NOVEL SMALL MOLECULE SHC BLOCKERS USED FOR TREATING LIVER DISEASE AND METABOLIC DISEASE

Abstract

The subject matter disclosed herein is directed to novel She inhibitors of Formula (II). These compounds are useful for treating impaired insulin sensitivity, glucose tolerance, obesity, diabetes, metabolic syndrome, NAFLD, NASH, PSC, PBC, or other metabolic syndrome component conditions.

##STR00001##

Claims

1.-140. (canceled)

141. A compound of Formula II: ##STR00109## wherein, Ring M, J, J′, q, and w form ##STR00110## wherein J′ is naphthalenyl, w is 1, and q is 0; P is a bond; D is absent; G is C═O; R.sub.5 is selected from the group consisting of hydrogen, hydroxyl, and linear or branched C.sub.1-C.sub.3 alkyl; R.sub.6 is selected from the group consisting of alkyl-S(O).sub.m, haloalkyl-S(O).sub.m, alkenyl-S(O).sub.m, alkynyl-S(O).sub.m, cycloalkylalkyl-S(O).sub.m, aryl-S(O).sub.m, arylalkyl-S(O).sub.m, heterocycloalkyl-S(O).sub.m, and heteroaryl-S(O).sub.m, wherein S in —S(O).sub.m is optionally substituted 1 to 3 times, in each instance, with arylalkyl, aryl, heterocyclo, or heteroaryl; and m is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.

142. The compound of claim 141, wherein R.sub.5 is hydrogen.

143. The compound of claim 141, wherein R.sub.6 is alkyl-S(O).sub.m, wherein S in S(O).sub.m is optionally substituted 1 to 3 times, in each instance, with one or a combination of arylalkyl, aryl, or heteroaryl.

144. The compound of claim 143, wherein m is 2.

145. The compound of claim 143, wherein R.sub.6 is alkyl-S(O).sub.2, wherein S is substituted once with aryl or arylalkyl.

146. The compound of claim 145, wherein R.sub.6 is alkyl-S(O).sub.2, wherein S is substituted once with arylalkyl.

147. The compound of claim 146, wherein R.sub.6 is —CH.sub.2CH.sub.2—S(O).sub.2, wherein S is substituted once with benzyl.

148. The compound of claim 141, wherein said compound has the structure: ##STR00111##

149. A compound of Formula II: ##STR00112## wherein, Ring M, J, J′, q, and w form ##STR00113## wherein J′ is pyrrolyl, w is 1, and q is 0; P is a bond; D is absent; G is C═O; and R.sub.5 and R.sub.6 are taken together with the nitrogen to which they are attached to form a morpholinyl ring, wherein said morpholinyl ring is substituted with aryl, and wherein said aryl is substituted 1 to 3 times, in each instance, with branched or linear alkyl, alkoxy, or haloalkoxy; or a pharmaceutically acceptable salt thereof.

150. The compound of claim 149, wherein R.sub.5 and R.sub.6 are taken together with the nitrogen to which they are attached to form a morpholinyl ring, wherein said morpholinyl ring is substituted with phenyl, and wherein said phenyl ring is substituted 1 to 3 times, independently in each instance, with methoxy, difluoromethoxy, trifluoromethoxy, or methyl.

151. The compound of claim 150, wherein said morpholinyl ring is substituted once with phenyl, and wherein said phenyl ring is substituted once with difluoromethoxy.

152. The compound of claim 151, wherein said phenyl ring is substituted with difluoromethoxy in the meta position.

153. The compound of claim 152, wherein R.sub.5 and R.sub.6 are taken together with the nitrogen to which they are attached to form ##STR00114## wherein indicates the point of attachment to G.

154. The compound of claim 149, wherein the compound has the structure ##STR00115##

155. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of claim 141, and a carrier acceptable for human administration.

156. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of claim 149, and a carrier acceptable for human administration.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0120] FIG. 1 shows binding response data for compounds examined herein at various concentrations and response ratios (i.e. binding of molecule to full-length Shc vs. Shc from which PTB has been deleted), by Biolayer Interferometry.

[0121] FIG. 2 shows data for compounds examined herein. The compound information refers to the number of compounds out of 210 that exhibited biological activity under the category designated within each column (top affinity, top insulin, palmitate, alcohol, amyloid, and overall). “Top affinity” refers to compounds that exhibited binding to Shc protein having KD (equilibrium dissociation constant) values less than 1 μM. “Top insulin 34” refers to the top 34 compounds exhibiting a 2-fold change in insulin-dependent P-Akt activation over vehicle in assay screens. “Palmitate” refers to compounds that expressed 2 standard deviations different from the assay mean, and exhibited a 10% false discovery rate estimate in protection of primary hepatocyte from palmitate toxicity assays. “Alcohol” refers to compounds that expressed 2 standard deviations different from the assay mean, and had a 10% false discovery rate estimate in protection of primary hepatocyte from alcohol toxicity assays. “Amyloid” refers to compounds that expressed 2 standard deviations different form the assay mean, and had a 10% false discovery rate estimate in protection from amyloid beta toxicity in a N2A neuronal cell line assay. The number in the “Overall” column was determined by adding up the individual properties (top affinity, top insulin, palmitate, alcohol, and amyloid) for each compound.

[0122] FIG. 3 shows how compound 3 and compound 5 reduce glucose intolerance in the Corticosterone model of Insulin resistance. In a standard model of glucose intolerance and insulin insensitivity, corticosterone (CS) was dosed for 21 days, and in the drug treated group mice were administered Shc Blocker #3=RTX60933293 or #5=RTX73145433 at a dose of 10 mg/kg i.p. for the final 5 days of the 21-day CS treatment. As seen in (A) by the standard GTT=Glucose Tolerance Test, compound number 3 reduced glucose intolerance significantly at 4 time points after glucose administration; (B), compound number 5 reduced glucose significantly at 2 time points after glucose administration, and (C) Area Under the Curve (AUC) analysis demonstrates that both molecules significantly reduced glucose intolerance relative to the placebo.

[0123] FIG. 4 shows how Shc Blocker compound number 3 and compound number 5 inhibit fibrosis in a MCD model of Non-alcoholic Steatohepatitis (NASH). Mice were fed the Liver fibrosis-inducing Methionine Choline-Deficient (MCD) Mouse model NASH for 8 weeks, and the last 4 weeks they were dosed orally with 20 mg/kg of compound number 3 (RTX60933293), compound number 5 (RTX73145433), or placebo. After 8 weeks of MCD dosing, mice were sacrificed, and livers were extracted for nucleic acids and classical markers of liver fibrosis were assayed by QRTPCR. In this treatment regimen, compounds 3 and 5 significantly reduced many standard markers of NASH liver fibrosis, including: (A), alpha-smooth muscle actin (aSMA); (B), Collagen 1a1 (Col1); (C), Transforming Growth Factor beta (TGF-b); (D), Matrix Metalloproteinase 2 (MMP2); and (E), Tissue metallopeptidase inhibitor 1 (TIMP1). In addition, the classical liver fibrosis bio marker hydroxyproline was measured, and both compounds 3 and 5 significantly reduced this marker. *=p<0.05; **=p<0.01

DETAILED DESCRIPTION

[0124] I. General

[0125] The subject matter described herein identifies novel She inhibitors identified by a combination of in silico screening and various bioassays. These compounds are useful for treating impaired insulin sensitivity, glucose tolerance, obesity, diabetes, metabolic syndrome, NAFLD, NASH, PSC, PBC, or other metabolic syndrome component conditions.

[0126] II. Shc Protein

[0127] Unless otherwise apparent from the context, Shc refers to human Shc-1, for which the canonical form (p66Shc) is assigned Swiss Prot P29353. Allelic variants and isoforms of the canonical form are also included. The canonical form has 583 amino acids. Residues 156-339 constitute a phospho-tyrosine binding (PTB) domain. Residues 488-579 constitute a SH2 domain. At least three Shc protein isoforms including the canonical form are known to exist in mammals. These isoforms originate from alternative splicing followed by usage of alternative start codons at a single DNA locus and are p66Shc-minor, p52Shc-major (Swiss Prot P29353-2) or the metabolic isoform, and p46Shc—the mitochondrial isoform (Swiss-Prot P29353-3). P52Shc and p46Shc differ from the canonical form in omission of amino acids 1-110 and 1-155 respectively. Thus, the PTB domain runs from residues 378 to 469 in p52Shc and residues 333-424 in p46Shc.

[0128] Shc proteins are essential for insulin sensitivity and regulation of fuel selection by cells. Glucose metabolism is regulated by insulin. When sugar is not available, the cells switch on utilizing lipids, ketone bodies and proteins. Shc proteins are adaptors which interact with receptor tyrosine kinases and transmit growth signals towards induction of protein synthesis and cell division, and are known to interact with the insulin receptor by way of the phospho tyrosine binding (PTB) domain. Shc proteins also oppose metabolic insulin signaling, thus regulating fuel selection by the cell. The p52Shc isoform is preferred to identify compounds for Shc PTB domain binding because it is the most highly expressed of all Shc isoforms and is correctly folded and non-toxic in many mammalian cells lines.

[0129] III. Compounds

[0130] In certain embodiments, the subject matter described herein is directed to a compound of Formula II:

##STR00003##

wherein, [0131] ring M is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocyclo; [0132] J and J′ are each independently selected from the group consisting of halo, hydroxyl, linear or branched alkyl, alkoxy, nitro, mercapto, cyano, heterocyclo, cycloalkyl, aryl, and heteroaryl, wherein said aryl, heterocyclo, cycloalkyl, or heteroaryl is optionally substituted 1 to 3 times, in each instance, with one or a combination of alkoxy, linear or branched alkyl, halo, hydroxyl, or cyano; [0133] w and q are each independently 0 or 1; [0134] P is S, NH, or a bond; [0135] D is (CR.sub.3R.sub.4).sub.y, wherein y is 0 or 1; [0136] R.sub.3 and R.sub.4 are each hydrogen; [0137] G is CH.sub.2 or C═O; [0138] R.sub.5 is selected from the group consisting of hydrogen, linear or branched alkyl, hydroxyl, alkoxy, hydroxyalkyl, and halo; or, [0139] R.sub.5 is taken together with the nitrogen to which it is attached and G, D, and one of R.sub.3 and R.sub.4 to form a heterocyclo; [0140] R.sub.6 is selected from the group consisting of halo, linear or branched alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocycloalkyloxy, mercapto, —(CH.sub.2).sub.fNHC(O)-aryl, —(CH.sub.2).sub.fNHC(O)-heteroaryl, alkyl-S(O).sub.m, haloalkyl-S(O).sub.m, alkenyl-S(O).sub.m, alkynyl-S(O).sub.m, cycloalkyl-S(O).sub.m, cycloalkylalkyl-S(O).sub.m, aryl-S(O).sub.m, heteroaryl-S(O).sub.m, arylalkyl-S(O).sub.m, heterocyclo-S(O).sub.m, heterocycloalkyl-S(O).sub.m, amino, alkylamino, alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro, and cyano; wherein, [0141] f is 0, 1, 2, 3, 4, or 5; [0142] m is 0, 1, 2 or 3; and [0143] said heteroaryl, aryl, heterocyclo, heterocycloalkyl, cycloalkyl, or S in —S(O).sub.m is optionally substituted 1 to 3 times, in each instance, with one or a combination of linear or branched alkyl, —NR.sub.50C(O)(CH.sub.2).sub.bN(R.sub.60R.sub.70), halo, arylalkyl, aryl, hydroxyl, alkoxy, heterocycloalkyl, heteroarylalkyl, or heteroaryl; wherein, [0144] R.sub.50 is hydrogen or linear or branched alkyl; [0145] b is 0, 1, or 2; [0146] R.sub.60 and R.sub.70 are each independently selected from the group consisting of hydrogen, linear or branched alkyl, halo, and haloalkyl; and [0147] wherein said heterocycloalkyl, heterocyclo, heteroarylalkyl, aryl, or heteroaryl is optionally substituted 1 to 3 times, in each instance, with one or a combination of heterocyclo, cycloalkyl, alkoxy, halo, or linear or branched alkyl; or, [0148] R.sub.5 and R.sub.6 are taken together with the nitrogen to which they are attached to form a heteroaryl or heterocyclo, wherein said heteroaryl or heterocyclo is optionally substituted 1 to 3 times, in each instance, with one or a combination of branched or linear alkyl, aryl, hydroxyl, haloalkoxy, hydroxyalkyl, heteroaryl, arylalkyl, heterocyclo, halo, alkoxy, —(CH.sub.2).sub.fNHC(O)-aryl, or —(CH.sub.2).sub.fNHC(O)-heteroaryl, wherein said heteroaryl, aryl, heterocyclo, or arylalkyl is optionally substituted 1 to 3 times, in each instance, with one or a combination of branched or linear alkyl, heterocyclo, halo, nitro, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, heteroaryl, or aryl, wherein said heteroaryl, heterocyclo, or aryl is optionally substituted 1 to 3 times, in each instance, with one or a combination of hydroxyl, aryl, branched or linear alkyl, alkoxy, haloalkoxy, or halo;
or pharmaceutically acceptable salt thereof.

[0149] In certain embodiments, the subject matter described herein is directed to a compound of Formula II:

##STR00004## [0150] wherein ring M is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocyclo; [0151] J and J′ are each independently selected from the group consisting of hydrogen, halo, hydroxyl, linear or branched alkyl, alkoxy, nitro, mercapto, cyano, heterocyclo, cycloalkyl, aryl, and heteroaryl, wherein said aryl or heteroaryl is optionally substituted 1 to 3 times with alkoxy, linear or branched alkyl, halo, hydroxyl, or cyano; [0152] w is 0 or 1 [0153] P is S, NH, or a bond; [0154] D is (CR.sub.3R.sub.4).sub.y, wherein y is 0 or 1; and [0155] R.sub.3 and R.sub.4 are each hydrogen; [0156] G is CH.sub.2 or C═O; [0157] R.sub.5 is selected from the group consisting of hydrogen, linear or branched alkyl, hydroxyl, alkoxy, hydroxyalkyl, and halo; [0158] R.sub.6 is selected from the group consisting of halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocycloalkyloxy, mercapto, —(CH.sub.2).sub.fNHC(O)-aryl, —(CH.sub.2).sub.fNHC(O)-heteroaryl, alkyl-S(O).sub.m, haloalkyl-S(O).sub.m, alkenyl-S(O).sub.m, alkynyl-S(O).sub.m, cycloalkyl-S(O).sub.m, cycloalkylalkyl-S(O).sub.m, aryl-S(O).sub.m, arylalkyl-S(O).sub.m, heterocyclo-S(O).sub.m, heteroaryl-S(O).sub.m, heterocycloalkyl-S(O).sub.m, amino, alkylamino, alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro or cyano, where f=0, 1, 2, 3, 4, or 5; m=0, 1, 2 or 3, and wherein the heteroaryl, aryl, heterocyclo, or S in —S(O).sub.m is optionally substituted 1 to 3 times with one or a combination of linear or branched alkyl, —NR.sub.50C(O)(CH.sub.2).sub.bN(R.sub.60R.sub.70), halo, arylalkyl, aryl, heterocyclo, heterocycloalkyl, heteroarylalkyl, or heteroaryl; wherein R.sub.50 is selected from hydrogen and linear or branched alkyl; [0159] b is 0, 1, or 2; [0160] R.sub.60 and R.sub.70 are each independently selected from the group consisting of hydrogen, linear or branched alkyl, halo, and haloalkyl; and wherein said heterocyclo, heterocycloalkyl, heteroarylalkyl, aryl, or heteroaryl is optionally substituted 1 to 3 times with one or a combination of heterocyclo, halo, or linear or branched alkyl; or, [0161] wherein R.sub.5 may be taken together with the nitrogen to which it is attached and G, D, and one of R.sub.3 and R.sub.4 to form a heterocyclo; or, [0162] R.sub.5 and R.sub.6 may be taken together with the nitrogen to which they are attached to form a heteroaryl or heterocyclo, wherein the heteroaryl or heterocyclo is optionally substituted 1 to 3 times with one or a combination of branched or linear alkyl, aryl, hydroxy, hydroxyalkyl, heteroaryl, arylalkyl, heterocyclo, halo, alkoxy, —(CH.sub.2).sub.fNHC(O)-aryl, or —(CH.sub.2).sub.fNHC(O)—heteroaryl, wherein said heteroaryl, heterocyclo, or arylalkyl is optionally substituted 1 to 3 times with one or a combination of branched or linear alkyl, halo, nitro, hydroxy, hydroxyalkyl, alkoxy, heteroaryl, or aryl, wherein said heteroaryl, heterocyclo, or aryl is optionally substituted 1 to 3 times with one or a combination of hydroxyl, branched or linear alkyl, haloalkoxy, or halo, or pharmaceutically acceptable salt thereof.

[0163] Useful compounds of Formula II include those where ring M is a C.sub.6-C.sub.12 aryl, 5- to 12-membered heterocyclo, or 5- to 12-membered heteroaryl, and wherein said heterocyclo or heteroaryl contains one, two, or three ring heteroatoms. Useful compounds of Formula II include those where M is selected from the group consisting of

##STR00005## [0164] wherein X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, X.sub.7, X.sub.8, X.sub.9, and X.sub.10 are each independently selected from the group consisting of O, N, NH, and S, where the squiggle line indicates the point of attachment to P. Useful compounds of Formula II include those where X.sub.4 is N. Useful compounds of Formula II include those where X.sub.3 is S. Useful compounds of Formula II include those where X.sub.3 is NH. Useful compounds of Formula II include those where X.sub.6 is N. Useful compounds of Formula II include those where X.sub.5 is N. Useful compounds of Formula II include those where X.sub.7 is N. Useful compounds of Formula II include those where X.sub.2 is O. Useful compounds of Formula II include those where X.sub.2 is NH. Useful compounds of Formula II include those where X.sub.9 and X.sub.10 are each N and X.sub.8 is O. Useful compounds of Formula II include those where J is selected from the group consisting of hydrogen, halo, hydroxyl, and linear or branched C.sub.1-C.sub.3 alkyl. Useful compounds of Formula II include those where J is selected from the group consisting of halo, hydroxyl, or linear or branched C.sub.1-C.sub.3 alkyl. Useful compounds of Formula II include those where, wherein halo is selected from the group consisting of fluoro, chloro, and bromo. Useful compounds of Formula II include those where halo is fluoro. Useful compounds of Formula II include those where J is selected from the group consisting of methyl, fluoro, and hydroxyl. Useful compounds of Formula II include those where J′ is selected from the group consisting of aryl, heteroaryl, heterocyclo, cycloalkyl, and halo, wherein said aryl or heteroaryl is optionally substituted 1 to 3 times with one or a combination of alkoxy, C.sub.1-C.sub.3 alkyl, halo, hydroxyl, or cyano. Useful compounds of Formula II include those where J′ is alkoxy. Useful compounds of Formula II include those where J′ is methoxy. Useful compounds of Formula II include those where J′ is selected from the group consisting of aryl, heteroaryl, heterocyclo, cycloalkyl, and halo, wherein said aryl, heteroaryl, heterocyclo, or cycloalkyl is optionally substituted 1 to 3 times, in each instance, with alkoxy, linear or branched C.sub.1-C.sub.3 alkyl, halo, hydroxyl, or cyano. Useful compounds of Formula II include those where J′ is selected from the group consisting of phenyl, naphthalenyl, dihydrobenzofuranyl, pyrrolyl, and pyrazolyl, optionally substituted 1 to 3 times, in each instance, with methoxy, fluoro, methyl, or cyano. Useful compounds of Formula II include those where q is 0. In other embodiments, useful compounds of Formula II include those where q is 1. Useful compounds of Formula II include those where w is 0. In other embodiments, useful compounds of Formula II include those where w is 1.

[0165] Useful compounds of Formula II include those where ring M is selected from the group consisting of

##STR00006##

In this embodiment, both ring M and each of J and J′ are depicted, if w and/or q are each 1.

[0166] Useful compounds of Formula II include those where G is C═O.

[0167] Useful compounds of Formula II include those where D is (CR.sub.3R.sub.4).sub.y, where R.sub.3 and R.sub.4 are each hydrogen. Useful compounds of Formula II include those where D is (CR.sub.3R.sub.4).sub.y and y is 0.

[0168] Useful compounds of Formula II include those where P is a bond.

[0169] Useful compounds of Formula II include those where R.sub.5 is selected from the group consisting of hydrogen, hydroxyl, and linear or branched C.sub.1-C.sub.3 alkyl. Useful compounds of Formula II include those where R.sub.5 is hydrogen. Useful compounds of Formula II include those where R.sub.5 is hydroxyl.

[0170] Useful compounds of Formula II include those where R.sub.6 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclo, alkyl-S(O).sub.m, haloalkyl-S(O).sub.m, alkenyl-S(O).sub.m, alkynyl-S(O).sub.m, cycloalkyl-S(O).sub.m, cycloalkylalkyl-S(O).sub.m, aryl-S(O).sub.m, arylalkyl-S(O).sub.m, heterocyclo-S(O).sub.m, heterocycloalkyl-S(O).sub.m, and heteroaryl-S(O).sub.m, wherein said aryl, heterocyclo, heteroaryl, aryl, heterocyclo, or S in —S(O).sub.m is optionally substituted 1 to 3 times with one or a combination of linear or branched C.sub.1-C.sub.3 alkyl, halo, arylalkyl, aryl, or heteroaryl, and wherein said aryl or heteroaryl is optionally substituted 1 to 3 times with one or a combination of heterocyclo, halo, or linear or branched C.sub.1-C.sub.3 alkyl. Useful compounds of Formula II include those where R.sub.6 is alkyl-S(O).sub.m, wherein S in S(O).sub.m is optionally substituted 1 to 3 times with one or a combination of linear or branched C.sub.1-C.sub.3 alkyl, arylalkyl, aryl, or heteroaryl. Useful compounds of Formula II include those where m is 2. Useful compounds of Formula II include those where R.sub.6 is —CH.sub.2CH.sub.2—S(O).sub.2, wherein S is substituted with benzyl. Useful compounds of Formula II include those where R.sub.6 is selected from the group consisting of aryl, heteroaryl, and, heterocyclo, optionally substituted 1 to 3 times with one or a combination of aryl, heteroaryl, arylalkyl, —NR.sub.50C(O)(CH.sub.2).sub.bN(R.sub.60R.sub.70), or heterocyclo, wherein said aryl, heteroaryl, arylalkyl, or heterocyclo is optionally substituted 1 to 3 times with one or a combination of cycloalkyl, linear or branched C.sub.1-C.sub.3 alkyl, or halo. Useful compounds of Formula II include those where R.sub.6 is phenyl, wherein said phenyl is substituted 1 to 3 times with one or a combination of aryl, heteroaryl, arylalkyl, or, heterocyclo, wherein said aryl, heteroaryl, arylalkyl, —NR.sub.50C(O)(CH.sub.2).sub.bN(R.sub.60R.sub.70), or heterocyclo is optionally substituted 1 to 3 times with one or a combination of cycloalkyl, linear or branched C.sub.1-C.sub.3 alkyl, or halo. Useful compounds of Formula II include those where R.sub.6 is heteroaryl, wherein said heteroaryl is selected from the group consisting of acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl and triazinyl, wherein said heteroaryl is substituted 1 to 3 times with one or a combination of aryl, heteroaryl, arylalkyl, or, heterocyclo, wherein said aryl, heteroaryl, arylalkyl, or heterocyclo is optionally substituted 1 to 3 times with one or a combination of cycloalkyl, linear or branched C.sub.1-C.sub.3 alkyl, or halo.

[0171] Useful compounds of Formula II include those where R.sub.6 is selected from the group consisting of

##STR00007##

wherein the double bonds are absent or present, Q′, Z″, L′, L, Z′, G′, F′, H, M′, N′, P, and R′ are each independently selected from the group consisting of N, O, S, NH, C, CH.sub.2, and CH, and wherein R.sub.6 is substituted 1 to 3 times with one or a combination of aryl, heteroaryl, arylalkyl, or, heterocyclo, wherein said aryl, heteroaryl, arylalkyl, or heterocyclo is optionally substituted 1 to 3 times with one or a combination of cycloalkyl, linear or branched C.sub.1-C.sub.3 alkyl, or halo, [0172] where the squiggle line is the point of attachment to N.

[0173] Useful compounds of Formula II include those where R.sub.6 is

##STR00008##

wherein G′, F′, and H′ are each CH and the double bonds are present, and wherein R.sub.6 is substituted 1 to 3 times with one or a combination of aryl, heteroaryl, arylalkyl, or, heterocyclo, wherein said aryl, heteroaryl, arylalkyl, or heterocyclo is optionally substituted 1 to 3 times with one or a combination of cycloalkyl, linear or branched C.sub.1-C.sub.3 alkyl, or halo.

##STR00009##

[0174] Useful compounds of Formula II include those where R.sub.6 is wherein the double bonds are present, Q′ is C; Z″, L′, L, are each CH; and Z′ is N (wherein Z′ is substituted), and wherein R.sub.6 is substituted 1 to 3 times with one or a combination of aryl, heteroaryl, arylalkyl, or, heterocyclo, wherein said aryl, heteroaryl, arylalkyl, or heterocyclo is optionally substituted 1 to 3 times with one or a combination of cycloalkyl, linear or branched C.sub.1-C.sub.3 alkyl, or halo.

##STR00010##

[0175] Useful compounds of Formula II include those where R.sub.6 is wherein each of the double bonds is absent, M′ is NH or N (wherein M′ is substituted), N′ is CH.sub.2, P′ is CH, and R′ is CH.sub.2, and wherein R.sub.6 is substituted 1 to 3 times with one or a combination of aryl, heteroaryl, arylalkyl, or, heterocyclo, wherein said aryl, heteroaryl, arylalkyl, or heterocyclo is optionally substituted 1 to 3 times with one or a combination of cycloalkyl, linear or branched C.sub.1-C.sub.3 alkyl, or halo.

[0176] Useful compounds of Formula II include those where R.sub.6 is substituted with a substituent selected from the group consisting of phenyl, benzyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl, wherein said substitutent is optionally substituted 1 to 3 times with one or a combination of cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, methyl, ethyl, propyl, chloro, fluoro, bromo, methoxy, or ethoxy.

[0177] Useful compounds of Formula II include those where R.sub.6 is substituted with a substituent selected from the group consisting of phenyl, benzyl, and tetrazolyl, wherein said substituent is optionally substituted 1 to 3 times with one or a combination of cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, methyl, ethyl, propyl, chloro, fluoro, bromo, methoxy, or ethoxy.

[0178] Useful compounds of Formula II include those where R.sub.6 is phenyl substituted with tetrazolyl, wherein said tetrazolyl is substituted with cyclopropyl.

[0179] Useful compounds of Formula II include those where R.sub.6 is pyrrolidin-2-one, wherein said pyrrolidin-2-one is substituted with phenyl, and wherein said phenyl is substituted twice with chloro and fluoro.

[0180] Useful compounds of Formula II include those where R.sub.6 is pyridin-2-one, wherein said pyridin-2-one is substituted with benzyl, and wherein said benzyl is substituted with methyl.

[0181] Useful compounds of Formula II include those where R.sub.5 and R.sub.6 may be taken together with the nitrogen to which they are attached to form a heteroaryl or heterocyclo, wherein the heteroaryl or heterocyclo is optionally substituted 1 to 3 times with one or a combination of branched or linear alkyl, hydroxyl, hydroxyalkyl, heteroaryl, arylalkyl, heterocyclo, halo, alkoxy, —(CH.sub.2).sub.fNHC(O)-aryl, or —(CH.sub.2).sub.fNHC(O)-heteroaryl, wherein said heteroaryl, heterocyclo, or arylalkyl is optionally substituted 1 to 3 times with one or a combination of branched or linear alkyl, halo, hydroxyl, hydroxyalkyl, alkoxy, heteroaryl, or aryl, wherein said heteroaryl or aryl is optionally substituted 1 to 3 times with hydroxyl, branched or linear alkyl, haloalkoxy, or halo.

[0182] Useful compounds of Formula II include those where R.sub.5 and R.sub.6 may be taken together with the nitrogen to which they are attached to form a 5-10-membered mono, bridged, fused, or spiro heterocyclo wherein said heterocyclo or heteroaryl contains one or two heteroatoms, and wherein said heterocyclo is optionally substituted 1 to 3 times with aryl, hydroxy, hydroxyalkyl, linear or branched C.sub.1-C.sub.6 alkyl, haloalkoxy, heteroaryl, heterocyclo, or —(CH.sub.2).sub.fNHC(O)-heteroaryl, wherein f is 1, and wherein said aryl, heteroaryl, or heterocyclo is optionally substituted 1 to 3 times with haloalkoxy, halo, linear or branched C.sub.1-C.sub.6 alkyl.

[0183] Useful compounds of Formula II include those where R.sub.5 and R.sub.6 may be taken together with the nitrogen to which they are attached to form a 9-membered spiro heterocyclo, wherein said spiro heterocyclo is

##STR00011##

wherein P.sub.6, P.sub.7, P.sub.8, P.sub.9, and P.sub.10 are each independently selected from the group consisting of NH O, S, and CH.sub.2, wherein the squiggle line represents the point of attachment to G, and wherein the spiro heterocyclo is optionally substituted 1 to 3 times with aryl, hydroxy, hydroxyalkyl, linear or branched C.sub.1-C.sub.6 alkyl, haloalkoxy, heteroaryl, heterocyclo, or —(CH.sub.2).sub.fNHC(O)-heteroaryl, wherein f is 1, and wherein said aryl, heteroaryl, or heterocyclo is optionally substituted 1 to 3 times with haloalkoxy, halo, linear or branched C.sub.1-C.sub.6 alkyl.

[0184] Useful compounds of Formula II include those where P.sub.6 is O. In certain embodiments, P.sub.7, P.sub.8, P.sub.9, and P.sub.10 are each CH.sub.2.

[0185] Useful compounds of Formula II include those where the spiro heterocyclo is substituted with a heterocyclo, wherein said heterocyclo is further substituted with C.sub.1-C.sub.6 alkyl.

[0186] Useful compounds of Formula II include those where the spiro heterocyclo is substituted with a pyrazole, wherein said pyrazole is further substituted with isobutyl.

[0187] Useful compounds of Formula II include those where R.sub.5 and R.sub.6 may be taken together with the nitrogen to which they are attached to form a compound selected from the group consisting of pyrrolidine, piperidine, or morpholine, wherein said pyrrolidine, piperidine, or morpholine is optionally substituted 1 to 3 times with one or a combination of aryl, hydroxy, hydroxyalkyl, linear or branched C.sub.1-C.sub.6 alkyl, haloalkoxy, heteroaryl, heterocyclo, or —(CH.sub.2).sub.fNHC(O)-heteroaryl, wherein f is 1, and wherein said aryl, heteroaryl, or heterocyclo is optionally substituted 1 to 3 times with one or a combination of haloalkoxy, halo, and linear or branched C.sub.1-C.sub.6 alkyl.

[0188] Useful compounds of Formula II include those where R.sub.5 and R.sub.6 may be taken together with the nitrogen to which they are attached to form a pyrrolidine, wherein said pyrrolidine ring is substituted with hydroxyalkyl and benzyl, wherein said benzyl is substituted with fluoro.

[0189] Useful compounds of Formula II include those where R.sub.5 and R.sub.6 may be taken together with the nitrogen to which they are attached to form a pyrrolidine, wherein said pyrrolidine ring is substituted with methyl and —(CH.sub.2).sub.fNHC(O)-heteroaryl, wherein f is 1 and said heteroaryl is isoquinolinyl.

[0190] Useful compounds of Formula II include those where R.sub.5 and R.sub.6 may be taken together with the nitrogen to which they are attached to form a pyrrolidine, wherein said pyrrolidine is substituted with isobutyl and hydroxyalkyl.

[0191] Useful compounds of Formula II include those where R.sub.5 and R.sub.6 may be taken together with the nitrogen to which they are attached to form a morpholine ring, wherein said morpholine ring is substituted with phenyl, and wherein said phenyl ring is substituted with haloalkoxy.

[0192] Useful compounds of Formula II include those where R.sub.5 and R.sub.6 may be taken together with the nitrogen to which they are attached to form a piperidine ring, wherein said piperidine ring is substituted with an imidazole ring, and wherein said imidazole ring is substituted with phenyl, and wherein said phenyl is substituted with fluoro.

[0193] Useful compounds of Formula II include those where P is S.

[0194] Useful compounds of Formula II include those where y is 1.

[0195] Useful compounds of Formula II include those where R.sub.5 may be taken together with the nitrogen to which it is attached and G, D, and one of R.sub.3 and R.sub.4 to form a heterocyclo.

[0196] Useful compounds of Formula II include those where the heterocyclo is a 5 or 6 membered heterocyclo containing one or two heteroatoms.

[0197] Useful compounds of Formula II include those where R.sub.6 is selected from the group consisting of aryl, heteroaryl, heterocyclo, and cycloalkyl, and wherein said aryl or heteroaryl is optionally substituted 1 to 3 times with one or a combination of linear or branched C.sub.1-C.sub.3 alkyl, hydroxyl, alkoxy, or halo.

[0198] Useful compounds of Formula II include those where R.sub.6 is aryl, optionally substituted 1 to 3 times with alkoxy or hydroxyl.

[0199] Useful compounds of Formula II include those where R.sub.6 is phenyl, optionally substituted 1 to 3 times with methoxy.

[0200] Useful compounds of Formula II include those where R.sub.6 is phenyl substituted twice with methoxy.

##STR00012##

[0201] Useful compounds of Formula II include those where M is wherein X.sub.8, X.sub.9, and X.sub.10 are each independently selected from N, NH, or O.

##STR00013##

[0202] Useful compounds of Formula II include those where M is wherein X.sub.8 is O and X.sub.9 and X.sub.10 are each N.

[0203] Useful compounds of Formula II include those where J is C.sub.6-C.sub.10 aryl.

[0204] Useful compounds of Formula II include those where w is 0.

[0205] Useful compounds of Formula II include those where M is aryl.

[0206] Useful compounds of Formula II include those where M is phenyl.

[0207] Useful compounds of Formula II include those where J′ is selected from the group consisting of aryl, heteroaryl, heterocyclo, and cycloalkyl, wherein said aryl or heteroaryl is optionally substituted 1 to 3 times with one or a combination of alkoxy, C.sub.1-C.sub.3 alkyl, halo, hydroxyl, or cyano. Useful compounds of Formula II include those where J′ is phenyl substituted with cyano.

[0208] Useful compounds of Formula II include those where w is 1.

[0209] Useful compounds of Formula II include those where P is a bond.

[0210] Useful compounds of Formula II include those where G is CH.sub.2.

[0211] Useful compounds of Formula II include those where y is 0.

[0212] Useful compounds of Formula II include those where R.sub.5 is selected from the group consisting of hydroxyalkyl, hydrogen, halo, and alkoxy. Useful compounds of Formula II include those where R.sub.5 is hydroxyalkyl. Useful compounds of Formula II include those where R.sub.5 is hydroxyethyl.

[0213] Useful compounds of Formula II include those where R.sub.6 is selected from the group consisting of halo, linear or branched C.sub.1-C.sub.6 alkyl, haloalkyl, alkenyl, and alkynyl. Useful compounds of Formula II include those where R.sub.6 is linear or branched C.sub.1-C.sub.6 alkyl. Useful compounds of Formula II include those where R.sub.6 is neo-pentyl.

[0214] Useful compounds of Formula II include those selected from the group consisting of

TABLE-US-00001 Compound No. Structure RTX57548183 (Compound 1) [00014] RTX06107454 (Compound 2) [00015] RTX60933293 (Compound 3) [00016] RTX26466486 (Compound 4) [00017] RTX73145433 (Compound 5) [00018] RTX45332746 (Compound 6) [00019] RTX04306230 (Compound 7) [00020] RTX70558122 (Compound 8) [00021] RTX95655369 (Compound 9) [00022] RTX71280707 (Compound 10) [00023] RTX89483884 (Compound 11) [00024] RTX24380616 (Compound 12) [00025]

[0215] The compounds bind to the PTB domain of She and sensitize liver cells to insulin as shown in the Examples. The compounds can also reduce insulin intolerance and related conditions in animal models, as shown in the Examples.

[0216] IV. Subjects Amenable to Treatment

[0217] Subjects amenable to treatment include individuals at risk of a condition but not showing symptoms, as well as subjects presently showing symptoms of impaired insulin sensitivity, glucose tolerance, obesity, diabetes, metabolic syndrome, NAFLD, NASH, PSC, PBC, or other metabolic syndrome component conditions. For example, the subject can be presently exhibiting symptoms of impaired insulin sensitivity, glucose tolerance, obesity, diabetes, metabolic syndrome, or other metabolic syndrome component conditions. For example, the subject can have a body mass index of at least 30, or have body weight 30% or more above what is considered normal.

[0218] The present methods are useful for subjects who have a known genetic risk of impaired insulin sensitivity, glucose tolerance, obesity, diabetes, metabolic syndrome, NAFLD, NASH, PSC, PBC, or other metabolic syndrome component conditions, whether they are asymptomatic or showing symptoms of a condition. For example, the subject can be asymptomatic but has familial and/or genetic risk factors for developing impaired insulin sensitivity, glucose tolerance, obesity, diabetes, metabolic syndrome, or other metabolic syndrome component conditions. Such individuals include those having relatives who have experienced this condition (e.g., a parent, a grandparent, a sibling), and those whose risk is determined by analysis of genetic and/or biochemical markers. For example, such individuals include those having normal insulin sensitivity and blood glucose but a family history of diabetes or a genetic predisposition to obesity.

[0219] Genetic markers of risk toward impaired insulin sensitivity, glucose tolerance, obesity, diabetes, metabolic syndrome, or other metabolic syndrome component diseases are well-known. For example, genes that have been implicated in predisposition to obesity include UCP1 and UCP2 (whose gene products regulate body temperature), LEP (whose gene product, leptin, acts on the hypothalamus to reduce appetite and increase the body's metabolism), LEPR (leptin receptor), PCSK1 (whose gene product, proprotein convertase subtilisin/kexin type 1, processes hormone precursors such as POMC), POMC (whose gene product, among other functions, stimulates adrenal glands), MC4R (whose gene product is a melanocortin 4 receptor) and Insig2 (whose gene product regulates fatty acid and cholesterol synthesis).

[0220] Other genes, which have been associated or linked with human obesity phenotypes now number above 200. Obesity gene map databases are available on the worldwide web and genes and gene maps are described in the scientific literature (see, e.g., Perusse et al., Obesity Res. 13:381-490, 2005). Any of these factors can be taken into consideration when determining a subject's risk of obesity.

[0221] Some genes implicated in developing type 2 diabetes encode the sulfonylurea receptor (ABCC8), the calpain 10 enzyme (CAPN10), the glucagon receptor (GCGR), the enzyme glucokinase (GCK), the glucose transporter (GLUT2), the transcription factor HNF4A, the insulin hormone (INS), the insulin receptor (INSR), the potassium channel KCNJ11, the enzyme lipoprotein lipase (LPL), the transcription factor PPAR gamma, the regulatory subunit of phosphorylating enzyme (PIK3R1) and others. These genes can be evaluated when identifying a subject who may benefit from the present methods. About 18 regions of the genome have been linked with type 1 diabetes risk (see, e.g., Dean et al., “The Genetic Landscape of Diabetes,” National Center for Biotechnology Information (NCBI)). These regions, each of which may contain several genes, have been labeled IDDM1 to IDDM18. The most well-studied is IDDM1, which contains the HLA genes that encode immune response proteins. There are two other non-HLA genes which have been identified thus far. One, IDDM2, is the insulin gene, and the other maps close to CTLA4, which has a regulatory role in the immune response.

[0222] The present methods are also useful in suppressing the negative sequelae associated with impaired insulin sensitivity, glucose tolerance, obesity, diabetes, metabolic syndrome, NAFLD, NASH, PSC, PBC, or other metabolic syndrome component conditions. Accordingly, patients amenable to treatment include individuals having one or more of these negative sequelae, including atherosclerosis, angina, claudication, heart attack, stroke, congestive heart failure, myocardial infarction, sleep apnea, and arthritis, vascular degeneration, macrophage proliferation and hyperactivity, plaque formation, hyperglycemia, hyper fatty acidemia, increased tumor necrosis factor and resistin levels, hypoadiponectinemia, hyper or hypo insulinemia, impaired thiol redox status (hypo-glutathione and cysteine-emia), PPARγ inactivity, and mitochondrial energy uncoupling with elevated H.sub.2O.sub.2, OHOO, cytoplasmic cytochrome c, high blood pressure, high blood cholesterol, dyslipidemia, hyperlipidemia, dyslipidemia, atherosclerotic condition including stroke, coronary artery condition or myocardial infarction, hyperinsulinemia and/or hyperproinsulinemia, microalbuminuria, delayed insulin release, diabetic complications, including coronary heart condition, angina pectoris, congestive heart failure, stroke, cognitive functions in dementia, retinopathy, peripheral neuropathy, nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive enephrosclerosis, some types of cancer (such as endometrial, breast, prostate, and colon), complications of pregnancy, poor female reproductive health (such as menstrual irregularities, infertility, irregular ovulation, polycystic ovarian syndrome (PCOS)), lipodystrophy, cholesterol related conditions, such as gallstones, cholecystitis and cholelithiasis, gout, obstructive sleep apnea and respiratory problems, osteoarthritis, and prevention and treatment of bone loss, e.g. osteoporosis.

[0223] Patients amenable to treatment include also individuals undergoing premature aging (e.g., biological age greater than chronological age), or even individuals undergoing normal aging (biological age equal to chronological age) with a view to slowing the aging process.

[0224] Some subjects are free of a condition treatable with the compounds other than the conditions disclosed herein (e.g., diabetes, obesity, metabolic syndrome and its components, or premature aging).

[0225] V. General Procedures for Preparing Compounds of Formula II

[0226] Compounds can be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein, and those for other compounds described in: Comprehensive Heterocyclic Chemistry II, Editors Katritzky and Rees, Elsevier, 1997, e.g., Volume 3; Liebigs Annalen der Chemie, (9):1910-16, (1985); Helvetica Chimica Acta, 41:1052-60, (1958); Arzneimittel-Forschung, 40(12):1328-31, (1990), each of which are expressly incorporated by reference. Starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wis.) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-23, Wiley, N.Y. (1967-2006 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database). DTT refers to dithiothreitol. DHAA refers to dehydroascorbic acid.

[0227] Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing compounds and necessary reagents and intermediates are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3.sup.rd Ed., John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.

[0228] Compounds may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, or 10 to 100 compounds. Libraries of compounds of Formula II may be prepared by a combinatorial ‘split and mix’ approach or by multiple parallel syntheses using either solution phase or solid phase chemistry, by procedures known to those skilled in the art. Thus, according to a further aspect, there is provided a compound library comprising at least 2 compounds, or pharmaceutically acceptable salts thereof.

[0229] The General Procedures and Examples provide exemplary methods for preparing compounds. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds. Although specific starting materials and reagents are depicted and discussed in the Schemes, General Procedures, and Examples, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the exemplary compounds prepared by the described methods can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0230] VI. Methods of Treatment and Prophylaxis

[0231] The subject may already exhibit symptoms of a condition or be diagnosed as having impaired insulin sensitivity, glucose tolerance, obesity, diabetes, metabolic syndrome, NAFLD, NASH, PSC, PBC, or other metabolic syndrome component condition. In such subjects, administration of the present compounds can reverse or delay progression of and or reduce the severity of symptoms.

[0232] The effectiveness of treatment can be determined by comparing a baseline measure of a parameter of a condition before administration of the present compounds is commenced to the same parameter one or more time points after the present compounds has been administered. The parameter of a condition can be one or more of the signs or symptoms of impaired insulin sensitivity, glucose tolerance, obesity, diabetes, metabolic syndrome, NAFLD, NASH, PSC, PBC, or other metabolic syndrome component conditions described herein. Measurement of a level of various biomarkers described herein in response to treatment can indicate that treatment is effective.

[0233] In certain embodiments, the compounds of Formula II are useful in the prophylactic or therapeutic treatment of amyloidogenic diseases and conditions that are characterized by the presence of deposits of amyloid proteins, such as amylin or Aβ peptide. Such diseases include, but are not limited to, Alzheimer's disease, Down's syndrome and cognitive impairment, type II diabetes, Parkinson's disease, amyloidoses such as hereditary or systemic amyloidoses, and diseases caused all or in part by prion infection. In certain embodiments, the subject matter described herein is directed to a method of inhibiting beta amyloid toxicity in a subject, comprising administering to a subject in need thereof an effective regime of a compound of Formula II. In certain embodiments, the subject matter described herein is directed to a method of treating an amyloid-β related disease in a subject, comprising administering to a subject in need thereof an effective regime of a compound of Formula II. In certain embodiments, the amyloid-β related disease is Alzheimer's disease.

[0234] For the purposes of prophylaxis, the subject may be asymptomatic, but have one or more risk factors (genetic or non-genetic) described herein. For example, subjects may be asymptomatic but judged to be at high risk based on genetic tests, or other predictive tests. Alternatively, the subject may be exhibiting symptoms of early stages of a condition. In such subjects, administration of one of the present compounds can inhibit or delay onset or progression of conditions into later stages of conditions, and/or reduce the severity of the condition once present.

[0235] Measurable parameters for evaluating the effectiveness of the prevention regime are as discussed herein for therapy and monitoring.

[0236] VII. Formulation and Administration of Compounds

[0237] a. Formulation

[0238] The compounds described herein or pharmaceutically acceptable salts thereof can be administered orally, parenterally, (intravenously (IV), intramuscularly (IM), depo-IM, subcutaneously (SQ), and depo-SQ), sublingually, intranasally (e.g., inhalation, nasal mist or drops), intrathecally, topically, transmucosally, bucally, sublingually, ionophoretically or rectally.

[0239] Compositions are provided that contain therapeutically effective amounts of one of the present compounds. The compounds are preferably formulated into suitable pharmaceutical preparations such as tablets, capsules, or elixirs for oral administration or in sterile solutions or suspensions for parenteral administration.

[0240] The present compounds can be administered in the “native” form or, if desired, in the form of pharmaceutically acceptable salts, esters, amides, prodrugs, derivatives, and the like, provided the salt, ester, amide, prodrug or derivative is suitable pharmacologically, i.e., effective in the present method(s). Salts, esters, amides, prodrugs and other derivatives of the compounds can be prepared using standard procedures described, for example, by March (1992) Advanced Organic Chemistry; Reactions, Mechanisms and Structure, 4th Ed. N.Y. Wiley-Interscience. Prodrugs of the compounds readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Conversion usually occurs after administration to a subject.

[0241] Such derivatives can be formulated by conventional methods. For example, the disulfide salts of a number of delivery agents are described in WO 2000/059863 which is incorporated herein by reference. Similarly, acid salts of compounds can be prepared from the free base using conventional methodology that typically involves reaction with a suitable acid. Generally, the base form of the drug is dissolved in a polar organic solvent such as methanol or ethanol and the acid is added thereto. The resulting salt either precipitates or can be brought out of solution by addition of a less polar solvent. Suitable acids for preparing acid addition salts include to both organic acids, e.g., acetic acid, carboxylic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, suberic acid, lactic acid, benzene sulfonic acid, p-tolylsulfonic acid, arginine, glucuronic acid, galactunoric acid phthalic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid isobutyric, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like (see, e.g., Berge et al., J. Pharm. Sci. 66, 1-19 (1977).

[0242] Although compounds can be supplied in the form of an HCl salt, acid salts with weaker acids (e.g., pKa 1-6-9 or preferably pKa 4-6.5) are preferred for parenteral administration. An acid addition salt can be reconverted to the free base by treatment with a suitable base. Preferred acid addition salts include halide salts, such as may be prepared using hydrochloric or hydrobromic acids. Basic salts of the compounds of this invention are prepared in a similar manner using a pharmaceutically acceptable base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine, or the like. For example, basic salts can include alkali metal salts, e.g., the sodium salt, and copper salts.

[0243] For the preparation of salt forms of basic drugs, the pKa of the counterion is preferably at least about 2 pH lower than the pKa of the drug. Similarly, for the preparation of salt forms of acidic drugs, the pKa of the counterion is preferably at least about 2 pH higher than the pKa of the drug. This permits the counterion to bring the solution's pH to a level lower than the pHmax to reach the salt plateau, at which the solubility of salt prevails over the solubility of free acid or base. The generalized rule of difference in pKa units of the ionizable group in the active pharmaceutical ingredient (API) and in the acid or base is meant to make the proton transfer energetically favorable. When the pKa of the API and counterion are not significantly different, a solid complex may form but may rapidly disproportionate (i.e., break down into the individual entities of drug and counterion) in an aqueous environment.

[0244] Preferably, the counterion is a pharmaceutically acceptable counterion. Suitable anionic salt forms include acetate, benzoate, besylate, benzylate, bitartrate, bromide, carbonate, chloride, citrate, edetate, edisylate, estolate, fumarate, gluceptate, gluconate, hydrobromide, hydrochloride, iodide, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methyl sulfate, mucate, napsylate, nitrate, pamoate (embonate), phosphate and diphosphate, salicylate and disalicylate, stearate, succinate, sulfate, tartrate, tosylate, triethiodide, valerate, and the like. Suitable cationic salt forms include aluminum, benzathine, calcium, ethylene diamine, lysine, magnesium, meglumine, potassium, procaine, sodium, tromethamine, zinc, and the like.

[0245] Preparation of esters can typically involve functionalization of hydroxyl and/or carboxyl groups that are present within the molecular structure of the compound. For example, the esters are typically acyl-substituted derivatives of free alcohol groups, i.e., moieties that are derived from carboxylic acids of the formula RCOOH where R is alky, and preferably is lower alkyl. Esters can be reconverted to the free acids, if desired, by using conventional hydrogenolysis or hydrolysis procedures.

[0246] Amides can also be prepared using techniques described in the pertinent literature. For example, amides may be prepared from esters, using suitable amine reactants, or they may be prepared from an anhydride or an acid chloride by reaction with ammonia or a lower alkyl amine.

[0247] About 1 to 1000 mg of a compound is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, and so forth, in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in those compositions or preparations is such that a suitable dosage in the range indicated is obtained. The compositions are preferably formulated in a unit dosage form, each dosage containing from about 1-1000 mg, 2-800 mg, 5-500 mg, 10-400 mg, 50-200 mg, e.g., about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg of the active ingredient. The term “unit dosage from” refers to physically discrete units suitable as unitary (i.e., single) dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0248] To prepare compositions, the one or more compounds is mixed with a suitable pharmaceutically acceptable carrier. On mixing or addition of the compound(s), the resulting mixture may be a solution, suspension, emulsion, or the like. Liposomal suspensions may also be suitable as pharmaceutically acceptable carriers. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for lessening or ameliorating at least one symptom of the condition may be empirically determined.

[0249] Pharmaceutical carriers or vehicles suitable for administration of the compounds provided herein include any such carriers known to be suitable for the particular mode of administration. In addition, the active materials can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, or have another action. The compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients.

[0250] Where the compounds exhibit insufficient solubility, methods for solubilizing may be used. Such methods include, using cosolvents such as dimethylsulfoxide (DMSO), using surfactants such as Tween™, and dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as salts or prodrugs may also be used in formulating effective pharmaceutical compositions.

[0251] The concentration of the one or more compounds is effective for delivery of an amount upon administration that lessens or ameliorates at least one symptom of the condition for which the compound is administered and/or that is effective in a prophylactic context. Typically, the compositions are formulated for single dosage (e.g., daily) administration.

[0252] The active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the patient treated. The therapeutically effective concentration may be determined empirically by testing the compounds in known in vitro and in vivo model systems for the treated condition. A therapeutically or prophylactically effective dose can be determined by first administering a low dose, and then incrementally increasing until a dose is reached that achieves the desired effect with minimal or no undesired side effects.

[0253] The compounds described herein, derivatives and/or pharmaceutically acceptable salts thereof can be enclosed in multiple or single dose containers. The enclosed compounds and compositions can be provided in kits, for example, including component parts that can be assembled for use. For example, a compound in lyophilized form and a suitable diluent may be provided as separated components for combination prior to use. A kit may include an compound and a second therapeutic compound for co-administration. The compound and the second therapeutic compound may be provided as separate component parts. A kit may include a plurality of containers, each container holding one or more unit dose of the one or more active compounds. The containers are preferably adapted for the desired mode of administration, including to tablets, gel capsules, sustained-release capsules, and the like for oral administration; depot products, pre-filled syringes, ampules, vials, and the like for parenteral administration; and patches, medipads, creams, and the like for topical or transdermal administration. Optionally, such containers contain a unit dose for single administration.

[0254] The concentration and/or amount of active compound in the drug composition depend on absorption, inactivation, and excretion rates of the active compound, the dosage schedule, and amount administered as well as other factors.

[0255] The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. The precise dosage and duration of treatment is a function of the condition being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. Concentrations and dosage values may also vary with the severity of the condition to be alleviated. For any particular subject, specific dosage regimens can be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.

[0256] If oral administration is desired, the compound can be provided in a formulation that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated in combination with an antacid or other such ingredient.

[0257] Oral compositions generally include an inert diluent or an edible carrier and may be compressed into tablets or enclosed in gelatin capsules. For the purpose of oral therapeutic administration, the active compound or compounds can be incorporated with excipients and used in the form of tablets, capsules, or troches. Pharmaceutically compatible binding agents and adjuvant materials can be included as part of the composition.

[0258] The tablets, pills, capsules, troches, and the like can contain any of the following ingredients or compounds of a similar nature: a binder such as, gum tragacanth, acacia, corn starch, or gelatin; an excipient such as microcrystalline cellulose, starch, or lactose; a disintegrating agent such as, alginic acid and corn starch; a lubricant such as magnesium stearate; a glidant, such as, colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; and a flavoring agent such as peppermint, methyl salicylate, or fruit flavoring.

[0259] When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials, which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents. The compounds can also be administered as a component of an elixir, suspension, syrup, wafer, medicated chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings, and flavors.

[0260] The active materials can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action.

[0261] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile diluent such as water for injection, saline solution, fixed oil, a naturally occurring vegetable oil such as sesame oil, coconut oil, peanut oil, cottonseed oil, and the like, or a synthetic fatty vehicle such as ethyl oleate, and the like, polyethylene glycol, glycerine, propylene glycol, or other synthetic solvent; antimicrobial agents such as benzyl alcohol and methyl parabens; antioxidants such as ascorbic acid and sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates, and phosphates; and agents for the adjustment of tonicity such as sodium chloride and dextrose. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass, plastic, or other suitable material. Buffers, preservatives, antioxidants, and the like can be incorporated as required.

[0262] Suitable carriers for intravenous administration include physiological saline, phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents such as glucose, polyethylene glycol, polypropyleneglycol, and mixtures thereof. Liposomal suspensions including tissue-targeted liposomes may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known for example, as described in U.S. Pat. No. 4,522,811.

[0263] The present compounds may be prepared with carriers that protect them against rapid elimination from the body, such as time-release formulations or coatings. Controlled release is a mechanism of formulation to release a drug over an extended time. Use of controlled release formulation may reduce the frequency of administration, reduce fluctuations in blood concentration and protect the gastrointestinal tract from side effects. The active compounds may be prepared with carriers that protect the compound against rapid elimination from the body, such as time-release formulations or coating. Such carriers include controlled release formulations (also known as modified, delayed, extended or sustained release or gastric retention dosage forms, such as the Depomed GR™ system in which agents are encapsulated by polymers that swell in the stomach and are retained for about eight hours, sufficient for daily dosing of many drugs). Controlled release systems include microencapsulated delivery systems, implants and biodegradable, biocompatible polymers such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient can also be modified by varying the particle size of the active ingredient(s). Examples of modified release include, e.g., those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6, 113,943; 6, 197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; and 6,699,500.

[0264] b) Route of Administration and Dosing

[0265] The compounds can be administered orally, parenterally (IV, IM, depo-IM, SQ, and depo-SQ), sublingually, intranasally (inhalation), intraspinally, intrathecally, topically, or rectally.

[0266] The compounds can be administered enterally or parenterally. Oral formulations include tablets and capsules as well as liquid dosage forms such as solutions, suspensions, and elixirs. When the solid dosage forms are used, it is preferred that they be of the sustained release type so that the one or more active agents need to be administered only once or twice daily (or less frequency).

[0267] The oral dosage forms can be administered to the patient 1, 2, 3, or 4 times daily or less frequently, such as on alternate days, every third day, twice a week or once a week. It is preferred that the one or more active agents be administered either three or fewer times, more preferably once or twice daily. Oral dosage forms are preferably designed so as to protect the one or more active agents from the acidic environment of the stomach, such as by enteric coated or by use of capsules filled with small spheres each coated to protect from the acidic stomach.

[0268] When administered orally, an administered amount therapeutically effective to prevent, mitigate or treat impaired insulin sensitivity, glucose tolerance, obesity, diabetes, aging, metabolic syndrome, or other metabolic syndrome component conditions is from about 0.1 mg/day to about 200 mg/day, for example, from about 1 mg/day to about 100 mg/day, for example, from about 5 mg/day to about 50 mg/day. The subject can be administered a compound at a dose of about 0.05 to about 0.50 mg/kg or 0.1 mg/kg-10 mg/kg or 0.5 mg/kg to 5 mg/kg, for example, about 0.05 mg/kg, 0.10 mg/kg, 0.20 mg/kg, 0.33 mg/kg, 0.50 mg/kg, 1 mg/kg, 5 mg/kg or 10 mg/kg. Although a patient may be started at one dose, that dose may be varied (increased or decreased, as appropriate) over time as the patient's condition changes. Depending on outcome evaluations, higher doses may be used. For example, in certain subjects, up to as much as 1000 mg/day can be administered, e.g., 200 mg/day, 300 mg/day, 400 mg/day, 500 mg/day, 600 mg/day, 700 mg/day, 800 mg/day, 900 mg/day or 1000 mg/day.

[0269] The present compounds can also be delivered in a nano crystal dispersion formulation (see U.S. Pat. No. 5,145,684 or 6,045,829). The nano crystalline formulations typically afford greater bioavailability of drug compounds.

[0270] The present compounds can be administered parenterally, for example, by IV, IM, depo-IM, SC, or depo-SC. When administered parenterally, a therapeutically effective amount of about 0.5 to about 1000 mg/day, preferably from about 5 to about 500 or 50-200 mg daily should be delivered. The parenteral dosage form can be a depo formulation in which case a larger amount of drug can be administered with reduced frequency.

[0271] The present compounds can be administered sublingually. When given sublingually, the one or more active agents and/or analogs thereof can be given one to four times daily in the amounts described above for IM administration.

[0272] The present compounds can be administered intranasally. Appropriate formulations include a nasal spray or dry powder. The dosage of the one or more active agents and/or analogs thereof for intranasal administration is the amount described above for IM administration.

[0273] The present compounds can be administered intrathecally in a parenteral formulation. The dosage of the one or more active agents and/or analogs thereof for intrathecal administration is the amount described above for IM administration.

[0274] The present compounds can be administered topically or transdermally. When given by this route, the appropriate dosage form is a cream, ointment, or patch. When administered topically, the dosage can be from about 0.5 mg/day to about 200 mg/day. Because the amount that can be delivered by a patch is limited, two or more patches may be used. The number and size of the patch is not important, what is important is that a therapeutically effective amount of the one or more active agents and/or analogs thereof be delivered. The one or more active agents and/or analogs thereof can be administered rectally by suppository. When administered by suppository, the therapeutically effective amount can be from about 0.5 mg to about 500 mg.

[0275] The present compounds can be administered by implants. When administering one or more active agents by implant, the therapeutically effective amount is the amount described above for depot administration.

[0276] The exact dosage and frequency of administration depends on the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular patient, and other medication the individual may be taking.

[0277] VII. Combination Therapies

[0278] The present compounds can be used in combination with each other or with other therapeutic agents or approaches used to treat, mitigate or prevent impaired insulin sensitivity, glucose tolerance, obesity, diabetes, metabolic syndrome, NAFLD, NASH, PSC, PBC, or other metabolic syndrome component conditions. For example, the one or more active agents described herein and/or analogs thereof can be co-administered with insulin. Insulin is frequently required in patients with long standing diabetes mellitus, and one or more active agents described herein may lower the insulin requirements. Insulin at high doses may have a proatherogenic effect. The combination drug will, therefore, have multiple benefits compared to insulin alone.

[0279] The present compounds can be co-administered with other diabetes drugs and obesity drugs. Diabetes drugs suitable for combination therapy include sulfonylurea agents such as glipizide, glyburide (glibenclamide), chlorpropamide, tolbutamide, tolazamide and glimepiride, or the pharmaceutically acceptable salt forms thereof (see, e.g., U.S. 2003/008869); biguanide agents such as metformin and its pharmaceutically acceptable salt forms (see, e.g., U.S. patent Pub. No. 2003/0018028); thiazolidinedione agents pioglitazone or rosiglitazone, or a pharmaceutically acceptable salt form thereof (see, e.g., U.S. 2002/0198203); alpha-glucosidase inhibitors such as miglitol or acarbose, or a pharmaceutically acceptable salt form thereof (see, e.g., U.S. 2003/0013709); antilipemic agents (also known as antihyperlipidemic agents) such as bile acid sequestrants, fibric acid derivatives, HMG-CoA reductase inhibitors and nicotinic acid compounds (see, e.g., U.S. Patent Application No. 2002/0198202); angiotensin converting enzyme (ACE) inhibitors such as quinapril, ramipril, verapamil, captopril, diltiazem, clonidine, hydrochlorothiazide, benazepril, prazosin, fosinopril, lisinopril, atenolol, enalapril, perindopril, perindopril tert-butylamine, trandolapril and moexipril, or a pharmaceutically acceptable salt form thereof (see, e.g., U.S. Patent Application No. 2003/0055058); aldose reductase inhibitors (preventing eye and nerve damage in people with diabetes) such as minalrestat Tolrestat, Sorbinil, Methosorbinil, Zopolrestat, Epalrestat, Zenarestat Imirestat, and Ponalrestat or the pharmaceutically acceptable salt forms thereof (see, e.g., U.S. Patent Application No. 2002/0198201). Obesity drugs suitable for combination therapy include central nervous system (CNS) stimulants such as phentermines (e.g., those sold under the tradenames Ionamin® and Adipex-P®) (see, e.g., U.S. Pat. No. 5,019,594). The phentermines are members of a class of drugs known as the sympathomimetics for their ability to mimic stimulation of the central nervous system; re-uptake inhibitors such as 5HT-2C inhibitors (e.g., Meridia® (sibutramine), Lorcaserin (APD-356)) (see, e.g., U.S. Pat. No. 4,929,629); CB-1 antagonists such as rimonabant (Acomplia®) and CP-945598 (see, e.g., U.S. Pat. No. 5,624,941); and GLP-1 agonists or mimetics such as exenatide (Byetta®) (see, e.g., U.S. Pat. No. 5,424,286).

[0280] IX. Monitoring Efficacy

[0281] Clinical efficacy can be monitored by measuring one or more of the condition parameters or physical symptoms of impaired insulin sensitivity, glucose tolerance, obesity, diabetes, metabolic syndrome, NAFLD, NASH, PSC, PBC, or other metabolic syndrome component conditions, including blood pressure, blood insulin, free fatty acid, bodyweight, triglyceride levels, blood glucose levels, high body mass index. Observation of the stabilization, improvement and/or reversal of one or more symptoms indicates that the treatment or prophylaxis regime is efficacious. Observation of the progression, increase or exacerbation of one or more symptoms indicates that the treatment or prophylaxis regime is not efficacious.

[0282] Clinical efficacy can also be monitored using biomarkers. Biomarkers for assessing treatment are preferably assessed at the protein level, but measurement of mRNA encoding biomarkers can also be used as a surrogate measure of biomarker expression. Such a level can be measured in a blood sample, e.g., on PBMC's. The level of some biomarkers are reduced in subjects with impaired insulin sensitivity, glucose tolerance, obesity, diabetes, metabolic syndrome, NAFLD, NASH, PSC, PBC, or other metabolic syndrome component conditions relative to a control population of normal individuals (i.e., free of known conditions). An increase in level of such a marker provides an indication of a favorable treatment response, whereas an unchanged or decreasing levels provides an indication of unfavorable or at least non-optimal treatment response. The level of other biomarkers is increased in subjects with impaired insulin sensitivity, glucose tolerance, obesity, diabetes, metabolic syndrome, NAFLD, NASH, PSC, PBC, or other metabolic syndrome component conditions relative to a control population of normal individuals. An decrease in level of such a biomarker provides an indication of a favorable treatment response, whereas an unchanged or increasing levels provides an indication of unfavorable or at least non-optimal treatment response.

[0283] The monitoring methods can entail determining a baseline value of a measurable biomarker or condition parameter in a subject before administering a dosage of the one or more active agents described herein, and comparing this with a value for the same measurable biomarker or parameter after a course of treatment.

[0284] In other methods, a control value (i.e., a mean and standard deviation) of the measurable biomarker or parameter is determined for a control population. A suitable control population is one in which subjects have not received prior treatment and do not have a target condition, nor are at known risk of developing a target condition. In such methods, if the value of the measurable biomarker or clinical parameter approaches the control value, then treatment is considered efficacious. In other methods, the individuals in the control population have not received prior treatment and have been diagnosed with a target condition. In such methods, if the value of the measurable biomarker or clinical parameter approaches the control value, then treatment is considered inefficacious.

[0285] In other methods, a subject who is not presently receiving treatment but has undergone a previous course of treatment is monitored for one or more of the biomarkers or clinical parameters to determine whether a resumption of treatment is required. The measured value of one or more of the biomarkers or clinical parameters in the subject can be compared with a value previously achieved in the subject after a previous course of treatment. Alternatively, the value measured in the subject can be compared with a control value (mean plus standard deviation or preferably two standard deviations) determined in population of subjects after undergoing a course of treatment. Alternatively, the measured value in the subject can be compared with a control value in populations of prophylactically treated subjects who remain free of symptoms of a condition, or populations of therapeutically treated subjects who show amelioration of the condition's characteristics. In such cases, if the value of the measurable biomarker or clinical parameter approaches the control value, then treatment is considered efficacious and need not be resumed. On the other hand, a significant difference relative to the control level (i.e., more than one or preferably two standard deviations) is an indicator that treatment should be resumed in the subject.

[0286] The subject matter described herein is directed to the following embodiments: 1B. A compound of Formula II:

##STR00026##

wherein, [0287] ring M is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocyclo; [0288] J and J′ are each independently selected from the group consisting of halo, hydroxyl, linear or branched alkyl, alkoxy, nitro, mercapto, cyano, heterocyclo, cycloalkyl, aryl, and heteroaryl, wherein said aryl, heterocyclo, cycloalkyl, or heteroaryl is optionally substituted 1 to 3 times, in each instance, with one or a combination of alkoxy, linear or branched alkyl, halo, hydroxyl, or cyano; [0289] w and q are each independently 0 or 1; [0290] P is S, NH, or a bond; [0291] D is (CR.sub.3R.sub.4).sub.y, wherein y is 0 or 1; [0292] R.sub.3 and R.sub.4 are each hydrogen; [0293] G is CH.sub.2 or C═O; [0294] R.sub.5 is selected from the group consisting of hydrogen, linear or branched alkyl, hydroxyl, alkoxy, hydroxyalkyl, and halo; or, [0295] R.sub.5 is taken together with the nitrogen to which it is attached and G, D, and one of R.sub.3 and R.sub.4 to form a heterocyclo; [0296] R.sub.6 (A) is selected from the group consisting of halo, linear or branched alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocycloalkyloxy, mercapto, —(CH.sub.2).sub.fNHC(O)-aryl, —(CH.sub.2).sub.fNHC(O)-heteroaryl, alkyl-S(O).sub.m, haloalkyl-S(O).sub.m, alkenyl-S(O).sub.m, alkynyl-S(O).sub.m, cycloalkyl-S(O).sub.m, cycloalkylalkyl-S(O).sub.m, aryl-S(O).sub.m, heteroaryl-S(O).sub.m, arylalkyl-S(O).sub.m, heterocyclo-S(O).sub.m, heterocycloalkyl-S(O).sub.m, amino, alkylamino, alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro, and cyano; wherein, [0297] f is 0, 1, 2, 3, 4, or 5; [0298] m is 0, 1, 2 or 3; and [0299] said heteroaryl, aryl, heterocyclo, heterocycloalkyl, cycloalkyl, or S in —S(O).sub.m (A) is optionally substituted 1 to 3 times, in each instance, with one or a combination of linear or branched alkyl, —NR.sub.50C(O)(CH.sub.2).sub.bN(R.sub.60R.sub.70), halo, arylalkyl, aryl, hydroxyl, alkoxy, heterocycloalkyl, heteroarylalkyl, or heteroaryl (B); wherein, [0300] R.sub.50 is hydrogen or linear or branched alkyl; [0301] b is 0, 1, or 2; [0302] R.sub.60 and R.sub.70 are each independently selected from the group consisting of hydrogen, linear or branched alkyl, halo, and haloalkyl; and [0303] wherein said heterocycloalkyl, heterocyclo, heteroarylalkyl, aryl, or heteroaryl (B) is optionally substituted 1 to 3 times, in each instance, with one or a combination of heterocyclo, cycloalkyl, alkoxy, halo, or linear or branched alkyl; or, [0304] R.sub.5 and R.sub.6 are taken together with the nitrogen to which they are attached to form a heteroaryl or heterocyclo, wherein said heteroaryl or heterocyclo (C) is optionally substituted 1 to 3 times, in each instance, with one or a combination of branched or linear alkyl, aryl, hydroxyl, haloalkoxy, hydroxyalkyl, heteroaryl, arylalkyl, heterocyclo, halo, alkoxy, —(CH.sub.2).sub.fNHC(O)-aryl, or —(CH.sub.2).sub.fNHC(O)-heteroaryl (D), wherein said heteroaryl, aryl, heterocyclo, or arylalkyl (D) is optionally substituted 1 to 3 times, in each instance, with one or a combination of branched or linear alkyl, heterocyclo, halo, nitro, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, heteroaryl, or aryl (E), wherein said heteroaryl, heterocyclo, or aryl (E) is optionally substituted 1 to 3 times, in each instance, with one or a combination of hydroxyl, aryl, branched or linear alkyl, alkoxy, haloalkoxy, or halo; or pharmaceutically acceptable salt thereof. [0305] 1A. A compound of Formula II:

##STR00027## [0306] wherein ring M is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocyclo; [0307] J and J′ are each independently selected from the group consisting of hydrogen, halo, hydroxyl, linear or branched alkyl, alkoxy, nitro, mercapto, cyano, heterocyclo, cycloalkyl, aryl, and heteroaryl, wherein said aryl or heteroaryl is optionally substituted 1 to 3 times with one or a combination of alkoxy, linear or branched alkyl, halo, hydroxyl, or cyano; [0308] w is 0 or 1 [0309] P is S, NH, or a bond; [0310] D is (CR.sub.3R.sub.4).sub.y, wherein y is 0 or 1; [0311] R.sub.3, and R.sub.4 are each hydrogen; [0312] G is CH.sub.2 or C═O; [0313] R.sub.5 is selected from the group consisting of hydrogen, linear or branched alkyl, hydroxyl, alkoxy, hydroxyalkyl, and halo; [0314] R.sub.6 is selected from the group consisting of halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocycloalkyloxy, mercapto, —(CH.sub.2).sub.fNHC(O)-aryl, —(CH.sub.2).sub.fNHC(O)-heteroaryl, alkyl-S(O).sub.m, haloalkyl-S(O).sub.m, alkenyl-S(O).sub.m, alkynyl-S(O).sub.m, cycloalkyl-S(O).sub.m, cycloalkylalkyl-S(O).sub.m, aryl-S(O).sub.m, arylalkyl-S(O).sub.m, heterocyclo-S(O).sub.m, heteroaryl-S(O).sub.m, heterocycloalkyl-S(O).sub.m, amino, alkylamino, alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro or cyano, wherein f=0, 1, 2, 3, 4, or 5; m=0, 1, 2 or 3, and wherein the heteroaryl, aryl, heterocyclo, or S in —S(O).sub.m is optionally substituted 1 to 3 times with one or a combination of linear or branched alkyl, —NR.sub.50C(O)(CH.sub.2).sub.bN(R.sub.60R.sub.70), halo, arylalkyl, aryl, heterocyclo, heterocycloalkyl, heteroarylalkyl, or heteroaryl; [0315] wherein R.sub.50 is hydrogen or linear or branched alkyl; [0316] b is 0, 1, or 2; [0317] R.sub.60 and R.sub.70 are each independently selected from the group consisting of hydrogen, linear or branched alkyl, halo, and haloalkyl; and [0318] wherein said heterocyclo, heterocycloalkyl, heteroarylalkyl, aryl, or heteroaryl is optionally substituted 1 to 3 times with one or a combination of heterocyclo, halo, or linear or branched alkyl; or, [0319] R.sub.5 may be taken together with the nitrogen to which it is attached and G, D, and one of R.sub.3 and R.sub.4 to form a heterocyclo; or [0320] R.sub.5 and R.sub.6 may be taken together with the nitrogen to which they are attached to form a heteroaryl or heterocyclo, wherein the heteroaryl or heterocyclo is optionally substituted 1 to 3 times with one or a combination of branched or linear alkyl, aryl, hydroxy, hydroxyalkyl, heteroaryl, arylalkyl, heterocyclo, halo, alkoxy, —(CH.sub.2).sub.fNHC(O)-aryl, or —(CH.sub.2).sub.fNHC(O)-heteroaryl, wherein said heteroaryl, heterocyclo, or arylalkyl is optionally substituted 1 to 3 times with one or a combination of branched or linear alkyl, halo, nitro, hydroxy, hydroxyalkyl, alkoxy, heteroaryl, or aryl, wherein said heteroaryl, heterocyclo, or aryl is optionally substituted 1 to 3 times with one or a combination of hydroxyl, branched or linear alkyl, haloalkoxy, or halo, [0321] or pharmaceutically acceptable salt thereof. [0322] 2A. The compound of embodiment 1A or 1B, wherein M is a C.sub.6-C.sub.12 aryl, 5-12 membered heterocyclo, or 5-12 membered heteroaryl, containing one, two, or three ring heteroatoms. [0323] 3A. The compound of embodiment 1A, 1B, or 2A, wherein M is selected from the group consisting of

##STR00028## [0324] wherein X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, X.sub.7, X.sub.8, X.sub.9, and X.sub.10 are each independently selected from the group consisting of O, N, NH, and S, and where the squiggle line indicates the point of attachment to P. [0325] 4A. The compound of any one of embodiments 1A-3A, wherein J is selected from the group consisting of hydrogen, halo, hydroxyl, and linear or branched C.sub.1-C.sub.3 alkyl. [0326] 5A. The compound of embodiment 4A, wherein halo is selected from the group consisting of fluoro, chloro, and bromo. [0327] 6A. The compound of embodiment 5A, wherein halo is fluoro. [0328] 7A. The compound of any one of embodiments 1B or 1A-6A, wherein J′ is selected from the group consisting of aryl, heteroaryl, heterocyclo, cycloalkyl, and halo, wherein said aryl or heteroaryl is optionally substituted 1 to 3 times with alkoxy, C.sub.1-C.sub.3 alkyl, halo, hydroxyl, or cyano. [0329] 8A. The compound of embodiment 7A, wherein halo is fluoro. [0330] 9A. The compound of embodiment 7A, wherein alkoxy is methoxy. [0331] 10A. The compound of any one of embodiments 1B or 1A-7A, wherein G is C═O. [0332] 11A. The compound of any one of embodiments 1B or 1A-10A, wherein y is 0. [0333] 12A. The compound of any one of embodiments 1B or 1A-11A, wherein P is a bond. [0334] 13A. The compound of any one of embodiments 1B or 1A-12A, wherein R.sub.5 is selected from the group consisting of hydrogen, hydroxyl, and linear or branched C.sub.1-C.sub.3 alkyl. [0335] 14A. The compound of any one of embodiments 1B or 1A-13A, wherein R.sub.5 is hydrogen. [0336] 15A. The compound of any one of embodiments 1B or 1A-14A, wherein R.sub.6 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclo, alkyl-S(O).sub.m, haloalkyl-S(O).sub.m, alkenyl-S(O).sub.m, alkynyl-S(O).sub.m, cycloalkyl-S(O).sub.m, cycloalkylalkyl-S(O).sub.m, aryl-S(O).sub.m, arylalkyl-S(O).sub.m, heterocyclo-S(O).sub.m, heterocycloalkyl-S(O).sub.m, and heteroaryl-S(O).sub.m, wherein said aryl, heterocyclo, heteroaryl, aryl, heterocycloalkyl, or S in —S(O).sub.m is optionally substituted 1 to 3 times with one or a combination of linear or branched C.sub.1-C.sub.3 alkyl, halo, arylalkyl, aryl, or heteroaryl, and wherein said aryl or heteroaryl is optionally substituted 1 to 3 times with one or a combination of heterocyclo, halo, or linear or branched C.sub.1-C.sub.3 alkyl. [0337] 16A. The compound of any one of embodiments 1B or 1A-15A, wherein R.sub.6 is alkyl-S(O).sub.m, wherein S in S(O).sub.m is optionally substituted 1 to 3 times with one or a combination of linear or branched C.sub.1-C.sub.3 alkyl, arylalkyl, aryl, or heteroaryl. [0338] 17A. The compound of any one of embodiments 1B or 1A-16A, wherein m is 2. [0339] 18A. The compound of embodiment 17A, wherein R.sub.6 is —CH.sub.2CH.sub.2—S(O).sub.2, wherein S is substituted with benzyl. [0340] 19A. The compound of embodiment 18A, wherein said compound has the structure

##STR00029## [0341] 20A. The compound of embodiment 15A, wherein R.sub.6 is selected from the group consisting of aryl, heteroaryl, and heterocyclo, optionally substituted 1 to 3 times with one or a combination of aryl, heteroaryl, arylalkyl, —NR.sub.50C(O)(CH.sub.2).sub.bN(R.sub.60R.sub.70), or heterocyclo, wherein said aryl, heteroaryl, arylalkyl, or heterocyclo is optionally substituted 1 to 3 times with one or a combination of cycloalkyl, linear or branched C.sub.1-C.sub.3 alkyl, or halo. [0342] 21A. The compound of embodiment 20A, wherein R.sub.6 is phenyl, wherein said phenyl is substituted 1 to 3 times with one or a combination of aryl, heteroaryl, arylalkyl, —NR.sub.50C(O)(CH.sub.2).sub.bN(R.sub.60R.sub.70), or heterocyclo, wherein said aryl, heteroaryl, arylalkyl, or heterocyclo is optionally substituted 1 to 3 times with one or a combination of cycloalkyl, linear or branched C.sub.1-C.sub.3 alkyl, or halo. [0343] 22A. The compound of embodiment 20A, wherein R.sub.6 is heteroaryl, wherein said heteroaryl is selected from the group consisting of acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl and triazinyl, wherein said heteroaryl is substituted 1 to 3 times with one or a combination of aryl, heteroaryl, arylalkyl, or, heterocyclo, and wherein said aryl, heteroaryl, arylalkyl, or heterocyclo is optionally substituted 1 to 3 times with one or a combination of cycloalkyl, linear or branched C.sub.1-C.sub.3 alkyl, or halo. [0344] 23A. The compound of embodiment 20A, wherein R.sub.6 is selected from the group consisting of

##STR00030##

wherein the double bonds are absent or present, Q′, Z″, L′, L, Z′, G′, F′, H, M′, N′, P, and R′ are each independently selected from the group consisting of N, O, S, NH, C, CH.sub.2, and CH, and wherein R.sub.6 is optionally substituted 1 to 3 times with one or a combination of aryl, heteroaryl, arylalkyl, or, heterocyclo, wherein said aryl, heteroaryl, arylalkyl, or heterocyclo is optionally substituted 1 to 3 times with one or a combination of cycloalkyl, linear or branched C.sub.1-C.sub.3 alkyl, or halo, and where the squiggle line is the point of attachment to N. [0345] 24A. The compound of embodiment 23A, wherein R.sub.6 is

##STR00031##

wherein G′, F′, and H′ are each CH, the double bonds are present, and wherein R.sub.6 is optionally substituted 1 to 3 times with one or a combination of aryl, heteroaryl, arylalkyl, or, heterocyclo, wherein said aryl, heteroaryl, arylalkyl, or heterocyclo is optionally substituted 1 to 3 times with one or a combination of cycloalkyl, linear or branched C.sub.1-C.sub.3 alkyl, or halo. [0346] 25A. The compound of embodiment 23A, wherein R.sub.6 is

##STR00032##

wherein the double bonds are present, Q′ is C; Z″, L′, L, are each CH; and Z′ is N (wherein Z′ is substituted); and wherein R.sub.6 is optionally substituted 1 to 3 times with one or a combination of aryl, heteroaryl, arylalkyl, or, heterocyclo, wherein said aryl, heteroaryl, arylalkyl, or heterocyclo is optionally substituted 1 to 3 times with one or a combination of cycloalkyl, linear or branched C.sub.1-C.sub.3 alkyl, or halo. [0347] 26A. The compound of embodiment 23A, wherein R.sub.6 is

##STR00033##

wherein each of the double bonds is absent, M′ is NH or N (wherein M′ is substituted), N′ is CH.sub.2, P′ is CH, and R′ is CH.sub.2, and wherein R.sub.6 is optionally substituted 1 to 3 times with one or a combination of aryl, heteroaryl, arylalkyl, or, heterocyclo, wherein said aryl, heteroaryl, arylalkyl, or heterocyclo is optionally substituted 1 to 3 times with one or a combination of cycloalkyl, linear or branched C.sub.1-C.sub.3 alkyl, or halo. [0348] 27A. The compound of embodiment 20A, wherein R.sub.6 is substituted with a substituent selected from the group consisting of phenyl, benzyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl, wherein said substituent is optionally substituted 1 to 3 times with one or a combination of cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, methyl, ethyl, propyl, chloro, fluoro, bromo, methoxy, or ethoxy. [0349] 28A. The compound of embodiment 27A, wherein R.sub.6 is substituted with a substituent selected from the group consisting of phenyl, benzyl, and tetrazolyl, wherein said substituent is optionally substituted 1 to 3 times with one or a combination of cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, methyl, ethyl, propyl, chloro, fluoro, bromo, methoxy, or ethoxy. [0350] 29A. The compound of any one of embodiments 1B or 1A-28A, wherein said compound is selected from the group consisting of

##STR00034## [0351] 30A. The compound of any one of embodiments 1B or 1A-12A, wherein R.sub.5 and R.sub.6 may be taken together with the nitrogen to which they are attached to form a heteroaryl or heterocyclo, wherein the heteroaryl or heterocyclo is optionally substituted 1 to 3 times with one or a combination of branched or linear alkyl, hydroxyl, hydroxyalkyl, heteroaryl, arylalkyl, heterocyclo, halo, alkoxy, —(CH.sub.2).sub.fNHC(O)-aryl, or —(CH.sub.2).sub.fNHC(O)-heteroaryl, wherein said heteroaryl, heterocyclo, or arylalkyl is optionally substituted 1 to 3 times with one or a combination of branched or linear alkyl, halo, hydroxyl, hydroxyalkyl, alkoxy, heteroaryl, or aryl, wherein said heteroaryl or aryl is optionally substituted 1 to 3 times with one or a combination of hydroxyl, branched or linear alkyl, haloalkoxy, or halo. [0352] 31A. The compound of embodiment 30A, wherein R.sub.5 and R.sub.6 may be taken together with the nitrogen to which they are attached to form a 5-10-membered mono, bridged, fused, or spiro heterocyclo, wherein said heterocyclo or heteroaryl contains one or two heteroatoms, and wherein said heterocyclo is optionally substituted 1 to 3 times with one or a combination of aryl, hydroxy, hydroxyalkyl, linear or branched C.sub.1-C.sub.6 alkyl, haloalkoxy, heteroaryl, heterocyclo, or —(CH.sub.2).sub.fNHC(O)-heteroaryl, wherein f is 1, and wherein said aryl, heteroaryl, or heterocyclo is optionally substituted 1 to 3 times with haloalkoxy, halo, linear or branched C.sub.1-C.sub.6 alkyl. [0353] 32A. The compound of any one of embodiments 1B or 1A-31A, wherein R.sub.5 and R.sub.6 may be taken together with the nitrogen to which they are attached to form a 9-membered spiro heterocyclo, wherein said spiro heterocyclo is

##STR00035##

wherein P.sub.6, P.sub.7, P.sub.8, P.sub.9, and P.sub.10 are each independently selected from the group consisting of N, NH O, S, and CH.sub.2, wherein the squiggle line represents the point of attachment to G, and wherein the spiro heterocyclo is optionally substituted 1 to 3 times with aryl, hydroxy, hydroxyalkyl, linear or branched C.sub.1-C.sub.6 alkyl, haloalkoxy, heteroaryl, heterocyclo, or —(CH.sub.2).sub.fNHC(O)-heteroaryl, wherein f is 1, and wherein said aryl, heteroaryl, or heterocyclo is optionally substituted 1 to 3 times with one or a combination of haloalkoxy, halo, linear or branched C.sub.1-C.sub.6 alkyl. [0354] 33A. The compound of embodiment 32A, wherein, P.sub.6 is O and P.sub.7, P.sub.8, P.sub.9, and P.sub.10 are each hydrogen. [0355] 34A. The compound of embodiment 32A or 33A, wherein the spiro heterocyclo is substituted with a heterocyclo, wherein said heterocyclo is further substituted with C.sub.1-C.sub.6 alkyl. [0356] 35A. The compound of any one of embodiments 32A-34A, wherein the spiro heterocyclo is substituted with a pyrazole, and wherein said pyrazole is substituted with isobutyl. [0357] 36A. The compound of embodiment 32A, wherein R.sub.5 and R.sub.6 may be taken together with the nitrogen to which they are attached to form a compound selected from the group consisting of pyrrolidine, piperidine, or morpholine, wherein said pyrrolidine, piperidine, or morpholine is optionally substituted 1 to 3 times with one or a combination of aryl, hydroxy, hydroxyalkyl, linear or branched C.sub.1-C.sub.6 alkyl, haloalkoxy, heteroaryl, heterocyclo, or —(CH.sub.2).sub.fNHC(O)-heteroaryl, wherein f is 1, and wherein said aryl, heteroaryl, or heterocyclo is optionally substituted 1 to 3 times with one or a combination of haloalkoxy, halo, and linear or branched C.sub.1-C.sub.6 alkyl. [0358] 37A. The compound of any one of embodiments 30A-36A, wherein said compound is selected from the group consisting of

##STR00036## ##STR00037## [0359] 38A. The compound of any one of embodiments 1B or 1A-10A, where P is S. [0360] 39A. The compound of embodiment 38A, wherein D is (CR.sub.3R.sub.4).sub.y, wherein R.sub.3 and R.sub.4 are each hydrogen, and y is 1. [0361] 40A. The compound of embodiment 38A or 39A, where R.sub.5 may be taken together with the nitrogen to which it is attached and G, D, and one of R.sub.3 and R.sub.4 to form a heterocyclo. [0362] 41A. The compound of embodiment 40A, wherein the heterocyclo is a 5- or 6-membered heterocyclo containing one or two heteroatoms. [0363] 42A. The compound of any one of embodiments 38A-41A, wherein R.sub.6 is selected from the group consisting of aryl, heteroaryl, heterocyclo, and cycloalkyl, and wherein said aryl or heteroaryl is optionally substituted 1 to 3 times with one or a combination of linear or branched C.sub.1-C.sub.3 alkyl, hydroxyl, alkoxy, or halo. [0364] 43A. The compound of embodiment 42A, wherein R.sub.6 is aryl, optionally substituted 1 to 3 times with alkoxy or hydroxyl. [0365] 44A. The compound of embodiment 42A or 43A, wherein R.sub.6 is phenyl, optionally substituted 1 to 3 times with methoxy. [0366] 45A. The compound of any one of embodiments 38A-44A, wherein M is

##STR00038##

wherein X.sub.8, X.sub.9, and X.sub.10 are each independently selected from N, NH, or O. [0367] 46A. The compound of any one of embodiments 38A-45A, wherein M is

##STR00039##

wherein X.sub.8 is O and X.sub.9 and X.sub.10 are each N. [0368] 47A. The compound of any one of embodiments 38A-46A, wherein J is C.sub.6-C.sub.10 aryl. [0369] 48A. The compound of any one of embodiments 38A-47A, wherein w is 0. [0370] 49A. The compound of embodiment 48A, wherein said compound is

##STR00040## [0371] 50A. The compound of embodiment 1B, 1A or 2A, wherein M is aryl. [0372] 51A. The compound of embodiment 50A, wherein M is phenyl. [0373] 52A. The compound of embodiment 50A or 51A, wherein J is hydrogen. [0374] 53A. The compound of any one of embodiments 50A-52A, wherein J′ is selected from the group consisting of aryl, heteroaryl, heterocyclo, and cycloalkyl, wherein said aryl or heteroaryl is optionally substituted 1 to 3 times with one or a combination of alkoxy, C.sub.1-C.sub.3 alkyl, halo, hydroxyl, or cyano. [0375] 54A. The compound of embodiment 53A, wherein J′ is aryl substituted with cyano. [0376] 55A. The compound of any one of embodiments 50A-54A, wherein P is a bond. [0377] 56A. The compound of any one of embodiments 50A-55A, wherein G is CH.sub.2. [0378] 57A. The compound of any one of embodiments 50A-56A, wherein y is 0. [0379] 58A. The compound of any one of embodiments 50A-57A, wherein R.sub.5 is selected from the group consisting of hydroxyalkyl, hydrogen, halo, and alkoxy. [0380] 59A. The compound of embodiment 58A, wherein R.sub.5 is hydroxyalkyl. [0381] 60A. The compound of embodiment 58A or 59A, wherein R.sub.5 is hydroxyethyl. [0382] 61A. The compound of any one of embodiments 50A-60A, wherein R.sub.6 is selected from the group consisting of halo, linear or branched C.sub.1-C.sub.6 alkyl, haloalkyl, alkenyl, and alkynyl. [0383] 62A. The compound of embodiment 61A, wherein R.sub.6 is linear or branched C.sub.1-C.sub.6 alkyl. [0384] 63A. The compound of embodiment 61A or 62A, wherein R.sub.6 is neo-pentyl. [0385] 64A. The compound of embodiment 63A, wherein said compound is

##STR00041## [0386] 2B. The compound of embodiment 1B, wherein ring M is a C.sub.6-C.sub.12 aryl, 5- to 12-membered heterocyclo, or 5- to 12-membered heteroaryl, and wherein said heterocyclo or heteroaryl contains one, two, or three ring heteroatoms. [0387] 3B. The compound of embodiment 1B or 2B, wherein ring M is selected from the group consisting of

##STR00042## [0388] wherein X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, X.sub.7, X.sub.8, X.sub.9, and X.sub.10 are each independently selected from the group consisting of O, N, NH, and S, and wherein indicates the point of attachment of ring M to P. [0389] 4B. The compound of embodiment 3B, wherein X.sub.2 is S; X.sub.3 is NH; X.sub.4 is N; X.sub.5 is N; X.sub.6 is N; X.sub.7 is N; X.sub.9 and X.sub.10 are each N, and X.sub.8 is O. [0390] 5B. The compound of embodiment 3B or 4B, wherein J is selected from the group consisting of halo, hydroxyl, or linear or branched C.sub.1-C.sub.3 alkyl. [0391] 6B. The compound of any one of embodiments 1B-5B, wherein J is selected from the group consisting of methyl, fluoro, and hydroxyl. [0392] 7B. The compound of any one of embodiments 1B-6B, wherein J′ is selected from the group consisting of aryl, heteroaryl, heterocyclo, cycloalkyl, and halo, wherein said aryl, heteroaryl, heterocyclo, or cycloalkyl is optionally substituted 1 to 3 times, in each instance, with alkoxy, linear or branched C.sub.1-C.sub.3 alkyl, halo, hydroxyl, or cyano. [0393] 8B. The compound of embodiment 7B, wherein J′ is selected from the group consisting of phenyl, naphthalenyl, dihydrobenzofuranyl, pyrrolyl, and pyrazolyl, optionally substituted 1 to 3 times, in each instance, with methoxy, fluoro, methyl, or cyano. [0394] 9B. The compound of any one of embodiments 1B-8B, wherein q is 0. [0395] 10B. The compound of any one of embodiments 1B-8B, wherein q is 1. [0396] 11B. The compound of any one of embodiments 1B-10B, wherein w is 0. [0397] 12B. The compound of any one of embodiments 1B-10B, wherein w is 1. [0398] 13B. The compound of embodiment 1B, wherein ring M is selected from the group consisting of

##STR00043## [0399] 14B. The compound of any one of embodiments 1B-13B, wherein G is C═O. [0400] 15B. The compound of any one of embodiments 1B-14B, wherein y is 0. [0401] 16B. The compound of any one of embodiments 1B-15B, wherein P is a bond. [0402] 17B. The compound of any one of embodiments 1B-16B, wherein R.sub.5 is selected from the group consisting of hydrogen, hydroxyl, and linear or branched C.sub.1-C.sub.3 alkyl. [0403] 18B. The compound of any one of embodiments 1B-17B, wherein R.sub.5 is hydrogen. [0404] 19B. The compound of embodiment 17B or 18B, wherein R.sub.6 (A) is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclo, alkyl-S(O).sub.m, haloalkyl-S(O).sub.m, alkenyl-S(O).sub.m, alkynyl-S(O).sub.m, cycloalkyl-S(O).sub.m, cycloalkylalkyl-S(O).sub.m, aryl-S(O).sub.m, arylalkyl-S(O).sub.m, heterocyclo-S(O).sub.m, heterocycloalkyl-S(O).sub.m, and heteroaryl-S(O).sub.m, wherein said heterocyclo, heteroaryl, aryl, or S in —S(O).sub.m (A) is optionally substituted 1 to 3 times, in each instance, with one or a combination of linear or branched C.sub.1-C.sub.3 alkyl, halo, arylalkyl, aryl, heterocyclo, or heteroaryl (B), and wherein said aryl or heteroaryl (B) is optionally substituted 1 to 3 times, in each instance, with one or a combination of heterocyclo, halo, cycloalkyl, alkoxy, or linear or branched C.sub.1-C.sub.3 alkyl. [0405] 20B. The compound of embodiment 19B, wherein R.sub.6 is alkyl-S(O).sub.m, wherein S in S(O).sub.m is optionally substituted 1 to 3 times, in each instance, with one or a combination of linear or branched C.sub.1-C.sub.3 alkyl, arylalkyl, aryl, or heteroaryl. [0406] 21B. The compound of embodiment 20B, wherein m is 2. [0407] 22B. The compound of embodiment 20B or 21B, wherein R.sub.6 is alkyl-S(O).sub.2, wherein S is substituted once with aryl or arylalkyl. [0408] 23B. The compound of embodiment 22B, wherein R.sub.6 is —CH.sub.2CH.sub.2—S(O).sub.2, wherein S is substituted once with benzyl. [0409] 24B. The compound of embodiment 23B, wherein ring M is a 5-membered heterocyclo.

##STR00044## [0410] 25B. The compound of embodiment 24B, wherein ring M is, wherein X.sub.7 is N. [0411] 26B. The compound of embodiment 25B, wherein w is 1. [0412] 27B. The compound of embodiment 26B, wherein J′ is aryl. [0413] 28B. The compound of embodiment 27B, wherein J′ is naphthalenyl. [0414] 29B. The compound of embodiment 28B, wherein q is 0. [0415] 30B. The compound of any one of embodiments 24B-29B, wherein ring M is

##STR00045## [0416] 31B. The compound of embodiment 30B, wherein said compound has the structure:

##STR00046## [0417] 31B. The compound of embodiment 19B, wherein R.sub.6 (A) is selected from the group consisting of aryl, heteroaryl, and heterocyclo, optionally substituted 1 to 3 times, in each instance, with one or a combination of aryl, heteroaryl, arylalkyl, or heterocyclo (B), wherein said aryl, heteroaryl, arylalkyl, or heterocyclo (B) is optionally substituted 1 to 3 times, in each instance, with one or a combination of cycloalkyl, alkoxy, linear or branched C.sub.1-C.sub.3 alkyl, or halo. [0418] 32B. The compound of embodiment 31B, wherein R.sub.6 (A) is phenyl, wherein said phenyl is optionally substituted 1 to 3 times, in each instance, with one or a combination of aryl, heteroaryl, arylalkyl, or heterocyclo (B), wherein said aryl, heteroaryl, arylalkyl, or heterocyclo (B) is optionally substituted 1 to 3 times, in each instance, with one or a combination of cycloalkyl, alkoxy, linear or branched C.sub.1-C.sub.3 alkyl, or halo. [0419] 33B. The compound of embodiment 31B, wherein R.sub.6 (A) is heteroaryl, wherein said heteroaryl is selected from the group consisting of acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl and triazinyl, wherein said heteroaryl (A) is optionally substituted 1 to 3 times, in each instance, with one or a combination of aryl, heteroaryl, arylalkyl, or, heterocyclo (B), and wherein said aryl, heteroaryl, arylalkyl, or heterocyclo (B) is optionally substituted 1 to 3 times, in each instance, with one or a combination of cycloalkyl, alkoxy, linear or branched C.sub.1-C.sub.3 alkyl, or halo. [0420] 34B. The compound of embodiment 31B, wherein R.sub.6 (A) is selected from the group consisting of

##STR00047##

wherein the double bonds are each absent or present, Q′, Z″, L′, L, Z′, G′, F′, H′, M′, N′, P′, and R′ are each independently selected from the group consisting of N, O, S, NH, C, CH.sub.2, and CH, and wherein R.sub.6 (A) is optionally substituted 1 to 3 times, in each instance, with one or a combination of aryl, heteroaryl, arylalkyl, or, heterocyclo (B), wherein said aryl, heteroaryl, arylalkyl, or heterocyclo (B) is optionally substituted 1 to 3 times, in each instance, with one or a combination of cycloalkyl, linear or branched C.sub.1-C.sub.3 alkyl, alkoxy or halo, and wherein indicates the point of attachment to N in Formula II. [0421] 35B. The compound of embodiment 34B, wherein R.sub.6 (A) is

##STR00048##

wherein G′, F′, and H′ are each CH, each double bond is present, and wherein R.sub.6 (A) is optionally substituted 1 to 3 times, in each instance, with one or a combination of aryl, heteroaryl, arylalkyl, or, heterocyclo (B), and wherein said aryl, heteroaryl, arylalkyl, or heterocyclo (B) is optionally substituted 1 to 3 times, in each instance, with one or a combination of cycloalkyl, alkoxy, linear or branched C.sub.1-C.sub.3 alkyl, or halo. [0422] 36B. The compound of embodiment 35B, wherein R.sub.6 (A) is substituted once with heteroaryl (B), and wherein said heteroaryl (B) is substituted once with cyclopropyl, cyclobutyl, or cyclopentyl. [0423] 37B. The compound of embodiment 36B, wherein R.sub.6 is substituted once with tetrazolyl, and wherein said tetrazolyl is substituted once with cyclopropyl.

##STR00049## [0424] 38B. The compound of embodiment 37B, wherein R.sub.6 is

##STR00050## [0425] 39B. The compound of embodiment 34B, wherein R.sub.6 (A) is L each double bond is present, Q′ is C; Z″, L′, L, are each CH; and Z′ is NH or N (wherein Z′ is substituted); and wherein R.sub.6 (A) is optionally substituted 1 to 3 times, in each instance, with one or a combination of aryl, heteroaryl, arylalkyl, or, heterocyclo (B), wherein said aryl, heteroaryl, arylalkyl, or heterocyclo (B) is optionally substituted 1 to 3 times, in each instance, with one or a combination of cycloalkyl, alkoxy, linear or branched C.sub.1-C.sub.3 alkyl, or halo. [0426] 40B. The compound of embodiment 39B, wherein R.sub.6 is substituted once with arylalkyl, and wherein said arylalkyl is substituted once with methyl, ethyl, or cyclopropyl. [0427] 41B. The compound of embodiment 40B, wherein R.sub.6 is substituted once with benzyl, wherein said benzyl is substituted once with methyl. [0428] 42B. The compound of embodiment 41B, wherein R.sub.6 is

##STR00051## [0429] 43B. The compound of embodiment 34B, wherein R.sub.6 (A) is

##STR00052##

wherein each double bond is absent, M′ is NH or N (wherein M′ is substituted), N′ is CH.sub.2, P′ is CH, and R′ is CH.sub.2, and wherein R.sub.6 (A) is optionally substituted 1 to 3 times, in each instance, with one or a combination of aryl, heteroaryl, arylalkyl, or, heterocyclo (B), wherein said aryl, heteroaryl, arylalkyl, or heterocyclo (B) is optionally substituted 1 to 3 times, in each instance, with one or a combination of cycloalkyl, alkoxy, linear or branched C.sub.1-C.sub.3 alkyl, or halo. [0430] 44B. The compound of embodiment 43B, wherein R.sub.6 is substituted once with aryl, and wherein said aryl is substituted twice with halo. [0431] 45B. The compound of embodiment 44B, wherein R.sub.6 is substituted once with phenyl, and wherein said phenyl is substituted once with fluoro and once with chloro. [0432] 46B. The compound of embodiment 45B, wherein R.sub.6 is

##STR00053## [0433] 47B. The compound of embodiment 31B, wherein R.sub.6 (A) is substituted with a substituent selected from the group consisting of phenyl, benzyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl (B), wherein said substituent (B) is optionally substituted 1 to 3 times, in each instance, with one or a combination of cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, methyl, ethyl, propyl, chloro, fluoro, bromo, methoxy, or ethoxy. [0434] 48B. The compound of embodiment 47B, wherein R.sub.6 (A) is substituted with a substituent selected from the group consisting of phenyl, benzyl, and tetrazolyl (B), wherein said substituent (B) is optionally substituted 1 to 3 times, in each instance, with one or a combination of cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, methyl, ethyl, propyl, chloro, fluoro, bromo, methoxy, or ethoxy. [0435] 48bb. The compound of any one of embodiments 31B-48B, wherein ring M is selected from the group consisting of

##STR00054##

wherein J′ is selected from the group consisting of aryl and heterocyclo, wherein said aryl or heterocyclo is optionally substituted with halo or alkoxy; and wherein J is linear or branched C.sub.1-C.sub.3 alkyl.

##STR00055## [0436] 48bb1. The compound of embodiment 48bb, wherein ring M is wherein X.sub.3 is S, J′ is phenyl, wherein said phenyl is substituted with methoxy, w is 1, and q is 0. [0437] 48bb2. The compound of embodiment 48bb1, wherein ring M is

##STR00056## [0438] 48bb3. The compound of embodiment 48bb, wherein ring M is

##STR00057##

wherein X.sub.4 is N, J′ is dihydrobenzofuranyl, w is 1, and q is 0. [0439] 48bb4. The compound of embodiment 48bb3, wherein ring M is

##STR00058## [0440] 48bb5. The compound of embodiment 48bb, wherein ring M is

##STR00059##

wherein X.sub.3 is NH, J′ is phenyl, wherein said phenyl is substituted with fluoro, w is 1, and q is 1. [0441] 48bb6. The compound of embodiment 48bb5, wherein ring M is

##STR00060## [0442] 49B. The compound of any one of embodiments 31B-48B, 48bb, 48bb1, 48bb2, 48bb3, 48bb4, 48bb5, or 48bb6, wherein ring M is selected from the group consisting of

##STR00061## [0443] 50B. The compound of embodiment 49B, wherein said compound is selected from the group consisting of

##STR00062## [0444] 51B. The compound of embodiment 16B, wherein R.sub.5 and R.sub.6 are taken together with the nitrogen to which they are attached to form a heteroaryl or heterocyclo (C), wherein said heteroaryl or heterocyclo (C) is optionally substituted 1 to 3 times, in each instance, with one or a combination of branched or linear alkyl, hydroxyl, hydroxyalkyl, heteroaryl, aryl, arylalkyl, heterocyclo, halo, alkoxy, —(CH.sub.2).sub.fNHC(O)-aryl, or —(CH.sub.2).sub.fNHC(O)-heteroaryl (D), wherein said heteroaryl, aryl, heterocyclo, or arylalkyl (D) is optionally substituted 1 to 3 times, in each instance, with one or a combination of branched or linear alkyl, halo, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxy, heteroaryl, or aryl (E), and wherein said heteroaryl or aryl (E) is optionally substituted 1 to 3 times, in each instance, with one or a combination of aryl, hydroxyl, alkoxy, branched or linear alkyl, haloalkoxy, or halo. [0445] 52B. The compound of embodiment 51B, wherein R.sub.5 and R.sub.6 are taken together with the nitrogen to which they are attached to form a 5-10-membered mono, bridged, fused, or spiro heterocyclo (C), wherein said heterocyclo (C) contains one or two heteroatoms, and wherein said heterocyclo is optionally substituted 1 to 3 times, in each instance, with one or a combination of aryl, arylalkyl, hydroxy, hydroxyalkyl, linear or branched C.sub.1-C.sub.6 alkyl, haloalkoxy, heteroaryl, heterocyclo, or —(CH.sub.2).sub.fNHC(O)-heteroaryl (D), wherein said aryl, arylalkyl, heteroaryl, or heterocyclo (D) is optionally substituted 1 to 3 times, in each instance, with aryl, haloalkoxy, halo, or linear or branched C.sub.1-C.sub.6 alkyl (E), and wherein said aryl (E) is optionally substituted 1 to 3 times, in each instance, with one or a combination of linear or branched C.sub.1-C.sub.3 alkyl, alkoxy, or halo. [0446] 53B. The compound of embodiment 52B, wherein R.sub.5 and R.sub.6 are taken together with the nitrogen to which they are attached to form a pyrrolidinyl, piperidinyl, or morpholinyl ring (C), wherein said pyrrolidinyl, piperidinyl, or morpholinyl ring (C) is optionally substituted 1 to 3 times, in each instance, with one or a combination of aryl, arylalkyl, hydroxyl, hydroxyalkyl, linear or branched C.sub.1-C.sub.6 alkyl, haloalkoxy, heteroaryl, heterocyclo, or —CH.sub.2NHC(O)-heteroaryl (D), wherein said aryl, arylalkyl, heteroaryl, or heterocyclo (D) is optionally substituted 1 to 3 times, in each instance, with one or a combination of aryl, haloalkoxy, halo, or linear or branched C.sub.1-C.sub.6 alkyl (E), and wherein said aryl (E) is optionally substituted 1 to 3 times, in each instance, with one or a combination of linear or branched C.sub.1-C.sub.3 alkyl, alkoxy, or halo. [0447] 54B. The compound of embodiment 53B, wherein R.sub.5 and R.sub.6 are taken together with the nitrogen to which they are attached to form a morpholinyl ring, wherein said morpholinyl ring is optionally substituted with phenyl, and wherein said phenyl ring is optionally substituted 1 to 3 times, in each instance, with methoxy, difluoromethoxy, trifluoromethoxy, or methyl. [0448] 55B. The compound of embodiment 54B, wherein R.sub.5 and R.sub.6 are taken together with the nitrogen to which they are attached to form a morpholinyl ring, wherein said morpholinyl ring is substituted once with phenyl, and wherein said phenyl ring is substituted once with difluoromethoxy. [0449] 56B. The compound of embodiment 55B, wherein R.sub.5 and R.sub.6 are taken together with the nitrogen to which they are attached to form

##STR00063##

wherein indicates the point of attachment to G. [0450] 57B. The compound of embodiment 53B, wherein R.sub.5 and R.sub.6 are taken together with the nitrogen to which they are attached to form a piperidinyl ring, wherein said piperidinyl ring is optionally substituted with imidazolyl, wherein said imidazolyl is optionally substituted with phenyl, and wherein said phenyl ring is optionally substituted 1 to 3 times, in each instance, with one or a combination of fluoro, chloro, methoxy, or methyl. [0451] 58B. The compound of embodiment 57B, wherein R.sub.5 and R.sub.6 are taken together with the nitrogen to which they are attached to form a piperidinyl ring, wherein said piperidinyl ring is substituted once with imidazolyl, wherein said imidazolyl is substituted once with phenyl, and wherein said phenyl is substituted once with fluoro. [0452] 59B. The compound of embodiment 58B, wherein R.sub.5 and R.sub.6 are taken together with the nitrogen to which they are attached to form

##STR00064##

wherein indicates the point of attachment to G. [0453] 60B. The compound of embodiment 53B, wherein R.sub.5 and R.sub.6 are taken together with the nitrogen to which they are attached to form a pyrrolidinyl ring, wherein said pyrrolidinyl ring is optionally substituted 1 to 3 times, in each instance, with one or a combination of hydroxyalkyl, linear or branched C.sub.1-C.sub.6 alkyl, benzyl, or —CH.sub.2NHC(O)-heteroaryl, wherein said benzyl is optionally substituted one to three times, in each instance, with fluoro, chloro, methyl, or methoxy. [0454] 61B. The compound of embodiment 60B, wherein hydroxyalkyl is hydroxymethyl. [0455] 61bb. The compound of embodiment 60B, wherein R.sub.5 and R.sub.6 are taken together with the nitrogen to which they are attached to form a pyrrolidinyl ring, wherein said pyrrolidinyl ring is substituted once with hydroxymethyl and once with butyl. [0456] 61bb1. The compound of embodiment 61bb, wherein butyl is iso-butyl. [0457] 61bb2. The compound of embodiment 60B, wherein R.sub.5 and R.sub.6 are taken together with the nitrogen to which they are attached to form a pyrrolidinyl ring, wherein said pyrrolidinyl ring is substituted once with hydroxymethyl and once with benzyl, wherein said benzyl is substituted once with fluoro. [0458] 61bb3. The compound of embodiment 60B, wherein R.sub.5 and R.sub.6 are taken together with the nitrogen to which they are attached to form a pyrrolidinyl ring, wherein said pyrrolidinyl ring is substituted with once with methyl and once with —CH.sub.2NHC(O)-heteroaryl. [0459] 61bb4. The compound of embodiment 61bb3, wherein said heteroaryl in —CH.sub.2NHC(O)-heteroaryl is isoquinolinyl. [0460] 62B. The compound of embodiment 60B or 61B, wherein R.sub.5 and R.sub.6 are taken together with the nitrogen to which they are attached to form

##STR00065##

wherein indicates the point of attachment to G. [0461] 63B. The compound of embodiment 52B, wherein R.sub.5 and R.sub.6 taken together with the nitrogen to which they are attached form a 9-membered spiro heterocyclo (C), wherein said spiro heterocyclo is

##STR00066##

wherein P.sub.6, P.sub.7, P.sub.8, P.sub.9, and P.sub.10 are each independently selected from the group consisting of NH O, S, and CH.sub.2, wherein indicates the point of attachment to G, and wherein said spiro heterocyclo (C) is optionally substituted 1 to 3 times, in each instance, with aryl, hydroxy, hydroxyalkyl, linear or branched C.sub.1-C.sub.6 alkyl, haloalkoxy, heteroaryl, heterocyclo, or —(CH.sub.2).sub.fNHC(O)-heteroaryl (D), and wherein said aryl, heteroaryl, or heterocyclo (D) is optionally substituted 1 to 3 times, in each instance, with haloalkoxy, halo, or linear or branched C.sub.1-C.sub.6 alkyl. [0462] 64B. The compound of embodiment 63B, wherein, P.sub.6 is O and P.sub.7, P.sub.8, P.sub.9, and P.sub.10 are each CH.sub.2. [0463] 65B. The compound of embodiment 63B or 64B, wherein said spiro heterocyclo is substituted with a heteroaryl, wherein said heteroaryl is further substituted with linear or branched C.sub.1-C.sub.6 alkyl. [0464] 66B. The compound of embodiment 65B, wherein said spiro heterocyclo is substituted with imidazolyl or pyrazolyl, and wherein said imidazolyl or pyrazolyl is substituted once with methyl, ethyl, propyl, butyl, pentyl, or hexyl. [0465] 66bb. The compound of embodiment 66B, wherein said spiro heterocyclo is substituted with pyrazolyl, wherein said pyrazolyl is substituted with butyl. [0466] 66bb1. The compound of embodiment 66bb, wherein said butyl is isobutyl. [0467] 67B. The compound of embodiment 66B, wherein said spiro heterocyclyl is

##STR00067## [0468] 69B. The compound of embodiment 68B, wherein ring M is

##STR00068## [0469] 70B. The compound of embodiment 69B, wherein J′ is heteroaryl. [0470] 71B. The compound of embodiment 70B, wherein J′ is selected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl, pyrimidinyl, and pyridinyl. [0471] 72B. The compound of embodiment 71B, wherein J′ is pyrrolyl. [0472] 73B. The compound of embodiment 69B, wherein q is 0. [0473] 74B. The compound of embodiment 69B, wherein w is 1. [0474] 75B. The compound of embodiment 69B, wherein ring M is

##STR00069## [0475] 76B. The compound of any one of embodiments 56B or 68B-75B, wherein the compound is

##STR00070## [0476] 76bb. The compound of embodiment 59B, wherein ring M is

##STR00071##

wherein J′ is heteroaryl, wherein said heteroaryl is optionally substituted with linear or branched C.sub.1-C.sub.3 alkyl, and J is halo. [0477] 76bb1. The compound of embodiment 76bb, wherein J′ is pyrazolyl, wherein said pyrazolyl is substituted once with methyl, and J is fluoro. [0478] 77B. The compound of any one of embodiments 59B, 76bb, or 76bb1, wherein ring M is

##STR00072## [0479] 78B. The compound of embodiment 77B, wherein the compound is

##STR00073## [0480] 78bb. The compound of embodiment 62B, wherein ring M is

##STR00074##

wherein J′ is heteroaryl and J is selected from the group consisting of hydroxy and linear or branched C.sub.1-C.sub.3 alkyl. [0481] 78bb1. The compound of embodiment 78bb, wherein ring M is

##STR00075##

wherein w is 0, q is 1, and J is hydroxy.

##STR00076## [0482] 78bb2. The compound of embodiment 78bb1, wherein ring M is. [0483] 78bb3. The compound of embodiment 78bb, wherein ring M is

##STR00077##

X.sub.6 is N, and q and w are each 0. [0484] 78bb4. The compound of embodiment 78bb, wherein ring M is

##STR00078##

wherein J′ is w is 1, q is 0, and J′ is pyrrolyl. [0485] 78bb5. The compound of embodiment 78bb, wherein ring M is

##STR00079## [0486] 79B. The compound of any one of embodiments 62B, 78bb, 78bb1, 78bb2, 78bb3, or 78bb4, wherein ring M is

##STR00080## [0487] 80B. The compound of embodiment 79B, wherein the compound is selected from the group consisting of

##STR00081## [0488] 80bb. The compound of embodiment 67B, wherein ring M is

##STR00082##

wherein J and J′ are each halo. [0489] 80bb1. The compound of embodiment 80bb, wherein X.sub.5 is N, J and J′ are each fluoro, and w and q are each 1. [0490] 81B. The compound of any one of embodiments 67B, 80bb, or 80bb1, wherein ring M is

##STR00083## [0491] 82B. The compound of embodiment 81B, wherein the compound is

##STR00084## [0492] 83B. The compound of embodiment 1B, where P is S. [0493] 84B. The compound of embodiment 83B, wherein G is C═O. [0494] 85B. The compound of embodiment 84B, wherein y is 1. [0495] 86B. The compound of any one of embodiments 83B-85B, where R.sub.5 is taken together with the nitrogen to which it is attached and G, D, and one of R.sub.3 and R.sub.4 to form a heterocyclo. [0496] 87B. The compound of embodiment 86B, wherein said heterocyclo is a 5- or 6-membered heterocyclo containing one or two heteroatoms. [0497] 88B. The compound of embodiment 87B, wherein R.sub.6 is selected from the group consisting of aryl, heteroaryl, heterocyclo, and cycloalkyl, wherein said aryl, heteroaryl, heterocyclo, or cycloalkyl is optionally substituted 1 to 3 times, in each instance, with one or a combination of linear or branched C.sub.1-C.sub.3 alkyl, hydroxyl, alkoxy, or halo. [0498] 89B. The compound of embodiment 88B, wherein R.sub.6 is aryl, optionally substituted 1 to 3 times, in each instance, with alkoxy or hydroxyl. [0499] 90B. The compound of embodiment 89B, wherein R.sub.6 is phenyl, optionally substituted 1 to 3 times with methoxy. [0500] 91B. The compound of c embodiment 90B, wherein R.sub.6 is

##STR00085## [0501] 92B. The compound of any one of embodiments 83B-91B, wherein ring M is

##STR00086##

wherein X.sub.9 and X.sub.10 are each N and X.sub.8 is selected from the group consisting of NH and O.

##STR00087## [0502] 93B. The compound of embodiment 92B, wherein ring M is wherein X.sub.8 is O and X.sub.9 and X.sub.10 are each N. [0503] 94B. The compound of embodiment 93B, wherein J′ is C.sub.6-C.sub.10 aryl. [0504] 95B. The compound of embodiment 94B, wherein J′ is naphthalenyl. [0505] 96B. The compound of embodiment 93B, wherein w is 1. [0506] 97B. The compound of embodiment 93B, wherein q is 0. [0507] 98B. The compound of any one of embodiments 92B-97B, wherein ring M is

##STR00088## [0508] 99B. The compound of embodiment 98B, wherein said compound is

##STR00089## [0509] 100B. The compound of embodiment 3B, wherein ring M is

##STR00090## [0510] 101B. The compound of embodiment 100B, wherein J′ is selected from the group consisting of aryl, heteroaryl, and heterocyclo, wherein said aryl, heteroaryl, or heterocyclo is optionally substituted 1 to 3 times, in each instance, with one or a combination of alkoxy, linear or branched C.sub.1-C.sub.3 alkyl, halo, hydroxyl, or cyano. [0511] 102B. The compound of embodiment 101B, wherein J′ is aryl, optionally substituted once with cyano, methyl, hydroxyl, or methoxy. [0512] 103B. The compound of embodiment 102B, wherein J′ is phenyl, substituted with cyano. [0513] 104B. The compound of embodiment 103B, wherein q is 0. [0514] 105B. The compound of embodiment 104B, wherein ring M is

##STR00091## [0515] 106B. The compound of any one of embodiments 100-105, wherein P is a bond. [0516] 107B. The compound of embodiment 106B, wherein G is CH.sub.2. [0517] 108B. The compound of embodiment 107B, wherein y is 0. [0518] 109B. The compound of any one of embodiments 106B-108B, wherein R.sub.5 is selected from the group consisting of hydroxyalkyl, hydrogen, halo, and alkoxy. [0519] 110B. The compound of embodiment 109B, wherein R.sub.5 is hydroxyalkyl. [0520] 111B. The compound of embodiment 110B, wherein R.sub.5 is selected from the group consisting of hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl. [0521] 112B. The compound of any one of embodiment 109B-111B, wherein R.sub.6 is selected from the group consisting of halo, linear or branched C.sub.1-C.sub.6 alkyl, haloalkyl, alkenyl, and alkynyl. [0522] 113B. The compound of embodiment 112B, wherein R.sub.6 is linear or branched C.sub.1-C.sub.6 alkyl. [0523] 114B. The compound of embodiment 113B, wherein R.sub.6 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl. [0524] 115B. The compound of embodiment 114B, wherein R.sub.6 is neopentyl. [0525] 116B. The compound of embodiment 115B, wherein said compound is

##STR00092## [0526] 117B. The compound of any one of embodiments 1A-64A or 1B-116B, wherein the compound is selected from the group consisting of:

TABLE-US-00002 Compound No. Structure RTX57548183 (Compound 1) [00093] RTX06107454 (Compound 2) [00094] RTX60933293 (Compound 3) [00095] RTX26466486 (Compound 4) [00096] RTX73145433 (Compound 5) [00097] RTX45332746 (Compound 6) [00098] RTX04306230 (Compound 7) [00099] RTX70558122 (Compound 8) [00100] RTX95655369 (Compound 9) [00101] RTX71280707 (Compound 10) [00102] RTX89483884 (Compound 11) [00103] RTX24380616 (Compound 12) [00104]
or a pharmaceutically acceptable salt thereof. [0527] 118B. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of any one of embodiments 1A-64A or 1B-116B, and a carrier acceptable for human administration. [0528] 119B. The pharmaceutical composition of embodiment 118B, formulated for oral administration. [0529] 120B. The pharmaceutical composition of embodiment 118B, formulated as a pill or capsule. [0530] 121B. The pharmaceutical composition of embodiment 118B, formulated for parenteral administration. [0531] 122B. The pharmaceutical composition of embodiment 118B, packaged in a vial containing a unit dose of the compound. [0532] 123B. A method of treating or effecting prophylaxis of impaired insulin sensitivity, glucose tolerance, or obesity, comprising administering to a subject having the impaired insulin sensitivity, glucose tolerance, or obesity an effective regime of a compound or pharmaceutical composition of any one of embodiments 1A-64A or 1B-116B. [0533] 124B. The method of embodiment 123B, wherein the subject has type 2 diabetes. [0534] 125B. The method of embodiment 123B, wherein the subject has a body mass index of at least 30. [0535] 126B. The method of embodiment 123B, wherein the subject is obese. [0536] 127B. The method of embodiment 123B, wherein the subject has impaired insulin sensitivity and/or glucose tolerance. [0537] 128B. The method of embodiment 123B, wherein the subject has hyperglycemia. [0538] 129B. The method of embodiment 123B, wherein the subject has dyslipidemia. [0539] 130B. The method of embodiment 123B, wherein the subject has microalbuminuria. [0540] 131B. A method of treating a subject having non-alcoholic fatty liver disease (NAFLD), comprising administering to the subject an effective regime of a compound of any one of embodiments 1A-64A or 1B-116B. [0541] 132B. The method of embodiment 131B, wherein the subject has nonalcoholic steatohepatitis (NASH). [0542] 133B. The method of embodiment 131B, wherein the subject has fibrosis. [0543] 134B. The method of embodiment 131B, further comprising monitoring the subject for change(s) in sign(s) and/or symptom(s) of NAFLD responsive to administering the compound. [0544] 135B. A method of treating a subject having nonalcoholic steatohepatitis (NASH) comprising administering to the subject an effective regime of a compound of any one of embodiments 1A-64A or 1B-116B. [0545] 136B. The method of embodiment 135B, wherein the subject has fibrosis. [0546] 137B. The method of embodiment 135B, further comprising monitoring the subject for change(s) in sign(s) and/or symptom(s) of NASH responsive to administering. [0547] 138B. A method of treating a subject having primary sclerosing cholangitis (PSC) comprising administering to the subject an effective regime of a compound of any one of embodiments 1A-64A or 1B-116B. [0548] 139B. A method of treating a subject having primary biliary cholangitis (PBC) comprising administering to the subject an effective regime of a compound of any one of embodiments 1A-64A or 1B-116B. [0549] 140B. A method of inhibiting beta amyloid toxicity in a subject, comprising administering to a subject in need thereof an effective regime of a compound of any one of embodiments 1A-64A or 1B-116B.

[0550] The following examples are offered by way of illustration and not by way of limitation.

EXAMPLES

Example 1: Assay Results of Novel Compounds

[0551] Unless indicated otherwise, all cells were incubated at 37° C. in 5% CO.sub.2.

Example 1A: Screening of Compounds for Protection of Primary Hepatocytes from Palmitate Toxicity

[0552] Primary hepatocytes were isolated from 3-month-old C57Bl6 male mice and plated onto Nunc 384-well polystyrene black 384 well plates, Cat #164564 (Thermo Fisher Scientific, Rochester, N.Y.), 2,000 cells per well, in DMEM 10% FBS, 25 mM glucose medium, and were allowed to attach for 3 hours. Media was replaced with DMEM 1% FBS, 0.2 nM insulin, and compounds were supplemented to 1 uM and 10 uM; palmitate was supplemented to 200 mM. Cells were incubated for 24 hours, washed with Calcein-AM DW assay buffer, Cat #4892-010-02 (Trevigen, Gaithersburg, Md.), and stained with Calcein AM, Cat #4892-010-01 (Trevigen, Gaithersburg, Md.) according to manufacturer instructions; fluorescence was measured using 490Ex/520Em wavelengths. Hits were identified as 2 Standard Deviations different from the assay mean, and exhibited a 10% false discovery rate estimate. Each compound was tested 28 times at 1 uM and 28 times at 10 uM concentrations. The number of times a compound was a significant hit was counted and plotted.

Example 1B: Screening of Compounds for Protection of Primary Hepatocytes from Alcohol Toxicity

[0553] Primary hepatocytes were isolated from 3-month-old C57Bl6 male mice and plated onto Nunc 384-well polystyrene black 384 well plates, Cat #164564 (Thermo Fisher Scientific, Rochester, N.Y.), 2,000 cells per well, in DMEM 10% FBS, 25 mM glucose medium, and were allowed to attach for 3 hours. Media was replaced with DMEM 1% FBS, 0.2 nM insulin, and compounds were supplemented to 1 uM and 10 uM; alcohol was supplemented to 720 mM. Cells were incubated for 48 hours. Calcein-AM staining was performed as described above. Hits were identified as 2 Standard Deviations different from the assay mean, and had a 10% false discovery rate estimate. Each compound was tested 16 times at 1 uM and 16 times at 10 uM concentrations. The number of times a compound was a significant hit was counted and plotted.

Example 1C: Screening of Compounds for Protection from Amyloid Beta Toxicity in N2A Neuronal Cell Line

[0554] The N2A cells were seeded onto Nunc 384-well polystyrene black 384 well plates, Cat #164564 (Thermo Fisher Scientific, Rochester, N.Y.), 7,000 cells per well, in 50% DMEM 50% OptiMEM 5% FBS, 25 mM glucose medium, and allowed to attach for 24 hours. Media was replaced with FBS free DMEM, 0 glucose; compounds were supplemented to 1 uM and 10 uM; aged amyloid beta was supplemented to 50 mM; cells were incubated for 72 hours; Calcein-AM staining was performed as described above. Hits were identified as 2 Standard Deviations different from the assay mean, and had a 10% false discovery rate estimate. Each compound was tested 8 times at 1 uM and 16 times at 10 uM concentrations. The number of times a compound was a significant hit was counted and plotted.

[0555] The results of all HTS for protection from palmitate, alcohol, beta-amyloid, HTS insulin sensitization, binding to p52Shc-PTB domain, affinity, and chemical scaffolding information were compared. The selected compounds were tested for insulin sensitization potency by measuring the insulin sensitivity of FL83B liver cells in the presence of 2 mM compounds and 0.1 nM insulin, as described below.

Example 1D: Insulin Sensitization Potency

[0556] The liver cell line FL83B was plated onto 24 well plates, 200,000 cells per well in 1 ml of DMEM-F12 10% FBS, 25 mM glucose medium, and allowed to grow for 48 hours. The media was changed to FBS-free DMEM-F12 25 mM glucose, and cells were incubated for 16 hours. Compounds were supplemented to 2 uM concentration in duplicates, and cells were incubated for 1 hour and stimulated with 0.1 nM insulin for 10 minutes. Cells were lysed with CelLytic MT Cell Lysis Reagent, Cat #3228-500 ML (Sigma, St. Louis, Mass.); lysates were analyzed with the Simple Western Capillary Electrophoresis instrument “Jess,” Cat #004-650 (Protein Simple, Santa Clara, Calif.) for insulin-dependent activation of P-Akt with anti-Akt (pan) (40D4) Mouse monoclonal Antibody, Cat #2920 (Cell Signaling Technology Inc., Danvers, Mass.), anti-Phospho-Akt (Ser473) (193H12) Rabbit monoclonal Antibody, Cat #4058 (Cell Signaling Technology Inc., Danvers, Mass.), anti-beta actin antibody mouse monoclonal antibody, Cat #MAB8929 (R&D Systems, Minneapolis, Minn.); dilution factors were 50, 50, 100 respectively. The signals were normalized to total protein loaded on each capillary using protein normalization staining for Protein Capillary Electrophoresis, Cat #AM-PN01 (Protein Simple, Santa Clara, Calif.), the fold changes of insulin dependent P-Akt activation over vehicle were determined and plotted. No changes in total Akt or Actin were detected for any compounds (FIG. 2).

[0557] Provided in FIG. 1 and FIG. 2 are assay results exhibiting the effectiveness of the compounds in Shc protein binding, affinity in KD, Potency of insulin sensitization, potency of hepatocyte protection in palmitate assays in hepatocyte cell lines and in mouse hepatocytes ex vivo, hepatoprotection in the context of alcohol toxicity, and protection of neurons in the context of beta-amyloid toxicity.

Example 1E: Novel Shc Blockers Make Insulin-Resistant Animals More Glucose-Tolerant

[0558] By blocking the interaction of Shc protein with phosphotyrosines on the Insulin Receptor, a Shc blocker redirects more signaling to the insulin-sensitizing and glucose tolerizing phospho-Akt. Thus, peripheral cells become more sensitive per molecule insulin, and consequently more glucose tolerant. This prediction is borne out in the Corticosteroid model. Corticosterone is a known model of Type 2 Diabetes and Metabolic Syndrome, as Corticosterone induces peripheral insulin insensitivity. As shown in FIG. 3, both compound 3=RTX60933293 and compound 5=RTX73145433 are significantly glucose tolerizing.

Example 1F: Novel Shc Blockers Reduce Liver Fibrosis in NASH Models

[0559] Without wishing to be bound by theory, NASH could be considered the next-most common metabolic disturbance after Type 2 Diabetes in the USA, and currently has no approved treatment. There is a usual progression from NAFLD (fatty liver) to the more fibrotic/cirrhotic NASH. While the precise mechanism of the transition of NAFLD to NASH is not completely understood, hepatocyte death and resulting fibrosis has been proposed. Fibrosis and fibrotic scarring are thought to be the most important pathophysiological endpoints to end-stage NASH, which typically necessitates an expensive and difficult liver transplant. As shown in other examples, Shc blockers through their sensitization to insulin, IGF-1 and other growth factors, are cytoprotective. Thus, by inhibiting hepatocyte death which promotes fibrosis, they should also be anti-fibrotic. Furthermore, as shown in FIG. 4, when fed to mice on the strongly liver fibrotic MCD diet, Shc blockers significantly reduced 6 out of 6 biomarkers of liver fibrosis, which suggests that they could be of benefit in human liver fibrosis.

Example 2: Synthetic Preparation of Compounds of Formula II

Example 2A: Preparation of RTX73145433 (Compound 5)

[0560] Scheme 1 depicts the preparation of an exemplary compound.

##STR00105## ##STR00106##

[0561] Step A: TMSCN, SnI.sub.2, in Et.sub.2O. 18 h, rt (Linn, J. A. et al. PCT Int. Appl., 2008024634).

[0562] Step B: a) LiAlH.sub.4, in Et.sub.2O, 20 min, reflux; 3 h, reflux; b) NaOH, in H.sub.2O (Linn, J. A. et al. PCT Int. Appl., 2008024634).

[0563] Step C: EtOH, 2 h, rt; rt.fwdarw.0° C. (Yang, X. et al. Journal of the American Chemical Society, 134(42), 17605-17612; 2012).

[0564] Step D: NaBH.sub.4, 0° C.; 1 h, 0° C.; b) NaOH, in H.sub.2O; c) HCl, in H.sub.2O (Yang, X. et al. Journal of the American Chemical Society, 134(42), 17605-17612; 2012).

[0565] Step E: Et.sub.3N, in CH.sub.2Cl.sub.2, 1 h, 0° C. (Iwema Bakker, W. I. et al. PCT Int. Appl., 2011023795).

[0566] Step F: R:KOH, in i-PrOH, 3 h, rt (Iwema Bakker, W. I. et al. PCT Int. Appl., 2011023795).

[0567] Step G: a) BH.sub.3-THF, in THF, 0° C.; 1 h, 0° C.; 0° C..fwdarw.rt; 2 h, rt; b) MeOH, 0° C.; 30 min, rt; c) NaOH, in H.sub.2O-MeOH, 1 h, reflux (Iwema Bakker, W. I. et al. PCT Int. Appl., 2011023795).

[0568] Step H: H.sub.2, Pd(OH).sub.2, in MeOH, overnight, rt (Iwema Bakker, W. I. et al. PCT Int. Appl., 2011023795).

[0569] Step I: AcOH, 10 min, 170° C. (Brindisi, M. et al. Future Medicinal Chemistry, 8(13), 1573-1587; 2016).

[0570] Step J: NaOH, in H.sub.2O-MeOH, 12 h, 25° C.; b) HCl, in H.sub.2O, 25° C. (Brindisi, M. et al. Future Medicinal Chemistry, 8(13), 1573-1587; 2016).

[0571] Step K: EDC, HOBT, in DMF, rt, 24 h.

Example 2B: Preparation of RTX60933293 (Compound 3)

[0572] Scheme 2 depicts the preparation of an exemplary compound.

##STR00107##

[0573] Step A: Et.sub.3N, in DMF, 1 h, rt (Sami, S. M. et al. Journal of Medicinal Chemistry, 32(3), 703-8; 1989).

[0574] Step B: H.sub.2O.sub.2, in H.sub.2O—AcOH, 0° C.; 2 h; b) Na.sub.2SO.sub.3, in H.sub.2O, rt (Kilburn, John Paul et al. PCT Int. Appl., 2007051811).

[0575] Step C: N.sub.2H4-H.sub.2O, in EtOH—CHCl.sub.3, 0° C.; overnight, rt (Kilburn, John Paul et al. PCT Int. Appl., 2007051811).

[0576] Step D (in situ): in DMF, rt, 1 h (Bogolubsky, A. V. et al. ACS Combinatorial Science (2014), 16(6), 303-8).

[0577] Step E: Mg, in THF, reflux, 2 h; b) in Et.sub.2O; rt, overnight; b) NH.sub.4C.sub.1, in H.sub.2O (Pinkerton, Anthony et al. PCT Int. Appl., 2014100501).

[0578] Step F: HCl in H.sub.2O (Lee, Y. et al. Journal of the American Chemical Society, 124(41), 12135-12143; 2002).

[0579] Step G: DBU, in DMF, rt, 4 h (Bogolubsky, A. V. et al. ACS Combinatorial Science (2014), 16(6), 303-8).

Example 2C: Preparation of RTX04306230 (Compound 7)

[0580] Scheme 3 depicts the preparation of an exemplary compound.

##STR00108##

[0581] Step A: Br.sub.2, in CHCl3, at 20° C. (LABORATORIOS ALMIRALL, S.A. WO200846598, 2008, A1).

[0582] Step B: DIPEA, in MeCN, rt, overnight (Zhang, Yang et al, PCT Int. Appl., 2015124063).

[0583] Step C: NH.sub.4OAc, in PhMe, reflux overnight (Zhang, Yang et al. PCT Int. Appl., 2015124063).

[0584] Step D: TFA, in CH.sub.2Cl.sub.2, 0° C.; 4 h, rt (Zhang, Yang et al. PCT Int. Appl., 2015124063).

[0585] Step E: SOCl.sub.2, in CH.sub.2Cl.sub.2, 3.5 h, rt.fwdarw.85° C.; b) MeOH, rt, 30 min (Corte, J. et al. PCT Int. Appl., 2005123680).

[0586] Step F: Pd(PPh.sub.3).sub.4, Na.sub.2CO.sub.3, in dioxane-H.sub.2O, 90° C., 8 h (Jones, Alison et al. PCT Int. Appl., 2016156816).

[0587] Step G: LiOH, S:THF—H.sub.2O, rt, 3 h (Jones, Alison et al. PCT Int. Appl., 2016156816).

[0588] Step H: EDC, HOBT, in DMF, rt, 24 h.