorder (e.g., type I and/or type II diabetes mellitus) or one or more symptoms thereof, comprising administering an effective amount of a compound of formula (IX):
X4, X5, R7S, R79, Rso, Rsi, Rs2, Rs3, Rs4, Res, R97, B2, q and r are defined as above.
In another embodiment, the invention encompasses a method for preventing, treating, managing, or ameliorating a metabolic disorder (e.g., type I and/or type II diabetes mellitus) or one or more symptoms thereof, comprising administering an effective amount of a compound of formula (X):
(X) or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein Xe3 X7, X4, X5, R-78, R79, R-80, Rsi, Rs2, Rs3, Rs4, Rs5, R97, B2, q and r are defined as above. One or more of the compounds of the invention may be used as a first, second, third, fourth or fifth line for the treatment of a metabolic disorder. The invention provides methods for preventing, treating, managing, or ameliorating a metabolic disorder or one or more symptoms thereof in a subject refractory (either partially or completely) to conventional therapies for such a disorder, said methods comprising administering to said subject a dose of an effective amount of one or more compounds of the invention. The invention also provides methods of preventing, treating, managing, or ameliorating a metabolic disorder or one or more symptoms thereof, said methods comprising administering to a subject in need thereof one or more compounds of the invention and one or more other therapies (e.g., one or more prophylactic or therapeutic agents that are currently being used, have been used, are known to be useful or in development for use in the prevention, treatment or amelioration of one or more symptoms associated with said metabolic disorder).
In one embodiment, the invention provides methods of preventing, treating, managing, or ameliorating a metabolic disorder or one or more symptoms thereof, said methods comprising administering to a subject in need thereof an effective amount of one or more compounds of the invention and an effective amount of one or more other therapies such as prophylactic or therapeutic agents. In a specific embodiment, the invention provides a method of preventing, treating, managing, or ameliorating diabetes mellitus (type I and/or type II), and/or a symptom, condition and/or complication associated therewith, said method comprising administering to a subject in need thereof a dose of an effective amount of one or more compounds of the invention and an effective amount of one or more other therapies such as prophylactic or therapeutic agents. In another embodiment, the invention provides a
method of achieving one, two, three or more of the following: (i) reducing blood glucose levels, (ii) improving blood lipid levels, (iii) improving blood insulin levels, and (iv) improving insulin sensitivity, said method comprising administering to a subject in need thereof an effective amount of a compound of formula (I), (II), (DI), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof and an effective amount of one or more other therapies such as prophylactic or therapeutic agents. Non-limiting examples of such agents include those in Section 5.5 infra.
The invention also provides methods of treating inflammatory bowel disease comprising administering to a subject in need thereof one or more compounds of the invention and one or more other therapies {e.g., one or more prophylactic or therapeutic agents that are currently being used, have been used, are known to be useful or in development for use in the treatment or amelioration of one or more symptoms associated with said inflammatory bowel disease). The prophylactic or therapeutic agents of the combination therapies of the invention can be administered sequentially or concurrently. In a specific embodiment, the combination therapies of the invention comprise one or more compounds and at least one other therapy {e.g., another prophylactic or therapeutic agent) which has the same mechanism of action as said compounds. In another specific embodiment, the combination therapies of the invention comprise one or more compounds of the invention and at least one other therapy {e.g., another prophylactic or therapeutic agent) which has a different mechanism of action than said compounds. In certain embodiments, the combination therapies of the present invention improve the prophylactic or therapeutic effect of one or more compounds of the invention by functioning together with the compounds to have an additive or synergistic effect. In certain embodiments, the combination therapies of the present invention reduce the side effects associated with the therapies (e.g., prophylactic or therapeutic agents).
The prophylactic or therapeutic agents of the combination therapies can be administered to a subject, preferably a human subject, in the same pharmaceutical composition. In alternative embodiments, the prophylactic or therapeutic agents of the combination therapies can be administered concurrently to a subject in separate pharmaceutical compositions. The prophylactic or therapeutic agents may be administered to a subject by the same or different routes of administration.
In a specific embodiment, a pharmaceutical composition comprising one or more compounds of the invention is administered to a subject, preferably a human, to prevent, treat, manage, or ameliorate one or more symptoms associated with a metabolic disorder. In accordance with the invention, pharmaceutical compositions of the invention may also comprise one or more other agents (e.g., prophylactic or therapeutic agents which are currently being used, have been used, or are known to be useful in the prevention, treatment or amelioration of said metabolic disorder or a symptom thereof).
The invention provides methods for preventing, managing, treating or ameliorating a metabolic disorder or one or more symptoms thereof in a subject refractory (either completely or partially) to existing single agent therapies for such a metabolic disorder, said methods comprising administering to said subject a dose of an effective amount of one or more compounds of the invention and a dose of an effective amount of one or more therapies (e.g., one or more prophylactic or therapeutic agents useful for the prevention, treatment, management, or amelioration of a metabolic disorder or a symptom thereof). The invention also provides methods for preventing, treating, managing, or ameliorating a metabolic disorder or a symptom thereof by administering one or more compounds of the invention in combination with any other therapy(ies) to patients who have proven refractory to other therapies but are no longer on these therapies.
The compounds of the invention and/or other therapies can be administered to a subject by any route known to one of skill in the art. Examples of routes of administration include, but are not limited to, parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), intranasal, transdermal (topical), transmucosal, and rectal administration.
Agents Useful In Combination With the Compounds of the Invention
Without wishing to be bound by theory, compounds of this invention may act by a new mechanism and may advantageously represent a new option for treating and preventing metabolic disorders. Compounds of the invention appear to reduce blood glucose levels, reduce insulin levels in hyperinsulinic patients, and alleviate insulin resistance in animal models of diabetes. These compounds have independent activity but surprisingly, in some embodiments, can also act synergistically to enhance the activity of certain conventional diabetes drugs, such as metformin and rosiglitazone. As a result, compounds of this invention can be used as single agents or in combination therapy with other agents.
The present invention provides methods for preventing, managing, treating, or ameliorating metabolic disorders comprising administering to a subject in need thereof one or more compounds of the invention and one or more therapies (e.g., one or more prophylactic or therapeutic agents) other than compounds of the invention. The present invention also provides compositions comprising one or more compounds of the invention and one or more prophylactic or therapeutic agents other than compounds of the invention and methods of preventing, managing, treating, or ameliorating a metabolic disorder utilizing said compositions. Therapeutic or prophylactic agents include, but are not limited to, small molecules, synthetic drugs, peptides, polypeptides, proteins, nucleic acids (e.g., DNA and RNA nucleotides including, but not limited to, antisense nucleotide sequences, RNAi, triple helices and nucleotide sequences encoding biologically active proteins, polypeptides or peptides), antibodies, synthetic or natural inorganic molecules, mimetic agents, and synthetic or natural organic molecules.
Any agent which is known to be useful, or which has been used, is currently being used for or is in development for the prevention, management, treatment, or amelioration of a metabolic disorder (such as diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof) or one or more symptoms thereof can be used in combination with a compound of the invention in accordance with the invention described herein. See, e.g., Gilman et ah, Goodman and Gilman's: The Pharmacological Basis of Therapeutics, Tenth Ed., McGraw-Hill, New York, 2001; The Merck Manual of Diagnosis and Therapy, Berkow, M.D. et a (eds.), 17th Ed., Merck Sharp & Dohme Research Laboratories, Rahway, NJ, 1999; Cecil Textbook of Medicine, 20th Ed., Bennett and Plum (eds.), W.B. Saunders, Philadelphia, 1996 for information regarding prophylactic or therapeutic agents which have been or are currently being used for preventing, treating, managing, or ameliorating metabolic disorders or one or more symptoms thereof. Non- limiting examples of agents include anti-diabetic agents, anti-obesity agents, and lipid lowering agents.
Anti-diabetic agents include, without limitation, insulin and oral hypoglycemic agents. Insulin can be in any form and delivered by any acceptable route. For example, insulin can be intravenously delivered as premixed insulin (such as Humalog Mix (Eli Lilly) and
NovoMix/Novolog Mix (Novo Nordisk)) or short-acting isophane. Human insulins include Humulin (Eli Lilly), Actrapid/Novolin (Novo Nordisk), Insuman (Aventis), and
Wosulin (Wockhardt). Short-acting insulin analogues include Humalog (Eli Lilly), NovoRapid/Novolog (Novo Nordisk), and Insulin glulisine (Apidra, Aventis). There are also controlled-release insulins such as Basulin (BMS) and inhaled insulins such as Exubera (Pfϊzer/Aventis/Nektar) . Newer insulin-related agents in development include agents that switch on insulin receptors (e.g., PTPl 12 (American Home Products), fast acting insulin (1964 (Aventis)), insulin sensitizers (such as Dexlipotam (Aventis), FK614 (Fujisawa), balaglitazone (NN2344, Novo Nordisk), CRE 16336 and 16258 (Merck KGaA), MXC 3255 (Maxia), KP 102 (Kinetek) and PNU 182716 (Pharmacia)), long acting insulin (such as Insulin detemir (Levemir, Novo Nordisk) and Lantus (Aventis) and Levemir (Novo Nordisk)), pulmonary delivered insulin, transdermal insulin (such as that under development by Dong shin) and oral insulin (such as Beodas (Elan) and the insulin and pro-insulin analogs, AI 401 and LY 197535 (Lilly)).
Oral hypoglycemic agents include, but are not limited to: I. Biguanides. These compounds act by keeping the liver from releasing too much glucose. Non-limiting examples include metformin (Glucophage, Bristol-Myers Squibb) and glyburide/metformin (Glucovance, Bristol-Myers Squibb).
II. Perioxisomes Proliferator Activated Receptor γ (PP ARγ) agonists of the thiazolidinedione class. These compounds enhance muscle cell sensitivity to insulin. Non- limiting examples include pioglitazone (Actos, Lilly), rosiglitazone (Avandia,
GlaxoSmithKline), isaglitazone (such as MCC555 (Johnson & Johnson)) and troglitizone. •
III. Insulinotropic agents. These compounds act by stimulating the pancreas to release more insulin. Non-limiting examples include the non-sulfonylurea secretagogues repaglinide (Prandin, Novo Nordisk), nateglinide (Starlix, Novartis) and glyburide (Micronase, Upjohn).
IV. Sulphonylureas. These compounds stimulate the pancreas to release more insulin. Non-limiting examples include glimepiride (Amaryl, Aventis) and glipizide (Glucotrol, Pfizer).
V. α-glucosidase inhibitors. These compounds slow carbohydrate metabolism. Non-limiting examples include miglitol (Glyset, Bayer) and acarbose (Glucobay and
Precose, Bayer).
New diabetes drugs in development fall into a number of additional categories, including:
I. PPARγ agonists (non-thiazolidinediones) (one reported to be under development by Novo Nordisk).
II. PPAR α and PPAR α/γ agonists (such as NN622 (Novo Nordisk), AZ242 (Astra Zeneca), BMS 298585 (Bristol-Myers Squibb), PNU 182716 (Pharmacia), JEO297 (Merck) and DRF 4158 (Novartis)) .
III. Glucagon-Like Peptides (GLPs such as the secretagogue GLP-I) and analogues (such as liraglutide (NN2211, Novo Nordisk), a GLP-I analogue under development by Lilly, AC2993 (Amylin) and Ave-0010 (Aventis)).
IV. Dipeptidylpeptidase IV inhibitors (such as LAF237 (Novartis), P32/98 (ProBiodrug) and DPP 728 (Novartis)).
VI. Glycogen phosphorylase inhibitors (such as NN4201 (isofagamine, Novo Nordisk) and CP 368296 (Pfizer)).
VII. Tyrosine phosphatase inhibitors.
VIII. GLUT 4-mediated glucose transport modulators. IX. Immunoregulatory vaccines.
X. Amylin receptor antagonists (such as Symlin (pramlintide acetate, Amylin)).
XI. Selective β adrenergic agonists (such as the β3 adrenergic agonists BMS 194449, 196085 and 201620 (BMS) and GW427353 and SB418790 (GlaxoSmithKline).
XII. gluconeogenesis inhibitors (such as CS-917 (Sankyo/Metabasis)). Xiπ. potassium channel openers (such as NN414 (Novo Nordisk)).
XIV.' PPAR pan agonists (such as 677954 (GSK)).
XV. T cell inhibitors (such as NBI-6024 (Neurocrine)).
XVI. T cell modulators (such as AVE-0277 (Aventis)).
XVπ 11 beta HSDl enzyme inhibitors (such as BVT3498 (Amgen/Biovitrum)). Combination diabetic therapies are also under development (such as an
Avandia/Metfomin combination being developed by GlaxoSmithKline and glipizide/metformin, BMS). In these combination therapies, the agents are typically selected from two or more classes of agents having different mechanisms of action.
Anti-obesity drugs can also be used in combination therapies according to this invention. Such drugs include, without limitation, appetite suppressants and fat blockers. Appetite suppressants include noradrenergic and serotonergic agents. Noradrenergic drugs affect weight loss through action in the appetite center and include phenylpropanolamine (Dexatrim) and phentermine (Ionamin) Phentermine was previously used in combination with fenfluramine (Pondimin) to improve weight loss and counteract the adverse effects of
use of phentermine but because of the withdrawal of fenfluramine from the U.S. market, phentermine is now used as a single weight-loss agent.
Serotonergic drugs partially inhibit the reuptake of serotonin and release serotonin into the synaptic cleft, thus acting on the hypothalamus to decrease satiety. Fenfluramine and dexfenfiuramine (Redux), the first serotonergic agents labeled for the treatment of obesity, were withdrawn from the U.S. market in September 1997 because of case reports of valvular heart disease and primary pulmonary hypertension. Selective serotonin reuptake inhibitors (SSRIs) may also be used as serotonergic drugs. For example, fluoxetine (Prozac) is a highly selective serotonin reuptake inhibitor that has also been studied in the treatment of obesity. Additional SSRIs currently on the market include Paxil, Effexor, Zoloft, Celexa and Luvox. Others are well known to those of ordinary skill in the art.
Adrenergic/serotonergic agents may also be used in combination with the compounds of this invention. Sibutramine (Meridia) is an adrenergic/serotonergic agent recently labeled by the FDA for use in the management of obesity. Sibutramine and its metabolite inhibit monoamine uptake, suppressing appetite in a fashion similar to SSRIs.
Thermogenic agents form another category of anti-obesity drugs that are useful in combination with the compounds of this invention. For example, the combination of ephedrine and caffeine possesses anorectic and thermogenic properties with only mild, transient side effects. Ephedrine increases the release of norepinephrine, which modulates food intake and acts as a sympathomimetic agent to stimulate heart rate and blood pressure, and enhance thermogenesis. Caffeine, an adenosine antagonist, reduces the breakdown of norepinephrine within the synaptic junction.
Digestive inhibitors interfere with the breakdown, digestion and absorption of dietary fat in the gastrointestinal tract. Gastric and pancreatic lipases aid in the digestion of dietary triglycerides by forming them into free fatty acids that are then absorbed at the brush border of the small intestine. Inhibition of these enzymes leads to inhibition of the digestion of dietary triglycerides and decreased cholesterol absorption, and may decrease absorption of lipid-soluble vitamins (A, D, E and K). Orlistat (Xenical), the first lipase inhibitor labeled by the FDA for treatment of obesity, is a potent and irreversible inhibitor of gastric and pancreatic lipases, preventing the absorption of about 30 percent of dietary fat.
The goal of fat substitutes is to decrease caloric value from fat while maintaining the creaminess and richness derived from fat. The most recent fat-based substitute, olestra (Olean), contains zero kcal per gram. Olestra is a sucrose polyester, labeled by the FDA for use as a food additive in prepackaged snacks (potato, corn and tortilla chips, and crackers) to
replace 100 percent of the fat. As a sucrose polyester with six to eight fatty-acid side chains, it is too large to be hydrolyzed by digestive enzymes and, therefore, is not absorbed and has no caloric value.
The gastrointestinal tract and central nervous system also contain several peptides and hormones that regulate feeding behavior. For example, cholecystokinin and serotonin act to decrease appetite and food intake. Conversely, neuropeptide Y increases food intake and decreases energy expenditure. Leptin may limit food intake, decrease plasma insulin and increase energy expenditure. Therefore, agonists and antagonists of these hormones and peptides are currently under investigation for the treatment of obesity and may be useful in the combination therapies of this invention.
Lipid lowering agents include without limitation cholestyramine, gemfibrozil, fenofibrate, nicotinic acid and related compounds and statins (such as pravastatin and lovastatin).
Compositions and Methods for Administering Therapies The present invention provides compositions for the treatment, prophylaxis, and amelioration of metabolic disorders. In a specific embodiment, a composition comprises one or more compounds of the invention, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In another embodiment, a composition of the invention comprises one or more prophylactic or therapeutic agents other than a compound of the invention, or a pharmaceutically acceptable salt, solvate or hydrate thereof. In another embodiment, a composition of the invention comprises one or more compounds of the invention, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and one or more other prophylactic or therapeutic agents. In another embodiment, the composition comprises a compound of the invention, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
In a preferred embodiment, a composition of the invention is a pharmaceutical composition or a single unit dosage form. Pharmaceutical compositions and dosage forms of the invention comprise one or more active ingredients in relative amounts and formulated in such a way that a given pharmaceutical composition or dosage form can be used to treat or prevent metabolic disorders, such as diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof. Preferred pharmaceutical compositions and dosage forms comprise a compound of formula (I), (II), (DT), (IV), (V), (VI), (VII), (VQT), (IX)5 (X), (XI), (XIL), (XHT), (XTV), (XV), (XVI), (XVE), or Table 1, or a pharmaceutically
acceptable prodrug, salt, solvate, or clathrate thereof, optionally in combination with one or more additional active agents.
A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include, but are not limited to, parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), intranasal, transdermal (topical), transmucosal, and rectal administration. In a specific embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to human beings. In a preferred embodiment, a pharmaceutical composition is formulated in accordance with routine procedures for subcutaneous administration to human beings.
Single unit dosage forms of the invention are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), or transdermal administration to a patient. Examples of dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.
The composition, shape, and type of dosage forms of the invention will typically vary depending on their use. For example, a dosage form suitable for mucosal administration may contain a smaller amount of active ingredient(s) than an oral dosage form used to treat the same indication. This aspect of the invention will be readily apparent to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences (1990) 18th ed., Mack Publishing, Easton PA. Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in
which the dosage form will be administered to a patient. For example, oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms.
The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active ingredients can be accelerated by some excipients such as lactose, or when exposed to water. Active ingredients that comprise primary or secondary amines (e.g., N-desmethylvenlafaxine and N,N-didesmethylvenlafaxine) are particularly susceptible to such accelerated decomposition. Consequently, this invention encompasses pharmaceutical compositions and dosage forms that contain little, if any, lactose. As used herein, the term "lactose-free" means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient. Lactose-free compositions of the invention can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmocopia (USP) SP (XXI)/NF (XVI). In general, lactose-free compositions comprise active ingredients, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Preferred lactose-free dosage forms comprise active ingredients, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.
This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e.g., Jens T. Carstensen (1995) Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 379-80. In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.
Anhydrous pharmaceutical compositions and dosage fonns of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine are preferably anhydrous. If substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected, a lactose-free composition or dosage form is < preferred.
An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are preferably packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
The invention further encompasses pharmaceutical compositions and dosage forms that comprise one or more' compounds that reduce the rate by which an active ingredient will decompose. Such compounds, which are referred to herein as "stabilizer" include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
Oral Dosage Forms
Pharmaceutical compositions of the invention that are suitable for oral administration can be presented as discrete dosage foπns, such as, but are not limited to, tablets (e.g., chewable tablets), cap lets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences (1990) 18th ed., Mack Publishing, Easton PA.
Typical oral dosage forms of the invention are prepared by combining the active ingredient(s) in an admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
For example, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free- flowing form such as powder or granules, optionally mixed with an excipient. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
Examples of excipients that can be used in oral dosage forms of the invention include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre- gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof. Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as A VICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVlCEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. One specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH- 103 J and Starch 1500 LM.
Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. The binder or filler in pharmaceutical compositions of the invention is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
Disintegrants are used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms of the invention. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. Typical pharmaceutical compositions
comprise from about 0.5 to about 15 weight percent of disintegrant, preferably from about 1 to about 5 weight percent of disintegrant.
Disintegrants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
Lubricants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, for example, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Piano, TX), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
Controlled Release Dosage Forms
Active ingredients of the invention can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients of the invention. The invention thus encompasses single unit dosage
forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.
All controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled- release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
A particular extended release formulation of this invention comprises a therapeutically or prophylactically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, or prodrug thereof, in spheroids which further comprise microcrystalline cellulose and, optionally, hydroxypropylmethyl- cellulose coated with a mixture of ethyl cellulose and hydroxypropylmethylcellulose. Such extended release formulations can be prepared according to U.S. Patent No. 6,274,171, the entirely of which is incorporated herein by reference.
A specific controlled-release formulation of this invention comprises from about 6% to about 40% a compound of formula (I) by weight, about 50% to about 94% microcrystalline cellulose, NF, by weight, and optionally from about 0.25% to about 1% by weight of hydroxypropyl-methylcellulose, USP, wherein the spheroids are coated with a film coating composition comprised of ethyl cellulose and hydroxypropylmethylcellulose.
Parenteral Dosage Forms
Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions. Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms of the invention.
Transdermal, Topical, and Mucosal Dosage Forms
Transdermal, topical, and mucosal dosage forms of the invention include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences (1980 & 1990) 16th and 18th eds., Mack Publishing, Easton PA and Introduction to Pharmaceutical Dosage Forms (1985) 4th ed., Lea & Febiger, Philadelphia. Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels. Further, transdermal dosage forms include "reservoir type" or "matrix type" patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredients. Suitable excipients {e.g., carriers and diluents) and other materials that can be used to provide transdermal, topical, and mucosal dosage forms encompassed by this invention are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to
which a given pharmaceutical composition or dosage form will be applied. With that fact in mind, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane- 1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form lotions, tinctures, creams, emulsions, gels or ointments, which are non-toxic and pharmaceutically acceptable. Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences (1980 & 1990) 16th and 18th eds., Mack Publishing, Easton PA.
Depending on the specific tissue to be treated, additional components may be used prior to, in conjunction with, or subsequent to treatment with active ingredients of the invention. For example, penetration enhancers can be used to assist in delivering the active ingredients to the tissue. Suitable penetration enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water-soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).
The pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied, may also be adjusted to improve delivery of one or more active ingredients. Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery. In this regard, stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration-enhancing agent. Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition.
Dosage & Frequency of Administration The amount of the compound or composition of the invention which will be effective in the prevention, treatment, management, or amelioration of a metabolic disorder or an inflammatory bowel disease, or one or more symptoms thereof will vary with the nature and severity of the disease or condition, and the route by which the active ingredient is administered. The frequency and dosage will also vary according to factors specific for each
patient depending on the specific therapy {e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the patient. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems. Suitable regiments can be selected by one skilled in the art by considering such factors and by following, for example, dosages reported in the literature and recommended in the Physician 's Desk Reference (57th ed., 2003).
Exemplary doses of a small molecule include milligram or microgram amounts of the small molecule per kilogram of subject or sample weight (e.g., about 1 microgram per kilogram to about 500 milligrams per kilogram, about 100 micrograms per kilogram to about 5 milligrams per kilogram, or about 1 microgram per kilogram to about 50 micrograms per kilogram). For antibodies, proteins, polypeptides, peptides and fusion proteins encompassed by the invention, the dosage administered to a patient is typically 0.0001 mg/kg to 100 mg/kg of the patient's body weight. Preferably, the dosage administered to a patient is between 0.0001 mg/kg and 20 mg/kg, 0.0001 mg/kg and 10 mg/kg, 0.0001 mg/kg and 5 mg/kg, 0.0001 and 2 mg/kg, 0.0001 and 1 mg/kg, 0.0001 mg/kg and 0.75 mg/kg, 0.0001 mg/kg and 0.5 mg/kg, 0.0001 mg/kg to 0.25 mg/kg, 0.0001 to 0.15 mg/kg, 0.0001 to 0.10 mg/kg, 0.001 to 0.5 mg/kg, 0.01 to 0.25 mg/kg or 0.01 to 0.10 mg/kg of the patient's body weight. Generally, human antibodies have a longer half-life within the human body than antibodies from other species due to the immune response to the foreign polypeptides. Thus, lower dosages of human antibodies and less frequent administration is often possible. Further, the dosage and frequency of administration of antibodies of the invention or fragments thereof may be reduced by enhancing uptake and tissue penetration of the antibodies by modifications such as, for example, lipidation. In general, the recommended daily dose range of a compound of the invention for the conditions described herein lie within the range of from about 0.01 mg to about 1000 mg per day, given as a single once-a-day dose preferably as divided doses throughout a day. In one embodiment, the daily dose is administered twice daily in equally divided doses. Specifically, a daily dose range should be from about 5 mg to about 500 mg per day, more specifically, between about 10 mg and about 200 mg per day. In managing the patient, the therapy should be initiated at a lower dose, perhaps about 1 mg to about 25 mg, and increased if necessary up to about 200 mg to about 1000 mg per day as either a single dose or divided doses, depending on the patient's global response. It may be necessary to use dosages of the active ingredient outside the ranges disclosed herein in some cases, as will be
apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response.
Different therapeutically effective amounts may be applicable for different metabolic diseases, as will be readily known by those of ordinary skill in the art. Similarly, amounts sufficient to prevent, manage, treat or ameliorate such metabolic disorders, but insufficient to cause, or sufficient to reduce, adverse effects associated with the compounds of the invention are also encompassed by the above described dosage amounts and dose frequency schedules. Further, when a patient is administered multiple dosages of a compound of the invention, not all of the dosages need be the same. For example, the dosage administered to the patient may be increased to improve the prophylactic or therapeutic effect of the compound or it may be decreased to reduce one or more side effects that a particular patient is experiencing.
In a specific embodiment, the dosage of the composition of the invention or a compound of the invention administered to prevent, treat, manage, or ameliorate a metabolic disorder or one or more symptoms thereof in a patient is 150 μg/kg, preferably 250 μg/kg, 500 μg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg, 75 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, or 200 mg/kg or more of a patient's body weight. In another embodiment, the dosage of the composition of the invention or a compound of the invention administered to prevent, treat, manage, or ameliorate a metabolic disorder or one or more symptoms thereof in a patient is a unit dose of 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 12 mg, 0.1 mg to 10 mg, 0.1 mg to 8 mg, 0.1 mg to 7 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 to 8 mg, 0.25 mg to 7m g, 0.25 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 8 mg, 1 mg to 7 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.
The dosages of prophylactic or therapeutic agents other than compounds of the invention, which have been or are currently being used to prevent, treat, manage, or ameliorate a metabolic disorder or one or more symptoms thereof can be used in the combination therapies of the invention. Preferably, dosages lower than those which have been or are currently being used to prevent, treat, manage, or ameliorate a metabolic disorder or one or more symptoms thereof are used in the combination therapies of the invention. The recommended dosages of agents currently used for the prevention, treatment, management, or amelioration of a metabolic disorder or one or more symptoms thereof can obtained from any reference in the art including, but not limited to, Hardman et ah, eds.,
1996, Goodman & Gilman's The Pharmacological Basis Of Basis Of Therapeutics 9th Ed, Mc-Graw-Hill, New York; Physician's Desk Reference (PDR) 57th Ed., 2003, Medical Economics Co., Inc., Montvale, NJ, which are incorporated herein by reference in its entirety. In various embodiments, the therapies (e.g., prophylactic or therapeutic agents) are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, -at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours part. In preferred embodiments, two or more therapies (e.g., prophylactic or therapeutic agents) are administered within the same patent visit.
In certain embodiments, one or more compounds of the invention and one or more other the therapies (e.g., prophylactic or therapeutic agents) are cyclically administered. Cycling therapy involves the administration of a first therapy (e.g., a first prophylactic or therapeutic agents) for a period of time, followed by the administration of a second therapy (e.g., a second prophylactic or therapeutic agents) for a period of time, followed by the administration of a third therapy (e.g., a third prophylactic or therapeutic agents) for a period of time and so forth, and repeating this sequential administration, i.e., the cycle in order to reduce the development of resistance to one of the agents, to avoid or reduce the side effects of one of the agents, and/or to improve the efficacy of the treatment.
In certain embodiments, administration of the same compound of the invention may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In other embodiments, administration of the same prophylactic or therapeutic agent may be repeated and the administration may be separated by at least at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
In a specific embodiment, the invention provides a method of preventing, treating, managing, or ameliorating a metabolic disorder or one or more symptoms thereof, said methods comprising administering to a subject in need thereof a dose of at least 150 μg/kg,
preferably at least 250 μg/kg, at least 500 μg/kg, at least 1 mg/kg, at least 5 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, or at least 200 mg/kg or more of one or more compounds of the invention once every day, preferably, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 10 days, once every two weeks, once every three weeks, or once a month.
The present invention provides methods of preventing, treating, managing, or preventing a metabolic disorder (e.g., diabetes mellitus), or one or more symptoms thereof, said method comprising: (a) administering to a subject in need thereof one or more doses of an effective amount of one or more compounds of the invention; and (b) monitoring the mean blood glucose levels, blood insulin levels and/or insulin sensitivity in said subject after administration of a certain number of doses of the said compounds of the invention. Moreover, preferably, said certain number of doses is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 12 of an effective amount of the one or more compounds of the invention. In a specific embodiment, the invention provides a method of preventing, treating, managing, or ameliorating a metabolic disorder (e.g., diabetes mellitus) or one or more symptoms thereof, said method comprising: (a) administering to a subject in need thereof a dose of at least 150 μg/kg, preferably at least 250 μg/kg, at least 500 μg/kg, at least 1 mg/kg, at least 5 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, or at least 200 mg/kg or more of one or more compounds of the invention; and (b) administering one or more subsequent doses to said subject when the mean blood glucose levels, blood insulin levels and/or insulin sensitivity in said subject is not within normal range (i.e., the range obtained from normal subjects without a metabolic disorder). In another embodiment, the invention provides a method of preventing, treating, managing, or ameliorating a metabolic disorder (e.g., diabetes mellitus), or one or more symptoms thereof, said method comprising: (a) administering to a subject in need thereof one or more doses of at least 150 μg/kg, preferably at least 250 μg/kg, at least 500 μg/kg, at least 1 mg/kg, at least 5 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, or at least 200 mg/kg or more of one or more compounds of the invention; (b) monitoring the mean blood glucose levels, blood insulin levels and/or insulin sensitivity in said subject after the administration of a certain number of doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or more doses); and (c) administering a subsequent dose of the compound(s) of the invention when the mean
blood glucose levels, blood insulin levels and/or insulin sensitivity in said subject is not within normal range.
In another embodiment, the invention provides a method of preventing, treating, managing, or ameliorating a metabolic disorder (e.g., diabetes mellitus), or one or more symptoms thereof, said method comprising: (a) administering to a subject in need thereof one or more doses of an effective amount of one or more compounds of the invention; and (b) administering a subsequent dose of the compound(s) of the invention to maintain a normal range of blood glucose levels, blood insulin levels and/or insulin sensitivity. The normal range for blood glucose levels, blood insulin levels and/or insulin sensitivity can be obtained or determined by one of skill in the art using well-known techniques.
In another embodiment, the invention provides a method of preventing, treating, managing, or ameliorating a metabolic disorder (e.g., diabetes mellitus), or one or more symptoms thereof, said method comprising: (a) administering to a subject in need thereof one or more doses of at least 150 μg/kg, preferably at least 250 μg/kg, at least 500 μg/kg, at least 1 mg/kg, at least 5 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, or at least 200 mg/kg or more of one or more compounds of the invention; and (b) administering a subsequent dose of the compound(s) of the invention a normal range of blood glucose levels, blood insulin levels and/or insulin sensitivity.
Biological Assays
Several aspects of the pharmaceutical compositions or compounds of the invention are preferably tested in vitro, in a cell culture system, and in an animal model organism, such as a rodent animal model system, for the desired therapeutic activity prior to use in humans. For example, assays which can be used to determine whether administration of a specific pharmaceutical composition or a specific combination of therapies is indicated, include cell culture assays in which a patient tissue sample is grown in culture, and exposed to or otherwise contacted with a pharmaceutical composition, and the effect of such composition upon the tissue sample is observed. The tissue sample can be obtained by biopsy from the patient. This test allows the identification of the therapeutically most effective therapy (e.g., prophylactic or therapeutic agent(s)) for each individual patient. In various specific embodiments, in vitro assays can be carried out with representative cells of cell types involved in a metabolic disorder (e.g., insulin-producing cells or beta cells in the pancreas, steriodogenic cells and adipocytes), to determine if a pharmaceutical composition of the
invention has a desired effect upon such cell types. As an alternative to the use of tissue, tissue samples, cell lines can be used in in vitro assays.
The pharmaceutical compositions and compounds of the invention can be assayed for their ability to modulate insulin production of beta cells of the pancreas. Modulation of insulin production by beta cells can be determined by measuring, e.g., changes in the level of expression insulin. Techniques known to those of skill in the art, including, but not limited to, immunoprecipitation followed by Western blot analysis, ELISAs, flow cytometry, Northern blot analysis, and RT-PCR can be used to measure the expression of insulin. The pharmaceutical compositions and compounds of the invention can also be assayed for their ability to modulate insulin sensitivity using techniques well-known in the art.
The pharmaceutical compositions and compounds of the invention can be tested in suitable animal model systems prior to use in humans. Such animal model systems include, but are not limited to, rats, mice, chicken, cows, monkeys, pigs, dogs, rabbits, etc. Any animal system well-known in the art may be used. In a specific embodiment of the invention, the pharmaceutical compositions and compounds of the invention are tested in a mouse model system. Such model systems are widely used and well-known to the skilled artisan. Examples of such animal models include, but are not limited to, leptin resistant animals (e.g., db/db mice), melanocortin-4 receptor knockout mice (MR-4-/~), leptin- deficient mice (ob/ob), tubby mice (tubby protein deficiency), the fa/fa (Zucker Diabetic Fatty or ZDF) rat, melanocortin-3 receptor knockout mice, POMC-deficient mice, fat/fat mice, the DgatltmlFar mice, Ins2Mody mice, and Ppargtm2Rev mice (see, e.g., Barsh et al, 2000, Nature 404:644-651; Fisher et al., 1999, Int. J. Obes. ReI. Metab. Disord. 23 Suppl:54-58; Giridharan, 1998, Indian J. Med. Res. 108:225-242; Zhang et al., 1994, Nature 372:425-432; Noben-Trauth et al., 1996, Nature 380:534-538; Iida et al., 1996, BBRC 224:597-604; Phillips et al., 1996, Nature Genetics 13:18-19; Chen et al., 2000, Nature Genetics 26:97- 102; Butler et al., 2000, Endocrinology 141:3518-3521; Yawen et al., 1999, Nature Medicine 5:1066-1070; Naggert et al., 1995, Nature Genetics 10: 135-142; and Smith et al., 2000, Nature Genetics 25:87-90). In the case of diabetes mellitus, ICR-CDI mice are typically used for measuring the effect of test compound on controlling blood glucose levels. HbAIc is a valuable measure for monitoring the treatment of diabetes in humans and is often used as a parameter of efficacy in clinical trials. A 1-2% reduction is generally seen across most classes of diabetes drugs when used as a monotherapy. An additional 0.5% can sometimes be obtained when combining drugs having different mechanisms.
Further, any assays known to those skilled in the art can be used to evaluate the prophylactic and/or therapeutic utility of the pharmaceutical compositions and compounds of the invention for the disorders disclosed herein.
The toxicity and/or efficacy of the pharmaceutical compositions and compounds of the invention can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ ED50. Phannaceutical compositions and compounds of the invention that exhibit large therapeutic indices are preferred. While pharmaceutical compositions and compounds of the invention that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compositions and compounds to the site of affected tissue in order to minimize potential damage to unaffected cells and, thereby, reduce side effects. The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage of the pharmaceutical compositions and compounds of the invention for use in humans. The dosage of such agents lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any agent used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography (HPLC) and radioimmunasssay (RIA). The pharmacokinetics of a prophylactic or therapeutic can be determined, e.g., by measuring parameters such as peak plasma level (Cmax), area under the curve (AUC, which is measured by plotting plasma concentration of the agent versus time, and reflects bioavailability), half- life of the compound (ti/2), and time at maximum concentration.
Efficacy in preventing or treating a metabolic disorder such as diabetes may be demonstrated, e.g., by detecting the ability of the pharmaceutical compositions and compounds of the invention to reduce the blood glucose, increase hypoinsulinemic insulin levels, increase insulin sensitivity, reduce the dose requirements of other anti-diabetic
agents, or reduce the severity of one or more symptoms associated with diabetes are identified in human subjects having diabetes. In accordance with this embodiment, a compound of the invention or a control compound is administered to a human subject having diabetes, and the effect of the compound of the invention on blood glucose levels, blood insulin levels, insulin sensitivity, dose requirements of other anti-diabetic agents, or one or more symptoms of diabetes is determined. A compound of the invention that reduces the blood glucose, increase blood hypoinsulinemic insulin levels, increases insulin sensitivity, reduces the dose requirements of other anti-diabetic agents, or reduces one or more symptoms can be identified by comparing the subjects treated with a control compound to the subjects treated.
Kits
The invention encompasses kits that can simplify the administration of a compound of the invention to a subject. A typical kit of the invention comprises a unit dosage form of a compound. In one embodiment, the unit dosage form is a container, preferably a sterile container, containing an effective amount of a compound of the invention and a pharmaceutically acceptable carrier or excipient. The kit can further comprise a label or printed instructions regarding the use of compounds or other informational material that advises the physician, technician or patient on how to appropriately prevent or treat the metabolic disorder in question. In other words, the kit includes instruction means indicating or suggesting a dosing regimen including, but not limited to, actual doses, monitoring procedures {e.g., monitoring blood glucose levels and blood insulin levels), and other monitoring information. The kit can also further comprise a unit dosage form of another prophylactic or therapeutic agent, for example, a container containing an effective amount of another prophylactic or therapeutic agent. In a specific embodiment, the kit comprises a container containing an effective amount of a compound of the invention and a pharmaceutically acceptable carrier or excipient and a container containing an effective amount of another prophylactic or therapeutic agent and a pharmaceutically acceptable carrier or excipient. Examples of other prophylactic or therapeutic agents include, but are not limited to, those listed above. As with any pharmaceutical product, the packaging material and container included in the kit are designed to protect the stability of the product during storage and shipment.
Kits of the invention can further comprise devices that are useful for administering the unit dosage forms. Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers.
Kits of the invention can further comprise pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients (e.g., a compound of the invention). For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and nonaqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
Other Embodiments
The compounds of the invention may be used as research tools (for example, to evaluate the mechanism of action of new drug agents, to isolate new drug discovery targets using affinity chromatography, as antigens in an ELISA or ELISA-like assay, or as standards in in vitro or in vivo assays). These and other uses and embodiments of the compounds and compositions of this invention will be apparent to those of ordinary skill in the art.
The invention is further defined by reference to the following examples describing in detail the preparation of compounds of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the purpose and interest of this invention. The following examples are set forth to assist in understanding the invention and should not be construed as specifically limiting the invention described and claimed herein. Such variations of the invention, including the substitution of all equivalents now known or later developed, which would be within the purview of those skilled in the art, and changes in formulation or minor changes in experimental design, are to be considered to fall within the scope of the invention incorporated herein.
EXAMPLES
Reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). 1H-NMR and 13C-NMR spectra were recorded on a Varian 300MHz NMR spectrometer. Significant peaks are tabulated in the order: δ (ppm): chemical shift, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet), coupling constant(s) in Hertz (Hz) and number of protons.
EXAMPLE 1 : Synthesis of Compound 52
A solution of 4-methylene-oxetan-2-one (15.3ml, 200mmol) in methylene chloride(200ml) was cooled to -78°C in a acetone/dry ice bath. 75mg of 4- dimethylaminopyridine (DMAP) was added to the reaction mixture. To this -780C reaction mixture, ethylamine in THF (2M, 100ml) was added over a 20-minute period. Once the addition was complete the reaction was allowed to warm to room temperature (2hr). The solvent was then removed by rotary evaporation. This reddish oil was carried on to the next step.
The oil was then dissolved in a 20OmL of a 2M solution of ammonia in ethanol. The reaction mixture was capped and heated to 350C for 18 hours. The solvent was then removed via rotary evaporation leaving a reddish solid. This solid was washed with diethyl ether to produce 17.62 grams of pure enamine.
NH2 O
To a solution of dihydropyridine in acetone was added CAN at O0C. The reaction was stirred at O0C for 2 hours. A solution of NaHCO3(sat) was added to the reaction and stirred until no more bubbling occurred. After diluting with methylene chloride, the solution was filtered through a pad of celite. The solid that was filtered off was transferred to a beaker and washed again with methylene chloride. The solution was then added to a seperatory funnel and the aqueous phase was washed with methylene chloride. The combined organic phase was dried over sodium sulfate. After filtration the solvent was removed and the solid was recrystallized from acetone to give 35 grams (76% yield) of Compound 52 as a light yellow solid.
EXAMPLE 2:
The method from Example 1, shown above, was utilized with appropriate starting materials and reagents to produce the following compounds of the invention. Choice of the appropriate starting materials and reagents will be readily apparent to one of skill in the art for these and other compounds of this invention.
Compound 1
1H-NMR (CD3Cl) δ (ppm), 8.61(m, IH), 8.35 (m, IH), 4.77 (s, 2H), 3.98(q, J=6.3 Hz, 2H), 3.55 (t, J= 3.18(d, J=5.1Hz, 2H), 3.12 (s, 2H), 2.84 (t, J=5.1Hz, 2H), 2.47(d, J=3.6Hz, 2H),
1.39(s, 2H), 1.12(s, 3H), 1.10(s, 3H), 0.93 (t, J=6.3Hz, 2H). ESMS clcd for C22H27N3O4: 397.20; Found: 398.2 (M+H)+.
Compound 9 1H-NMR (CDCl3) δ (ppm), 1.16(s, 6H), 2.52(m, 2H), 2.84(s, 3H), 3.18(m, 2H). 7.35-8.80 (m, 4H). ESMS clcd for C18HnN3O: 291.14; Found: 292.1 (M+H)+.
Compound 16 1H-NMR (CD3Cl) δ 4.4 l(q, J =6.3 Hz, 2H), 2.99 (s, 2H), 2.55 (s, 6H), 2.39(m, IH), 1.39(t, J=6.3Hz, 2H), 1.12(s, 6H), 0.98 (m, 2H), 0.38 (m, 2H). ESMS clcd for C18H23NO3: 301.17; Found: 302.0 (M+H)+.
Compound 29 1H-NMR (CDCl3) δ (ppm), 0.39(m, 2H), 0.98(m, 2H), 1.16(s, 6H), 1.42(t, J=6.5, 3H), 2.28 (m, 2H), 2.38(s, 3H), 3.16(s, 2H), 4.41(dxd, J=6.5, 13, 2H) ESMS clcd for C18H23NO4: 317.16; Found: 318.2 (M+H)+.
Compound 32 1H NMR (CDCl3): δ (ppm) 0.95 (t, J=7.2, 3H), 1.12 (m, 6H), 2.49 (m, 2H), 2.93 (s, 3H), 3.16 (s, 2H), 3.31-3.24 (m, 2H), 3.1-3.68 (m, 2H), 4.05-3.98 (q, J=7.2 Hz, 2H), 4.78 (m, 2H), 5.44 (m, IH), 7.34-7.30 (m, IH), 7.52-7.48 (m, IH), 8.35 (m, IH), 8.62 (m, IH). ESMS calcd (C23H29N3O6S): 475.56; found: 476.5 (M+H)+
Compound 35
1H NMR (CDCl3): δ (ppm) 0.32 (m, 2H), 0.98 (m, 2H), 1.09 (m, 6H), 1.41 (t, J=7.2 Hz, 3H), 2.39 (m, 5H), 2.54 (s, 2H), 2.98 (s, 2H), 3.62 (m, 4H), 3.74 (s, 2H), 4.39 (q, J=7.2 Hz, 2H). ESMS calcd (C22H30N2O4): 386.48; found: 387.4 (M+H)4
Compound 39
1H NMR (CDCl3): δ (ppm) 0.38 (m, 2H), 0.98 (m, 4H), 1.05 (m, 6H), 1.17 (m, 2H), 1.40 (t, J=7.2 Hz, 3H), 2.05 (m, IH), 2.35 (m, IH), 2.49 (s, 2H), 2.88 (s, 2H), 4.44 (q, J=7.2 Hz, 2H). ESMS calcd (C20H25NO3): 327.42; found: 328.4 (M+H)+
Compound 43
1H NMR (CDCl3): δ (ppm) 0.35 (m, 2H), 1.01 (m. 2H), 1.08 (m, 6H), 1.27-1.24 (m, 3H), 1.36 (t, J=7.2 Hz, 3H), 2.38 (m, IH), 2.55 (s, 2H), 3.00 (s, 2H), 4.07 (s, 2H), 4.22 (q, J=7.2 Hz, 2H), 4.41- 4.38 (m, 2H), 4.81 (s, 2H). ESMS calcd (C22H29NO6): 403.47; found: 404.4 (M+H)+
Compound 45
1H NMR (CDCl3): δ (ppm) 0.35 (m, 2H), 0.98 (m, 2H), 1.09 (m, 6H), 1.39 (t, J=7.2 Hz, 3H), 2.38 (m, IH), 2.55 (s, 2H), 2.99 (s, 2H), 3.35 (s, 3H), 3.58-3.51 (m, 4H), 4.40 (q, J=7.2 Hz, 2H), 4.74 (s, 2H). ESMS calcd (C2]H29NO5): 375.46; found: 376.4 (M+H)+
Compound 51
1H NMR (300 MHz, CDCl3) δ 0.35-0.41 (m, 2H), 0.96-1.03 (m, 2H), 1.11 (s, 6H), 1.24 (t, J=7.2Hz, 3H), 1.25 (t, J=7.8Hz, 3H), 2.31-2.41 (m, IH), 2.55 (s, 2H), 2.63 (q, J=7.8Hz, 2H), 2.89 (q, J=7.2Hz, 2H), 3.01 (s, 2H) ppm. ESMS calcd. (Ci9H25NO2): 299.2; found: 300.2 (M + H).
Compound 52 1H NMR (300 MHz, CDCl3) δ 0.76 (t, J=7.5Hz, 3H), 1.09 (s, 3H), 1.13 (s, 3H), 2.46 (d, J= 7.2Hz, 2H), 2.64 (s, 3H), 2.08-3.15 (m, 4H), 5.64 (s, IH), 7.33 (ddd, J=0.9, 4.6, 8.4Hz, IH), 7.56 (dt, J= 1.8Hz, 7.8Hz, IH), 8.28 (dd, J= 0.9, 1.5Hz, IH), 8.56 (dd, J= 1.2, 4.6Hz, IH). ppm ESMS calcd. (C20H23N3O2): 337.2; found: 338.2 (M + H).
Compound 53
1H NMR (CDCl3): δ (ppm) 0.34 (m, 2H), 0.96 (m, 2H), 1.09 (m, 6H), 2.36 (m, IH), 2.53 (s, 2H), 2.99 (s, 2H), 3.07 (t, J=7.2 Hz, 2H), 3.33 (s, 3H), 3.74 (t, J=7.2 Hz, 2H), 3.34 (s, 3H). ESMS calcd (C19H25NO4): 331.41; found: 332.4 (M+H)+
Compound 54
1H NMR (300 MHz, CDCl3) δ 0.47-0.52 (m, 2H), 0.93-0.99 (m, 2H)5 1.04 (s, 6H), 1.28 (t, J=7.2Hz, 3H), 2.21-2.27 (m, IH), 2.46 (s, 2H), 2.53 (s, 3H), 2.89 (s, 2H), 3.47-3.56 (m, 2H), 6.48 (t, J=5.3Hz, IH) ppm ESMS calcd. (C18H24N2O2): 300.2; found: 301.2 (M + H).
Compound 55
1H-NMR (CD3Cl) δ 4.0(111, IH), 3.74 (m, 3H), 3.59 (m, IH), 3.25 (m, 2H), 2.99 (s, 2H), 2.50 (m, 4H), 2.23(m, IH), 1.62(s, 2H), 1.10(s, 6H), 0.98 (m, 2H), 0.25 (m, 2H). ESMS clcd for C20H26N2O3: 342.19; Found: 343.0 (M+H)+.
Compound 71
1H NMR δ (300 MHz, CDCl3) 0.342-0.399 (m, 2H), 0.90-0.97 (m, 2H), 1.04 (s, 6H), 1.34 (t, J=7.5Hz, 3H), 2.26-2.36 (m, IH), 2.43 (s, 3H), 2.49 (s, 2H), 2.92 (s, 2H), 3.05 (q, 7.5Hz, 2H) ppm.
ESMS calcd. (Ci8H23NO2S): 317.1; found: 318.1 (M + H).
Compound 72
1H NMR (300 MHz, CDCl3) δ 0.18-0.27 (m, IH), 0.84-0.91 (m, IH), 0.98-11.1 (m, 10H), 2.21-2.31 (m, IH), 2.49 (d, J=15.3Hz, IH), 2.50 (s, 3H), 2.62 (d, J=15.3Hz, IH), 3.00 (s, 2H), 3.11-3.33 (m, 2H), 3.48 (dq, J=7.2, 13.8Hz, IH), 3.79 (dq, J=7.2, 13.8Hz, IH) ppm. ESMS calcd. (C20H28N2O2): 328.2; found: 329.2 (M + H).
Compound 73 1H NMR (300 MHz, CDCl3, mixture of rotomers) δ 0.14-0.26 (m, IH), 0.87-1.06 (m, 3H), 1.10 (s, 6H), 1.24-1.28 (m, IH), 1.87-2.16 (m, 4H), 2.22-2.40 (m, 2H), 2.42-2.64 (m, 5H), 3.00 (s, 2H), 3.27-3.40 (m, 1.5H), 3.50 (s, 0.5H), 3.81 (s, 3H), 4.12 (q, J=6.9Hz, 0.46H), 4.68 (q, J=4.2Hz, 0.6H) ppm. ESMS calcd. (C22H28N2O4): 384.2; found: 385.2 (M + H).
Compound 79
1H NMR (CDCl3): δ (ppm) 0.34 (m, 2H), 1.01 (m, 2H), 1.09 (m, 6H), 1.38 (t, 1=1.2 Hz, 3H), 2.40 (m, IH), 2.57 (s, 2H), 2.85 (m, 3H), 3.00 (s, 2H), 4.04 (s, 2H), 4.38 (q, J=7.2, 2H), 4.71 (s, 2H), 7.03 (broad, IH). ESMS calcd (C2IH28N2O5): 388.46; found: 389.4 (M+H)+
Compound 95
1H NMR (300 MHz, CDCl3) δ 0.19-0.28 (m, IH), 0.86-0.98 (m, 2H), 0.99-1.08 (m, IH),
1.1 (s, 3H), 1.11 (s, 3H), 2.17-2.30 (m, 2H), 2.33 (s, 3H), 2.38-2.63 (m, 5H), 2.50 (s, 3H),
2.98 (s, 2H), 3.22-3.36 (m, 2H), 3.65-3.73 (m, IH), 4.02-4.09 (m, IH) ppm.
ESMS calcd. (C21H29N3O2): 355.2; found: 356.2 (M + H).
Compound 99
1H NMR (CDCl3): δ (ppm) 0.36 (m, 2H), 0.98 (m, 2H), 1.09 (m, 6H), 1.34 (t, J=7.2 Hz, 3H),
2.40 (m, 5H), 2.56 (s, 2H), 3.00 (s, 2H), 4.35 (q, J=7.2 Hz, 2H), 4.55 (s, 2H), 4.74 (s, 2H).
ESMS calcd (C23H28N2O5): 412.48; found: 413.4 (M+H)+
Compound 2
ESMS clcd for C2IH22ClN3O2: 383.14; Found: 384.0 (M+H)+.
Compound 4 ESMS clcd for C24H30N2O5: 426.22; Found: 427.1 (M+H)+.
Compound 7
ESMS clcd for C23H27N5O5: 453.20; Found: 454.2 (M+H)+.
Compound 8
ESMS clcd for C28H28FN5O4: 517.21; Found: 518.2 (M+H)+.
Compound 12
ESMS clcd for C22H27N3O5: 413.20; Found: 414.2 (M+H)+.
Compound 13
ESMS clcd for C20H23N3O4: 369.17; Found: 370.2 (M+H)+.
Compound 14
ESMS clcd for C20H22N2O3: 338.16; Found: 339.1 (M+H)+.
Compound 17 ESMS clcd for C20H28N2O4: 360.20; Found: 361.2 (M+H)+.
Compound 18
ESMS clcd for C16H2iNO3: 275.15; Found: 276.2 (M+H)+.
Compound 19
ESMS calcd (Ci5Hi9NO3): 261.32; found: 262.3 (M+H)+
Compound 20
ESMS calcd (Ci8H25NO3): 303.40; found: 304.4 (M+H)+
Compound 24
ESMS clcd for Ci6Hi8N2O: 254.14; Found: 255.1 (M+H)+.
Compound 26 ESMS calcd (C22H28N2O5): 400.47; found: 401.4 (M+H)+
Compound 28
ESMS calcd (C23H28N2O4): 396.48; found: 397.4 (M+H)+
Compound 30
ESMS calcd (C22H32N2O4): 388.50; found: 389.5 (M+H)+
Compound 31
ESMS clcd for Ci8H23NO3: 301.17; Found: 302.2 (M+H)+.
Compound 33
ESMS calcd (C24H29N3O5): 439.50; found: 440.5 (M+H)+
Compound 34
ESMS clcd for C20H25NO3: 327.18; Found: 328.2 (M+H)+.
Compound 36 ESMS calcd (C24H34N2O5): 430.54; found: 431.5 (M+H)+
Compound 37
ESMS calcd (Ci9H25NO3): 315.41; found: 316.4 (M+H)+
Compound 38
ESMS calcd (Ci9H25NO3): 315.41; found: 316.4 (M+H)+
Compound 41
ESMS calcd (C20H28N2O3): 344.45; found: 345.4 (M+H)+
Compound 42
ESMS clcd for C20H27NO3: 329.20; Found: 330.0 (M+H)+.
Compound 44 ESMS calcd (C17H2iNO3): 287.35; found: 288.3 (M+H)+
Compound 47
ESMS calcd (C18H20F3NO3): 355.35; found: 356.3 (M+H)+
Compound 48
ESMS calcd. (Ci9H23NO3): 313.2; found: 314.2 (M + H).
Compound 58
ESMS calcd. (Ci6Hi9NO3): 273.1; found: 274.1 (M + H).
Compound 59
ESMS calcd. (C22H30N2O4): 386.2; found: 387.2 (M + H).
Compound 60
ESMS calcd (C19H25NO4): 331.41; found: 332.4 (M+H)+
Compound 61 ESMS calcd (C20H27NO3): 329.43; found: 330.4 (M+H)+
Compound 62
ESMS calcd (C19H25NO4): 331.41; found: 332.4 (M+H)+
Compound 63
ESMS calcd (C21H29NO6S): 423.52; found: 424.5 (M+H)+
Compound 66
ESMS clcd for C22H30N2O5: 402.22; Found: 403.2 (M+H)+
Compound 67
ESMS calcd. (Ci6H20N2O2): 272.2; found: 273.2 (M + H).
Compound 68 ESMS calcd. (C19H26N2O2): 314.2; found: 315.2 (M + H).
Compound 69
ESMS calcd. (C20H26N2O2): 326.2; found: 327.2 (M + H).
Compound 70
ESMS calcd. (C19H26N2O2): 314.2; found: 315.2 (M + H).
Compound 74
ESMS calcd. (C20H27N3O2): 341.2; found: 342.2 (M + H).
Compound 76
ESMS calcd (C24H32N2O5): 428.52; found: 429.5 (M+H)+
Compound 78
ESMS clcd for C2]H30N2O6S: 438.18; Found: 439.2 (M+H)+.
Compound 82 ESMS calcd. (C20H26N2O2S): 358.2; found: 359.2 (M + H).
Compound 83
ESMS clcd for C22H30N2O6: 418.21; Found: 419.2 (M+H)+.
Compound 84
ESMS calcd (C20H27NO3): 329.43; found: 330.4 (M+H)+
Compound 85
ESMS calcd. (CiSH24N2O2): 300.2; found: 301.2 (M + H).
Compound 86
ESMS calcd (C20H26N2O5): 374.43; found: 375.4 (MH-H)+
Compound 87 ESMS calcd. (Ci8H23NO4): 317.2; found: 318.2 (M + H).
Compound 89
ESMS calcd. (C2iH23N3O2): 349.2; found: 350.2 (M + H).
Compound 90
ESMS calcd (C23H34NO7P): 467.49; found: 468.4 (M+H)+
Compound 91
ESMS calcd (C23H30N2O6): 430.49; found: 431.4 (M+H)+
Compound 93
ESMS calcd (C24H36N2O5): 432.55; found: 433.5 (M+H)+
Compound 94
ESMS calcd (C26H36N2O7): 488.57; found: 489.5 (M+H)+
Compound 102 ESMS calcd (C25H3INO6): 441.52; found: 442.5 (M+H)+
Compound 103
ESMS clcd for C2IH28N2O3: 356.21; Found: 357.2 (M+H)+.
Example 3: Synthesis of Tricyclic Compounds
A. Synthesis of Compound 271
Into a solution of the bromide (1.0Og, 2.62 mmol), N-hydroxyphthalimide (512 mg, 3.14 mmol) in acetonitrile (13 mL) at room temperature was added DIEA (650 mg, 5.0 mmol). The mixture was heated to 60 0C overnight, cooled to room temperature, taken up in ethyl acetate. The resulting solution was washed with a solution of saturated NaHCO3 (3x), with brine and dried (Na2SO^, filtered and concentrated under reduced pressure. The residue was taken up in acetone (13 mL). Into the resulting solution, eerie ammonium nitrate (3.62 g, 6.55 mmol) was added. The mixture was stirred at room temperature for 2 hours, neutralized with a solution of saturated NaHCO3, extracted with ethyl acetate (3x). The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on silica (eluted with CH2Cl2) to give the desire product (1.05g). 1H NMR (300 MHz, CDCl3) δ 0.28-0.35 (m, 2), 0.93-1.08 (m, 2), 1.08 (s, 6), 1.33 (t,
J= 7.2, 3), 2.47-2.32 (m, 1), 2.57 (s, 2), 2.99 (s, 2), 4.40 (q, J= 7.2, 2), 5.33 (s, 2), 7.80- 7.69 (m, 4).
Into a reaction flask containing (350 mg) was added a solution of 2M NH3 in EtOH (10 mL). The mixture was sealed and heated to 40 0C overnight, cooled to room
temperature, concentrated under reduced pressure. The residue was purified on silica (eluted with EtOAcrhexanes, 1:1) to give the tricyclic product Compound 271 (165 mg). ESMS calcd. (C16H18N2O3): 286; found: 287 (M + H).
1H NMR (300 MHz, CDCl3) δ 0.22-0.28 (m, 2), 1.12-1.26 (m, 2), 1.12 (s, 6), 2.62 (s, 2), 2.53-2.68 (m, 1), 3.03 (s, 2), 5.04 (s, 2), 8.77 (bs, 1).
B. Synthesis of Compound 270
Into a solution of heptane-3,5-dione (1.28 g, 10.0 mmol) and cyclopropyl carboxaldehyde (0.7Og, 10.0 mmol) in 2-propanol (10 mL) were added 2M NH3 in EtOH (28 mL), HOAc (4.0 mL), and 5,5-Dimethyl-cyclohexane-l,3-dione (1.42 g, 10.0 mmol). The mixture was heated to 80 0C overnight, cooled to room temperature, diluted with ethyl acetate, washed with a solution of saturated NaHCO3 (3x) then with brine and dried (Na2SO^, filtered and concentrated under reduced pressure. The residue was purified on silica (eluted with EtOAc:hexanes, 3:7) to give A (720 mg) followed by Compound 270 (810 mg).
C. Synthesis of Compound 267
Compound 270 Compound 267
To a solution of Compound 270 in acetone (HPLC grade) at O0C is added 2.5 eq of ammonium cerium (TV) nitrate (CAN) and the reaction was allowed to stir at O0C until
complete (~2 hrs). The reaction was then quenched with saturated aqueous Na2SO3 and extracted with ethyl acetate (EtOAc). The organic layer was then washed 3 times with water and 1 time with brine, dried, filtered and concentrated. A short column was then run to remove any remaining metal to yield Compound 267. ESMS calcd. (C20H25NO2): 311; found: 312 (M + H).
EXAMPLE 4: Synthesis of 2-(2-azido-ethoxymethyl)-4-(2-chloro-phenyI)-7,7-dimethyI- 5-oxo-l,4,5,6,7,8-hexa-hydro-quinoline-3-carboxyIic acid ethyl ester A. 4-(2-azido-ethoxy)-3-oxo-butγric acid ethyl ester
N -D τMF 
A solution of 2-azidoethanol (8.7g, 100 mmol) in THF (20 ml) was added to a suspension of sodium hydride (8.8 g, 220 mmol, 60% dispersion in oil) in THF (150ml). The mixture was stirred at room temperature for 1 h and then cooled to 0-50C. Ethyl-4- chloroacetoacetate (16.5g, 100 mmol) in THF (20 ml) was then added dropwise over a period of 0.5 h. The mixture was stirred at room temperature for additional 16 h and diluted with EtOAc (100 ml) and the pH was adjusted to 6-7 with 2 N HCl. Sufficient water was added to dissolve the solid, and the organic layer was then separated. The aqueous layer was further extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated. The product was purified by column chromatography on silica gel (Hexane - EtOAc, 95:5) to give 4-(2-azido-ethoxy)-3-oxo-butyric acid ethyl ester (16 g, 74.3 %) as yellow oil. 1H-NMR (CDCl3) δ (ppm), 4.24-4.17(m, 4H), 3.70(t, J=4.8Hz, 2H), 3.55(s, 2H), 3.43(t, J=5.1Hz, 2H), 1.28(t, J=7.2Hz, 3H).
B. 4-(2-azido-ethoxy)-2-(2-chIoro-benzylidene)-_3-oxo-butyric acid ethyl ester
,. cat. piperidine,
Jl 11 2-propanol
A solution of 2-chlorobenzaldehyde (1.41g, 10 mmol), 4-(2-azido-ethoxy)-3-oxo- butyric acid ethyl ester (2.15g, 10 mol), AcOH (0.05 ml), and piperidine (0.10 ml) in 2- propanol (8 ml) was heated under reflux for 20 min. After removal of the solvent, the residue was purified by flash chromatography on silica gel (Hexane -EtOAc, 95:5) to give 4- (2-azido-ethoxy)-2-(2-chloro-benzylidene)-3-oxo-butyric acid ethyl ester (2.8g, 82.9%) as yellow oil. 1H-NMR (CDCl3) δ (ppm), (mix two isomer), 8.07 and 7.99(s, IH), 7.46-7.22(ra, 5H), 4.53 and 4.18(s, 2H), 4.33 and 4.21(q, J=7.2Hz, J=15.0Hz, 2H), 3.72 and 3.59(t, J=4.8Hz, 2H), 3.45 and 3.38(t, J=5.1Hz, 2H), 1.35 and 1.15(t, J=7.2Hz, 3H); ESMS clcd for Ci5Hi6ClN3O4: 337.08; Found: 360.1(M+Na)+.
C. 2-(2-azido-ethoxymethyI)-4-(2-chloro-phenyl)-7,7-dimethyl-5-oxo- l,4,5,6,7,8-hexa-hydro-quinoIine-3- carboxylic acid ethyl ester
AcONH4 2-propanot
A mixture of 4-(2-azido-ethoxy)-2-(2-chloro-benzylidene)-3-oxo-butyric acid ethyl ester (2.7Og, 8.0 mmol), 5,5-dimethyl-l, 3-cyclohexanedione (1.18g, 8.0 mmol, 95% pure) and ammonium acetate (0.7Og, 9.1 mmol) in 2-propanol (8 ml) was heated under reflux for 16 h. After removal of the solvent, the residue was purified by column chromatography on silica gel (Hexane -EtOAc, 95:5, 9:1)) to give 2-(2-azido-ethoxymethyl)-4-(2-chloro- phenyl)-7,7-dimethyl-5-oxo-l,4,5,6,7,8-hexa-hydro-quinoline-3-carboxylic acid ethyl ester (2.28g, 62%). 1H-NMR (CDCl3) δ (ppm), 7.40(d, J=7.8Hz, IH), 7.27-7.23(m, 2H), 7.16- 7.02(m, 2H), 5.41(s, IH), 4.83(d, J=15.0Hz, IH), 4.79 (d, J=15.0 Hz, IH), 4.08-3.96(m, 2H), 3.82-3.75 (m, 2H), 3.54-3.48(m, 2H), 2.42-2.10(m, 4H), 1.17(t, J=7.2Hz, 3H), 1.08(s, 3H), 0.96(s, 3H); ESMS clcd for C23H27ClN4O4: 458.17; Found: 459.2 (M+H)+.
EXAMPLE 5: Synthesis of 2-(2-amino-ethoxymethyI)-4-(2-chloro-phenyI)-7,7- dimethyl-5-oxo-l, 4,5,6,7,8- Hexahydro-quinoline-3-carboxylic acid ethyl ester
Compound 272 can be prepared by Route A or Route B, each set forth below. Route A
A mixture of 2-(2-azido-ethoxymethyl)-4-(2-chloro-phenyl)-7,7-dimethyl- 5-oxo- l,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl ester (2.12g, 4.6 mmol) and tin (II) chloride (2.18g, 11.5 mmol) in CH2Cl2/Me0H (2:1, 12 ml) containing 2 drops of water was stirred at room temperature for about 6h. The reaction mixture was diluted with CH2Cl2 (100 ml) and a saturated solution OfNaHCO3 was added to adjust the pH to 9-10, and the layers were then separated. The aqueous layer was further extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered and evaporated. The product was purified by column chromatography on silica gel (CH2Cl2: MeOH, 95:5) to give 2-(2-amino- ethoxymethyl)-(2-chloro-phenyl)-7,7-dimethyl-5-oxo-l,4,5,6,7,8-hexahydro-quinoline-3- carboxylic acid ethyl ester (1.65g, 82.8%) as yellow sold. 1H-NMR (CDCl3) δ (ppm), 8.3O(s, IH), 7.43(d, J=6Hz, IH), 7.30-7.25(m, IH), 7.18-7.02(m, 2H), 5.43(s, IH), 4.85 and 4.78(2d, J=16.8Hz,each IH), 4.10-4.02(m, 2H), 3.65-3.60(m, 2H), 3.02(t, J=4.5Hz, 2H), 2.46-2.30(m, 2H), 2.28-2.12(m, 2H), 1.35(bs, 2H), 1.19 (t, J=7.2Hz, 3H),1.10(s, 3H), 0.98(s, 3H); ESMS clcd for C23H29ClN2O4: 432.18; Found: 433.2 (M+H)+.
Route B
5,5-Dimethyl-cyclohexane-l,3-dione, 2-Chloro-benzaldehyde and 3-Amino-but-2- enoic acid ethyl ester in 2L of 2-PrOH were added into a 5L 4-necked round bottomed flask equipped with a mechanical stirrer, a thermometer and a heating mantle underneath. The mixture was stirred and the reaction temperature was brought to about 400C. About 4mL of acetic acid was added while stirring. The reaction was stirred for about 2h at about 80 0C. The reaction was then cooled overnight and the precipitate was collected via filtration using a Buchner funnel and washed successively with ethyl acetate (about 1.5L) to obtain a white
crystalline material. The product was then vacuum dried in a round bottomed flask to give 4-(2-Chloro-phenyl)-2,7,7-trimethyl-5-oxo-l,4,5,6,7,8-hexahydro-quinoline-3-carboxylic acid ethyl ester (1.33 kg, 89% yield, 99% purity). 1H-NMR (CDCl3) δ (ppm), 7.39(d, J=7.5 Hz, IH), 7.23(d, J=6.6Hz, IH), 7.15-7.08(m, IH), 7.05-7.00(m, IH), 6.06(s, IH), 5.38(s, IH), 4.10-4.00(m, 2H), 2.34-2.10(m, 4H), 2.30(s, 3H), 1.17(t, J=7.2Hz, 3H), 1.07(s, 3H), 0.95(s, 3H). ESMS clcd for C2IH24ClNO3: 373.14; Found: 374.1 (M+H)+.
2-Bromomethyl-4-(2-chloro-phenyl)-7,7-dimethyl-5-oxo-l, 4,5,6,7, 8-hexahydro- quinoline-3-carboxylic acid ethyl ester (459.0 g, 1.23 mol) pyridine (110 ml, 1.35 mol) and MeCN were added to a 5L 4-necked round bottomed flask equipped with a mechanical stirrer, a thermometer and a cooling bath underneath. The reaction mixture was cooled down to about -10 0C and Py.Br3 (436.3 g, 1.23 mol) was added in portions over a period of about 10 min while maintaining the temperature of the reaction below about -50C. The reaction was stirred for about an additional 1.5h at about -5°C and then poured into about 12L of an ice-water mixture. The resulting slurry was stirred and left standing overnight. The precipitates were collected using filtration, washed with water (50OmL x 4) and washed with with ether (20OmL x 2). The resulting yellow solid was then dried under vacuum for about 1O h over a water bath of about 50 °C for 1Oh to give 2-Bromomethyl-4-(2-chloro- phenyl)-7,7-dimethyl-5-oxo-l,4,5,6,7,8-hexahydro-quinoline-3-carboxylic acid ethyl ester (523.0 g, 94% yield, 78.6% purity). 1H-NMR (CDCl3) δ (ppm), 7.38(d, J=7.5 Hz, IH), 7.25(d, /=6.6Hz, IH), 7.14-7.03(m, 2H), 6.42(s, IH), 5.40(s, IH), 4.73(q, J=9.3Hz, J=15.3Hz, 2H), 4.15-4.03(m, 2H), 2.40-2.10(m, 4H), 1.19(t, J=7.2Hz, 3H), 1.09(s, 3H), 0.95(s, 3H). ESMS clcd for C2IH23BrClNO3: 451.05; Found: 452.0 (M+H)+.
2-(2-Hydroxy-ethyl)-isoindole-l,3-dione (102.2 g, 0.534 mol) was added over a period of about 30 min to a stirred suspension of sodium hydride (12.82 g, 0.534 mol) in 2.25L of anhydrous DMF at room temperature in a 5L 4-necked round bottomed flask equipped with a mechanical stirrer and a thermometer. The reaction was stirred for about 1.5h at room temperature until the solution solidified (i.e., was difficult to stir). 40OmL of anhydrous DMF and 24OmL of hexane were added resulting in a uniformed slurry. The reaction temperature was reduced to about 00C and 2-Bromomethyl-4-(2-chloro-phenyl)-7,7- dimethyl-5-oxo-l,4,5,6,7,8-hexahydro-quinoline-3-carboxylic acid ethyl ester (110.0 g, 0.243 mol) in solid form was added in portions over a period of about 10 min. The reaction mixture was then stirred for about 1.5Ii at room temperature (until TLC analysis indicated the completion of the reaction) and the mixture was then poured into about 1OL of an ice- water mixture. The mixture was stirred left standing overnight. The precipitate was filtered, washed successively with water (50OmL x 3), hexane (2L x 1), and dried in vacuo for about . 24 hours. The powdered product was then added in portions to about 1.6L of warm MeOH (about 450C) with vigorous stirring, during which time the impurities were dissolved and 4- (2-Chloro-phenyl)-2-[2-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-ethoxymethyl]-7,7-dimethyl- 5-oxo-l,4,5, 6,7,8-hexahydro-quinoline-3-carboxylic acid ethyl ester appeared as a new precipitate. The solution was then cooled to about room temperature (about Ih). The precipitate was collected using filtration, washed with 20OmL of MeOH and drained well. The solid crude product was taken up in about IL of MeOH in a 2L round bottomed flask, stirred with heating (bath temperature of about 70 0C) for about 25 min to homogenize the product. The flask was then cooled to about room temperature (about Ih) and the product was filtered, drained well and vacuum dried (405 g, 74% yield, 99.5% purity). 1H-NMR (CDCl3) δ (ppm), 7.89-7.86(m, 2H), 7.80-7.77(m, 2H), 7.60(s, IH), 7.35(d, /=7.5 Hz, IH), 7.20(d, J=7.8Hz, IH), 7.10-6.99(m, 2H), 5.36(s, IH), 4.71-4.68(m, 2H), 4.03-
3.96(m,4H),3.80-3.74(m, 2H), 2.46-2.44(m, 2H),2.17-2.15(m, 2H), 1.13(t, J=7.2Hz, 3H), l.l l(s, 3H), 0.99(s, 3H). ESMS clcd for C3IH3IClN2O6: 562.19; Found: 563.2 (M+H)+.
Hydrazine hydrate (26 ml, 0.520 mol) was added over a period of about 12 rain to a stirred solution of 4-(2-Chloro-phenyl)-2-[2-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)- ethoxymethyl]-7,7-dimethyl-5-oxo- 1,4,5, 6,7, 8-hexahydro-quinoline-3-carboxylic acid ethyl ester in anhydorous ethanol (800 ml) in a 5L 4-necked round bottomed flask equipped with a mechanical stirrer, a thermometer and a heating mantle underneath. The reaction mixture was then stirred at about 78 0C for about 30 min. and the heating mantle was removed. The mixture was allowed to cool overnight and and filtered. The filtrate was concentrated in vacuo (removing approximately 98% of solvent) while keeping the bath temperature less than, about 5O0C. The resulting residue was then taken up in a separatory funnel with about 1.0 L Of CH2Cl2 and 700 mL of water and washed with about 50 mL of brine. The organic layer was washed again with about 600 mL of water and about 100 mL of brine, dried over MgSO4 and concentrated. The crude product was taken into a 1 : 1 mixture of 40OmL of hexane/ethyl acetate and stirred at about 550C for about 30 min to homogenize the precipitate. After cooling, the precipitate was filtered, washed with about 100 mL of ether and vacuum dried to give 2-(2-Amino-ethoxymethyl)-4-(2-chloro-phenyl)-7,7-dimethyl-5- oxo-l,4,5,6,7,8-hexahydro-quinoline-3-carboxylic acid ethyl ester (236 g, 78,4% yield, 99.4% purity).
The benzenesulfonate salt of 2-(2-Amino-ethoxymethyl)-4-(2-chloro-phenyl)-7,7- dimethyl-5-oxo-l, 4,5,6,7, 8-hexahydro-quinoline-3-carboxylic acid ethyl ester was prepared by adding the compound (590.0 g, 1.37 mol) to ethyl alcohol (2360 mL: 4mL ethanol per gram of amine) in a 4 L flask followed by stirring with heat until a clear solution was obtained (about 40-450C, solution temperature). After removal of the heating apparatus, benzenesulfonic acid (216.3 g, 1.37 mol) was added as a solid in one portion with stirring.
After the addition of benzenesulfonic acid, the resulting mixture was stirred for about 30 seconds. The stirring was stopped and yellow precipitates started to form immediately. The reaction mixture was then allowed to stand for about 3 hours at room temperature. When the reaction mixture reached room temperature, the precipitate was collected by filtration, washed with ethanol 3 times (total 1 L). The collected solid was vacuum dried to give the benzenesulfonic acid salt product as a light yellow crystalline powder (738.2 g, 91.5% yield, 99.8% purity).
EXAMPLE 6: Synthesis of 2-(2-amino-ethoxymethyI)-7,7-dimethyI~5-oxo-4-pyridin-2- yl-l,4,5,6,7,8-hexahydro-quinoline-3-carboxylic acid ethyl ester
NaH
/X/OH +
N3 Cl T THHFF,, D] MF 3^-/ O' O O O O
A solution of 2-azidoethanol (8.7g, 100 mmol) in THF (20 ml) was added to suspension of sodium hydride (8.8 g, 220 mmol, 60% dispersion in oil) in THF (150ml). The mixture was stirred at room temperature for about 1 h and then cooled to 0-50C. Ethyl-4- chloroacetoacetate (16.5g, 100 mmol) in THF (20 ml) was then added drop wise over a period of about 0.5 h. The mixture was stirred at room temperature for about 16 h and diluted with EtOAc (100 ml) and the pH was adjusted to 6-7 with 2 N HCl. Sufficient water was added to dissolve the solid, and the layers were then separated. The aqueous layer was further extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated. The product was purified by column chromatography on silica gel (Hexane - EtOAc, 95:5) to give 4-(2-azido-ethoxy)-3-oxo-butyric acid ethyl ester (16 g, 74.3 %) as yellow oil.
1H-NMR (CDCl3) δ (ppm), 4.24-4.17(m, 4H), 3.70(t, J=4.8Hz, 2H), 3.55(s, 2H), 3.43(t, J=5.1Hz, 2H), 1.28(t, J=7.2Hz, 3H);
ne,
AcONH4 2-propanol
A solution of 2-pyridinecarboxaldehyde (0.540mg, 5 mmol), 4-(2-azido-ethoxy)- 3- oxo-butyric acid ethyl ester (1.075g, 5 mmol), AcOH (0.03 ml), and piperidine (0.06 ml) in 2-propanol (8 ml) was heated under reflux for 20 min. After cooling, dimedone (5,5- dimethyl-l,3-cyclohexanedione) (0.74Og, 5.0 mmol, 95% pure) and ammonium acetate (0.47Og, 6.0 mmol) was added and the reaction was heated under reflux for 16 h. After removal of the solvent, the residue was purified by column chromatography on silica gel (Hexane -EtOAc 1: 1 and EtOAc) to give 2-(2-azido-ethoxymethyl)-7,7-dimethyl-5 -oxo-4- pyridin-2-yl-l,4,5,6,7,8- hexa-hydro-quinoline-3-carboxylic acid ethyl ester (0.87Og , 41%).
1H-NMR (CDCl3) δ (ppm), 8.52(s, IH), 7.58-7.48(m, 2H), 7.30-7.28(m, IH), 7.04- 7.0(m, IH), 5.26 (s, IH), 4.95(d, J=15.0Hz, IH), 4.84 (d, J=15.0 Hz, IH), 4.20-4.07(m, 2H), 3.84-3.78(m, 2H), 3.54-3.48(m, 2H), 2.42-2.10(m, 4H), 1.21(t, J=7.2Hz, 3H), 1.14(s, 3H), 1.02 (s, 3H); ESMS clcd for C22H27N5O4: 425.21; Found: 426.2 (M+H)+.
A mixture of 2-(2-azido-ethoxymethyl)-7,7-dimethyl-5-oxo-4-pyridin-2-yl- 1,4,5, 6,7,8-hexa-hydro-quinoline-3-carboxylic acid ethyl ester (0.43Og, 1.0 mmol) and tin (E) chloride ( 1.2g, 6.0 mmol) in mixture CH2Cl2-MeOH (2: 1, 8ml) containing 2 drops of water was stirred at room temperature for 6h. The reaction mixture was diluted with CH2Cl2 (20ml) and saturated solution OfNaHCO3 was added to pH 9-10, and the layers were then
separated. The aqueous layer was further extracted with CILCl2. The combined organic extracts were dried over MgSO4, filtered and evaporated. The product was purified by column chromatography on silica gel (CH2Cl2: MeOH, 9: 1) to give 2-(2-amino- ethoxymethyl)-7,7-dimethyl-5-oxo- 4-pyridin-2-yl-l,4,5,6,7,8-hexahydro-quinoline-3- carboxylic acid ethyl ester (0.28Og, 69,5%) as yellow sold.
1H-NMR (CDCl3) δ (ppm), 8.42(s, IH), 8.08(bs, IH), 7.51-7.39(m, 2H), 7.00- 6.96(m, IH), 5.17(s, IH), 4.79(s, 2H), 4.01(q, J=14.1Hz, J=7.2 Hz, 2H), 3.67-3.57(m, 2H), 2.96(t, J=5.1Hz, 2H), 239-2.08(m, 4H), 1.15(t, J=7.2Hz, 3H), 1.06(s, 3H), 0.94(s, 3H), ESMS clcd for C22H29N3O4: 399.22; Found: 400.2 (M+H)+.
EXAMPLE 7: Synthesis of S-(-)-2-(2-amino-ethoxymethyl)-4-(2-chloro-phenyl)-7,7- dimethyI-5-oxo-l,4,5,6,7,8-hexahydroquinoIine-3-carboxy!ic acid ethyl ester
S-(-)-2-(2-amino-ethoxymethyl)-4-(2-chloro-phenyl)-7,7-dimethyl-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carboxylic acid ethyl ester was resolved from the racemic Compound 272 mixture on a supercritical fluid column (SFC) as follows:
The following analytical data were obtained:
1H-NMR (CDCl3) δ (ppm) : 8.23 (s, IH), 7.32 (d, J=8.4 Hz, IH), 7.26 (dd, J;=8.4 Hz, J2=2Λ Hz, IH), 7.09 (dd, J,=8.4 Hz, J2=Ll Hz, IH), 5.33 (s, IH), 4.69-4.84 (m, 2H), 4.00 (q, J=6.9 Hz, 2H), 3.67-3.69 (m, 2H), 3.06-3.09 (m, 2H), 2.00-2.35 (m, 4H), 1.16 (t, J=6.9 Hz, 3H), 1.05 (s, 3H), 0.93 (s, 3H); ESMS clcd for C23H28Cl2N2O4: 466.14; Found: 467.2 (M+H)+.
The methods from Examples 4-6, shown above, were utilized with appropriate starting materials and reagents to produce the following compounds of the invention.
Choice of the appropriate starting materials and reagents will be readily apparent to one of skill in the art for these and other compounds of this invention.
2-(2-amino-ethoxymethyI)-4-benzo[l,3]-dioxol-5-yl-7,7-dimethyl-5-oxo-l,4,5,6,7,8- hexahydroquinoline- 3-carboxylic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 8.10(s, IH), 6.77-6.74(m, 2H), 6.61(d, J=7.8Hz, IH), 5.84-5.82(m, 2H), 4.94(s, IH), 4.79 and 4.72(2d, J=16.8Hz each IH), 4.02(q, J=14.1 Hz, J=7.2Hz, 2H), 3.58-3.52(m,2H), 2.94(t, J=4.8 Hz, 2H),2.38-2.10(m, 4H), 1.48(bs,lH), 1.18(t, /=7.2Hz, 3H), 1.04(s, 3H), 0.93(s, 3H); ESMS clcd for C24H30N2O6: 442.21; Found: 443.3 (M+H)+.
2-(2-amino-ethoxymethyl)-4-(2-chloro-phenyI)-l,7,7-trimethyl-5-oxo- 1,4,5,6,7,8- hexahydro-quinoline-3-carboxyIic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 7.23-7.19(m, 2H), 7.10-6.96(m, 2H), 5.48(s, IH), 4.82(d, J=12.9 Hz, IH), 4.6(d, J=12.9 Hz, IH), 4.08-4.02(m, 2H), 3.50(t, J=5.4Hz, 2H), 3.36(s, 3H), 2.84(t, /=5.1Hz, 2H), 2.54 (d, J=16.8Hz, IH), 2.33(d, J=17.1 Hz, IH), 2.15-2.13(m, 2H), 1.65(bs, 2H), 1.20(t, ./=6.9 Hz, 3H), 1.05(s, 3H), 0.97(s, 3H); ESMS clcd for C24H3IClN2O4: 446.20; Found: 447.2 (M+H)+. 2-(2-amino-ethoxymethyl)-4-(2-chloro-phenyl)-7,7-dimethyl-5-oxo-l,4,5,6,7,8- hexahydro-quinoIine-3-carboxyIic acid ethyl ester; complex with benzene sulfonic acid
1H-NMR (CDCl3) δ (ppm), 7.88-7.80(m, 3H), 7-49-7.19(m, 4H), 7.08-7.00(m, 2H), 5.33(s, IH), 4.74(d, J=15 Hz, 1 H), 4.64(d, J-15 Hz, IH), 4.08-3.95(m, 2H), 3.68-3.60(m,
2H), 3.10-3.05(m, 2H), 2.19-1.98(m, 4H), 1.14 (t, J=6.9 Hz, 3H), 0.81(s, 3H), 0.69(s, 3H).
2-(2-amino-ethoxymethyl)-4-(2,3-dichloro-phenyl)-7,7-dimethyI-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carboxylic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 8.37(s,lH), 7.34-7.21(m, 2H), 7.05(t, J=7.8Hz, IH), 5.44(s, IH), 4.82(d, J=15Hz, IH), 4.73(d, J=15Hz, IH), 4.05-3.99(m, 2H), 3.59(t, J=5.7Hz, 2H), 2.99(t, J=5.4Hz, 2H), 2.40-2.12(m,4H), 1.14(t, J=6,9 Hz, 3H), 1.07(s, 3H), 0.95(s, 3H); ESMS clcd for C23H28Cl2N2O4: 466.14; Found: 469.2;
2-(2-amino-ethoxymethyl)-7,7-dimethyI-4-(3-nitro-phenyl)-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carboxyIic acid ethyl ester 1H-NMR (CDCl3) δ (ppm), 8.58(s, IH), 8.13-8.05(m, IH), 7.98-7.94(m, IH), 7.73-
7.70(m, IH), 7.40-7.34(m, IH), 5.15(s, IH), 4.80(s, 2H), 4.043(q, J=14.1Hz, J=6.9Hz, 2H), 3.68-3.60(m, 2H), 2.99-2.94(m, 2H), 2.42-2.04 (m, 4H), 1.19(t, J=6.6Hz, 3H),1.09(s, 3H), 0.93(s, 3H); ESMS clcd for C23H29N3O6: 443.21; Found: 444.3 (M+H)+.
2-(2-amino-ethoxymethyl)-4-(3-amino-phenyI)-7,7-dimethyI-5-oxo-l,4,5,6,7,8- hexahydroquinoIine-3-carboxylic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 8.15(s, IH), 6.99(t, J=7.8Hz, IH), 6.72-6.69(m, 2H), 6.47-6-44(m, IH), 4.99(s, IH), 4.81(s, 2H), 4.06(q, J=14.4Hz, J=7.2Hz, 2H), 3.63-
3.58(m, 2H), 2.98(t, J=5.4Hz, 2H), 2.40-2.18(m, 4H), 1.21(t, J=7.2Hz, 3H), 1.08(s, 3H), 0.97(s, 3H); ESMS clcd for C23H3IN3O4: 413.23; Found: 414.3 (M+H)+.
2-(2-amino-ethoxymethyl)-4-(2-chloro-phenyI)-5-oxo-l,4,5,6,7,8-hexahydro-quinoIine- 3-carboxylic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 8.55(s, IH), 7.51(d, J=7.8Hz, IH), 7.40-7.33(m, IH), 7.26-7.12(m, 2H), 5.52(s, IH), 4.94(d, J=ISHz, IH), 4.84(d, J=18Hz, IH), 4.16-4.08(m, 2H), 3.71Ct, J=5.1Hz, 2H), 3.10(t, J=4.8Hz, 2H), 2.62-2.58(m, 2H), 2.44-2.39(m, 2H), 2.12- 2.00(m, 2H), 1.27(t, J=7.2Hz, 3H); ESMS clcd for C2IH25ClN2O4: 404.15; Found: 405.2 (M+H)+.
2-(2-amino-ethoxymethyl)-7,7-dimethyl-4-(2-nitro-phenyl)-5~oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carboxylic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 8.58(bs, IH), 7.70(d, J=8.1Hz, IH), 7.49-7.40(m, 2H), 7.21Ct, J=6.9Hz, IH), 5.86(s, IH), 4.80(s, 2H), 4.10-3.92(m, 2H), 3.66-3.52(m, 2H), 2.99(t, J=5.1Hz, 2H), 2.40-2.04(m, 4H), 1.06(t, J=6.9Hz, 3H), 1.03(s, 3H), 0.87(s, 3H); ESMS clcd for C23H29N3O6: 443.21; Found: 444.2 (M+H)+.
2-(2-amino-ethoxymethyl)-4-(2-fluoro-phenyl)-7,7-dimethyl- 5-oxo-l, 4,5,6,7,8- hexahydroquinoIine-3-carboxyIic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 8.23(s, IH), 7.38-7.7.23 (m, IH), 7.18-6.82(m, 3H), 5.18(s, IH), 4.80(d, J=17.7Hz, IH), 4.70(d, J=17.7Hz, IH), 3.97(q, J=14.4Hz, /=7.2Hz, 2H), 3.55 (t,J=5.1H,2H), 2.94(t,J=5.4Hz,2H), 2.38-2.01(m,4H), 1.54(bs,2H), 1.14(t,J=7.2Hz,3H), 1.04(s,3H), 0.90(s, 3H); ESMS clcd for C23H29FN2O4: 416.21; Found: 417.2 (M+H)+.
2-(2-amino-ethoxymethyl)-4-(2-chloro-phenyl)~7-isopropyl-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carboxylic acid ethyl ester 1H-NMR (CDCl3) δ (ppm), 8.34 (s, 0.6 H),8.24(s, 0.4 H),7.40-7.36(m, IH), 7.26-
7.20(m,lH), 7.12-7.00(m, 2H), 5.39(s, 0.6H), 5.35(s, 0.4H), 4.82-4.68(m, 2H), 4.02-3.96(m, 2H),3.59(t, J=4.8Hz, 2H), 2.97(t, J=4.8Hz, 2H), 2.5-2.25(m, 2H), 2.05-1.50(m, 4H), 1.14(t,
J=7.2Hz, 3H), 0.88(t, J=6.3Hz, 6H); ESMS clcd for C24H3]ClN2O4: 446.20; Found: 447.5 (M+H)+.
2-(2-amino-ethoxymethyl)-4-(2-chloro-phenyl)-7-methyl-5-oxo-l,4,5,6,7,8-hexahydro- quinoline-3-carboxylic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 8.40(s, 0.75H)5 8.25(s, 0.25H), 7.37-7.33(m, IH), 7.20- 7.18(m, IH), 7.10-6.95(m, 2H), 5.37-5.34(m, IH), 4.80-4.68(m, 2H), 4.00-3.94(m, 2H), 3,58-3.56(m, 2H), 2.94(t, J=4.8Hz, 2H), 2.50-1.92(m, 5H), 1.63(bs, 2H), 1.16-1.09(m, 3H),
1.02-0.96(m, 3H); ESMS clcd for C22H27ClN2O4: 418.17; Found: 419.1 (M+H)+.
2-(2-Amino-ethoxymethyl)-4-(4-chloro-phenyl)-7,7-dimethyl-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carboxylic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 8.17 (s, IH), 7.24 (d, J=7.8Hz, 2H), 7.16 (d, J=7.8Hz, 2H), 5.02(s, IH), 4.81 (s, 2H), 4.31 (bs, IH), 4.03 (q, J=6.9 Hz), 3.67-3.63 (m, 2H), 3.05- 3.02 (m, 2H), 2.44-2.31 (m, 2H), 2.20-2.11 (m, 2H), 2.04 & 2.00 (s, each IH), 1.26 & 1.18 (t, J=6.9 Hz, each 3H), 1.07 (s, 3H), 0.92 (s, 3H); ESMS clcd for C23H29ClN2O4: 432.18; Found: 433.2 (M+H)\
2-(2-Amino-ethoxymethyl)-4-(2-methoxy-phenyl)-7,7-dimethyl-5-oxo-l,4,5,6,7,8- hexahydro-quinoIine-3-carboxyIic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 8.01 (s, IH), 7.34-7.27 (m, IH), 7.11-7.06 (m, IH), 6.86- 6.77 (m, IH), 5.31 & 5.30 (2s, each IH), 4.83-4.68 (m, 2H), 4.01-3.98 (m, 2H), 3.80 (s, 3H), 3.65-3.56 (m, 2H), 2.41-2.04 (m, 8H), 1.19 (t, J=6.9 Hz), 1.08 (s, 3H), 0.94 (s, 3H); ESMS clcd for C24H32N2O5: 428.23; Found: 429.2 (M+H)+
2-(2-Amino-ethoxymethyl)-4-(2-cyano-phenyl)-7,7-dimethyl-5-oxo-l,4,5,6,7,8- hexahydro-quinoIine-3-carboxylic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 8.81 (bs, IH), 7.59-7.53 (m, 4H), 7.44 (dd, Jl= J27.5 Hz, IH), 7.20 (dd, Jl= J2=7.5 Hz, IH), 5.39 (bs, 2H), 5.30 (s, IH), 4.91-4.72 (m, 2H), 4.05-3.91 (m, 2H), 3.83-3.72 (m, 2H), 3.12 (bs, 2H), 2.56-2.38 (m, 2H), 2.22-2.02 (m, 4H), 1.14 (t, J=7.2 Hz, IH), 1.06 (s, 3H), 0.96 (s, 3H); ESMS clcd for C24H29N3O4: 423.22; Found: 424.2 (M+H)+
4-(2-Chloro-phenyl)-2-[2-(2-hydroxy-3-phenoxy-propylamino)-ethoxymethyI]-7,7- dimethyl-5-oxo-l,4,5,6,7,8-hexahydro-quinoline-3-carboxyIic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 7.62(s, IH), 7.40-7.23(m, 4H), 7.13(t, J=7.5Hz, IH), 7.05-6.97(m, 4H), 5.39(s, IH), 4.77(d, J=8.1Hz, 2H), 4.13(bs, IH), 4.02-4.08(m, 4H), 3.71-
3.65(m, 2H), 3.56(s, 3H), 2.96-2.85(m, 4H), 2.41-2.25(m, 2H), 2.22-2.07(m, 2H), 1.16(t, J=7.2Hz,3H), 1.05(s, 3H), 0.93(s, 3H); ESMS clcd for C32H39ClN2O6: 582.25; Found: 583.3 (M+H)+.
2-(2-amino-ethoxymethyl)-4-(2-chloro-phenyI)-7,7-dimethyl-5-oxo-l,4,5,6,7,8- hexahydro-quinoIine-3-carboxylic acid methyl ester
1H-NMR (CDCl3) δ (ppm), 8.27(s, IH), 7.36(d, J=7.2Hz, IH), 7.26-7.22(m, IH), 7.18-7.01(m, 2H), 5.39(s, IH), 4.81 and 4.75(2d, J=16.8Hz,each IH), 3.62-3.56(m, 2H), 3.56(s, 3H), 2.98(t, /=5.1Hz, 2H), 2.40-2.31(m, 2H), 2.22-2.12(m, 2H), 1.67(bs, 2H), 1.07(s, 3H), 0.95(s, 3H); ESMS clcd for C22H27ClN2O4: 418.17; Found: 419.2 (M+H)+.
2-(2-amino-ethoxymethyl)-4-(2-chloro-phenyl)-7,7-dimethyI-5-oxo-l,4,5,6,7,8- hexahydro-quinoIine-3-carboxylic acid methyl ester complex with benzenesulfonic acid
1H-NMR (CDCl3) δ (ppm), 7.89-7.85(m, 2H), 7.48-7.36(m, 2H), 7.7.30-7.18(m, 3H), 7.10-7.98(m, 2H), 5.34(s, IH), 4.72(d, J=15 Hz, 1 H), 4.65(d, J=15 Hz, IH), 3.70-3.62(m, 2H), 3.55(s, 3H), 3.48(s, IH), 3.18-3.08(m, 2H), 2.16-1.98(m, 4H), 0.84(s, 3H), 0.72(s, 3H); ESMS clcd for C28H33ClN2O7S: 577.09; Found: 419.2
2-(2-Amino-ethoxymethyI)-4-{5-chloro-2-[4-(2-hydroxy-3-phenoxy-propylamino)- butoxyJ-phenylj^^-dimethyl-S-oxo-l^jSjθ^jS-hexahydro-quinoline-S-carboxylic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 8.41-8.35(m, IH), 7.42-7.37(m, 3H), 7.14-7.00(m, 4H), 6.77(d, J=8.7Hz, IH), 5.3 l(s, IH), 4.94-4.79(m,2H), 4.23-4.00(m, 6H), 3.75-3.68(m, 2H), 3.10-2.80(m, 8H), 2.47-2.45(m, 2H), 2.29-2.24(m, 3H), 2.00-1.85(m, 4H), 1.29(t, J=7.2Hz, 3H), 1.17(s, 3H), 1.05(s, 3H); ESMS clcd for C36H48ClN3O7: 669.32; Found: 670.5 (M+H)+.
4-(2-ChIoro-phenyl)~2-[2-(2-hydroxy-3-phenoxy-propylamino)-ethoxymethyI]-7,7- dimethyl-5-oxo-l,4,5,6,7,8-hexahydroquinoline-3-carboxyIic acid methyl ester
1H-NMR (CDCl3) 5 (ppm), 7.62(s, IH), 7.37-7.23(m, 4H), 7.1 l(t, J=7.5Hz, IH), 7.05-6.97(m, 2H), 6.92(d, J=87Hz, 2H), 5.39(s, IH), 4.77(d, J=8.1Hz, 2H), 4.13(bs, IH), 4.02-4.00(m, 2H), 3.71-3.65(m, 2H), 3.56(s, 3H), 2.96-2.85(m, 4H), 2.41-2.25(m, 2H), 2.22- 2.07(m, 2H), 1.05(s, 3H), 0.93(s, 3H); ESMS clcd for C3iH37ClN2O6: 568,23; Found: 569.4 (M+H)+. 2-(2-Amino-ethoxymethyl)-4-(2-chloro-phenyl)-6,6-dimethyl-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carboxylic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 8.23(s, IH), 7.36(d, J=7.8Hz, IH), 7.23-7.21(m, IH), 7.12-7.01(m, 2H), 5.36(s, IH), 4.76(d, J=6.3Hz, 2H), 4.01(t, J=7.5Hz, 2H), 3.59(t, J=4.8Hz,
2H), 2.97(t, J=5.7 Hz, 2H), 2.52-2.48(m, 2H), 1.79(t, J=6.6Hz, 2H), 1.16(t, J=7.2Hz, 3H), 1.08(s, 3H), 0.94(s, 3H); ESMS clcd for C23H29ClN2O4: 432.18; Found: 433.3 (M+H)+.
2-(2-Amino-ethoxymethyl)-4-(2-fluoro-phenyl)-7-methyl-5-oxo-l,4,5,6,7,8- hexahydroquinoline-3-carboxylic acid ethyl ester
Mixture of diastereomers. 1H NMR (300 MHz, CDCl3), δ (ppm): 8.51, 8.40 (two br s from two diastereomers, total IH); 6.83-7.35 (m, 4H); 5.68 (br s, 2H); 5.21, 5.19 (two s, total IH); 4.81 (dd, J= 34.8 Hz, 15.3 Hz, 2H); 4.00 (q, J= 7.2 Hz, 2H); 3.76 (br s, 2H); 3.18 (br s, 2H); 1.94-2.72 (m, 5H); 1.50 (t, J= 7.2 Hz, 3H); 0.91-1.00 (m, 3H); ESMS clcd . for C22H28FN2O4 (M + H)+: 403.3; Found: 403.3.
2-(2-Amino-ethoxymethyl)-4-(2-fluoro-phenyI)-7-isopropyI-5-oxo-l,4,5,6,7,8- hexahydroquinoIine-3-carboxyIic acid ethyl ester
Mixture of diastereomers. 1H NMR (300 MHz, CDCl3), δ (ppm): 8.41, 8.30 (two br s from two diastereomers, total IH); 6.84-7.37 (m, 4H); 5.23, 5.19 (two s, total IH); 4.77 (dd, J= 25.5 Hz, 16.5 Hz, 2H); 4.00 (q, J= 7.5 Hz, 2H); 3.64 (t, J= 4.8 Hz, 2H); 3.11 (br s, 2H); 3.02 (t, J= 4.8 Hz, 2H); 1.48-2.60 (m, 6H); 1.16 (t, J= 7.5 Hz, 3H); 0.86-0.92 (m, 6H); ESMS clcd . for C24H32FN2O4 (M + H)+: 431.3; Found: 431.4. 2-(2-Amino-ethoxymethyI)-4-(2-cyano-phenyI)-7-methyI-5-oxo-l,4,5,6,7,8- hexahydro- quinoline-3-carboxylic acid ethyl ester
Mixture of diastereomers. 1H NMR (300 MHz, CDCl3), δ (ppm): 8.90 (br s, IH); 7.15-7.56 (m, 4H); 5.28, 5.27 (two s, total IH); 4.79 (s, 2H); 3.95-4.04 (m, 2H); 3.65 (t, J= 4.8 Hz, 2H); 2.99 (t, J= 4.8 Hz, 2H); 1.94-2.70 (m, 7H); 1.12-1.17 (m, 3H); 1.00-1.06 (m, 3H); ESMS clcd . for C23H28N3O4 (M + H)+: 410.2; Found: 410.2.
2-(2-Amino-ethoxymethyl)-4-(2-cyano-phenyI)-7-isopropyI-5-oxo-l,4,5,6,7,8- hexahydro- quinoline-3-carboxyIic acid ethyl ester
Mixture of diastereomers. 1H NMR (300 MHz, CDCl3), δ (ppm): 8.85, 8.88 (two br s from two diastereomers, total IH); 7.18-7.57 (m, 4H); 5.28, 5.25 (two s, total IH); 4.79 (dd, J= 24.3 Hz, 18.3 Hz, 2H); 3.96-4.03 (m, 2H); 3.63-3.72 (m, 2H); 2.93-3.05 (m, 2H); 1.52-2.54 (m, 8H); 1.14 (t, J= 7.2 Hz, 3H); 0.87-0.92 (m, 6H); ESMS clcd . for C25H32N3O4 (M + H)+: 438.2; Found: 438.2. 2-(2-Amino-ethoxymethyl)-4-(2-cyano-phenyl)-5-oxo-l,4,5,6,7,8-hexahydroquinoline-3- carboxylic acid ethyl ester
Mixture of diastereomers. ESMS clcd . for C22H26N3O4 (M + H)+: 396.2; Found: 396.2.
l-Cl-Amino-ethoxyinethyO-^CS^-dichloro-phenyO-TjT-dimethyl-S-oxo-l^jSjό,?^- hexahydro-quinoline-3-carboxylic acid ethyl ester 1H-NMR (CDCl3) δ (ppm) : 8.42 (s, IH), 7.18 (d, J=2.1 Hz, 2H), 7.11 (d, J=2.1 Hz,
IH), 5.01 (s, IH), 4.80 (s, 2H), 4.03-4.08 (m, 2H), 3.59-3.64 (m, 2H), 2.98-3.02 (m, 2H), 2.00-2.39 (m, 4H), 1.21 (t, J=6.9 Hz, 3H), 1.08 (s, 3H), 0.97 (s, 3H) ESMS clcd for C23H28Cl2N2O4: 466.14; Found: 467.2 (M+H)+. 2-(2-Amino-ethoxymethyl)-4-(3,4-dichloro-phenyl)-7,7-dimethyI-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carboxyIic acid ethyl ester
1H-NMR (CDCl3) δ (ppm) : 8.31 (s, IH), 7.34 (d, J=I.8 Hz, IH), 7.26 (d, J=9.6 Hz, IH), 7.16 (dd, J;=9.6, J2=1.8 Hz, IH), 4.98 (s, IH), 4.79-4.81 (s, 2H), 3.99-4.06 (m, 2H), 3.71-3.75 (m, 2H), 3.02-3.14 (m, 2H), 2.04-2.38 (m, 4H), 1.23 (t, J=6.9 Hz, 3H), 1.03 (s, 3H), 0.91 (s, 3H); ESMS clcd for C23H28Cl2N2O4: 466.14; Found: 467.2 (M+H)+.
2-(2-Amino-ethoxymethyl)-4-2,3-dichloro-phenyI)-7-isopropyI-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carboxylic acid ethyl ester
1H-NMR (CDCl3) δ (ppm) : 8.35 (s, IH), 7.34 (d, J=2.7 Hz, IH), 7.16 (d, J=8.4 Hz, IH), 7.01 (dd, J1=IJ Hz, J2=8.4 Hz, IH), 5.33 (s, IH), 4.76-4.78 (m, 2H), 4.02 (q, J=6.9 Hz, 2H), 3.50-3.63 (m, 2H), 2.99-3.02 (m, 2H), 2.04-2.35 (m, 4H), 1.17 (t, J=6.9 Hz, 3H), 1.06 (s, 3H), 0.96 (s, 3H); ESMS clcd for C23H28Cl2N2O4: 466.14; Found: 467.2 (M+H)+.
2-(2-Amino-ethoxymethyI)-4-(2,3-dichloro-phenyl)-7-methyI-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carboxylic acid ethyl ester
1H-NMR (CDCl3) δ (ppm) : 8.47 (s, IH), 7.37 (d, J=2.7 Hz, IH), 7.18 (d, J=8.4 Hz, IH), 7.06 (dd, J;=2.7 Hz, J2=8.4 Hz, IH), 5.39 (s, IH), 4.67-4.83 (m, 2H), 3.94 (q, J=6.9 Hz, 2H), 3.70-3.74 (m, 2H), 3.01-3.11 (m, 2H), 2.03-2.58 (m, 4H), 1.14 (t, J=6.9 Hz, 3H),
0.95 (s, 3H); ESMS clcd for C22H26Cl2N2O4: 452.13; Found: 453.1 (M+H)+.
2-(2-Amino-ethoxymethyI)-4-(2,6-dichloro-phenyl)-7,7-dimethyl-5-oxo-l,4,5,6,7,8- hexahydro-quinoIine-3-carboxyIic acid ethyl ester
1H-NMR (CDCl3) δ (ppm) : 8.34 (s, IH), 7.56-7.59 (m, 3H), 4.97 (s, IH), 4.79-4.81 (s, 2H), 4.00-4.05 (m, 2H), 3.53-3.59 (m, 2H), 2.98-3.01 (m, 2H), 2.06-2.45 (m, 4H), 1.16 (t, J=6.9 Hz, 3H), 1.05 (s, 3H), 0.96 (s, 3H); ESMS clcd for C23H28Cl2N2O4: 466.14; Found: 467.2 (M+H)+.
2-(2-Amino-ethoxymethyl)-4-(2,5-dichloro-phenyI)-7,7-dimethyl-5-oxo-l,4,5,6,7,8- hexahydroquinoline-3-carboxyIic acid ethyl ester
1H-NMR (CDCl3) δ (ppm) : 8.35 (s, IH), 7.34 (d, J=2.7 Hz, IH), 7.16 (d, J=8.4 Hz, IH), 7.01 (dd, J7=2.7 Hz, J2=SA Hz, IH), 5.33 (s, IH), 4.76-4.78 (m, 2H), 4.02 (q, J=6.9 Hz, 2H), 3.50-3.63 (m, 2H), 2.99-3.02 (m, 2H), 2.04-2.35 (ra, 4H), 1.17 (t, J=6.9 Hz, 3H), 1.06 (s, 3H), 0.96 (s, 3H); ESMS clcd for C23H28Cl2N2O4: 466.14; Found: 467.2 (M+H)+.
2-(2-Amino-ethoxymethyl)-4-(2,4-dichIoro-phenyl)-7,7-dimethyl-5-oxo-l,4,5,6,7,8- hexahydro-quinoIine-3-carboxylic acid ethyl ester 1H-NMR (CDCl3) δ (ppm) : 8.23 (s, IH), 7.32 (d, J=8.4 Hz, IH), 7.26 (dd, J7 =8.4
Hz, J2=2.1 Hz, IH), 7.09 (dd, J7=8.4 Hz, J2=2.1 Hz, IH), 5.33 (s, IH), 4.69-4.84 (m, 2H), 4.00 (q, J=6.9 Hz, 2H), 3.67-3.69 (m, 2H), 3.06-3.09 (m, 2H), 2.00-2.35 (m, 4H), 1.16 (t, J=6.9 Hz, 3H), 1.05 (s, 3H), 0.93 (s, 3H); ESMS clcd for C23H28Cl2N2O4: 466.14; Found: 467.2 (M+H)+.
2-(2-AcetyIamino-ethoxymethyl)-4-(2-chloro-phenyl)-7,7-dimethyl-5-oxo-l,4,5,6,7,8- hexahydro-quinoIine-3-carboxylic acid ethyl ester
H-NMR (CDCl3) δ (ppm) 0.94 (s, 3H), 1.07 (s, 3H), 1.14 (t, J=7.2 Hz, 3H), 1.80 (bs, IH), 2.00 (s, 3H), 2.15 (m, 2H), 2.38 (m, 2H), 3.6 (m, 4H), 3.99 (m, 2H), 4.70 (q, 2H), 5.38 (s, IH), 7.03(m, IH), 7.10 (m, IH), 7.20 (m, IH), 7.35 (m, IH), 7.6 (bs, IH); ESMS clcd for C25H3IClN2O5: 474.2; Found: 475.1 (M+H)+.
2-(2-Amino-ethoxymethyl)-4-(2-chloro-phenyl)-7,7-dimethyI-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carboxylic acid 1H-NMR (CD3OD) δ (ppm) 1.11 (s, 3H), 1.20 (s, 3H), 2.13 (m, 3H), 2.53 (m, 2H),
3.3 (t, J= 4.2 Hz, 2H), 3.81 (m, 2H), 4.60 (q, J= 6.9 Hz, 2H), 5.62 (s, IH), 7.21 (m, 3H),
+
7.51 (d, J= 6.6 Hz, IH); ESMS clcd for C2IH25ClN2O4: 404.2; Found: 405.1 (M+Hf.
2-(2-Amino-ethoxymethyI)-7,7-dimethyl-5-oxo-4-pyridin-3-yl-l,4,5,6,7,8-hexahydro- quinoline-3-carboxylic acid ethyl ester
1H-NMR (CDCl3) δ (ppm) 0.93 (s, 3H), 1.08 (s, 3H), 1.18 (t, J= 7.2 Hz, 3H), 1.56 (bs, 2H), 2.28 (m, 4H), 2.99 (t, J= 4.5 Hz, 2H), 3.60 (t, J= 5.1 Hz, 2H), 4.04 (q, J= 7.2 Hz, 2H), 4.89 (m, 2H), 5.05 (s, IH), 7.14 (m, IH), 7.64, (m, IH), 8.33 (m, IH), 8.45 (bs, IH), 8.53 (d, J= 1.5 Hz, IH); ESMS clcd for C22H29N3O4: 399.22; Found: 400.0 (M+H)+.
4-(2-Chloro-phenyI)-2-(2-ethylamino-ethoxymethyl)-7,7-dimethyl-5-oxo-l,4,5,6,7,8- hexahydro-quinoIine-3-carboxylic acid ethyl ester
1H-NMR (CDCl3) δ (ppm) 0.94 (s, 3H), 1.07 (s, 3H), 1.18 (m, 6H), 2.29 (m, 4H), 2.90 (q, J= 7.1 Hz, 2H), 3.02 (t, J= 4.5 Hz, 2H), 3.75 (t, J= 5.1 Hz, 2H), 4.04 (m, 2H), 4.84 (m, 2H), 5.45 (s, IH)5 7.14 (m, 2H), 7.38, (m, IH), 7.49 (m, IH), 8.37 (bs, IH); ESMS clcd for C25H33ClN2O4: 460.2; Found: 461.2 (M+H)+.
2-(2-Amino-ethoxymethyl)-4-(2-chloro-phenyl)-7,7-dimethyl-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carbonitrile
1H-NMR (CDCl3) δ (ppm) 1.03 (s, 3H), 1.09 (s, 3H), 1.61 (bs, 2H), 2.20(m, 4H), 2.96(m, 2H), 3.58 (m, 2H), 4.35 (m, 2H), 5.18 (s, IH), 7.25 (m, 4H), 8.65 (bs, IH); ESMS clcd for C2IH24ClN3O2: 385.2; Found: 386.4 (M+H)+.
Benzenesulfonate2-(3-ethoxycarbonyl-7,7-dimethyl-5-oxo-4-pyridin-3-yl-l,4,5,6,7,8- hexahydro-quinoIin-2-ylmethoxy)-ethyl-ammonium
1H-NMR (CDCl3) δ (ppm) 0.84 (s, 3H), 0.95 (s, 3H), 1.21 (t, J= 7.2 Hz, 3H), 2.17 (m, 3H), 2.68 (bs, IH), 3.16 (m, IH), 3.24 (m, IH), 3.77 (m, 2H), 4.04 (q, J= 7.2 Hz, 2H), 4.70 (m, 2H), 5.02 (s, IH), 7.2 (m, 5H), 7.63, (d, J= 7.2 Hz, 2H), 7.82 (d, J= 6.9 Hz, IH), 8.18 (m, IH), 8.75 (m, 4H); ESMS clcd for C28H35N3O7S : 557.22; Found: 400.4 (M+H - C6H6SO3)+.
2-(2-Amino-ethoxymethyl)-7,7-dimethyl-5-oxo-4-quinolin-3-yl-l,4,5,6,7,8-hexahydro- quinoline-3-carboxyIic acid ethyl ester
1H-NMR (CDCl3) δ (ppm) 0.86 (s, 3H), 1.01 (s, 3H), 1.13 (t, J= 6.3 Hz, 3H), 1.59 (bs, 2H), 2.22 (m, 4H), 2.92 (m, 2H), 3.55 (m, 2H), 3.97 (q, J= 6.3 Hz, 2H), 4.78 (m, 2H), 5.20 (s, IH), 7.45 (t, J= 7.2 Hz, IH), 7.57 (t, J= 6.9 Hz, IH), 7.73, (d, J= 8.4 Hz, IH), 7.99 (m, 2H), 8.60 (bs, IH), 8.89 (d, J= 1.8 Hz, IH); ESMS clcd for C26H31N3O4: 449.2; Found: 450.1 (M+H)+.
4-(2-Chloro-phenyI)-7,7-dimethyl-2-(2-methyIamino-ethoxymethyl)-5-oxo-l,4,5,6,7,8~ hexahydro-quinoIine-3-carboxylic acid ethyl ester 1H-NMR (CDCl3) δ 0.95 (s, 3H), 1.05 (s, 3H), 1.15 (t, 3H, J =7), 1.6-1.9 (m, IH),
2.1-2.2 (q, 2H), 2.2-2.4 (q, 2H), 2.5 (d, 3H), 2.8-2.9 (m, 2H), 3.6 (t, 2H, J=5), 3.9-4.1 (m, 2H), 4.7-4.9 (q, 2H), 5.4 (s, IH), 7.0-7.4 (m, 4H), 8.5 (s, IH) ppm; ESMS clcd for C24H31ClN2O4: 446.1; Found: 447.1 (M+H)+.
2-(2-Amino-ethoxymethyl)-7,7-dimethyl-5-oxo-4-pyridin-4-yl-l,4,5,6,7,8-hexahydro- quinoIine-3-carboxylic acid ethyl ester
1H-NMR (CDCl3) δ 0.95 (s, 3H), 1.1 (s, 3H), 1.2 (t, 3H, J =7), 1.45 (bs, 2H), 2.1-2.4 (m, 4H), 2.9-3.1 (m, 2H), 3.6-3.7 (m, 2H), 4.0-4.1 (m, 2H), 4.8 (s, 2H), 5.1 (s, IH), 7.2-7.3 (m, 2H), 8.4-8.5 (m, 3H)ppm; ESMS clcd for C22H29N3O4: 399.2; Found: 400.2 (M+H)+.
2-(2-Amino-ethoxymethyI)-5-oxo-4-pyridin-3-yl-l,4,5,6,7,8-hexahydro-quinoIine-3- carboxylic acid ethyl ester
1H-NMR (CDCl3) δ 1.1 (t, 3H, J =7), 1.5 (bs, 2H)5 1.8-2.1 (m, 2H), 2.2-2.4 (m, 2H), 2.4-2.6 (m, 2H), 3.0 (t, 2H, J=5), 3.6 (t, 2H, J=5), 4.0-4.1 (m, 2H), 4.8 (q, 2H), 5.1 (s, IH), 7.0-7.2 (m, IH), 7.6-7.7 (m, IH), 8.4 (m, IH), 8.5 (s, IH), 8.7 (s, lH)ppm; ESMS clcd for C20H25N3O4: 371.2; Found: 372.2 (M+H)+.
2-(2-Amino-ethoxymethyI)-4-(4-chloro-l,2,4,5-tetradeutiurn-phenyl)-7,7-dimethyl-5- oxo-l,4,5,6,7,8-hexahydroquinoline-3-carboxyIic acid ethyl ester
1H-NMR (CDCl3) δ 0.95 (s, 3H), 1.1 (s, 3H), 1.2 (t, 3H, J =7), 2.2 (q, 2H), 2.4 (q, 2H), 3.1 (m, 2H), 3.4 (bs, 2H), 3.6-3.7 (m, 2H), 4.0-4.1 (m, 2H), 4.8 (q, 2H), 5.0 (s, IH), 8.2 (s, lH)ppm; ESMS clcd for C23H25D4ClN2O4: 436.2; Found: 437.2 (M+H)+.
2-[2-(l,3-Dioxo-l,3-dihydro-isoindol-2-yl)-ethoxymethyl]-7,7-dimethyl-5-oxo-4-pyridin- 4-yl-l,4,5,6,7,8-hexahydroquinoIine-3-carboxyIic acid ethyl ester 1H-NMR (CDCl3) δ 1.0 (s, 3H), 1.1 (s, 3H), 1.2 (t, 3H, J =7), 2.2 (q, 2H), 2.5 (q, 2H),
3.7-3.8 (m, 2H), 4.0-4.2 (m, 4H), 4.8 (s, 2H), 5.1 (s, IH), 7.2 (d, 2H, J=7), 7.7-8.0 (m, 5H), 8.4 (d, 2H, J=7)ppm; ESMS clcd for C30H31N3O6: 529.2; Found: 530.2 (M+H)+.
2-[2-(l,3-Dioxo-l,3-dihydro-isoindoI-2-yI)-ethoxymethyI]-5-oxo-4-pyridin-3-yl- l,4,5,6,7,8-hexahydro-quinoline-3-carboxyIic acid ethyl ester
1H-NMR (CDCl3) δ 1.2 (t, 3H, J =7), 1.9-2.1 (m, 2H), 2.3-2.4 (m, 2H), 2.5-2.8 (m, 2H), 3.7-3.8 (m, 2H), 3.9-4.2 (m, 4H), 4.7 (q, 2H), 5.1 (s, IH), 7.1 (q, IH), 7.2 (d, IH, J=7), 7.7-8.0 (m, 5H), 8.3 (d, IH, J=5), 8.5 (s, lH)ppm; ESMS clcd for C28H27N3O6: 501.2; Found: 502.2 (M+H)+.
2-(2-Azido-ethoxymethyl)-7,7-dimethyI-4-(3-nitro-phenyI)-5-oxo-l,4,5,6,7,8-hexahydro- quinoline-3-carboxyIic acid ethyl ester
1H-NMR (CDCl3) δ 0.95 (s, 3H), 1.05 (s, 3H), 1.2 (t, 3H, J =7), 2.1-2.4 (m, 4H), 3.4- 3.6 (m, 2H), 3.7-3.8 (m, 2H), 4.0-4.1 (m, 2H), 4.8 (q, 2H), 5.2 (s, IH), 7.2-7.4 (m, 2H), 7.7 (d, IH, J=7), 8.0 (d, IH, J=7), 8.1 (s,lH)ppm; ESMS clcd for C23H27N5O6: 469.2; Found: 470.2 (M+H)+.
2-(2-azido-ethoxymethyI)-4-benzo[l,3]dioxol-5-yl-7,7-dimethyI-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carboxyIic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 7.19(s, IH), 6.83-6.79(m, 2H), 6.69-6.67(m, IH), 5.90(s, 2H), 5.01(s, IH), 4.88 and 4.83(2d, J=16.8Hz each IH), 4.12-4.06(m, 2H), 3.83-3.78(m, 2H), 3.56-3.48(m, 2H)5 2.37-2.23(m, 4H), 1.25(t, J=10.8 Hz, 3H), l.ll(s, 3H), 1.00(s, 3H); ESMS clcd for C24H28N4O6: 468.20; Found: 469.2 (M+H)+.
2-(2-azido-ethoxymethyI)-4-(2-chloro-phenyI)-l,7,7-trimethyl-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carboxyIic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 7.30-7.250(m, 2H), 7.14-7.05(m, 2H), 5.55(s, IH), 4.94(d, J=12.9 Hz, IH), 4.76(d, J=12.9Hz, IH), 4.16-4.10(m, 2H), 3.75-3.71(m, 2H), 3.44(s, 3H), 3.41-3.38(111, 2H), 2.60(d, J=16.8Hz, IH), 2.38(d, J=16.8Hz, IH), 2.20(s, 2H), 1.26(t, J=6.9Hz, 3H), l.l l(s, 3H), 1.03(s, 3H); ESMS clcd for C24H29ClN4O4: 472.19; Found: 473.1 (M+H)+.
2-(2-amino-ethoxymethyl)-4-(2-chloro-phenyI)-5-oxo-4,5,6,7-tetrahydro-lH- [l]pyrindine-3-carboxylic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 9.19(s, IH), 7.29-7.24(m, 2H), 7.16-7.05(ra, 2H), 5.31(s, IH), 4.83(s, 2H), 3.99-3.92(m, 2H), 3.65-3.59(m, 2H), 3.01(t, J=5.1Hz, 2H), 2.61-2.58(m, 2H), 2.36-2.5 l(m, 2H), 1.07(t, J=7.2Hz, 3H); ESMS clcd for C20H23ClN2O4: 390.13; Found: 391.2 (M+H)+.
9-(2-chloro-phenyl)-6,6-dimethyl-5,6,7,9-tetrahydro-3H,4H-furo[3,4-b]quinoline-l,8- dione
1H-NMR (CDCl3) δ (ppm), 10.13(s, IH), 7.288-7.1 l(m, 4H), 5.05(s, IH), 4.86(s, 2H), 2.50-2.39(m, 2H), 2.18(d, J=16.8Hz, IH), 2.00(d, J=16.8Hz, IH), 1.02(s, 3H), 0.94(s, 3H); ESMS clcd for Ci9H18ClN O3: 343.10; Found: 344.0 (M+H)+.
(+)-(R)-2-(2-amino-ethoxymethyl)-4-(2-chloro-phenyl)-7,7-dimethyI-5-oxo-l,4,5,6,7,8- hexahydro-quiαoline-3-carboxyIic acid ethyl ester; compound with benzenesulfonic acid
1H-NMR (DMSOd6) δ (ppm), 8.66(s, IH), 7.84-7.80(m, 3H), 7.60-7.58(m, 2H), 7.32-7.09(m, 6H), 5.22(s, IH), 4.66(d, J=15 Hz, 1 H), 4.60(d, J=15 Hz, IH), 4.08-3.93(m, 2H), 3.68-3.60(m, 2H), 3.10-3.05(m, 2H), 2.28-2.23(m, IH), 2.06-2.00(m, IH) 1.17 (t, J=6.9 Hz, 3H), 1.09(s, 3H), 0.92(s, 3H); ESMS clcd for C29H35ClN2O7S: 590.19; Found: 433.2.
(+)-(R)-2-(2-amino-ethoxymethyl)-4-(2-chloro-phenyl)-7,7-dimethyl-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carboxyIic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 8.24(s, IH), 7.40(d, J=6Hz, IH), 7.26-7.21(m, IH), 7.14- 7.02(m, 2H), 5.39(s, IH) 4.78 and 4.76(2d, J=16.8Hz,each IH), 4.03-3.98(m, 2H), 3.64- 3.60(m, 2H), 3.02(t, J=4.5Hz, 2H), 2.42-2.08(m, 6H), 1.15 (t, J=7.2Hz, 3H),1.07(s, 3H), 0.94(s, 3H); ESMS clcd for C23H29ClN2O4: 432.18; Found: 433.2 (M+H)+.
(-)-(S)-2-(2-amino-ethoxymethyl)-4-(2-chloro-phenyl)-7,7-dimethyl-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carboxylic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 8.21(s, IH), 7.40(d, J=6Hz, IH), 7.26-7.21(m, IH), 7.14- 7.02(m, 2H), 5.38(s, IH), 4.81 and 4.77(2d, J=16.8Hz,each IH), 4.02-3.98(m, 2H), 3.75- 3.68(m, 2H), 3.12(t, J=4.5Hz, 2H), 2.40(s, 2H), 2.22-2.06(m, 4H), 1.15 (t, J=7.2Hz, 3H), 1.05(s, 3H), 0.92(s, 3H); ESMS clcd for C23H29ClN2O4: 432.18; Found: 433.2 (M+H)+.
2-(2-Amino-ethoxymethyl)-4-(lH-indol-3-yl)-7,7-dimethyI-5-oxo-l,4,5,6,7,8-hexahydro- quinoIine-3-carboxyIic acid ethyl ester
1H-NMR (300MHz, CDCl3): δ 9.67 (s, IH), 8.04 (s, IH), 7.78-7.72 (m, IH), 7.34- 7.28 (m, IH), 7.20-7.06 (m, 2H), 6.71 (s, IH), 4.80 (s, IH), 4.69 (s, IH), 4.18-4.06 (m, 2H), 3.98 (s, IH), 3.65-3.50 (m, 2H), 2.90-2.65 (m, 2H), 2.56-2.22 (m, 4H), 1.23 (t, J = 6.9Hz, 3H), 1.13 (s, 3H), 1.11 (s, 3H); ES-MS calculated for C25H31N3O4 (M+H)+: 437.23; Found: 438.2.
4-(2-Chloro-phenyl)-2-ethoxycarbonylmethoxymethyl-7,7-dimethyl-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carboxylic acid ethyl ester
1H-NMR (300MHz, CDCl3): δ 7.89 (s, IH), 7.39 (dd, J= 1.5, 7.8Hz , IH), 7.23 (dd, J= 1.5, 7.8Hz, IH), 7.12 (td, J= 1.5, 7.5Hz, IH), 7.02 (td, J= 1.5, 7.5Hz5 IH), 5.40 (s, IH), 4.85 (d, J= 4.5Hz, 2H), 4.27 (q, J= 6.9Hz, 2H), 4.22 (d, J= 4.5Hz, 2H), 4.15-3.92 (m, 2H), 2.44-2.09 (m, 4H), 1.32 (t, J= 7.2Hz, 3H), 1.16 (t, J= 6.9Hz, 3H), 1.08 (s, 3H), 0.96 (s, 3H); ES-MS Calculated for C25H30C1NO6 (M+l)+: 475.18, Found: 476.1.
4-(2-Chloro-phenyI)-2-(hydroxyI-ethoxymethyl)-7,7-dimethyI-5-oxo-l,4,5,6,7,8- hexahydro-quinoIine-3-carboxylic acid ethyl ester
1H-NMR (300MHz, CDCl3): δ 7.65 (s, IH), 7.39 (dd, J= 1.8, 7.8Hz, IH), 7.23 (dd, J= 1.4, 7.8Hz, IH), 7.12 (td, J= 1.8, 7.8Hz, IH), 7.03 (td, J= 1.8, 7.8Hz, IH), 5.40 (s, IH), 4.83 (d, J= 16.8Hz, IH), 4.76 (d, J= 16.8Hz, IH), 4.08-3.96 (m, 2H), 3.88 (t, J= 4.5Hz,
2H), 3.78-3.64 (m, 2H), 2.40-2.09 (m, 4H), 1.16 (t, J= 7.2Hz, 3H), 1.07 (s, 3H), 0.97 (s, 3H); ES-MS Calculated for C23H28ClNO5 (M+H)+: 433.17; Found 434.1.
9-(2-Chloro-phenyl)-4-ethyl-6,6-dimethyI-5,6,7,9-tetrahydro-3H,4H- furo[3,46]quinoline-l,8-dione
1H-NMR (300MHz, DMSO-d6): δ 7.28 (d, J= 7.5Hz, IH), 7.25-7.10 (m, 3H), 5.08- 5.02 (m, 3H), 3.70-3.52 (m, 2H), 2.64 (s, 2H), 2.20 (d, J= 15.9Hz, IH), 1.98 (d, J= 15.9Hz, IH), 1.25 (t, J= 7.2Hz, 3H), 1.06 (s, 3H), 0.94 (s, 3H), ES-MS calculated for C21H22C1NO3 (M+H)+: 371.13, Found: 372.1.
4-(2-Chloro-phenyI)-7,7-dimethyI-5-oxo-2-piperazin-l-ylmethyl-l,4,5,6,7,8-hexahydro- quinoIine-3-carboxylic acid ethyl ester
1H-NMR (300MHz, CDCl3): δ 8.10 (s, IH), 7.36 (dd, J= 1.8, 7.5Hz, IH), 7.23 (dd, J= 1.5, 8.1Hz, IH), 7.11 (dt, J= 1.5, 7.5Hz, IH), 7.03 (td, J= 1.8, 7.5Hz, IH), 5.39 (s, IH), 4.08-3.96 (m, 2H), 3.77 (s, 2H), 3.48 (s, IH), 2.98 (t, J= 4.8Hz, 4H), 2.64-2.50 (m, 4H), 2.38-2.09 (m, 4H), 1.16 (t, J= 7.2Hz, 3H), 1.09 (s, 3H), 0.98 (s, 3H); ES-MS calculated for C25H32C1N3O3 (M+H)+: 457.21; Found: 458.3.
4-(2-ChIoro-phenyl)-2-{[(2-hydroxy-ethyl)-methyl-amino]-methyl}-7,7-dimethyI-5-oxo- l,4,5,6,7.8-hexahydro-quinoIine-3-carboxylic acid ethyl ester
1H-NMR (SOOMHz, CDCl3): δ 8.46 (s, IH), 7.38 (dd, J= 1.8, 7.8Hz, IH), 7.22 (dd, J= 1.5,.7.8Hz, IH), 7.11 (td, J= 1.5, 7.5Hz, IH), 7.02 (td, J= 1.8, 7.8Hz, IH), 5.40 (s, IH), 4.13-3.91 (m, 3H), 3.84 (d, J= 11. IHz, 2H), 3.77-3.73 (m, 2H), 2.61 (t, J= 5.1Hz, 2H), 2.40 (s, 3H), 2.34-2.06 (m, 4H), 1.16 (t, J= 7.2Hz, 3H), 1.05 (s, 3H), 0.93 (s, 3H); ES-MS calculated for C24H3IClN2O4 (M+H)+: 446.20; Found: 447.20.
2-(2-Amino-ethoxymethyl)-4-(2-hydroxy-phenyI)-7,7-dimethyl-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carboxylic acid ethyl ester
1H-NMR (CDCl3) δ (ppm) 9.3 (br, IH), 8.6 (br, IH), 6.7-7.1 (m, 4H), 5.12 (s, IH), 4.9 (m, 2H), 3.9 (m, 2H), 3.6 (t, J=6 Hz, 2H), 3.0 (t, J=6 Hz, 2H), 2.3 (m, 4H), 1.02 (s, 3H), 1.0 (t, J=8 Hz, 3H), 0.84 (s, 3H); ESMS clcd for C23H30N2O5: 414.2; Found: 415.4 (M+H)+.
2-(2-Amino-ethoxymethyl)-7,7-dimethyI-5-oxo-4-pyridin-3-yI~l,4,5,6,7,8-hexahydro- quinoIine-3-carboxyIic acid methyl ester 1H-NMR (CDCl3) δ (ppm) 8.6 (m, IH), 8.5 (br, IH), 8.4 (m, IH), 7.7 (m, IH), 7.2
(m, IH), 5.06 (s, IH), 4.8 (m, 2H), 3.60 (s, 3H), 3.6 (m, 2H), 3.0 (t, J=6 Hz, 2H), 2.4 (m,
2H), 2.2 (m,2H), 1.06 (s, 3H), 0.96 (s, 3H); ESMS clcd for C21H27N3O4: 385.2; Found: 386.1 (M+H)+.
2-(2-Amino-ethoxymethyI)-l,7,7-trimethyl-5-oxo-4-pyridin-3-yI-l,4,5,6,7,8-hexahydro- quinoline-3-carboxylic acid ethyl ester
1H-NMR (CDCl3) δ (ppm) 8.4 (m, 2H), 7.6 (m, IH), 7.2 (m, IH), 5.20 (s, IH), 4.7- 5.1 (m, 2H), 4.1 (m, 2H), 3.5 (m, 2H), 3.39 (s, 3H), 2.8 (m, 2H), 2.3-2.6 (m, 2H), 2.2 (m,2H), 1.1 (t, J=8 Hz, 3H), 1.12 (s, 3H), 1.00 (s, 3H); ESMS clcd for C23H3]N3O4: 413.2; Found: 414.1 (M+H)+.
2-(2-Hydroxy-ethoxymethyI)-7,7-dimethyl-5-oxo-4-pyridin-3-yl-l,4,5,6,7,8-hexahydro- quinoline-3-carboxyIic acid ethyl ester
1H-NMR (CDCl3) δ (ppm) 8.6 (br, IH), 8.4 (m, 2H), 7.9 (br, IH), 7.7 (m, IH), 7.2 (m, IH), 5.06 (s, IH), 4.8 (m, 2H), 4.0 (m, 2H), 3.8 (m, 2H), 3.7 (m, 2H), 2.1-2.4 (m, 4H), 1.2 (t, J=8 Hz, 3H), 1.06 (s, 3H), 0.90 (s, 3H); ESMS clcd for C22H28N2O5: 400.2; Found: 401.1 (M+H)+.
2-(2-Dimethylamino-ethoxymethyl)-7,7-dimethyl-5-oxo-4-pyridin-3yl-l,4,5,6,7,8,- hexahydro-quinoline-3-carboxyIic acid ethyl ester 1H-NMR (CD3OD) δ (ppm) 8.82 (s, IH), 8.56-7.05 (m, 4H), 5.04 (s, IH), 4.79 (m,
2H), 4.02(dd, J=IOHz, 2H),3.75-3.57 (m, 2H), 2.65-2.01(m, 6H), 2.37(s, 6H), 1.19(t, J=IOHz , 3H), 1.09(s, 3H), 0.93(s, 3H); ESMS clcd for C24H33N3O4: 427.25; Found: 428.2 (M+H)+.
2-(4-Amino-butyl)-7,7-dimethyl-5-oxo-4-pyridin-3yI-l,4,5,6,7,8,-hexahydro-quinoIine- 3-carboxyIic acid ethyl ester
1H-NMR (CD3OD) δ (ppm) 8.58-7.16 (m, 4H), 5.03 (s, IH), 4.02(dd, J=IOHz, 2H), 2.86-1.43 (m, 12H), 1.18 (t, J=IOHz, 3H), 1.09 (s, 3H), 0.91(s, 3H); ESMS clcd for C23H3IN3O3; 397.24; Found: 398.2(M+H)+.
2-(2-Amino-ethoxymethyl)-4-(2-chloro-phenyI)-7,7-dimethyI-4,6,7,8-tetrahydro-lH- quinoIin-5-one
1HNMR (CDCl3): δ 7.63 (brs, IH), 7.28 (dd, J= 7.5 and 1.2 Hz, IH), 7.21-7.13 (m,
2H), 7.04 (td, J= 6.9 and 2.1 Hz, IH), 5.06 and 4.98 (ABq, JAB = 4.6 Hz, 2H), 3.96 and 3.84 (ABq, JAB = 16.2 Hz, 2H), 3.41 (m, IH), 3.40 (s, IH), 2.92 (m, 2H), 2.85 (t, J= 4.8 Hz, 2H),
2.38 (m, 2H); 2.24 and 2.13 (ABq, JAB = 16.2 Hz, 2H), 1.11 (s, 3H), 1.09 (s, 3H); ESMS clcd for C20H25ClN2O2: 360.16; Found: 361.4 (M+l)+.
4-(2-Chloro-phenyl)-2-(2-dimethylaraino-ethoxymethyl)-7,7-dimethyl-5-oxo-l,4,5,6,7,8- hexahydro-quiiioline-3-carboxylic acid ethyl ester
1H-NMR (CDCl3) δ 0.95 (s, 3H), 1.05 (s, 3H), 1.15 (t, 3H, J =7), 1.9-2.3 (m, 2H), 2.4 (s, 2H), 2.6 (s, 6H), 2.9 (t, 2H, J=5), 3.7 (t, 2H, J=5), 3.9-4.1 (m, 2H), 4.8 (q, 2H, J=I 6, 28), 5.4 (s, IH), 7.05 (t, IH, J=8), 7.15 (t, IH, J=8), 7.25 (t, IH, J=8), 7.45 (t, IH, J=8), 8.45 (s, IH) ppm; ESMS clcd for C25H33ClN2O4: 460.2; Found: 461.2 (M+H)+.
(+)-(R)-2-(2-Amino-ethoxymethyl)-7,7-dimethyl-5-oxo-4-pyridin-3-yl-l,4,5,6,7,8- hexahydro-quinoIine-3-carboxyIic acid ethyl ester
1H-NMR (CDCl3) δ (ppm) 0.93 (s, 3H), 1.08 (s, 3H), 1.18 (t, J= 7.2 Hz, 3H), 1.56 (bs, 2H), 2.28 (m, 4H), 2.99 (t, J= 4.5 Hz, 2H), 3.60 (t, J= 5.1 Hz, 2H), 4.04 (q, J= 7.2 Hz, 2H), 4.89 (m, 2H), 5.05 (s, IH), 7.14 (m, IH), 7.64, (m, IH), 8.33 (m, IH), 8.45 (bs, IH), 8.53 (d, J= 1.5 Hz, IH); ESMS clcd for C22H29N3O4: 399.22; Found: 400.0 (M+H)+.
4-Cyclopropyl-2-hydroxymethyl-7,7-dimethyl-5-oxo-l,4,5,6,7,8-hexahydro-quinoline-3- carbonitrile 1H-NMR (CDCl3) δ (ppm), 7.15(s, IH), 4.39(d, J=Il, 2H), 3.18(d, J=Yl, IH), 2.50-
2.05-1.80(m, 4H)5 1.18(s, 3H), 0.96(s, 3H), 0.88-0.75 (m, IH), 0.58-0.22(m,4H). ESMS clcd for Ci6H20N2O2: 272.15; Found: 273.2 (M+H)+.
7-spirocycIopentyl-4-cycIopropyl-2-raethyl-5-oxo-l,4,5,6,7,8-hexahydro-quinoIine-3- carboxylic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 5.63(s, IH), 4.29-4.07(m, 2H), 3.81(d, J=I l, IH),
3.18(d, J=12, IH), 2.48-1.79(m, 7H), 1.78-40(m, 8H), 1.27(t, J=l l,3H), 0.84-0.67 (m, IH), 0.28-0.16(m,4H). ESMS clcd for C20H27NO3: 329.20; Found: 330.2 (M+H)+.
2,7,7-trimethyl-4-(l-methyl-cyclopropyl)-5-oxo-l,4,5,6,7,8-hexahydro-quinoline-3- carboxylic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 5.6 l(s, IH), 4.24-4.10(m, 2H), 3.59(s, IH), 2.40-2.15(m, 7H), 1.27(t, J=5, 3H), 1.17(s, 3H), 1.21(s, 3H), 0.84 (s, 3H), 0.82-0.1 l(m,4H). ESMS clcd for C19H27NO3: 317.20; Found: 318.2 (M+H)+.
^Cyclopropyl-ljTjT-trimethyl-S-oxo-l^jSjβjTjS-hexahydro-quinoline-S-carbonitrile
1H-NMR (CDCl3) δ (ppm), 6.07(s, IH), 3.21(d, J=12, IH), 2.39-2.02(m, 5H), 1.61(s, 2H), 1.13(s, 6H),0.92-0.80(m,lH), 0.58-0.37(m, 4H). ESMS clcd for Ci6H20N2O: 256.16; Found: 257.2 (M+H)+.
2-(2-Amino-ethoxymethyl)-4-cyclopropyl-7,7-dimethyl-5-oxo-l,4,5,6,7,8-hexahydro- quinoIine-3-carboxylic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 7.92(s, IH), 4.78(s, 2H), 4.28-4.02(m, 2H),3.80(d, J=U, IH), 3.62-3.50(m, 2H), 2.98-2.90(m, 2H), 2.41-1.22(m, 9H), 1.14(s, 3H), 1.10(s, 3H),0.92- 0.79(m,lH), 0.33-0.20(m, 4H). ESMS clcd for C20H30N2O4: 362.22; Found: 363.2 (M+H)+.
4-Cyclopropyl-2,7,7-trimethyl-5-oxo-l,4,5,6,7,8-hexahydro-quinoline-3-carboxyIic acid ethyl ester
1H-NMR (CD3Cl) δ (ppm), 5.92(s, IH), 4.31-4.08(m, 2H), 3.78(d, J=12, IH), 2.40- 1.22(m, 10H), 1.1 l(s, 3H), 1.07(s, 3H),0.92-0.79(m,lH), 0.33-0.17(m, 4H). ESMS clcd for Ci8H25FNO3: 303.18; Found: 304.2 (M+H)+.
4-Cyclohexyl-2,7,7-trimethyl-5-oxo-l,4,5,6,7,8-hexahydro-quinoIine-3-carboxyIic acid ethyl ester 1H-NMR (CDCl3) δ (ppm), 5.58 (s, IH), 4.22-4.08 (m, 2H), 3.99 (d, J=7.2Hz, IH),
2.31-2.18 (m, 7H), 1.62-1.54 (m, 7H), 1.28 (m, 4H), 1.12-0.86 (m, 9H); ESMS clcd for C2iH3iNO3: 345.23; Found: 346.2 (M+H)+.
4-Isopropyl-2,7,7-trimethyl-5-oxo-l,4,5,6,7,8-hexahydro-quiαoIine-3-carboxyIic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 5.98 (s, IH), 4.16-4.12 (m, 2H), 3.99 (d, J=4.5Hz, IH), 2.31-2.24 (m, 7H), 1.69 (m, 1H),1.3O-1.25 (m, 3H), 1.11 (s, 3H), 1.09 (s, 3H), 0.74 (d, J=4.5Hz, 6H); ESMS clcd for Ci8H27NO3: 305.20; Found: 306.2 (M+H)+.
2-(2-Amino-ethoxymethyl)-4-isopropyI-7,7-dimethyl-5-oxo-l,4,5,6,7,8-hexahydro- quinoline-3-carboxyIic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 7.92 (s, 2H), 4.76 (s, 2H), 4.17-4.08 (m, 2H), 4.01 (d, J=4.5 Hz, IH), 3.57-3.53 (t, J=4.8 Hz, 2H), 2.96-2.93 (t, J=4.8 Hz, 2H), 2.34-2.26 (m, 4H),
4.62 (s, 2H), 1.30-1.25 (t, J=7.2 Hz, 3H), 1,25-1.09 (ss, 6H), 0.76-0.74 (ss, 6H) ESMS clcd TOr C20H32N2O4: 364.20; Found: 365.2 (M+H)+.
4-Cyclopentyl-2,7,7-trimethyl-5-oxo-l,4,5,6,7,8-hexahydro-quinoIine-3-carboxyIic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 5.90 (s, IH), 4.23-4.11 (m, 2H), 2.32-2.22 (m, 7H), 1.82 (m, 1H),1.61-1.38 (m, 9H), 1.26 (t, J=7.2 Hz, 3H),1.12-1.10 (m, 7H); ESMS clcd for C20H29NO3: 331.20; Found: 332.2 (M+H)+.
2-(2-Amino-ethoxymethyI)-4-cyclopentyl-7,7-dimethyl-5-oxo-l,4,5,6,7,8-hexahydro- quinoline-3-carboxylic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 7.94 (s, 2H), 4.75 (s, 2H), 4.16-4.09 (m, 2H), 3.55-3.53 (m, 2H), 2.96-2.92 (m, 2H), 2.34-2.26 (m, 4H), 1.78 (m, IH), 1.54-1.50 (m, 8H), 1.25 (t, J=7.2 Hz, 3H),1.11-1.09 (m, 8H); ESMS clcd for C22H34N2O4: 390.20; Found: 391.2 (M+H)+.
4-tert-Butyl-2,7,7-trimethyl-5-oxo-l,4,5,6,7,8-hexahydro-quinoIine-3-carboxylic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 6.28 (s, IH), 4.28-4.05 (m, 2H), 3.99 (s, IH), 2.35-2.24 (m, 7H), 1.27 (t, J=7.2 Hz, 3H), 1.16 (s, 3H), 1.09 (s, 3H), 0.71 (s, 9H); ESMS clcd for Ci9H29NO3: 319.20; Found: 320.2 (M+H)+.
4-Cyclopropyl-7,7-dimethyl-2-morphoIin-4-ylmethyl-5-oxo-l,4,5,6,7,8-hexahydro- quinoline-3-carboxyIic acid ethyl ester 1H-NMR (CDCl3) δ (ppm), 7.82 (s, IH), 4.27-4.05 (m, 2H), 3.78-3.71 (m, 6H), 2.53-
2.50 (m, 4H), 2.29-2.26 (m, 4H), 1.29 (t, J=7.2 Hz, 3H), 1.12-1.10 (ss, 6H), 0.92 (m, 2H), 0.24-0.21 (m, 4H); ESMS clcd for C22H32N2O4: 388.20; Found: 389.2 (M+H)+.
4-CycIopropyl-7,7-dimethyI-2-(2-morphoIin-4-yI-ethoxymethyI)-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carboxyIic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 7.38 (s, IH), 4.75 (s. 2H), 4.22-4.11 (m, 2H), 3.80-3.64 (m, 6H), 2.62-2.51 (m, 5H), 2.34-2.26 (m, 3H), 1.67 (m, 3H), 1.27 (t, J=7.2 Hz, 3H), 1.14 (ss, 6H), 0.82 (m, IH), 0.23-0.20 (m, 4H); ESMS clcd for C24H36N2O5: 432.20; Found: 433.2 (M+H)+.
4-Cyclopropyl-7J-dimethyl-5-oxo-2-trifluoromethyl-l,4,5,6,7,8-hexahydro-quinoline- 3-carboxyIic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 6.26 (s, IH), 4.15 (q, J=7.2 Hz5 2H), 3.58 (m, IH), 2.42- 2.12 (m, 3H), 1.38-1.22 (m, 3H), 1.05 (m, 6H), 0.92-0.80 (m, 2H), 0.38-0.22 (m, 4H); ESMS clcd for Ci8H22F3NO3: 357.20; Found: 358.2 (M+H)+.
2,4-Dicyclopropyl-7,7-dimethyl-5-oxo-l,4,5,6,7,8-hexahydro-quinoIine-3-carboxylic acid ethyl ester 1H-NMR (CDCl3) δ (ppm), 5.48 (s, IH), 4.25-4.12 (m, 2H), 3.78 (d, J=7.2 Hz, IH),
2.77-2.64 (m, IH), 2.27-2.16 (m, 4H), 1.30 (t, J=7.2 Hz, 3H), 1.10-1.1 (ss, 6H), 0.98-0.94 (m, 2H), 0.85-0.52 (m, 3H), 0.25-0.19 (m, 4H); ESMS clcd for C20H27NO3: 329.20; Found: 330.2 (M+H)+.
4-CycIopropyl-2-ethyl-7,7-dimethyl-5-oxo-l,4,5,6,7,8-hexahydro-quinoline-3-carboxylic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 5.72 (s, IH), 4.22-4.17 (m, 2H), 3.80 (d, J=7.2 Hz, IH), 2.74-2.71 (m, 2H), 2.37-2.20 (m, 7H), 1.32 (t, J=7.2 Hz, 3H), 1.20-1.10 (m, 6H), 0.92-0.78 (m IH), 0.24-Q.20 (m 4H); ESMS clcd for Ci9H27NO3: 317.20; Found: 318.2 (MH-H)+.
4-CyclopropyImethyl-2,7,7-trimethyI-5-oxo-l,4,5,6,7,8-hexahydro-quinoline-3- carboxylic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 5.62 (s, IH), 4.17-4.10 (m, 2H), 2.30-2.20 (m, 6H), 1.58 (s, 3H), 1.31-1.25 (m, 4H), 1.09 (s, 6H), 0.58 (m, IH), 0.32-0.29 (m, 2H), 0.06-0.08 (m 2H); ESMS clcd for Ci9H27NO3: 317.20; Found: 318.2 (M+H)+.
4-Isopropyl-7,7-dimethyl-2-morpholin-4-ylmethyI-5-oxo-l,4,5,6,7,8-hexahydro- quinoIine-3-carboxylic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 7.76 (s, IH), 4.21-4.02 (m, 3H), 3.77-3.71 (m, 6H), 2.52- 2.49 (m, 4H), 2.29-2.26 (m, 4H), 1.66 (m IH), 1.29 (t, J=7.2 Hz, 3H), 1.14 (ss, 6H), 0.74 (d, J=6.9 Hz, 6H); ESMS clcd for C22H34N2O4: 390.20; Found: 391.2 (M+H)+.
4-Isopropyl-7,7-dimethyl-2-(2-morpholin-4-yI-ethoxymethyl)-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carboxyIic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 7.42 (s, IH), 4.75 (s. 2H), 4.22-4.04 (m, 3H), 3.75-3.58 (m, 6H), 2.62-2.49 (m, 6H), 2.34-2.27 (m, 4H), 1.67 (m, 3H), 1.27 (t, J=7.2 Hz, 3H), 1.14 (ss, 6H), 0.74 (ss, 6H); ESMS clcd for C24H38N2O5: 434.20; Found: 435.2 (M+H)+.
2-(2-Amino-ethoxymethyl)-4-cyclohexyl-7,7-dimethyl-5-oxo-l,4,5,6,7,8-hexahydro- quinoIine-3-carboxyIic acid ethyl ester
1H-NMR (CDCl3) δ (ppm), 7.86 (s, IH), 4.75 (s, 2H), 4.15-3.98 (m, 3H), 3.54 (m, 2H), 2.96-2.92 (m, 2H), 2.33-2.25 (m, 4H), 1.62-1.55 (m, 8H), 1.30-0.82 (14H); ESMS clcd for C23H36N2O4: 404.20; Found: 405.2 (M+H)+.
2~MethyI-l,4-dihydro-4-(pyrid-3-yl)-6-(2-amino-ethoxymethyl)-pyridine-3,5- dicarboxylic acid diethyl ester
ESMS clcd for C20H27N3O5: 389.20; Found: 390.2 (M+H)+
2-(2-Amino-ethoxymethyI)-7,7-dimethyl-4-(pyrid-3-yl)-5-oxo-l,4,5,6,7,8-hexahydro- quinoline-3-carboxylic acid ethyl ester
ESMS clcd for C22H28N2O4: 384.20; Found: 385.2 (M+H)+
2-(2-Amino-ethoxymethyI)-7,7-dimethyl-4-(5-methyI-furan-2-yl)-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carboxyIic acid ethyl ester
ESMS clcd for C22H30N2O5: 402.22; Found: 401.2 (M-H)+
2-Propoxymethyl-7,7-dimethyI-4-(pyrid-3-yl)-5-oxo-l,4,5,6,7,8-hexahydro-quinoline-3- carboxylic acid ethyl ester ESMS clcd for C23H30N2O4: 398.22; Found: 399.2 (M+H)+
2-Ethoxymethyl-7,7-dimethyl-4-(5-methyl-furan-2-yl)-5-oxo-l,4,5,6,7,8-hexahydro- quinoline-3-carboxylic acid ethyl ester
ESMS clcd for C22H29NO5: 387.20; Found: 386.2 (M-H)+
2,7,7-Trimethyl-4-(5-methyl-furan-2-yl)-5-oxo-l,4,5,6,7,8-hexahydro-quinoline-3- carboxylic acid ethyl ester
ESMS clcd for C20H25NO4: 343.18; Found: 344.2 (M+H)+
2-Isopropoxyraethyl-7,7-dimethyl-4-(pyrid-3-yl)-5-oxo-l,4,5,6,7,8-hexahydro- quinoIine-3-carboxyIic acid ethyl ester
ESMS clcd for C23H30N2O4: 398.22; Found: 399.2 (M+H)+
2-(2-Amino-ethoxymethyl)-7,7-dimethyl-4-(4-methylpyrid-3-yl)-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carboxylic acid ethyl ester
ESMS clcd for C23H3]N3O4: 413.23; Found:414.2 (M+H)+
2-(2-Amino-ethoxymethyl)-7,7-dimethyl-4-(4-methoxypyrid-3-yI)-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carboxyIic acid ethyl ester
ESMS clcd for C23H3iN3O5: 429.23; Found:430.2 (M+H)+
2,7,7-Trimethyl-4-(pyrid-3-yl)-5-oxo-l,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile
ESMS clcd for Ci8Hi9N3O: 293.15; Found:294.2 (M+H)+
2-(2-Amino-ethyoxymethyl)-7,7-dimethyl-4-(2-methoxyphenyl)-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carbonitrile
ESMS clcd for C22H27N3O3: 381.21; Found:382.2 (M+H)+
2,7,7-Trimethyl~4-(2-methoxyphenyI)-5-oxo-l,4,5,6,7,8-hexahydro-quinoIine-3- carbonitrile
ESMS clcd for C20H22N2O2: 322.17; Found:323.2 (M+H)+
2-(2-Amino-ethoxymethyl)-7,7-dimethyI-4-(5-chloro-6-methoxy-pyrid-3-yI)-5-oxo- l,4,5,6,7,8-hexahydro-quinoIine-3-carboxylic acid ethyl ester
ESMS clcd for C22H27N3O3: 463.19; Foιmd:464.2 (M+H)+
2-(2-Amino-ethoxymethyl)-7,7-dimethyl-4-(6-hydroxypyrid-3-yl)-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carboxyIic acid ethyl ester ESMS clcd for C22H29N3O5: 415.21; Found:416.2 (M+H)+
2-(2-Amino-ethoxymethyl)-7,7-dimethyl-4-(3-chlorophenyl)-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carboxylic acid ethyl ester
ESMS clcd for C26H34ClN2O6: 505.21 Found:506.2 (M+H)+
2-(2-Amino-ethoxymethyl)-7,7-dimethyl-4-(2,4-dichlorophenyI)-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carboxyIic acid ethyl ester
ESMS clcd for C23H28Cl2N2O4: 466.14 Found:467.1 (M+H)+
2-(2-Araino-ethoxymethyI)-7,7-dimethyl-4-(3-cyanophenyl)-5-oxo-l,4,5,6,7,8- hexahydro-quinoline-3-carboxyIic acid ethyl ester
ESMS clcd for C24H3IN3O4: 425.23 Foιmd:497.1 (M+H)+
EXAMPLE 8: 2-(2-Amino-ethoxymethyl)-7,7-dimethyl-5-oxo-4-pyridin-3-yl-l,4,5,6,7,8- hexahydro-quinoIine-3-carboxylic acid ethyl ester
Compound 310 can also be prepared as follows. To a mechanically stirred suspension of NaH (15g, 0.375 mol, 60% dispersion in mineral oil) in THF (250 mL) and DMF (25 mL) was added N-(2-hydroxyethyl)-phtalimide (43 g, 0.225 mol). The mixture was stirred at room temperature for about 4 h and then cooled to about O0C in an ice bath. Ethyl-4-chloroacetate (21.4 mL, 0.15 mol) in THF (4 mL) was then added via an addition funnel over a period of about 0.5 h and the resulting mixture allowed to stir overnight. The mixture was then poured into a 2 L sepratory funnel containing 500 mL ice water and 700 mL EtOAc and separated. The organic layer was washed 2x with 500 mL of water and dried over MgSO4. The solution was then filtered through a 4-inch plug of silica and then concentrated in vacuo. The resulting yellow oil was then dissolved in 250 mL CH3CN and washed 2x with 30 mL hexane. The CH3CN layer was the concentrated in vacuo to yield 19.4g (40.5%) of 4-[2-(l,3-Dioxo-l,3-dihydro-isoindol-2-yl)-ethoxy]-3-oxo-butyric acid ethyl ester as a yellow oil. This crude compound was used for the next step.
To a suspension of 4-[2-(l,3-Dioxo-l,3-dihydro-isoindol-2-yl)-ethoxy]-3-oxo-butyric acid ethyl ester (19.4g, 0.061 mol) and 5,5-dimethyl-l,3-cyclohexadiketone (8.5g, 0.061 mol) in 60 mL PA and 24 mL AcOH was added 166 mL 2N NH3/EtOH. 3- Pyridinecarboxaldehyde (5.75 mL, 0.061 mol) was then added and the solution allowed to stir at reflux for about 3 hr and then cooled to room temperature overnight. The resulting solution was partially concentrated in vacuo and then placed in the refrigerator overnight. The precipitate was filtered and washed with Et2O to yield 14.5 g (45%) of 2-[2-(l,3-Dioxo- l,3-dihydro-isoindol-2-yl)-ethoxymethyl]-7,7-dimethyl-5-oxo-4-pyridin-3-yl-l, 4,5,6,7,8- hexahydro-quinoline-3-carboxylic acid ethyl ester as an off-white solid.
1H-NMR (CDCl3) δ (ppm) 0.94 (s, 3H), 1.07 (m, 6H), 2.05 (s, 3H), 2.15 (m, 2H), 2.38 (m, 2H), 3.75 (m, 2H), 4.01 (m, 4H), 4.65 (m, 2H), 5.06 (s, IH), 7.03(m, IH), 7.7 (m, 6H), 8.37 (d, IH), 8.51 (s, IH); ESMS clcd for C25H3,C1N2O5: 529.2; Found: 530.5 (M+H)+.
To a solution of Dioxo-l,3-dihydro-isoindol-2-yl)-ethoxymethyl]-7,7-dimethyl-5- oxo-4-pyridin-3-yl-l,4,5,6,7,8-hexahydro-quinoline-3-carboxylic acid ethyl ester (14.5g, 0.027 mol) in EtOH (250 mL) was added hydrazine monohydrate (6.7 mL, 0.135 mol) and the solution allowed to stir for about 45 min. The solution was then allowed to cool to room temperature and the solid was filtered off and washed with EtOH. The EtOH was then removed in vacuo, the residue re-suspended in CH2Cl2, washed with water (3x) and brine
(Ix), dried over MgSO4, filtered and concentrated to yield 9 g of 2-(2-Amino-ethoxymethyl)- 7,7-dimethyl-5-oxo-4-pyridin-3-yl-l,4,5,6,7,8-hexahydro-quinoline-3-carboxylic acid ethyl
ester as a yellow solid. 1H-NMR (CDCl3) δ (ppm) 0.93 (s, 3H), 1.08 (s, 3H), 1.18 (t, J= 7.2 Hz, 3H), 1.56 (bs, 2H), 2.28 (m, 4H), 2.99 (t, J= 4.5 Hz, 2H), 3.60 (t, J= 5.1 Hz, 2H), 4.04 (q, J= 7.2 Hz, 2H), 4.89 (m, 2H), 5.05 (s, IH), 7.14 (m, IH), 7.64, (m, IH), 8.33 (m, IH), 8.45 (bs, IH), 8.53 (d, J= 1.5 Hz, IH); ESMS clcd for C22H29N3O4: 399.22; Found: 400.0 (M+H)+.
Complete separation of the enantiomers of Compound 310 is accomplished using a Chiralpak AS (4.5 mm x 25 cm) column eluting with ethanol/2% triethylamine/CO2 (15/85) (flow rate: 2 mL/min, 135/100 bar, 350C).
EXAMPLE 9: Protocol for 7DBG study in db/db mice:
To determine the effect of a test compound on blood glucose levels in fed diabetic mice, 7 day baseline glucose (7DBG) studies were conducted. Six to eight week old, male db/db mice (C57BLKS/J-/M +/+ Leprdb /Iar), homozygous for a mutation in the gene encoding the leptin receptor, were purchased from the Institute for Animal Reproduction (Kasumigaura, Japan). Animals were housed four to a cage in micro-isolators with a 12hr/12hr light/dark cycle, acclimated for at least one week prior to use and fed normal laboratory chow ad libitum. Studies were conducted with animals between nine and fourteen weeks of age, and animals were used for a maximum of two consecutive studies, with a minimum recovery period of seven days between studies.
To perform a 7DBG study, the starting glucose levels of db/db mice in the fed state were determined on day 0, 24 hrs prior to the first drug dose on day 1. Animals were retro- orbitally bled and serum glucose levels measured by the mutarotase-glucose oxidase enzymatic method using a Glucose CII-Test Wako kit (Wako Pure Chemicals Industries,
Ltd., Osaka, Japan). Animals were then randomized into dosing groups of 6-7 animals, with each group having a similar starting average glucose level. On days 1-7, animals were orally dosed once per day with vehicle, a test compound or metformin by oral gavage at 5 ml/kg body weight. Test compounds and metformin were formulated fresh each day as suspensions or fully dissolved in 0.5% methylcellulose (400 cps) in water. Serum glucose levels were determined 3 hrs after dosing the first compound on days 3 and 7.
Figure 1 shows the results of the 7DBG study to determine the effects of orally dosing test compounds daily for seven days on glucose levels in fed db/db mice. The percent change in blood glucose levels from day 0 to day 3 or from day 0 to day 7 were
determined by averaging the serum glucose levels on days 3 or 7 as a percent of the serum glucose levels on day 0 for individual animals in each group (6-7 mice/group), calculated using the following formula: serum glucose for an animal on days 3 or 7 as a percent of day 0 = (serum glucose value for the animal on days 3 or 7/serum glucose value for the animal at day 0) x 100). The average values for test compound-treated groups were then normalized relative to the vehicle-treated group using the following formula: percent change in test article treated groups on days 3 or 7 relative to the vehicle treated group = ((average serum glucose for test article treated group on days 3 or 7 as a percent of day 0/average serum glucose for vehicle-treated group on days 3 or 7 as a percent of day 0) x 10O)-IOO). Doses of Compounds 1, 16, 17 and 22 were 125 micromoles/kg. The results for Compound 16 and metformin are the averages of two experiments; all other compounds were tested one time. As can be seen in Figure 1, baseline serum glucose levels were decreased by each compound relative to vehicle-treated animals.
EXAMPLE lO: Protocol for 7DBG combination dosing study in dh/db mice:
Combination dosing 7DBG studies can be preformed using the same method as described in Example 3 except that in these studies dosing of a test compound and metformin (or other hypoglycemic agents) is preformed by dosing one drug at -3 hrs and the other at -2 hrs. In such studies, each group receives a dose of vehicle or drug, followed 60 min later by a second dose of vehicle or drug as appropriate in order to keep the total dosage volume constant in all groups at 10ml/kg body weight. Test compounds and metformin are formulated fresh each day as suspensions or fully dissolved in 0.5% methylcellulose (400 cps) in water. Serum glucose levels are determined 3 hrs after dosing the first compound on days 3 and 7.
EXAMPLE 11: Compounds 52 and 276 Decrease Disease Severity in a Rat Inflammatory Bowel Disease Model
To investigate the activities of Compounds 52 and 276 in inflammatory bowel disease, the Compounds were tested in a rat model in which experimental colitis was induced by administration of 2, 4-dinitrobenzene sulfonic acid (DNBS) into the colon (Tran et al, Gut 5:636-642, 1999). Adult male Wistar rats were obtained from BioLASCO Taiwan Co., Ltd., (Taipei, Taiwan, R.O.C.). Animals were housed six/cage, with a 12hr/12hr light/dark cycle, acclimated for at least 1 week prior to use and fed Laboratory
Rodent Diet 5001 (PMI Nutrition International, U.S.A.) ad libitum. Animals were randomized based on body weights into dosing groups of 8, with each group having an average body weight of -196 g. On day 0 the animals were fasted for 24 hr, and then on days 1-7 the animals were orally dosed once per day with vehicle or test articles by oral gavage at 10 mL/kg bodyweight. Test articles were formulated fresh each day as suspensions in 0.5% methylcellulose (400 cps) vehicle in water. 2 hrs after dosing with vehicle or test articles on day 2, distal colitis was induced by a single intra-rectal instillation of 30 mg DNBS (TCI, Tokyo, Japan) dissolved in 0.5 mL 30% ethanol, after which 2 mL of air was gently injected through a cannula to ensure that the DNBS solution remained in the colon. The animals were weighed and sacrificed 24 hr after the final dose of vehicle or test articles on day 7, and each colon was removed and weighted.
The colon-to-body weight ratio as a measure of tissue edema was calculated for each animal according to the formula: colon weight (g) on day 8 / 100 g of body weight on day 8. These values were averaged together for each group, and the percent change in colon-to-body weight ratio relative to vehicle-treated animals was determined according to the formula: [(colon-to-body weight ratio for test article-treated group / colon-to-body weight ratio for vehicle-treated group) x 100] - 100.
As shown in Figure 2, daily oral treatment with both Compounds 52 and 276 resulted in a decrease in the colon-to-body weight ratios relative to vehicle-treated animals, indicative of decreased tissue edema and reduced inflammation of the colon.
All publications, patent applications, patents, and other documents cited herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Claims
What is claimed is:
1. A compound represented by formula (I):
or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein: n is O, 1, or 2;
A is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl or an optionally substituted heteroaryl;
Xi is N or N→O;
X2 is O, S, NRn, or >CR5R6;
X3 is O, S, or NRn;
Ri is CN, -C(O)Rn, -C(O)ORn, -C(O)SRn, -C(O)NRi2Ri3, -C(NRi4)Rn, -C(NR14)ORn, -C(NRi4)SRn, -C(NRi4)NRi2R13, -C(S)Rn, -C(S)ORn, -C(S)SRn, -C(S)NR]2Ri3, -OC(O)Rn, -OC(O)ORn, -OC(O)SRn, -OC(O)NRi2Ri3, -NRnC(O)Rn, -NRnC(O)ORn5 -NRnC(O)SRn, -NRnC(O)NRi2Ri3, -SC(O)Rn, -SC(O)OR115 -SC(O)SR11, -SC(O)NR12R13, -OC(NR14)Rn, -OC(NR14)ORn, -OC(NRi4)SRn, -OC(NR14)NRI2RI3, -NRnC(NR14)RiI5 -NRnC(NR14)OR11, -NRnC(NRi4)SRn5 -NRnC(NR14)NR12R13, -SC(NR14)Rn, -SC(NR14)OR115 -SC(NR14)SRn, -SC(NR14)NR12R13, -OC(S)R11, -OC(S)ORn, -OC(S)SRn, -OC(S)NR12Ri3,
-NR11C(S)Rn, -NR1 1C(S)OR115 -NR11C(S)SR11, -NRnC(S)NR12R13, -SC(S)R11, -SC(S)OR11, -SC(S)SR11, -SC(S)NR12R13, -P(O)(ORn)2, -P(O)(ORn)(R11), -P(O)(Rn)2, -P(S)(ORn),, -P(S)(ORn)(Rn), -P(S)(Rn)2, -P(O)(SRn)2, -P(O)(SR11)(R11), -P(O)(SRn)2, -P(O)(SR1 1)(Rn), -P(O)(OR11)(SR11), -P(S)(SRn)2, -P(S)(SR11)(R11), -P(S)(OR11)(SR11), -S(O)2R11, -NR11S(O)2R11,
-S(O)2NR12R13, -S(O)2OR11, or a bioisostere of an ester, amide or carboxylic acid;
R2, R5, RO R9 and R1O, for each occurrence are, independently, -H or a substituent; or R9 and R10, for each occurrence, taken together are
=0, =S, or =NR27; R7 and Rs are each, independently, -H or a substituent; or R7 and Rg, together with the carbon to which they are attached, form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl; or R7 and Rg together form =CR27R2s;
R11, for each occurrence, is, independently, -H, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R12 and R13, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R12 and R13, taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;
Ru is -H, halo, -OH, -NHR1S, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R15 is H, alkyl, aryl or acetyl; and
R27 and R28, for each occurrence, are independently, H or a lower alkyl; provided that when R2 is -OH, R1 is not -C(S)NH2;
provided that A is not methyl, when R2 is ethoxy; provided that R2 is not -NHRn, -SRn, or -SS-heteroaryl; provided that when R2 is cyclopentyl or isopropy, Ri is not p- trifluorobenzoyl; provided that when R2 is n-propyl, isopropyl or cyclopentyl, A is not p- fluorophenyl or 3,4-difluorophenyl; provided that when R2 is methyl, A is not an unsubstituted phenyl or a nitrophenyl; provided that when Ri is -C(O)ORi6 and R2 is methyl, A is not mono-or di- chlorophenyl, mono-or di-bromophenyl, or mono- or di-methoxyphenyl, wherein Ri6 is a lower alkyl group; provided that when A, R2, R7 and R8 are all methyl, Rj is not -CN or -C(O)OCH2CH3; and provided that when A is methyl or ethyl and Ri is -CN, R2 is not -SRn, -OH or -Cl.
2. The compound of Claim 1, wherein Xi is N, X2 is -CH2-, and X3 is O.
3. The compound of Claim 2, wherein A is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkyl, or a substituted or unsubstituted cycloalkyl.
4. The compound of Claim 3, wherein A is p-chlorophenyl, />-methoxyphenyl, pyrid-3- yl, 4-methoxypyrid-3-yl, 6-hydroxypyrid-3-yl, 5-methylfuran-2-yl, methyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, 1-methylcyclopropyl, or cyclopropylmethyl.
5. The compound of Claim 4, wherein R7 and R8 are each, independently, a lower alkyl.
6. The compound of Claim 4, wherein Ri is -C(O)ORn, -C(O)NRi2Ri3 or cyano.
7. The compound of Claim 4, wherein R2 a lower alkyl or a heteroalkyl.
8. A compound represented by formula (II) :
or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein: n is 0, 1, or 2;
A is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl or an optionally substituted heteroaryl;
Xi is N or N-→O;
X2 is O, S, NRπ, or >CR5R6;
X3 is O, S, or NRU;
R30 is -C(O)NR12R13, -OC(O)NRi2Ri3, -NRnC(O)Rn, -NRnC(O)ORiI, -NRnC(O)NR12Ri3, -NRnC(NRi4)NR12Ri3, -P(O)(ORn)2, -S(O)2Rn, -S(O)2NRi2R13, -S(O)2ORn, or a bioisostere of an ester, amide or carboxylic acid;
R2, R5, Re R9 and R10, for each occurrence are, independently, -H or a substituent; or R9 and R1O, for each occurrence, taken together are
-O, =S, or =NR27;
R31, and R32 are each, independently, a lower alkyl or a lower alkenyl; or R31 and R32, together with the carbon to which they are attached, form an optionally substituted cycloalkyl; or R31 and R32 are
Rn, for each occurrence, is, independently, -H, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R-12 and Rn, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri2 and Rn, taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;
Ri4 is -H, halo, -OH, -NHRi5, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; and
Ri 5 is H, alkyl, aryl or acetyl; and R27 and R28, for each occurrence, are independently, H or a lower alkyl.
9. The compound of Claim 8, wherein Xi is N, X2 is -CH2-, and X3 is O.
10. The compound of Claim 9, wherein A is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkyl, or a substituted or unsubstituted cycloalkyl.
11. The compound of Claim 10, wherein A is /7-chlorophenyl, jc-methoxyphenyl, pyrid- 3-yl, 4-methoxypyrid-3-yl, 6-hydroxypyrid-3-yl, 5-methylfuran-2-yl, methyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, 1-methylcyclopropyl, or cyclopropylmethyl.
12. The compound of Claim 11, wherein R30 is -C(O)NRi2Rn.
13. The compound of Claim 11 , wherein R2 a lower alkyl or a heteroalkyl.
14. A compound represented by formula (III);
or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein: n is 0, 1, or 2;
Ai is an optionally substituted aryl or an optionally substituted heteroaryl;
X2 is O, S, NRn, or >CR5R6;
X3 is O, S, or NRn;
R1 Is CN5 -C(O)Rn, -C(O)ORn, -C(O)SRn, -C(O)NRi2Ri3, -C(NR14)Rn, -C(NR14)OR11, -C(NR14)SRn, -C(NR14)NR12R13, -C(S)R11, -C(S)ORn, -C(S)SR11, -C(S)NRi2R13, -OC(O)Rn, -OC(O)ORn, -OC(O)SRn, -OC(O)NRi2R13, -NR11C(O)R11, -NR11C(O)ORn5 -NR11C(O)SR11, -NRnC(O)NR12R13, -SC(O)R11, -SC(O)OR115 -SC(O)SRn, -SC(O)NRi2Ri3, -OC(NR14)Rn, -OC(NR14)OR1 I5 -OC(NRI4)SR1 1, -OC(NR14)NR12R13, -NRnC(NR14)Rn, -NRnC(NR14)ORn, -NR11C(NR14)SRn, -NRnC(NRi4)NR12R13, -SC(NR14)R11, -SC(NR14)OR115 -SC(NRI4)SR11, -SC(NRI4)NR12R13, -OC(S)R11, -OC(S)ORn, -OC(S)SRn, -OC(S)NR12R13, -NR11C(S)R11, -NRnC(S)OR11, -NRnC(S)SRn, -NR11C(S)NR12R13, -SC(S)R11, -SC(S)ORn, -SC(S)SRn, -SC(S)NR12R13, -P(O)(ORH)2, -P(O)(OR11)(R11), -P(O)(Rn)2, -P(S)(ORn)2, -P(S)(OR11)(R11), -P(S)(Rn)2, -P(O)(SRn)2, -P(OXSRn)(R11), -P(O)(SRn)2, -P(O)(SR11)(R11), -P(O)(OR11)(SR11), -P(S)(SRn)2, -P(S)(SRn)(R11), -P(S)(OR11)(SRn)3 -S(O)2Rn, -NR11S(O)2R11, -S(O)2NR12Ri3, -S(O)2OR11, or a bioisostere of an ester, amide or carboxylic acid;
R2, R5, Rδ R9 and R10, for each occurrence are, independently, -H or a substituent; or R9 and R10, for each occurrence, taken together are =CR27R2s, =0, =S, or =NR27;
R7 and R8 are each, independently, -H or a substituent; or R7 and R8, together with the carbon to which they are attached, form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl; or R7 and R8 together form
Rn, for each occurrence, is, independently, -H, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Rn and R13, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri2 and R13, taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;
RH is -H, halo, -OH, -NHR1S, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Ri 5. is H, alkyl, aryl or acetyl; and
R27 and R28, for each occurrence, are independently, H or a lower alkyl; provided that when R2 is -OH, Ri is not -C(S)NH2; provided that R2 is not -NHRn, -SRn, or -SS-heteroaryl; provided that when R2 is cyclopentyl or isopropy, Ri is not p- trifluorobenzoyl; provided that when R2 is n-propyl, isopropyl or cyclopentyl, Ai is notp- fluorophenyl or 3,4-difluorophenyl; provided that when R2 is methyl, Ai is not an unsubstituted phenyl or a nitrophenyl; and
provided that when R) is -C(O)ORi6 and R2 is methyl, A] is not mono-or di- chlorophenyl, mono-or di-bromophenyl, or mono- or di-methoxyphenyl, wherein R] 6 is a lower alkyl group.
15. The compound of Claim 14, wherein Xi is N, X2 is -CH2-, and X3 is O.
16. The compound of Claim 15, wherein Ai is selected from the group consisting of a substituted or unsubstituted phenyl, a substituted or unsubstituted pyridyl, a substituted or unsubstituted furanyl, a substituted or unsubstituted anthracenyl, a substituted or unsubstituted fluorenyl, a substituted or unsubstituted indenyl, a substituted or unsubstituted azulenyl, a substituted or unsubstituted naphthyl, a substituted or unsubstituted 5,6,7,8-tetrahydronaphthyl, a substituted or unsubstituted thienyl, a substituted or unsubstituted pyrrolyl, a substituted or unsubstituted oxazolyl, a substituted or unsubstituted imidazolyl, a substituted or unsubstituted indolizinyl, a substituted or unsubstituted thiazolyl, a substituted or unsubstituted isoxazolyl, a substituted or unsubstituted pyrazolyl, a substituted or unsubstituted isothiazolyl, a substituted or unsubstituted pyridazinyl, a substituted or unsubstituted pyrimidinyl, a substituted or unsubstituted pyrazinyl, a substituted or unsubstituted triazinyl, a substituted or unsubstituted triazolyl, a substituted or unsubstituted thiadiazolyl, a substituted or unsubstituted quinolyl, a substituted or unsubstituted isoquniolyl, a substituted or unsubstituted indazolyl, a substituted or unsubstituted benzoxazolyl, a substituted or unsubstituted benzofuryl, a substituted or unsubstituted benzothiazolyl, a substituted or unsubstituted indolizinyl, a substituted or unsubstituted imidazopyridinyl, a substituted or unsubstituted isothiazolyl, a substituted or unsubstituted tetrazolyl, a substituted or unsubstituted benzimidazolyl, a substituted or unsubstituted benzoxazolyl, a substituted or unsubstituted benzothiazolyl, a substituted or unsubstituted benzothiadiazolyl, a substituted or unsubstituted benzoxadiazolyl, a substituted or unsubstituted indolyl, a substituted or unsubstituted tetrahydroindolyl, a substituted or unsubstituted azaindolyl, a substituted or unsubstituted imidazopyridyl, a substituted or unsubstituted qunizaolinyl, a substituted or unsubstituted purinyl, a substituted or unsubstituted pyrrolo[2,3]pyrimidyl, a substituted or unsubstituted pyrazolo[3,4]pyrimidyl or a substituted or unsubstituted benzo(b)thienyl.
17. The compound of Claim 16, wherein Ai is substituted with one or more substituents selected from the group consisting of an alkyl, an alkenyl, an alkynyl, an cycloalkyl, an cycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl, a heteraralkyl, a haloalkyl, -C(O)NRi sRi9, -NR2OC(O)R2I, a halo, -OR20, cyano, nitro, a haloalkoxy, -C(O)R20, -NR18R19, -SR20, -C(O)OR20, -OC(O)R20, -NR20C(O)NR18Ri9,
-OC(O)NR18R19, -NR20C(O)OR5, -S(O)pR20, and -S(O)PNR18R19, wherein: Ris and R19, for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri8 and R19 taken together with the nitrogen to which they are attached is optionally substituted heterocyclyl or optionally substituted heteroaryl; and R20 and R21 for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl.
18. The compound of Claim 16, wherein A1 is a substituted or unsubstituted phenyl, a substituted or unsubstituted pyridyl, or a substituted or unsubstituted furanyl,
19. The compound of Claim 18, wherein A1 is substituted with one or more substitutents selected from the group consisting of a halo, an alkoxy, hydroxyl and an alkyl.
20. The compound of Claim 15, wherein R7 and R8 are each, independently, a lower alkyl.
21. The compound of Claim 15, wherein R1 is -C(O)ORn, -C(O)NR12R13 or cyano.
22. The compound of Claim 15, wherein R2 is a lower alkyl or a heteroalkyl.
23. A compound represented by formula (FV):
or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein: n is 0, 1, or 2; ring A is substituted or unsubstituted;
X1, for each occurrence, is independently, N or N→O;
X2 is O, S, NRn, or ^R5R6;
X3 is O, S5 Or NRn;
R33 IS -C(O)R11, -C(O)OR11, -C(O)SR11, -C(O)NR12R13, -C(NR14)Ri1, -C(NR14)OR11, -C(NR14)SR11, -C(NR14)NR12R13, -C(S)R11, -C(S)OR11, -C(S)SR11, -C(S)NR12R13, -OC(O)R11, -OC(O)OR11, -OC(O)SRn, -OC(O)NR12R13, -NR11C(O)R11, -NR11C(O)ORi15 -NRnC(O)SR11, -NRnC(O)NR12R13, -SC(O)R11, -SC(O)OR115 -SC(O)SR11, -SC(O)NR12R13, -OC(NR14)R11, -OC(NR14)ORn, -OC(NR14)SR11, -OC(NR14)NR12R13, -NR11C(NR14)Rn, -NR11C(NR14)OR11, -NR11C(NR14)SR11, -NR11C(NR14)NR12R13, -SC(NRH)R1 1, -SC(NR14)OR11, -SC(NR14)SR11, -SC(NR14)NR12R13, -OC(S)R11, -OC(S)OR11, -OC(S)SR11, -OC(S)NR12R13, -NRnC(S)R11, -NR11C(S)OR115 -NR11C(S)SR11, -NRnC(S)NR12R13, -SC(S)R11, -SC(S)OR11, -SC(S)SRn, -SC(S)NR12R13, -P(O)(ORn)2, -P(O)(OR11)(R11), -P(O)(Rn)2, -P(S)(ORn)2, -P(S)(OR11)(R11), -P(S)(R11),, -P(O)(SR11),, -P(O)(SRn)(Rn)3 -P(O)(SRn)2, -P(O)(SR11)(R11), -P(O)(OR11)(SR11),
-P(S)(SRn)2, -P(S)(SR11)(R11), -P(S)(OR11)(SR11), -S(O)2R11, -NR11S(O)2R11, -S(O)2NR12Rn, -S(O)2OR11, or a bioisostere of an ester, amide or carboxylic acid;
R2, R5, R5 R9 and R1O, for each occurrence are, independently, -H or a substituent; or R9 and R1O, for each occurrence, taken together are
=0, =S, or =NR27;
R7 and Rg are each, independently, -H or a substituent; or R7 and Rg, together with the carbon to which they are attached, form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl; or R7 and R8 together form
R11, for each occurrence, is, independently, -H, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; R12 and Rn, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R12 and R13, taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;
R14 is -H, halo, -OH, -NHR1S, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R15 is H, alkyl, aryl or acetyl; and
R27 and R28, for each occurrence, are independently, H or a lower alkyl.
24. The compound of Claim 23, wherein X1 is N, X2 is -CH2-, and X3 is O.
25. The compound of Claim 24, wherein R7 and Rs are each, independently, a lower alkyl.
26. The compound of Claim 24, wherein R33 is -C(O)ORi i or -C(O)NRi2Ri3.
27. The compound of Claim 24, wherein R2 is a lower alkyl or a heteroalkyl.
28. The compound of Claim 24, wherein R33 is a bioisostere.
29. A compound represented by formula (V):
or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein: n is 0, 1, or 2;
A2 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloakenyl, or an optionally substituted heterocyclyl;
X, is N or N→O;
X2 is O, S, NRi i, or ^R5R6;
X3 is O, S, or NRn;
R33 is -C(O)Rn, -C(O)OR11, -C(O)SR11, -C(O)NR12R13, -C(NR14)Rn, -C(NR14)OR11, -C(NR14)SRn, -C(NR14)NR12R13, -C(S)Rn, -C(S)OR11, -C(S)SRn, -C(S)NR12R13, -OC(O)R11, -OC(O)ORn5 -OC(O)SR11, -OC(O)NRi2R13, -NR11C(O)R11, -NRnC(O)OR11, -NR11C(O)SR11, -NRnC(O)NR12R13, -SC(O)R11, -SC(O)ORn, -SC(O)SR11, -SC(O)NR12R13, -OC(NR14)Rn, -OC(NR14)OR115 -OC(NR14)SRn, -OC(NR14)NRi2Ri3, -NRnC(NRi4)Rn, -NR11C(NRI4)ORH, -NRnC(NR14)SR11,
-NRI 1C(NRI4)NRI2RI3, -SC(NR14)Rn, -SC(NR14)ORI 15 -SC(NR14)SR1 1, -SC(NR14)NRI2R13, -OC(S)R11, -OC(S)OR115 -OC(S)SR11, -OC(S)NRi2R13, -NR11C(S)R11, -NR1 1C(S)OR115 -NR11C(S)SR11, -NR11C(S)NR12R13, -SC(S)R11, -SC(S)0Rn, -SC(S)SRn, -SC(S)NR12R13, -P(O)(ORn)2, -P(O)(OR11)(R11), -P(O)(Rn)2, -P(S)(ORn)2, -P(S)(OR11)(Rn), -P(S)(Rn)2, -P(O)(SRn)2,
-P(O)(SR11)(Rn), -P(O)(SRn)2, -P(O)(SR11)(R11), -P(O)(OR11)(SRn), -P(S)(SRn)2, -P(S)(SRn)(Rn), -P(S)(OR11)(SRn)5 -S(O)2R11, -NR11S(O)2R11, -S(O)2NR12Ri3, -S(O)2OR11, or a bioisostere of an ester, amide or carboxylic acid;
R2, R5, Re R9 and R10, for each occurrence are, independently, -H or a substituent; or R9 and Rio, for each occurrence, taken together are
=0, =S, or =NR27;
R31, and R32 are each, independently, a lower alkyl or a lower alkenyl; or R31 and R32, together with the carbon to which they are attached, form an optionally substituted cycloalkyl; or R31 and R32 are
R11, for each occurrence, is, independently, -H, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R12 and Ri3, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri2 and Ri3, taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;
Ri4 is -H, halo, -OH, -NHR1S, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; and
R15 is H, alkyl, aryl or aralkyl; and
R.27 and R28, for each occurrence, are independently, H or a lower alkyl; provided that the compound is not 2,4,7, 7-tetramethyl-5-oxo-5,6,7,8- tetrahydroquinoline-3-carboxylic acid ethyl ester or 8,8-difluoro-4-isobutyl-7,7- dimethyl-5-oxo-2-trifluoromethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3- carboxylic acid methyl ester; and provided that R2 is not -SR29, wherein R29 is a substituted alkyl.
30. The compound of Claim 29, wherein Xi is N, X2 is -CH2-, and X3 is O.
31. The compound of Claim 30, wherein A2 is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl.
32. The compound of Claim 31, wherein A2 is substituted with one or more substituents selected from the group consisting of an alkyl, an alkenyl, an alkynyl, an cycloalkyl, an cycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl, a heteraralkyl, a haloalkyl, -C(O)NRi8Ri9, -NR2oC(0)R2i, a halo, -OR20, cyano, nitro, a haloalkoxy, -C(O)R20, -NR18Ri9, -SR20, -C(O)OR20, -OC(O)R20, -NR20C(O)NR18Ri9, -OC(O)NRi8Ri9, -NR20C(O)OR5, -S(O)pR20, -S(O)pNRi8Ri9, =0, =S, and =N-R20, wherein: Ris and Ri9, for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri8 and Ri9 taken together with the nitrogen to which they are attached is optionally substituted heterocyclyl or optionally substituted heteroaryl; and
R20 and R2] for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl.
33. The compound of Claim 31, wherein A2 is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n- decyl, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3- methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3- methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2- dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimtheylpentyl, 3,3-dimethylhexyl, 4,4- dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2- ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3- diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl, cyclopropyl, 1-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.
34. The compound of Claim 33, wherein A2 is methyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, 1-methylcyclopropyl, or cyclopropylmethyl.
35. The compound of Claim 30, wherein R31 and R32 are each, independently, a lower alkyl.
36. The compound of Claim 30, wherein R33 is -C(O)ORi 1 or -C(O)NRi2Ri3.
37. The compound of Claim 30, wherein R2 is a lower alkyl or a heteroalkyl.
38. The compound of Claim 30, wherein R33 is a bioisostere.
39. A compound represented by formula (VII):
X, is N orN→O; X6 and X7 are each, independently, =0, =S, or =NR86;
X4 is CR87R88, NR95, O, or S;
NR95;
B is an optionally substituted C2-C10 alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl; an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted bicyclic aryl group, an optionally substituted tricyclic aryl group, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or a phenyl group which is substituted with: i) one substituent selected from the group consisting of an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, a haloalkoxy, -OR9I, -SR95, cyano, -C(O)R95, -C(O)OR95, -C(O)SR95, -C(O)NR93R94, -C(S)R95, -C(S)OR95,
-C(S)SR95, -C(S)NR93R94, -C(NR86)R95, -C(NR86)OR95, -C(NR86)SR95, -C(NR86)NR93R94, -OC(O)R95, -OC(O)OR95, -OC(O)SR95, -OC(O)NR93R94, -OC(S)R95, -OC(S)OR95, -OC(S)SR95, -OC(S)NR93R94, -OC(NR86)R95, -OC(NR86)OR95, -OC(NR86)SR95, -OC(NR86)NR93R94, -NR95C(O)R95, -NR95C(O)OR95, -NR95C(O)SR95, -NR95C(O)NR93R94,
-NR95C(S)R95, -NR95C(S)OR95, -NR95C(S)SR95, -NR95C(S)NR93R94, -NR95C(NR86)R95, -NR95C(NR86)OR95, -NR95C(NR86)SR95, -NR95C(NR86)NR93R94, -S(O)PR95, or -S(O)PNR93R94; ii) two, four, five or six substituents, independently, selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted
heteraralkyl, a halo, nitro, a haloalkyl, a haloalkoxy, -OR95, -NR93R94, -SR95, cyano, -C(O)R95, -C(O)OR95, -C(O)SR95, -C(O)NR93R94, -C(S)R95, -C(S)OR95, -C(S)SR95, -C(S)NR93R94, -C(NR86)R95, -C(NR86)OR95, -C(NR86)SR95, -C(NR86)NR93R94, -OC(O)R95, -OC(O)OR95, -OC(O)SR95, -OC(O)NR93R94, -OC(S)R95, -OC(S)OR95, -OC(S)SR95, -OC(S)NR93R94,
-OC(NR86)R95, -OC(NR86)OR95, -OC(NR86)SR95, -OC(NR86)NR93R94, -NR95C(O)R95, -NR95C(O)OR95, -NR95C(O)SR95, -NR95C(O)NR93R94, -NR95C(S)R95, -NR95C(S)OR95, -NR95C(S)SR95, -NR95C(S)NR93R94, -NR95C(NR86)R95, -NR95C(NR86)OR95, -NR95C(NR86)SR95, -NR95C(NR86)NR93R94, -S(O)PR95, or -S(O)PNR93R94; or iii) three substituents, independently, selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a halo, nitro, a haloalkyl, a haloalkoxy, -OR92, -NR93R94, -SR95, cyano, -C(O)R95, -C(O)OR95, -C(O)SR95, -C(O)NR93R94, -C(S)R95, -C(S)OR95, -C(S)SR95, -C(S)NR93R94, -C(NR86)R95, -C(NR86)OR95, -C(NR86)SR95, -C(NR86)NR93R94, -OC(O)R95, -OC(O)OR95, -OC(O)SR95,
-OC(O)NR93R94, -OC(S)R95, -OC(S)OR95, -OC(S)SR95, -OC(S)NR93R94, -OC(NR86)R95, -OC(NR86)OR95, -OC(NR86)SR95, -OC(NR86)NR93R94, -NR95C(O)R95, -NR95C(O)OR95, -NR95C(O)SR95, -NR95C(O)NR93R94, -NR95C(S)R95, -NR95C(S)OR95, -NR95C(S)SR95, -NR95C(S)NR93R94, -NR95C(NR86)R95, -NR95C(NR86)OR95, -NR95C(NR86)SR95,
-NR95C(NR86)NR93R94, -S(O)PR95, or -S(O)PNR93R94; R78, R79, R82, R83, R84, Rs5, Rs7, Rss, Rs9, and R90 are each, independently, H or a substituent;
R8o and R81 are each, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl; or R80 and R8i taken together are =CR95R95; or R8o and R8i, together with the carbon to which they are attached form a cycloalkyl or a cycloalkenyl, provided that at least one of R8o and R81 is not H;
R.86, for each occurrence, is independently -H, a halo, an alkyl, -OR95, -NR93R94, -C(O)R95, -C(O)OR95, or -C(O)NR93R94;
R9I, for each occurrence, is independently, -H, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R92, for each occurrence, is independently, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R93 and R94, for each occurrence are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R93 and R94 taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted • heteroaryl;
R95, for each occurrence, is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; q and r are each, independently, 0 or l;and p is 1 or 2.
40. The compound of Claim 39, wherein B is a substituted phenyl, an optionally substituted heteroaryl, an optionally substituted C2-C10 alkyl, or an optionally substituted cycloalkyl.
41. The compound of Claim 40, wherein B is cyclopropyl, cyclopentyl, cyclohexyl, or 1- methylcyclopropyl .
42. The compound of Claim 40, wherein X5 is CRggRgo.
43. The compound of Claim 42, wherein R78, R79, R82, Rs3, Rs4, RBS, Rs9 and R90 are H.
44. The compound of Claim 43, wherein q is 1.
45. The compound of Claim 44, wherein R80 and R8) are each, independently, a lower alkyl; or R80 and R81 taken together are
or Rgo and R81 taken together with the carbon to which they are attached are cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein R96, for each occurrence, is independently, -H or a lower alkyl.
46. The compound of Claim 45, wherein X& and X7 are O.
47. The compound of Claim 46, wherein X4 is CH2.
48. The compound of Claim 46, wherein X4 is NR95.
49. The compound of Claim 48, wherein R95 is -H or a lower alkyl.
50. The compound of Claim 46, wherein X4 is O.
51. The compound of Claim 40, wherein X4 is NR95, X5 is O, q is 1 and r is 1.
52. The compound of Claim 51, wherein R78, R79, R82, Rs3, R84, and R8s are H.
53. The compound of Claim 52, wherein R8o and R8i are each, independently, a lower alkyl; or R80 and R8! taken together are =CR96R96, or R80 and R8i taken together with the carbon to which they are attached are cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein R96, for each occurrence, is independently, -H or a lower alkyl.
54. The compound of Claim 53, wherein Xe and X7 are O.
55. A compound represented by structural formula (IX):
(K) or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein:
Xe and X7 are each, independently, =0, =S, or
X4 is CR87RgS, NR95, O, or S;
X5 is CR89R90, O OrNR95;
B2 is an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, an optionally substituted cycloheptyl, an optionally substituted cyclooctyl, an optionally substituted cycloalkenyl, or an optionally substituted heterocyclyl;
R78, R79, R-82, Rδ3, Rδ4, Rss, Rδ7, Rss, Rs9, and R90 are each, independently, H or a substituent;
Rso and R81 are each, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl; or R80 and R8i taken together are =CR95R95; or R8o and R8i, together with the carbon to which they are attached form a cycloalkyl or a cycloalkenyl, provided that at least one of R8o and R81 is not H;
R86, for each occurrence, is independently -H, a halo, an alkyl, -OR95, -NR93R94, -C(O)R95, -C(O)OR95, or -C(O)NR93R94;
R93 and R94, for each occurrence are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted
heteraralkyl; or R93 and R94 taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;
R95, for each occurrence, is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; R97 is -H, an alkyl, -C(O)R98;
R9S is -H, -R99, -OR99 or -NR99R99;
R99, for each occurrence, is independently, -H, a lower alkyl, an aryl, or an aralkyl; and q and r are each, independently, 0 or 1.
56. The compound of Claim 55, wherein X5 is CR89R90.
57. The compound of Claim 56, wherein R78, R79, R82, Rs3, Rs4, Rss, Rs9 and R90 are H.
58. The compound of Claim 57, wherein q is 1.
59. The compound of Claim 58, wherein R80 and R8i are each, independently, a lower alkyl; or R8o and R81 taken together are
or R80 and R8i taken together with the carbon to which they are attached are cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein R96, for each occurrence, is independently, -H or a lower alkyl.
60. The compound of Claim 59, wherein Xe and X7 are O.
61. The compound of Claim 60, wherein X4 is CH2.
62. The compound of Claim 60, wherein X4 is NR95.
63. The compound of Claim 62, wherein R95 is -H or a lower alkyl.
64. The compound of Claim 60, wherein X4 is O.
65. The compound of Claim 60, wherein B2 is a cyclopropyl or cyclopentyl.
66. A pharmaceutical composition comprising a compound according to Claim 1, 39 or 55 and a pharmaceutically acceptable carrier or vehicle.
67. The pharmaceutical composition according to Claim 66, further comprising a one or more additional therapeutic agents.
68. The pharmaceutical composition according to Claim 67, wherein the additional therapeutic agent is selected from anti-diabetic agents, anti-obesity agents, lipid lowering agents or a mixture thereof.
69. A kit comprising a compound according to Claim 1, 39, or 55 and a device for administering the compound.
70. The kit of claim 69 comprising a label or printed instructions for use of the kit.
71. A method for treating or preventing metabolic disorder in a subject, comprising administering to the subject an effective amount of a compound represented by formula (VI):
or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein:
n is 0, I5 or 2;
A3 is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, or an optionally substituted heteroaralkyl;
Xi is N orN→O;
X2 is O, S, NRn, or >CR5RO;
X3 is O, S5 Or NRn; R1 is CN, -C(O)Rn, -C(O)ORn, -C(O)SRn, -C(O)NRi2Ri3,
-C(NRi4)Ri,, -C(NR14)OR11, -C(NR14)SRn, -C(NR14)NRi2Ri3, -C(S)Rn, -C(S)OR11, -C(S)SR11, -C(S)NR12R13, -OC(O)R11, -OC(O)ORn, -OC(O)SRn, -OC(O)NR12R13, -NR11C(O)R11, -NR11C(O)ORn5 -NRnC(O)SR11, -NR11C(O)NR12R13, -SC(O)R11, -SC(O)OR115 -SC(O)SR11, -SC(O)NR12R13, -OC(NR14)R115 -OC(NR14)ORn, -OC(NR14)SRiI5 -OC(NR14)NR12R13,
-NRnC(NR14)Rn, -NRnC(NR14)OR11, -NRnC(NR14)SRn, -NRnC(NRi4)NR12R13, -SC(NR14)R11, -SC(NR14)OR115 -SC(NRi4)SRn, -SC(NRi4)NRi2R13, -OC(S)Rn, -OC(S)ORn, -OC(S)SRn, -OC(S)NR,2R]3, -NRnC(S)Rn, -NRnC(S)ORiU -NR11C(S)SRn5 -NR11C(S)NR12R13, -SC(S)R11, -SC(S)OR115 -SC(S)SRn, -SC(S)NR12R13, -P(O)(ORn)2, -P(O)(ORn)(R11),
-P(O)(Rn)2, -P(S)(ORn)2, -P(S)(ORi1)(Rn), -P(S)(Rn)2, -P(O)(SRn)2, -P(O)(SRn)(Rn), -P(O)(SRn)2, -P(O)(SRn)(Rn), -P(O)(OR11)(SR11), -P(S)(SRn)2, -P(S)(SR11)(R11), -P(S)(OR11)(SRn)5 -S(O)2Rn5 -NRnS(O)2R11, -S(O)2NR12R13, -S(O)2OR11, or a bioisostere of an ester, amide or carboxylic acid; R2, R5, R6 R9 and R10, for each occurrence are, independently, -H or a substituent; of R9 and R1O, for each occurrence, taken together are
=0, =S, or =NR27;
R7 and Rg are each, independently, -H or a substituent; or R7 and Rg, together with the carbon to which they are attached, form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl; or R7 and R8 together form =CR27R2s;
Rn, for each occurrence, is, independently, -H5 an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Ri2 and RB, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri2 and Rn, taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;
RH is -H, halo, -OH, -NHRi5, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Ri 5 is H, alkyl, aryl or acetyl; and
R27 and R2S, for each occurrence, are independently, H or a lower alkyl; provided that when R2 is cyclopentyl or isopropy, Ri is not p- trifluorobenzoyl; provided that when R2 is n-propyl, isopropyl or cyclopentyl, A3 is notp- fluorophenyl or 3,4-difluorophenyl; and provided that when A3 is H and R2 is methyl, Ri is not -C(O)-guanidinyl.
72. The method according to Claim 71, wherein the disorder is diabetes mellitus, a condition associated with diabetes mellitus or complication of diabetes mellitus.
73 A method for treating or preventing a metabolic disorder in a subject, comprising administering to the subject an effective amount of a compound represented by formula (III):
or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein: n is 0, 1, or 2;
Ai is an optionally substituted aryl or an optionally substituted heteroaryl;
Xi is N or N→O;
X2 is O, S, NRn, or >CR5R6;
X3 is O, S, or NRn;
R1 is CN, -C(O)Rn, -C(O)ORn, -C(O)SR11, -C(O)NR12R13, -C(NR14)Rn, -C(NR14)OR11, -C(NR14)SRn, -C(NR14)NRi2R13, -C(S)Rn, -C(S)OR11, -C(S)SR11, -C(S)NR12R13, -OC(O)Rn, -OC(O)ORn, -OC(O)SR11, -OC(O)NRi2R13, -NRnC(O)Rn, -NR11C(O)ORn, -NRnC(O)SR11, -NRnC(O)NR12R13, -SC(O)R11, -SC(O)ORn, -SC(O)SR11, -SC(O)NRi2Rn, -OC(NR14)R11, -OC(NR14)OR115 -OC(NR14)SRn, -OC(NR14)NR12R13, -NR11C(NR14)R11, -NRnC(NR14)OR11, -NRnC(NR14)SR11, -NR1 1C(NR14)NR12R13, -SC(NRi4)R11, -SC(NRI4)OR1 15 -SC(NRI4)SR11, -SC(NR14)NR12R13, -OC(S)R11, -OC(S)OR11, -OC(S)SRn, -OC(S)NR12R13, -NR11C(S)R11, -NR11C(S)ORIh -NR11C(S)SR11, -NR11C(S)NR12R13, -SC(S)R11, -SC(S)OR11, -SC(S)SRn5 -SC(S)NR12R13, -P(O)(ORn)2, -P(O)(OR11)(R11), -P(O)(Rn)2, -P(S)(ORn)2, -P(S)(OR11)(R11), -P(S)(Rn)2, -P(O)(SRn)2, -P(O)(SR11)(R11), -P(O)(SRn)2, -P(O)(SR11)(R11), -P(O)(OR11)(SR11), -P(S)(SRn)2, -P(S)(SRn)(Rn), -P(S)(OR11)(SR11), -S(O)2R11, -NRnS(O)2Rn, -S(O)2NR12R13, -S(O)2OR11, or a bioisostere of an ester, amide or carboxylic acid;
R2, R5, Re R9 and R1O, for each occurrence are, independently, -H or a substituent; or R9 and Ri0, for each occurrence, taken together are =CR27R28, =0, =S, or =NR27;
R7 and Rg are each, independently, -H or a substituent; or R7 and Rg, together with the carbon to which they are attached, form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl; or R7 and Rg together form
Rn, for each occurrence, is, independently, -H, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Rn and RB, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri2 and RB, taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;
RH is -H, halo, -OH, -NHRi 5, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Ri 5 is H, alkyl, aryl or acetyl; and
R27 and R2S, for each occurrence, are independently, H or a lower alkyl; provided that when R2 is cyclopentyl or isopropy, Ri is notp- trifluorobenzoyl; provided that when R2 is n-propyl, isopropyl or cyclopentyl, Ai is notp- fluorophenyl or 3,4-difluorophenyl.
74. The method according to Claim 73, wherein the disorder is diabetes mellitus, a condition associated with diabetes mellitus or complication of diabetes mellitus.
A method for treating or preventing a metabolic disorder in a subject, comprising administering to the subject an effective amount of a compound represented by formula (V):
or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein: n is O, I, or 2;
A2 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloakenyl, or an optionally substituted heterocyclyl;
X2 is O, S, NRn, or >CR5R6;
X3 is O, S, or NRn;
R33 is -C(O)R11, -C(O)ORn, -C(O)SR11, -C(O)NR12R13, -C(NR14)R11, -C(NR14)OR11, -C(NR14)SR11, -C(NR14)NR12R13, -C(S)R11, -C(S)OR11, -C(S)SR11, -C(S)NRi2R13, -OC(O)R11, -OC(O)ORn, -OC(O)SRn, -OC(O)NRi2Ri3, -NRnC(O)R11, -NR11C(O)OR115 -NR1 IC(O)SRi1, -NR11C(O)NR12R13, -SC(O)R11, -SC(O)ORn, -SC(O)SR11, -SC(O)NR12R13, -OC(NR14)R11, -OC(NR14)OR113 -OC(NR14)SR11, -OC(NR14)NR12R13, -NR11C(NR14)R11, -NR11C(NR14)OR11, -NRnC(NR14)SR11, -NR11C(NR14)NRi2R13, -SC(NR]4)Rn, -SC(NRi4)ORiI3 -SC(NRi4)SRn, -SC(NRi4)NRi2R13, -OC(S)Rn, -OC(S)ORi13 -OC(S)SR11, -OC(S)NR12Ri3, -NRnC(S)Rn, -NR11C(S)OR11, -NR11C(S)SR11, -NRnC(S)NR12Ri3, -SC(S)R11, -SC(S)OR115 -SC(S)SR11, -SC(S)NR12R13, -P(O)(ORn)2, -P(O)(ORn)(Rn), -P(O)(R1O2, -P(S)(ORn)2, -P(S)(OR11)(R11), -P(S)(Rn),, -P(O)(SRn)2,
-P(O)(SR11)(Rn), -P(O)(SRn)2, -P(O)(SR11)(R11), -P(O)(OR11)(SR11), -P(S)(SRn)2, -P(S)(SR11)(Rn), -P(S)(OR11)(SR1O1 -S(O)2R11, -NR11S(O)2R1 1, -S(O)2NR12Ro, -S(O)2OR11, or a bioisostere of an ester, amide or carboxylic acid;
R2, R5, Rδ R9 and R1O, for each occurrence are, independently, -H or a substituent; or R9 and R1O, for each occurrence, taken together are
=0, =S,
Or =NR27;
R3!, and R32 are each, independently, a lower alkyl or a lower alkenyl; or Ra1 and R32, together with the carbon to which they are attached, form an optionally substituted cycloalkyl; or Rs1 and R32 are =CR27R28; Rn, for each occurrence, is, independently, -H, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R12 and R^, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Ri2 and R^, taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;
Ru is -H, halo, -OH, -NHR1S, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; and Ri 5 is H, alkyl, aryl or aralkyl; and R27 and R2s, for each occurrence, are independently, H or a lower alkyl.
76. The method according to Claim 75, wherein the disorder is diabetes mellitus, a condition associated with diabetes mellitus or complication of diabetes mellitus.
A method for treating or preventing a metabolic disorder in a subject, comprising administering to the subject an effective amount of a compound represented by formula (VEI):
(vm) or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein:
X1 is N or N→O;
Xβ and X7 are each, independently, =0, =S, or
X4 is CR87R88, NR95, O, or S;
X5 Is CR89R90= O Or NR95;
Bi is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl;
R78, R79, R82, Rδ3, R84, Rs5, R87, Rs8, Rs9, and R90 are each, independently, H or a substituent;
R8o and R81 are each, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl; or R80 and R8i taken together are =CR95R95; or R80 and Rg1, together with the carbon to which they are attached form a cycloalkyl or a cycloalkenyl, provided that at least one of R80 and R81 is not H;
R86, for each occurrence, is independently -H, a halo, an alkyl, -OR95, -NR93R94, -C(O)R95, -C(O)OR95, or -C(O)NR93R94;
R93 and R94, for each occurrence are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R93 and R94 taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;
R95, for each occurrence, is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; and q and r are each, independently, 0 or 1.
78. The method according to Claim 77, wherein the disorder is diabetes mellitus, a condition associated with diabetes mellitus or complication of diabetes mellitus.
79. The method of Claim 77, wherein
Bi is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclopropylmethyl, cyclopropyl, cyclopentyl, cyclohexyl, or 1-methylcyclopropyl;
O;
R78, R79, Rs2, Rs3, Rs4, Rs5, Rs9 and R90 are H; q is l;
Rgo and R8i are each, independently, a lower alkyl; or R80 and R8i taken together are =CR9OR96, or R8o and R8i taken together with the carbon to which they are attached are cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein R96, for each occurrence, is independently, -H or a lower alkyl; and Xe and X7 are O.
80. A method for treating or preventing a metabolic disorder in a subject, comprising administering to the subject an effective amount of a compound represented by formula (X):
(X) or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein:
Xe and X7 are each, independently, =0, =S, or
X4 is CR87R88, NR95, O, or S;
X5 is CR89R90, O Or NR95;
Bi is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl;
R78, R79, Rs2, R83, Rs4, R85, Rs7, R88, Rs9, and R90 are each, independently, H or a substituent;
Rso and R81 are each, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl; or Rso and R8) taken together are =CR95R95; or R8o and R8], together with the carbon to which they are attached form a cycloalkyl or a cycloalkenyl, provided that at least one of R8o and R81 is not H;
R86, for each occurrence, is independently -H, a halo, an alkyl, -OR95, -NR93R94, -C(O)R95, -C(O)OR95, or -C(O)NR93R94;
R93 and R94, for each occurrence are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R93 and R94 taken together with the nitrogen to which they are
attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;
R95, for each occurrence, is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R97 is -H, an alkyl, -C(O)R98;
R9S is -H, -R99, -OR99 or -NR99R99; R99, for each occurrence, is independently, -H, a lower alkyl, an aryl, or an aralkyl; and q and r are each, independently, 0 or 1.
81. The method according to Claim 80, wherein the disorder is diabetes mellitus, a condition associated with diabetes mellitus or complication of diabetes mellitus.
82. The method of Claim 80, wherein
Bi is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclopropylmethyl, cyclopropyl, cyclopentyl, cyclohexyl, or 1-methylcyclopropyl; X5 is O or CR89R90;
R78, R79, Rs2, Rs3, Rs4, Rs5, Rs9 and R90 are H; q is 1;
Rso and R81 are each, independently, a lower alkyl; or R8o and R81 taken together are =CR96R96, or R80 and R81 taken together with the carbon to which they are attached are cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein R96, for each occurrence, is independently, -H or a lower alkyl; and
X6 and X7 are O.
83. A method for treating an inflammatory bowel disease in a subject, comprising administering to the subject an effective amount of a compound represented by formula (VI):
or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein: n is 0, 1, or 2;
A3 is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, or an optionally substituted heteroaralkyl;
X2 is O, S, NR11, or ^R5R6;
X3 is O, S, Or NRn;
Ri is CN, -C(O)Ra, -C(O)ORn, -C(O)SRn, -C(O)NRi2Ri3, -C(NR14)Rn5 -C(NRi4)ORn, -C(NRi4)SRn, -C(NRI4)NRI2RI3, -C(S)R11, -C(S)OR11, -C(S)SR11, -C(S)NR12R13, -OC(O)Rn, -OC(O)OR1 15 -OC(O)SR11, -OC(O)NR12Ri3, -NRnC(O)R11, -NR11C(O)OR115 -NR11C(O)SR11, -NRnC(O)NRi2R13, -SC(O)Rn, -SC(O)OR115 -SC(O)SRn, -SC(O)NR12R13, -OC(NR14)R11, -OC(NR14)OR115 -OC(NRH)SR11, -OC(NR14)NR12R13, -NRnC(NR14)Rn, -NRnC(NRi4)ORn, -NR11C(NR14)SR11, -NR11C(NR14)NRi2R13, -SC(NR14)Rn, -SC(NR14)OR11, -SC(NR14)SRn, -SC(NR14)NR12Ri3, -OC(S)Rn, -OC(S)ORn, -OC(S)SRn, -OC(S)NRi2R13, -NRnC(S)Rn, -NRnC(S)OR115 -NR11C(S)SRn, -NR11C(S)NR12R13, -SC(S)Rn, -SC(S)OR115 -SC(S)SR11, -SC(S)NR12R13, -P(O)(ORn)2, -P(O)(OR11)(Rn), -P(O)(Rn)2, -P(S)(ORn)2, -P(S)(ORn)(Rn), -P(S)(Rn)2, -P(O)(SRn)2, -P(O)(SR11)(R11), -P(O)(SRn)25 -P(O)(SR11)(R11), -P(O)(ORn)(SRn),
-P(S)(SRn)2, -P(S)(SR11)(R11), -P(S)(OR11)(SR11), -S(O)2R11, -NR1 1S(O)2R11, -S(O)2NR]2Rn, -S(O)2OR11, or a bioisostere of an ester, amide or carboxylic acid;
R2, R5, RO R9 and R1O, for each occurrence are, independently, -H or a substituent; or R9 and Rio, for each occurrence, taken together are
=0, =S, or =NR27;
R7 and Rs are each, independently, -H or a substituent; or R7 and Rg, together with the carbon to which they are attached, form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl; or R7 and R8 together form =CR27R2s;
R11, for each occurrence, is, independently, -H, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; R12 and R13, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R12 and R13, taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;
Ru is -H, halo, -OH, -NHR1S, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R15 is H, alkyl, aryl or acetyl; and
R27 and R28, for each occurrence, are independently, H or a lower alkyl; provided that when R2 is cyclopentyl or isopropy, R1 is notp- trifluorobenzoyl; provided that when R2 is n-propyl, isopropyl or cyclopentyl, A3 is notp- fluorophenyl or 3,4-difluorophenyl; and provided that when A3 is H and R2 is methyl, R1 is not -C(O)-guanidinyl.
A method for treating an inflammatory bowel disease in a subject, comprising administering to the subject an effective amount of a compound represented by formula (III):
or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein: n is 0, 1, or 2;
Ai is an optionally substituted aryl or an optionally substituted heteroaryl;
X2 is O, S, NRn, or ^R5R6;
X3 is O, S, or NRn;
Ri is CN, -C(O)Rn, -C(O)ORn, -C(O)SRn, -C(O)NRi2Ri3, -C(NRi4)Rn, -C(NRi4)ORn, -C(NRi4)SRn, -C(NRi4)NRi2Ri3, -C(S)Rn, -C(S)ORn, -C(S)SRn, -C(S)NRI2RJ3, -OC(O)Rn, -OC(O)ORn, -OC(O)SRn, -OC(O)NRi2R13, -NRnC(O)Rn, -NRnC(O)ORn, -NRnC(O)SRn, -NRnC(O)NRi2Ri3, -SC(O)Rn, -SC(O)OR11, -SC(O)SRn, -SC(O)NRi2R]3, -OC(NRi4)Rn, -OC(NR14)ORn, -OC(NR14)SRn, -OC(NRi4)NRi2Ri3, -NRnC(NRi4)Rn, -NRnC(NRi4)ORiI, -NRnC(NR14)SRn, -NRnC(NR14)NR12R13, -SC(NRi4)Rn, -SC(NRM)ORn, -SC(NRi4)SRn, -SC(NRi4)NRi2R13, -OC(S)Rn, -OC(S)OR115 -OC(S)SRn, -OC(S)NR12Ri3, -NRnC(S)Rn, -NRnC(S)ORn, -NRnC(S)SRn, -NRnC(S)NRi2Ri3, -SC(S)Rn, -SC(S)ORn, -SC(S)SRii, -SC(S)NRi2Ri3, -P(O)(ORn)2, -P(O)(ORn)(Rn), -P(O)(Rn)2, -P(S)(ORn)2, -P(S)(ORn)(Rn), -P(S)(Rn)2, -P(O)(SRn)2, -P(O)(SRn)(Rn), -P(O)(SRn)2, -P(O)(SRn)(Rn), -P(O)(ORn)(SRn),
-P(S)(SRn)2, -P(S)(SR11)(Rn), -P(S)(ORn)(SRn)5 -S(O)2R11, -NR11S(O)2R1 1, -S(O)2NRi2Ru, -S(O)2OR11, or a bioisostere of an ester, amide or carboxylic acid;
R2, R5, RO R9 and Rio, for each occurrence are, independently, -H or a substituent; or Rg and Rio, for each occurrence, taken together are
=0, =S, or =NR27;
R7 and Rs are each, independently, -H or a substituent; or R7 and Rs, together with the carbon to which they are attached, form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl; or R7 and R8 together form =CR27R28;
Rn, for each occurrence, is, independently, -H, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Ri2 and R13, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R12 and R13, taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;
RH is -H, halo, -OH, -NHR1S, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R1S is H, alkyl, aryl or acetyl; and
R27 and R28, for each occurrence, are independently, H or a lower alkyl; provided that when R2 is cyclopentyl or isopropy, R1 is not p- trifluorobenzoyl; provided that when R2 is n-propyl, isopropyl or cyclopentyl, A1 is notjs- fluorophenyl or 3,4-difluorophenyl.
A method for treating an inflammatory bowel disease in a subject, comprising administering to the subject an effective amount of a compound represented by formula (V):
or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein: n is O, 1, or 2;
A2 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloakenyl, or an optionally substituted heterocyclyl;
Xi is N or N→O;
X2 is O, S, NRn, or >CR5R6;
X3 is O, S, Or NR11;
R33 Js -C(O)R11, -C(O)ORn, -C(O)SRn, -C(O)NR12R13, -C(NR14)Rn, -C(NR14)ORn, -C(NR14)SR11, -C(NR14)NR12R13, -C(S)R11, -C(S)OR11, -C(S)SRn, -C(S)NR12R13, -OC(O)R11, -OC(O)ORn, -OC(O)SRn, -OC(O)NR12R13, -NRnC(O)R11, -NR11C(O)OR113 -NRnC(O)SRn, -NR11C(O)NR12R13, -SC(O)R11, -SC(O)OR11, -SC(O)SRn, -SC(O)NRi2R13, -OC(NRi4)Rn, -OC(NRi4)ORn, -OC(NR14)SRn, -OC(NRi4)NR12R13, -NRnC(NR14)R11, -NRnC(NR14)OR11, -NRnC(NR14)SRn, -NRnC(NR14)NR12R13, -SC(NR14)Rn, -SC(NR14)ORI U -SC(NR14)SR1 I, -SC(NR14)NR12R13, -OC(S)Rn, -OC(S)OR115 -OC(S)SRn, -OC(S)NR12R13, -NRnC(S)Rn, -NRnC(S)OR115 -NRnC(S)SRn, -NR11C(S)NR12R13, -SC(S)R11, -SC(S)OR115 -SC(S)SR115 -SC(S)NR12R13, -P(O)(ORn)2, -P(O)(OR11)(R11), -P(O)(Rn)2, -P(S)(ORn)2, -P(S)(ORn)(Rn), -P(S)(Rn)2, -P(O)(SRn)2,
-P(O)(SR11)(R11), -P(O)(SRn)2, -P(O)(SR11)(R11), -P(O)(OR11)(SR11), -P(S)(SRn)2, -P(S)(SR11)(Rn), -P(S)(OR11)(SRn)5 -S(O)2R11, -NR11S(O)2R11, -S(O)2NR12RiS, -S(O)2ORn, or a bioisostere of an ester, amide or carboxylic acid;
R2, R5, Rό R9 and Rio, for each occurrence are, independently, -H or a substituent; or R9 and R10, for each occurrence, taken together are
=0, =S, or =NR27;
R31, and R32 are each, independently, a lower alkyl or a lower alkenyl; or R31 and R32, together with the carbon to which they are attached, form an optionally substituted cycloalkyl; or Rs1 and R32 are =CR27R2s; Rn, for each occurrence, is, independently, -H, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Ri2 and Rn, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R12 and R13, taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;
R14 is -H, halo, -OH, -NHR1S, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; and
Ri5 is H, alkyl, aryl or aralkyl; and R27 and R28, for each occurrence, are independently, H or a lower alkyl.
86. A method for treating an inflammatory bowel disease in a subject, comprising administering to the subject an effective amount of a compound represented by formula (Vm):
(VHI) or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein:
Xi is N or N→O;
Xe and X7 are each, independently, =0, =S, or
X4 is CR87R88, NRg5, O, or S;
X5 is CR89R90, O or NR95;
Bi is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl;
R7S, R79, R82, R83, Rs4, Rδ5, R87, Res, R89, and R90 are each, independently, H or a substituent;
Rgo and R81 are each, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl; or R80 and RSi taken together are =CR95R95; or R80 and R8i, together with the carbon to which they are attached form a cycloalkyl or a cycloalkenyl, provided that at least one of R80 and R81 is not H;
R86, for each occurrence, is independently -H, a halo, an alkyl, -OR95, -NR93R94, -C(O)R95, -C(O)OR95, or -C(O)NR93R94;
R93 and R94, for each occurrence are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted
heteraralkyl; or R93 and R94 taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;
R95, for each occurrence, is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; and q and r are each, independently, 0 or 1.
87. The method of Claim 86, wherein
Bi is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclopropylmethyl, cyclopropyl, cyclopentyl, cyclohexyl, or 1 -methylcyclopropyl; X5 Js CR89R90 Or O;
R78, R79, Rs2, R83, Rs4, Rs5, Rs9 and R90 are H; q is 1;
Rso and R8i are each, independently, a lower alkyl; or R80 and RS] taken together are
or R80 and R81 taken together with the carbon to which they are attached are cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein R96, for each occurrence, is independently, -H or a lower alkyl; and Xe and X7 are O.
88. A method for an treating inflammatory bowel disease in a subject, comprising administering to the subject an effective amount of a compound represented by formula (X):
X6 and X7 are each, independently, =0, =S, or =NR86;
X4 is CR87R8S, NR95, O, or S; X5 Is CR89R90, O Or NR95;
Bi is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl;
R78, R79, R-82, Rδ3, Rδ4, R85, Rδ7, Res, R89, and R90 are each, independently, H or a substituent;
R80 and R8] are each, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl; or R80 and Rs 1 taken together are =CR95R95; or R80 and R81, together with the carbon to which they are attached form a cycloalkyl or a cycloalkenyl, provided that at least one of Rs0 and RSi is not H;
R86, for each occurrence, is independently -H, a halo, an alkyl, -OR95, -NR93R94, -C(O)R95, -C(O)OR95, or -C(O)NR93R94;
R93 and R94, for each occurrence are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R93 and R94 taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;
R95, for each occurrence, is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R97 is -H, an alkyl, -C(O)R98; R9S is -H, -R99, -OR99 or -NR99R99;
R99, for each occurrence, is independently, -H, a lower alkyl, an aryl, or an aralkyl; and q and r are each, independently, O or 1.
89. The method of Claim 88, wherein
Bi is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclopropylmethyl, cyclopropyl, cyclopentyl, cyclohexyl, or 1-methylcyclopropyl; X5 is O or CR89R90;
R78, R79, R82, Rs3, Rs4, Rs5, Rs9 and R90 are H; q is 1;
Rso and R8i are each, independently, a lower alkyl; or R80 and R8i taken together are
or R8o and R81 taken together with the carbon to which they are attached are cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein R%, for each occurrence, is independently, -H or a lower alkyl; and Xe and X7 are 0.
90. A method for treating an inflammatory bowel disease in a subject, comprising administering to the subject an effective amount of a compound represented by formula (XI):
(XI) or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein: s is 0, 1, or 2;
D2 is an optionally substituted aryl or an optionally substituted heteroaryl;
R45 is -H or an alkyl;
R46 is -C(O)OR56, -C(O)R56, -C(O)NR57R58, -CN, -CH(OR56)R56, -C(=NR56)R56, -C(S)R56, -C(S)OR56, -C(S)NR57R58, -CH(NR57R58)R56; or -CH(SR56)R56;
R47 is H or a substituent; R48 and R49 are each, independently, -H, -OR56, or -NR57R58; or R48 and R49 taken together are =0, =S or =NR59, provided that at least one OfR48 or R49 is not -H;
R5o and R5] are each, independently, -H or a substituent;
R52 and R53 are each, independently, -H or a substituent; or R52 and R53, together with the carbon to which they are attached, form an optionally substituted cycloalkyl;
R54 and R55, for each occurrence, are, independently, -H or a substituent;
R56, for each occurrence, is, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R57 and R58, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R57 and R58, taken together with the nitrogen to which they are attached are an optionally substituted heterocycloalkyl or optionally substituted heteroaryl;
R59 is -H, halo, -OR6O, -NR6oR6o, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; and
R6o is H, alkyl, aryl or acetyl;
provided that when R47 is methyl, D2 is not chlorophenyl, dichlorophenyl, p- nitrophenyl, or 5-chloro-benzo[l,3]dioxolyl; provided that when R47 is isopropyl or cyclopentyl, either R46 is notp- (trifluoromethyl)benzoyl or D2 is not /"-fluorophenyl; and provided that R47 is not -NH2.
91. The method of Claim 90, wherein R4S and R49 together are =0; s is 1; D2 is selected from the group consisting of a substituted or unsubstituted phenyl, a substituted or unsubstituted benzo[l,3]dioxolyl, a substituted or unsubstituted pyridyl, a substituted or unsubstituted indolyl, a substituted or unsubstituted quinolinyl, a substituted or unsubstituted 1-oxo-pyridyl, a substituted or unsubstituted pyridazinyl, a substituted or unsubstituted pyrimidinyl, a substituted or unsubstituted pyrazinyl, a substituted or unsubstituted furanyl, a substituted or unsubstituted thienyl, a substituted or unsubstituted [l,3,5]triazinyl, a substituted or unsubstituted thiazolyl, a substituted or unsubstituted imidazolyl, a substituted or unsubstituted oxazolyl, a substituted or unsubstituted indolizinyl, a substituted or unsubstituted imidazo[l,2-a]pyridyl, a substituted or unsubstituted 2,3-dihydro- benzo[l,4]dioxinyl, and a substituted or unsubstituted naphthyl;
R52 and R53 are each, independently, a lower alkyl; R46 is -C(O)O-(lower alkyl), -C(O)OH, cyano, -C(O)NR65R65, -C(O)-(lower alkyl), wherein R65, for each occurrence, is -H or a lower alkyl; and
R47 is cyclopropyl, ethoxymethyl, 2-amino-ethoxymethyl, 2-azido- ethoxymethyl, 2-(2-hydroxy-3-phenoxy-propylamino)-ethoxymethyl, propoxymethyl, isopropoxymethyl, N-mesyl-2-aminoethoxymethyl, N-acetyl-2-aminoethoxymethyl, N-ethyl-2-aminoethoxymethyl, N-methyl-2-aminoethoxymethyl, 2-(l,3-dioxo-l,3- dihydro-isoindol-2-yl)-ethoxymethyl, morpholin-4-yl-methyl, 2-morpholin-4-yl- ethoxymethyl, N,N-dimethylaminomethyl, carbethoxycarbonylmethoxymethyl, N-(2- hydroxyethyl)-N-methylaminom ethyl, piperazin-1-yl-methyl, 2- hydroxyethoxymethyl, N,N-dimethylamino-ethoxymethyl, 4-aminobutyl, imidazol-5- yl-m ethoxymethyl, imidazol-4-yl-methoxymethyl, 2-imidazol-l-yl-ethoxym ethyl, 3- imidazol-1-yl-propyl, 3 -pyrazol-1-yl -propyl, propoxymethyl, isopropoxymethyl, methoxyethoxymethyl, pyrrol-3-yl-methoxymethyl, pyrrol-2-yl-methoxymethyl,
[l,2,4]triazol-3-yl-methoxymethyl, 2H-pyrazol-3-yl-methoxymethyl, 3H- [l,2,3]triazol-4-yl-methoxymethyl, or 2-pyiτol-l-yl-ethoxymethyl.
A method for treating an inflammatory bowel disease in a subject, comprising administering to the subject an effective amount of a compound represented by formula (XII):
Do is an optionally substituted aryl or an optionally substituted heteroaryl;
X9 is O, S, or -NR56-;
Y is O or S;
R45 is -H or an alkyl;
R46 is -C(O)OR56, -C(O)R56, -C(O)NR57R58, -CN, -CH(OR56)R56, -C(=NR56)R56, -C(S)R56, -C(S)OR56, -C(S)NR57R58, -CH(NR57R58)R56; or -CH(SR56)R56;
Rt7 is H or a substituent;
R48 and R49 are each, independently, -H, -OR56, or -NR57R58; or R48 and R49 taken together are =0, =S or =NR59, provided that at least one OfR48 or R49 is not -H;
R50 and R51 are each, independently, -H or a substituent;
R52 and R53 are each, independently, -H or a substituent; or R52 and R53, together with the carbon to which they are attached, form an optionally substituted cycloalkyl;
R54 and R55, for each occurrence, are, independently, -H or a substituent;
R56, for each occurrence, is, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rs7 and R58, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R57 and R58, taken together with the nitrogen to which they are attached are an optionally substituted heterocycloalkyl or optionally substituted heteroaryl; R59 is -H, halo, -ORβo, -NROOROO, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; and
Rβo is H, alkyl, aryl or acetyl; provided that when R47 is methyl, D2 is not chlorothienyl, methylthienyl, 1- oxo-pyridin-3-yl, l-oxo-2-chloropyridin-3-yl, l-oxo-2-methylpyridin-3-yl, 2-phenyl- 4-oxo-thiochromenyl, a substituted 4-oxo-benzopyranyl, or a substituted phenyl; and provided that when R47 is methoxymethyl or (CHa)2NCH2CH2-, D2 is not o- chlorophenyl.
93. The method of Claim 92, wherein
Y is =0; X9 is -O-; s is 1;
D2 is selected from the group consisting of a substituted or unsubstituted phenyl, a substituted or unsubstituted benzo[l,3]dioxolyl, a substituted or unsubstituted pyridyl, a substituted or unsubstituted indolyl, a substituted or
unsubstituted quinolinyl, a substituted or unsubstituted 1-oxo-pyridyl, a substituted or unsubstituted pyridazinyl, a substituted or unsubstituted pyrimidinyl, a substituted or unsubstituted pyrazinyl, a substituted or unsubstituted furanyl, a substituted or unsubstituted thienyl, a substituted or unsubstituted [l,3,5]triazinyl, a substituted or unsubstituted thiazolyl, a substituted or unsubstituted imidazolyl, a substituted or unsubstituted oxazolyl, a substituted or unsubstituted indolizinyl, a substituted or unsubstituted imidazo[l,2-a]pyridyl, a substituted or unsubstituted 2,3-dihydro- benzo[l,4]dioxinyl, and a substituted or unsubstituted naphthyl; R52 and R53 are each, independently, a lower alkyl; R46 Is -C(0)0-(lower alkyl), -C(O)OH, cyano, -C(O)NR65R6S,
-C(O)-(lower alkyl), wherein Res, for each occurrence, is -H or a lower alkyl; and
R47 is cyclopropyl, ethoxymethyl, 2-amino-ethoxymethyl, 2-azido- ethoxymethyl, 2-(2-hydroxy-3-phenoxy-propylamino)-ethoxymethyl, propoxymethyl, isopropoxymethyl, N-mesyl-2-aminoethoxymethyl, N-acetyl-2-aminoethoxymethyl, N-ethyl-2-aminoethoxym ethyl, N-methyl-2-aminoethoxymethyl, 2-( 1 ,3 -dioxo- 1 ,3 - dihydro-isoindol-2-yl)-ethoxymethyl, morpholin-4-yl-methyl, 2-morpholin-4-yl- ethoxymethyl, N,N-dimethylaminomethyl, carbethoxycarbonylmethoxymethyl, N-(2- hydroxyethyl)-N-methylaminomethyl, piperazin-1-yl-methyl, 2- hydroxyethoxymethyl, N,N-dimethylamino-ethoxymethyl, 4-aminobutyl, imidazol-5- yl-methoxymethyl, imidazol-4-yl-methoxymethyl, 2-imidazol-l-yl-ethoxymethyl, 3- imidazol-1-yl-propyl, 3-pyrazol-l-yl-propyl, propoxymethyl, isopropoxymethyl, methoxyethoxymethyl, pyrrol-3-yl-methoxymethyl, pyrrol-2 -yl-methoxymethyl, [ 1 ,2,4]triazol-3 -yl-methoxymethyl, 2H-pyrazol-3 -yl-methoxymethyl, 3H- [l,2,3]triazol-4-yl-methoxymethyl, or 2-pyrrol-l-yl-ethoxymethyl.
94. A method for treating an inflammatory bowel disease in a subject, comprising administering to a subject in need thereof an effective amount of a compound represented by formula (X]H):
D and E are independently selected from -H, -halo, -NO2, -CN, -OH, -N(R38)(R38), -OR38, -C(O)R38, -OC(O)R38, -C(O)NHC(O)R38, substituted or unsubstituted -(Ci-Cio)alkyl, substituted or unsubstituted -(C2-C io)alkenyl, substituted or unsubstituted -(C2-C io)alkynyl, substituted or unsubstituted -(C3- Cio)cycloalkyl, substituted or unsubstituted -(Cs-C^bicycloalkyl, substituted or unsubstituted -(C5-Cio)cycloalkenyl, substituted or unsubstituted 3-7 membered monocyclic heterocycle, substituted or unsubstituted 8-12 membered bicyclic heterocycle, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, -(Ci-Ct,)alkyl-Z-(Ci-CiO)alkyl-R44, -(C1-C1o)alkyl-R44, -(C1-C10)^yI-N(R38)(R38), -CO2R38, -C(O)OCH(R38)(R38), -NHC(O)R38, -NHC(O)NHR38, -C(O)NHR38, -OC(O)R38, -OC(O)OR38, -S(O)N(R38)(R38), -SR38, -S(O)R38, -S(O)2R38 and a substituted or unsubstituted aromatic or heteroaromatic ring, wherein if the ring is substituted, the substituents are independently selected from the group consisting of substituted or unsubstituted lower alkyl, -halo, -CN, -N(R38)(R38), -OR39, -C(O)R38, -C(O)2R38, -OC(O)R38, -NO2, and -C(O)N(R38)(R38), or two adjacent carbon atoms on the ring are linked by the group -0-(CH2)g-0- to form a bicyclic ring system, wherein g is an integer selected from 1, 2, 3 or 4;
X is selected from the group consisting of O, S, -NR38, and -C(R38)(R38);
Y is O or S;
Z is at each occurrence independently-O-, -S-, -N(R38)-, -C(O)-, -OC(O)-, -C(O)N(R38)C(O)-, substituted or unsubstituted -(Ci-Cio)alkyl-, substituted or unsubstituted -(C2-C1o)alkenyl-, substituted or unsubstituted -(C2-Cio)alkynyl-, substituted or unsubstituted -(C3-Ci0)cycloalkyl-, substituted or unsubstituted -(C8- C14)bicycloalkyl-, substituted or unsubstituted -(C5-Ci0)cycloalkenyl-, substituted or unsubstituted -(C3-Cκ))heterocycle-, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, -C(O)O-,
-C(O)OC(R38)(R38)-, -N(R38)C(O)-, -N(R38)C(O)NR38-, -C(O)NR38-, -OC(O)O-, -S(0)N(R38)-, -S(0)- or -S(0)2-;
R34 and R35 are at each occurrence independently selected from -H, -halo, -CN, -N3, -NO2, -CN, -OH, -N(R38)(R38), -OR38, -C(O)R38, -OC(O)R38, - C(O)NHC(O)R38, substituted or unsubstituted -(CrCi0)alkyl, substituted or unsubstituted -(C2-Ci0)alkenyl, substituted or unsubstituted -(C2-C io)alkynyl, substituted or unsubstituted -(C3-Cio)cycloalkyl, substituted or unsubstituted -(C8-
Ci4)bicycloalkyl, substituted or unsubstituted -(C5-Cio)cycloalkenyl, substituted or unsubstituted 3-7 membered monocyclic heterocycle, substituted or unsubstituted 8- 12 membered bicyclic heterocycle, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, -CO2R38, -C(O)OCH(R38)(R38), -NHC(O)R38 , -NHC(O)NHR38, -C(O)NHR38, -OC(O)R38,
-OC(O)OR38, -S(O)N(R38)(R38), -SR38, -S(O)R38, and -S(O)2R38;
R36 is at each occurrence independently -H, -C(O)R38 or substituted or unsubstituted -(Ci-Cio)alkyl;
R37 is at each occurrence independently -H, -halo, -CN, -N3, -NO2, -CN, -OH, -N(R38)(R38), -OR38, -C(O)R38, -OC(O)R38, -C(O)NHC(O)R38, substituted or unsubstituted -(Ci-Cio)alkyl, substituted or unsubstituted -(C2-Cio)alkenyl, substituted or unsubstituted -(C2-Ci0)alkynyl, substituted or unsubstituted -(C3- Cio)cycloalkyl, substituted or unsubstituted -(C8-C i4)bicycloalkyl, substituted or unsubstituted -(C5-Cio)cycloalkenyl, substituted or unsubstituted 3-7 membered monocyclic heterocycle, substituted or unsubstituted 8-12 membered bicyclic heterocycle, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, -CO2R38, -C(O)OCH(R38)(R38), -NHC(O)R38 , -NHC(O)NHR38, -C(O)NHR38, -OC(O)OR38, -S(O)N(R38)(R38), -SR38, -S(O)R38, -S(O)2R38 or a substituted or unsubstituted bioisosteric replacement of an ester; each R38 is at each occurrence independently H or substituted or unsubstituted -(C1-C10)alkyl; each R39 is at each occurrence independently H, substituted or unsubstituted -(Ci-Cio)alkyl or -(CH2)k-N(R38)-(Ci-C6)alkyl optionally substituted with one or more -OR38 or -O-aryl groups;
R44 is at each occurrence independently selected from -H, -halo, -CN, -N3, -NO2, -CN, -OH, -N(R38)(R38), -OR38, -C(O)R38, -OC(O)R38, -C(O)NHC(O)R38, substituted or unsubstituted -(Ci-Cio)alkyl, substituted or unsubstituted -(C2-
Cio)alkenyl, substituted or unsubstituted -(C2-C io)alkynyl, substituted or unsubstituted -(C3-Cio)cycloalkyl, substituted or unsubstituted -(Cs-C ^bicycloalkyl, substituted or unsubstituted -(C5-Cio)cycloalkenyl, substituted or unsubstituted 3-7 membered monocyclic heterocycle, substituted or unsubstituted 8-12 membered bicyclic heterocycle, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, -CO2R3S, -C(O)OCH(R38)(R3s), -NHC(O)R38 , -NHC(O)NHR38, -C(O)NHR38, -OC(O)R38, -OC(O)OR38, -S(O)N(R38)(R38), -SR38, -S(O)R38, and -S(O)2R38; s is an integer selected from 0-2; k is an integer selected from 1-6; wherein if X is O, s is not O; and if R36 is other than H, R34 and R35 are not both H.
95. A method for treating an inflammatory bowel disease in a subject, comprising administering to the subject an effective amount of a compound represented by formula (XVII):
(XVH)
or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein: s is O, 1, or 2;
Di is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, or an optionally substituted heterocycloalkyl;
X8 is O, S, -NR56-, or >CR50R5i;
R45 is -H or an alkyl;
R46 is -C(O)OR56, -C(O)R56, -C(O)NR57R58, -CN, -CH(OR56)R56, -C(=NR56)R56, -C(S)R56, -C(S)OR56, -C(S)NR57R58, -CH(NR57R58)R56; or -CH(SR56)R56; R47 is H or a substituent;
R48 and R49 are each, independently, -H, -OR56, or -NR57R58; or R48 and R49 taken together are =0, =S or =NR59, provided that at least one OfR4S or R49 is not -H;
R5o and R51 are each, independently, -H or a substituent; R52 and R53 are each, independently, -H or a substituent; or R52 and R53, together with the carbon to which they are attached, form an optionally substituted cycloalkyl;
R54 and R55, for each occurrence, are, independently, -H or a substituent;
R56, for each occurrence, is, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; R57 and R58, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R57 and R58, taken together with the nitrogen to which they are attached are an optionally substituted heterocycloalkyl or optionally substituted heteroaryl;
R59 is -H, halo, -OR6O, -NR6oR6o, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; and
R6o is H, alkyl, aryl or acetyl;
provided that when R47 is isopropyl or cyclopentyl, R46 is notp- (trifluoromethyl)benzoyl.
The method of Claim 95, wherein R48 and R49 together are =0;
X8 iS >CR50R51; s is 1;
Di is methyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, 1- methylcyclopropyl, or cyclopropylmethyl; R52 and R53 are each, independently, a lower alkyl;
R46 Is -C(O)O-(lower alkyl), -C(O)OH, cyano, -C(O)NR65ReS, -C(O)-(lower alkyl), wherein R65, for each occurrence, is -H or a lower alkyl; and
R47 is cyclopropyl, ethoxymethyl, 2-amino-ethoxymethyl, 2-azido- ethoxymethyl, 2-(2-hydroxy-3-phenoxy-propylamino)-ethoxymethyl, propoxymethyl, isopropoxymethyl, N-mesyl-2-aminoethoxymethyl, N-acetyl-2-aminoethoxymethyl,
N-ethyl-2-aminoethoxymethyl, N-methyl-2-aminoethoxymethyl, 2-(l,3-dioxo-l,3- dihydro-isoindol-2-yl)-ethoxymethyl, moφholin-4-yl-methyl, 2-morpholin-4-yl- ethoxymethyl, N,N-dimethylaminomethyl, carbethoxycarbonylmethoxymethyl, N-(2- hydroxyethyl)-N-methylaminom ethyl, piperazin-1-yl-methyl, 2- hydroxyethoxymethyl, N,N-dimethylamino-ethoxymethyl, 4-aminobutyl, imidazol-5- yl-methoxymethyl, imidazol-4-yl-methoxymethyl, 2-imidazol-l-yl-ethoxymethyl, 3- imidazol-1-yl-propyl, 3-pyrazol-l-yl-propyl, propoxymethyl, isopropoxymethyl, methoxyethoxymethyl, pyrrol-3-yl-methoxymethyl, pyrrol-2-yl-methoxymethyl, [l,2,4]triazol-3-yl-methoxymethyl, 2H-pyrazol-3-yl-methoxymethyl, 3H- [l,2,3]triazol-4-yl-methoxymethyl, or 2-pyrrol-l-yl-ethoxymethyl.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US63567304P | 2004-12-13 | 2004-12-13 | |
| US60/635,673 | 2004-12-13 | ||
| US66024605P | 2005-03-10 | 2005-03-10 | |
| US60/660,246 | 2005-03-10 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2006065842A2 true WO2006065842A2 (en) | 2006-06-22 |
| WO2006065842A3 WO2006065842A3 (en) | 2007-02-22 |
Family
ID=36579567
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2005/045136 WO2006065842A2 (en) | 2004-12-13 | 2005-12-13 | 5,6,7,8-tetrahydroquinolines and related compounds and uses thereof |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2006065842A2 (en) |
Cited By (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008103310A1 (en) | 2007-02-16 | 2008-08-28 | Synta Pharmaceuticals Corp. | Substituted fused-ring compounds for inflammation and immune-related uses |
| US7723355B2 (en) * | 2006-11-20 | 2010-05-25 | Bristol-Myers Squibb Company | 7,8-dihydro-1,6-naphthyridin-5(6H)-ones and related bicyclic compounds as inhibitors of dipeptidyl peptidase IV and methods |
| EP2322222A1 (en) * | 2008-08-07 | 2011-05-18 | Takeda Pharmaceutical Company Limited | Therapeutic agent for irritable bowel syndrome |
| WO2014061764A1 (en) * | 2012-10-19 | 2014-04-24 | 第一三共株式会社 | Xanthene derivative |
| US9266886B2 (en) | 2014-02-03 | 2016-02-23 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
| US9481674B1 (en) | 2016-06-10 | 2016-11-01 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
| US9663515B2 (en) | 2014-11-05 | 2017-05-30 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
| US9796710B2 (en) | 2014-10-14 | 2017-10-24 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
| US9845308B2 (en) | 2014-11-05 | 2017-12-19 | Vitae Pharmaceuticals, Inc. | Isoindoline inhibitors of ROR-gamma |
| US10112915B2 (en) | 2015-02-02 | 2018-10-30 | Forma Therapeutics, Inc. | 3-aryl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10183934B2 (en) | 2015-02-02 | 2019-01-22 | Forma Therapeutics, Inc. | Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors |
| US10301261B2 (en) | 2015-08-05 | 2019-05-28 | Vitae Pharmaceuticals, Llc | Substituted indoles as modulators of ROR-gamma |
| US10555935B2 (en) | 2016-06-17 | 2020-02-11 | Forma Therapeutics, Inc. | 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors |
| US10829481B2 (en) | 2016-01-29 | 2020-11-10 | Vitae Pharmaceuticals, Llc | Benzimidazole derivatives as modulators of ROR-gamma |
| US10913739B2 (en) | 2017-07-24 | 2021-02-09 | Vitae Pharmaceuticals, LLC (121374) | Inhibitors of RORγ |
| US11008340B2 (en) | 2015-11-20 | 2021-05-18 | Vitae Pharmaceuticals, Llc | Modulators of ROR-gamma |
| US11186573B2 (en) | 2017-07-24 | 2021-11-30 | Vitae Pharmaceuticals, Llc | Inhibitors of ROR gamma |
| US11661422B2 (en) | 2020-08-27 | 2023-05-30 | Incyte Corporation | Tricyclic urea compounds as JAK2 V617F inhibitors |
| US11691971B2 (en) | 2020-06-19 | 2023-07-04 | Incyte Corporation | Naphthyridinone compounds as JAK2 V617F inhibitors |
| US11753413B2 (en) | 2020-06-19 | 2023-09-12 | Incyte Corporation | Substituted pyrrolo[2,1-f][1,2,4]triazine compounds as JAK2 V617F inhibitors |
| US11767323B2 (en) | 2020-07-02 | 2023-09-26 | Incyte Corporation | Tricyclic pyridone compounds as JAK2 V617F inhibitors |
| US11780840B2 (en) | 2020-07-02 | 2023-10-10 | Incyte Corporation | Tricyclic urea compounds as JAK2 V617F inhibitors |
| US11919908B2 (en) | 2020-12-21 | 2024-03-05 | Incyte Corporation | Substituted pyrrolo[2,3-d]pyrimidine compounds as JAK2 V617F inhibitors |
| US11938134B2 (en) | 2017-03-10 | 2024-03-26 | Eikonizo Therapeutics, Inc. | Metalloenzyme inhibitor compounds |
| US11958861B2 (en) | 2021-02-25 | 2024-04-16 | Incyte Corporation | Spirocyclic lactams as JAK2 V617F inhibitors |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4576949A (en) * | 1984-05-07 | 1986-03-18 | The Upjohn Company | Use of 5,6,7,8-tetrahydroquinolines and 5,6-dihydropyrindines as leukotriene and lipoxygenase inhibitors and the novel 3-substituted compounds therein |
| DE19627419A1 (en) * | 1996-07-08 | 1998-01-15 | Bayer Ag | New aryl-cycloalkano:pyridine compounds |
| US6194428B1 (en) * | 1994-08-29 | 2001-02-27 | Bayer Aktiengesellschaft | Use of 5-substituted pyridine and hexahydroquinoline-3 carboxylic acid derivatives for treating diseases of the central nervous system |
| US6207671B1 (en) * | 1996-07-08 | 2001-03-27 | Bayer Aktiengesellschaft | Cycloalkano-pyridines |
| US6291477B1 (en) * | 1997-09-19 | 2001-09-18 | Bayer Aktiengesellschaft | Tetrahydroquinolines, processes for their preparation, pharmaceutical compositions containing them, and their use to prevent or treat hyperlipoproteinaemia |
| US6387929B1 (en) * | 1997-09-18 | 2002-05-14 | Bayer Aktiengesellschaft | 4-heteroaryl-tetrahydroquinolines and their use as inhibitors of the cholesterin-ester transfer protein |
| WO2003062203A1 (en) * | 2002-01-24 | 2003-07-31 | Astrazeneca Ab | Method |
| WO2005025507A2 (en) * | 2003-09-10 | 2005-03-24 | Synta Phamaceuticals Corp. | Dihydropyridine compounds for treating or preventing metabolic disorders |
| WO2005025504A2 (en) * | 2003-09-12 | 2005-03-24 | Kemia, Inc. | Modulators of calcitonin and amylin activity |
-
2005
- 2005-12-13 WO PCT/US2005/045136 patent/WO2006065842A2/en active Application Filing
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4576949A (en) * | 1984-05-07 | 1986-03-18 | The Upjohn Company | Use of 5,6,7,8-tetrahydroquinolines and 5,6-dihydropyrindines as leukotriene and lipoxygenase inhibitors and the novel 3-substituted compounds therein |
| US6194428B1 (en) * | 1994-08-29 | 2001-02-27 | Bayer Aktiengesellschaft | Use of 5-substituted pyridine and hexahydroquinoline-3 carboxylic acid derivatives for treating diseases of the central nervous system |
| DE19627419A1 (en) * | 1996-07-08 | 1998-01-15 | Bayer Ag | New aryl-cycloalkano:pyridine compounds |
| US6207671B1 (en) * | 1996-07-08 | 2001-03-27 | Bayer Aktiengesellschaft | Cycloalkano-pyridines |
| US6387929B1 (en) * | 1997-09-18 | 2002-05-14 | Bayer Aktiengesellschaft | 4-heteroaryl-tetrahydroquinolines and their use as inhibitors of the cholesterin-ester transfer protein |
| US6291477B1 (en) * | 1997-09-19 | 2001-09-18 | Bayer Aktiengesellschaft | Tetrahydroquinolines, processes for their preparation, pharmaceutical compositions containing them, and their use to prevent or treat hyperlipoproteinaemia |
| WO2003062203A1 (en) * | 2002-01-24 | 2003-07-31 | Astrazeneca Ab | Method |
| WO2005025507A2 (en) * | 2003-09-10 | 2005-03-24 | Synta Phamaceuticals Corp. | Dihydropyridine compounds for treating or preventing metabolic disorders |
| WO2005025504A2 (en) * | 2003-09-12 | 2005-03-24 | Kemia, Inc. | Modulators of calcitonin and amylin activity |
Non-Patent Citations (1)
| Title |
|---|
| ATTIA A M ET AL: "Synthesis of Some Novel Condensed Pyridine-2(1H)-thiones and Related Glycosides" TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 53, no. 51, 22 December 1997 (1997-12-22), pages 17441-17448, XP004106563 ISSN: 0040-4020 * |
Cited By (73)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7723355B2 (en) * | 2006-11-20 | 2010-05-25 | Bristol-Myers Squibb Company | 7,8-dihydro-1,6-naphthyridin-5(6H)-ones and related bicyclic compounds as inhibitors of dipeptidyl peptidase IV and methods |
| WO2008103310A1 (en) | 2007-02-16 | 2008-08-28 | Synta Pharmaceuticals Corp. | Substituted fused-ring compounds for inflammation and immune-related uses |
| EP2129219A1 (en) * | 2007-02-16 | 2009-12-09 | Synta Pharmaceuticals Corporation | Substituted fused-ring compounds for inflammation and immune-related uses |
| EP2129219A4 (en) * | 2007-02-16 | 2012-08-29 | Synta Pharmaceuticals Corp | Substituted fused-ring compounds for inflammation and immune-related uses |
| US8809396B2 (en) | 2007-02-16 | 2014-08-19 | Synta Pharmaceuticals Corp. | Substituted fused-ring compounds for inflammation and immune-related uses |
| EP2322222A1 (en) * | 2008-08-07 | 2011-05-18 | Takeda Pharmaceutical Company Limited | Therapeutic agent for irritable bowel syndrome |
| EP2322222A4 (en) * | 2008-08-07 | 2011-12-21 | Takeda Pharmaceutical | Therapeutic agent for irritable bowel syndrome |
| JPWO2010016552A1 (en) * | 2008-08-07 | 2012-01-26 | 武田薬品工業株式会社 | Drugs for irritable bowel syndrome |
| WO2014061764A1 (en) * | 2012-10-19 | 2014-04-24 | 第一三共株式会社 | Xanthene derivative |
| US11535614B2 (en) | 2014-02-03 | 2022-12-27 | Vitae Pharmaceuticals, Llc | Dihydropyrrolopyridine inhibitors of ROR-gamma |
| US10399976B2 (en) | 2014-02-03 | 2019-09-03 | Vitae Pharmaceuticals, Llc | Dihydropyrrolopyridine inhibitors of ROR-gamma |
| US9624217B2 (en) | 2014-02-03 | 2017-04-18 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
| US10047085B2 (en) | 2014-02-03 | 2018-08-14 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
| US10807980B2 (en) | 2014-02-03 | 2020-10-20 | Vitae Pharmaceuticals, Llc | Dihydropyrrolopyridine inhibitors of ROR-gamma |
| US9266886B2 (en) | 2014-02-03 | 2016-02-23 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
| US9796710B2 (en) | 2014-10-14 | 2017-10-24 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
| US10087184B2 (en) | 2014-10-14 | 2018-10-02 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of RORγ |
| US9663515B2 (en) | 2014-11-05 | 2017-05-30 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
| US9845308B2 (en) | 2014-11-05 | 2017-12-19 | Vitae Pharmaceuticals, Inc. | Isoindoline inhibitors of ROR-gamma |
| US11001583B2 (en) | 2014-11-05 | 2021-05-11 | Vitae Pharmaceuticals, Llc | Dihydropyrrolopyridine inhibitors of ROR-gamma |
| US10472337B2 (en) | 2015-02-02 | 2019-11-12 | Forma Therapeutics, Inc. | 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10829462B2 (en) | 2015-02-02 | 2020-11-10 | Valo Early Discovery, Inc. | 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US11891365B2 (en) | 2015-02-02 | 2024-02-06 | Valo Health, Inc. | 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10377726B2 (en) | 2015-02-02 | 2019-08-13 | Forma Therapeutics, Inc. | 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10214501B2 (en) | 2015-02-02 | 2019-02-26 | Forma Therapeutics, Inc. | 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10407418B2 (en) | 2015-02-02 | 2019-09-10 | Forma Therapeutics, Inc. | Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors |
| US10414738B2 (en) | 2015-02-02 | 2019-09-17 | Forma Therapeutics, Inc. | 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10421731B2 (en) | 2015-02-02 | 2019-09-24 | Forma Therapeutics, Inc. | 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10421732B2 (en) | 2015-02-02 | 2019-09-24 | Forma Therapeutics, Inc. | 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10428031B2 (en) | 2015-02-02 | 2019-10-01 | Forma Therapeutics, Inc. | 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10442776B2 (en) | 2015-02-02 | 2019-10-15 | Forma Therapeutics, Inc. | 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10450284B2 (en) | 2015-02-02 | 2019-10-22 | Forma Therapeutics, Inc. | 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10450283B2 (en) | 2015-02-02 | 2019-10-22 | Forma Therapeutics, Inc. | 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10457652B2 (en) | 2015-02-02 | 2019-10-29 | Forma Therapeutics, Inc. | 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10464910B2 (en) | 2015-02-02 | 2019-11-05 | Forma Therapeutics, Inc. | 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10464909B2 (en) | 2015-02-02 | 2019-11-05 | Forma Therapeutics, Inc. | 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10214500B2 (en) | 2015-02-02 | 2019-02-26 | Forma Therapeutics, Inc. | 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10479772B2 (en) | 2015-02-02 | 2019-11-19 | Forma Therapeutics, Inc. | 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10494353B2 (en) | 2015-02-02 | 2019-12-03 | Forma Therapeutics, Inc. | 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10494352B2 (en) | 2015-02-02 | 2019-12-03 | Forma Therapeutics, Inc. | 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10494351B2 (en) | 2015-02-02 | 2019-12-03 | Forma Therapeutics, Inc. | 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10494354B2 (en) | 2015-02-02 | 2019-12-03 | Forma Therapeutics, Inc. | 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10501424B2 (en) | 2015-02-02 | 2019-12-10 | Forma Therapeutics, Inc. | 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10513501B2 (en) | 2015-02-02 | 2019-12-24 | Forma Therapeutics, Inc. | 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US11702412B2 (en) | 2015-02-02 | 2023-07-18 | Valo Health, Inc. | Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors |
| US10183934B2 (en) | 2015-02-02 | 2019-01-22 | Forma Therapeutics, Inc. | Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors |
| US10822316B2 (en) | 2015-02-02 | 2020-11-03 | Valo Early Discovery, Inc. | 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10239845B2 (en) | 2015-02-02 | 2019-03-26 | Forma Therapeutics, Inc. | 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US11279681B2 (en) | 2015-02-02 | 2022-03-22 | Valo Health, Inc. | 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10829461B2 (en) | 2015-02-02 | 2020-11-10 | Valo Early Discovery, Inc. | 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US11274084B2 (en) | 2015-02-02 | 2022-03-15 | Valo Health, Inc. | 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10870645B2 (en) | 2015-02-02 | 2020-12-22 | Valo Early Discovery, Inc. | Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors |
| US11274085B2 (en) | 2015-02-02 | 2022-03-15 | Valo Health, Inc. | 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10112915B2 (en) | 2015-02-02 | 2018-10-30 | Forma Therapeutics, Inc. | 3-aryl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10988450B2 (en) | 2015-02-02 | 2021-04-27 | Valo Early Discovery, Inc. | 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
| US10301261B2 (en) | 2015-08-05 | 2019-05-28 | Vitae Pharmaceuticals, Llc | Substituted indoles as modulators of ROR-gamma |
| US10829448B2 (en) | 2015-08-05 | 2020-11-10 | Vitae Pharmaceuticals, Llc | Substituted benzoimidazoles as modulators of ROR-γ |
| US11008340B2 (en) | 2015-11-20 | 2021-05-18 | Vitae Pharmaceuticals, Llc | Modulators of ROR-gamma |
| US10829481B2 (en) | 2016-01-29 | 2020-11-10 | Vitae Pharmaceuticals, Llc | Benzimidazole derivatives as modulators of ROR-gamma |
| US9481674B1 (en) | 2016-06-10 | 2016-11-01 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
| US10874649B2 (en) | 2016-06-17 | 2020-12-29 | Valo Early Discovery, Inc. | 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors |
| US10555935B2 (en) | 2016-06-17 | 2020-02-11 | Forma Therapeutics, Inc. | 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors |
| US11730721B2 (en) | 2016-06-17 | 2023-08-22 | Valo Health, Inc. | 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors |
| US11938134B2 (en) | 2017-03-10 | 2024-03-26 | Eikonizo Therapeutics, Inc. | Metalloenzyme inhibitor compounds |
| US11186573B2 (en) | 2017-07-24 | 2021-11-30 | Vitae Pharmaceuticals, Llc | Inhibitors of ROR gamma |
| US10913739B2 (en) | 2017-07-24 | 2021-02-09 | Vitae Pharmaceuticals, LLC (121374) | Inhibitors of RORγ |
| US11691971B2 (en) | 2020-06-19 | 2023-07-04 | Incyte Corporation | Naphthyridinone compounds as JAK2 V617F inhibitors |
| US11753413B2 (en) | 2020-06-19 | 2023-09-12 | Incyte Corporation | Substituted pyrrolo[2,1-f][1,2,4]triazine compounds as JAK2 V617F inhibitors |
| US11767323B2 (en) | 2020-07-02 | 2023-09-26 | Incyte Corporation | Tricyclic pyridone compounds as JAK2 V617F inhibitors |
| US11780840B2 (en) | 2020-07-02 | 2023-10-10 | Incyte Corporation | Tricyclic urea compounds as JAK2 V617F inhibitors |
| US11661422B2 (en) | 2020-08-27 | 2023-05-30 | Incyte Corporation | Tricyclic urea compounds as JAK2 V617F inhibitors |
| US11919908B2 (en) | 2020-12-21 | 2024-03-05 | Incyte Corporation | Substituted pyrrolo[2,3-d]pyrimidine compounds as JAK2 V617F inhibitors |
| US11958861B2 (en) | 2021-02-25 | 2024-04-16 | Incyte Corporation | Spirocyclic lactams as JAK2 V617F inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2006065842A3 (en) | 2007-02-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2006065842A2 (en) | 5,6,7,8-tetrahydroquinolines and related compounds and uses thereof | |
| EP1663227A2 (en) | Dihydropyridine compounds for treating or preventing metabolic disorders | |
| AU2007208151B2 (en) | Vinyl-phenyl derivatives for inflammation and immune-related uses | |
| US8314130B2 (en) | Compounds inclunding substituted pyridines for inflammation and immune-related uses | |
| US8435996B2 (en) | Heterocycle-aryl compounds for inflammation and immune-related uses | |
| US20120196838A1 (en) | Compounds for inflammation and immune-related uses | |
| US20120225883A1 (en) | Compounds for inflammation and immune-related uses | |
| US20080207641A1 (en) | Cyclohexenyl-aryl compounds for inflammation and immune-related uses | |
| US20100249195A1 (en) | Pyridylphenyl compounds for inflammation and immune-related uses | |
| US20110052643A1 (en) | Compounds for inflammation and immune-related uses | |
| US20120064121A1 (en) | Pyridine compounds for inflammation and immune-related uses | |
| AU2011200458A1 (en) | Method for modulating calcium ion-release-activated calcium ion channels | |
| US20120183579A1 (en) | Compounds for inflammation and immune-related uses | |
| JPWO2012033069A1 (en) | Piperidine compounds that inhibit prostaglandin D synthase | |
| AU2012216699A1 (en) | Compounds for inflammation and immune-related uses |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LC LK LR LS LT LU LV LY MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
| NENP | Non-entry into the national phase in: |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 05853946 Country of ref document: EP Kind code of ref document: A2 |