Patent Application
20090099157
The present invention relates to certain tetrahydro-pyrazolo-pyridine thioether compounds, pharmaceutical compositions containing them, and methods of using them for the treatment of disease states, disorders, and conditions mediated by cathepsin S activity.
Cathepsin S is one of the major cysteine proteases expressed in the lysosome of antigen presenting cells, mainly dendritic cells, B cells and macrophages. Cathepsin S is best known for its critical function in the proteolytic digestion of the invariant chain chaperone molecules, thus controlling antigen presentation to CD4+ T cells by major histocompatibility complex class II molecules or to NK1.1+ T cells via CD1 molecules. Cathepsin S also appears to participate in direct processing of exogenous antigens for presentation by MHC class II to CD4+ T cells or crosspresentation by MHC class I molecules to CD8+ T cells. In addition, cathepsin S in secreted form is implicated in degradation of extracellular matrix, which may contribute to the pathology of a number of diseases, including arthritis, atherosclerosis, and chronic obstructive pulmonary disease. Therefore, inhibition of cathepsin S is a promising target for the development of novel therapeutics for a variety of indications. For a review, see: Thurmond, R. L. et al. Curr. Opin. Invest. Drugs 2005, 6(5), 473-482.
Pyrazole inhibitors of cathepsin S were disclosed in a series of applications from Ortho-McNeil, and additional publications on this work have also appeared (See: U.S. Pat. Appl. Publ. Nos. 2002/0040020, 2003/0078419, and 2002/0040019; Wei, J. et al. Bioorg. Med. Chem. Lett. 2007, 17, 5525-5528; Grice, C. A. et al. Bioorg. Med. Chem. Lett. 2006, 16, 2209-2212; and Gustin, D. J. et al. Bioorg. Med. Chem. Lett. 2005, 15, 1678-1691). See also: Thurmond, R. L. et al. J. Pharm. Exp. Ther. 2004, 308, 268-276; and Thurmond, R. L. et al. J. Med. Chem. 2004, 47, 4799-4801). However, there remains a need for potent cathepsin S modulators with desirable pharmaceutical properties.
In one aspect the invention relates to compounds of the following Formula (I):
wherein:
In certain embodiments, the compound of Formula (I) is a compound selected from those species described or exemplified in the detailed description below.
In a further aspect, the invention relates to pharmaceutical compositions each comprising: (a) an effective amount of at least one chemical entity selected from compounds of Formula (I), and pharmaceutically acceptable salts, prodrugs, and metabolites thereof; and (b) a pharmaceutically acceptable excipient.
In another aspect, the invention is directed to a method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by cathepsin S activity, comprising administering to the subject in need of such treatment an effective amount of at least one chemical entity selected from compounds of Formula (I), and pharmaceutically acceptable salts, prodrugs, and metabolites thereof. Diseases, disorders and medical conditions that are mediated by cathepsin S activity include those referred to herein.
In another aspect, the chemical entities of the present invention are useful as cathepsin S modulators. Thus, the invention is directed to a method for modulating cathepsin S activity, including when such receptor is in a subject, comprising exposing cathepsin S to an effective amount of at least one chemical entity selected from compounds of Formula (I), pharmaceutically acceptable salts of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I), and pharmaceutically active metabolites of compounds of Formula (I).
Additional embodiments, features, and advantages of the invention will be apparent from the following detailed description and through practice of the invention.
For the sake of brevity, the disclosures of the publications, including patents, cited in this specification are herein incorporated by reference.
As used herein, the terms “including”, “containing” and “comprising” are used herein in their open, non-limiting sense.
The term “alkyl” refers to a saturated, straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain. Examples of alkyl groups include methyl (Me, which also may be structurally depicted by a bond, “/”), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
The term “cycloalkyl” refers to a saturated or partially saturated, monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from 3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkyl groups include the following entities, in the form of properly bonded moieties:
A “heterocycloalkyl” refers to a monocyclic, or fused, bridged, or spiro polycyclic ring structure that is saturated or partially saturated and has from 3 to 12 ring atoms per ring structure selected from carbon atoms and up to three heteroatoms selected from nitrogen, oxygen, and sulfur. In preferred embodiments, heterocycloalkyl rings have one or two heteroatoms. The ring structure may optionally contain up to two oxo groups on carbon or sulfur ring members. Illustrative entities, in the form of properly bonded moieties, include:
The term “heteroaryl” refers to a monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle. Illustrative examples of heteroaryl groups include the following entities, in the form of properly bonded moieties:
Those skilled in the art will recognize that the species of heteroaryl, cycloalkyl, and heterocycloalkyl groups listed or illustrated above are not exhaustive, and that additional species within the scope of these defined terms may also be selected.
The term “halogen” represents chlorine, fluorine, bromine, or iodine. The term “halo” represents chloro, fluoro, bromo, or iodo.
The term “substituted” means that the specified group or moiety bears one or more substituents. The term “unsubstituted” means that the specified group bears no substituents. The term “optionally substituted” means that the specified group is unsubstituted or substituted by one or more substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system that yields a stable chemical structure.
Any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms. In particular, compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof, are considered within the scope of the formula. Thus, any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers. Additionally, any formula given herein is intended to represent hydrates, solvates, and polymorphs of such compounds, and mixtures thereof.
To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about”. It is understood that, whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and/or measurement conditions for such given value. Whenever a yield is given as a percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently.
Reference to a chemical entity herein stands for a reference to any one of: (a) the actually recited form of such chemical entity, and (b) any of the forms of such chemical entity in the medium in which the compound is being considered when named. For example, reference herein to a compound such as R—COOH, encompasses reference to any one of, for example, R—COOH(s), R—COOH(sol), and R—COO−(sol). In this example, R—COOH(s) refers to the solid compound, as it could be for example in a tablet or some other solid pharmaceutical composition or preparation; R—COOH(sol) refers to the undissociated form of the compound in a solvent; and R—COO−(sol) refers to the dissociated form of the compound in a solvent, such as the dissociated form of the compound in an aqueous environment, whether such dissociated form derives from R—COOH, from a salt thereof, or from any other entity that yields R—COO− upon dissociation in the medium being considered. In another example, an expression such as “exposing an entity to compound of formula R—COOH” refers to the exposure of such entity to the form, or forms, of the compound R—COOH that exists, or exist, in the medium in which such exposure takes place. In this regard, if such entity is for example in an aqueous environment, it is understood that the compound R—COOH is in such same medium, and therefore the entity is being exposed to species such as R—COOH(aq) and/or R—COO−(aq), where the subscript “(aq)” stands for “aqueous” according to its conventional meaning in chemistry and biochemistry. A carboxylic acid functional group has been chosen in these nomenclature examples; this choice is not intended, however, as a limitation but it is merely an illustration. It is understood that analogous examples can be provided in terms of other functional groups, including but not limited to hydroxyl, basic nitrogen members, such as those in amines, and any other group that interacts or transforms according to known manners in the medium that contains the compound. Such interactions and transformations include, but are not limited to, dissociation, association, tautomerism, solvolysis, including hydrolysis, salvation, including hydration, protonation, and deprotonation. No further examples in this regard are provided herein because these interactions and transformations in a given medium are known by any one of ordinary skill in the art.
Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 15N, 18O, 17O, 32P, 33P, 35S, 18F, 36Cl, and 125I, respectively. Such isotopically labelled compounds are useful in metabolic studies (preferably with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an 18F or 11C labeled compound may be particularly preferred for PET or SPECT studies. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
When referring to any formula given herein, the selection of a particular moiety from a list of possible species for a specified variable is not intended to define the same choice of the species for the variable appearing elsewhere. In other words, where a variable appears more than once, the choice of the species from a specified list is independent of the choice of the species for the same variable elsewhere in the formula, unless stated otherwise.
By way of a first example on substituent terminology, if substituent S1example is one of S1 and S2, and substituent S2example is one of S3 and S4, then these assignments refer to embodiments of this invention given according to the choices S1example is S1 and S2example is S3; S1example is S1 and S2example is S4; S1example is S2 and S2example is S3; S1example is S2 and S2example is S4; and equivalents of each one of such choices. The shorter terminology “S1example is one of S1 and S2, and S2example is one of S3 and S4” is accordingly used herein for the sake of brevity, but not by way of limitation. The foregoing first example on substituent terminology, which is stated in generic terms, is meant to illustrate the various substituent assignments described herein. The foregoing convention given herein for substituents extends, when applicable, to any generic substituent symbol used herein.
Furthermore, when more than one assignment is given for any member or substituent, embodiments of this invention comprise the various groupings that can be made from the listed assignments, taken independently, and equivalents thereof. By way of a second example on substituent terminology, if it is herein described that substituent Sexample is one of S1, S2, and S3, this listing refers to embodiments of this invention for which Sexample is S1; Sexample is S2; Sexample is S3; Sexample is one of S1 and S2; Sexample is one of S1 and S3; Sexample is one of S2 and S3; Sexample is one of S1, S2 and S3; and Sexample is any equivalent of each one of these choices. The shorter terminology “Sexample is one of S1, S2, and S3” is accordingly used herein for the sake of brevity, but not by way of limitation. The foregoing second example on substituent terminology, which is stated in generic terms, is meant to illustrate the various substituent assignments described herein. The foregoing convention given herein for substituents extends, when applicable, to any generic substituent symbol used herein.
The nomenclature “Ci-j” with j>i, when applied herein to a class of substituents, is meant to refer to embodiments of this invention for which each and every one of the number of carbon members, from i to j including i and j, is independently realized. By way of example, the term C1-3 refers independently to embodiments that have one carbon member (C1), embodiments that have two carbon members (C2), and embodiments that have three carbon members (C3).
The term Cn-malkyl refers to an aliphatic chain, whether straight or branched, with a total number N of carbon members in the chain that satisfies n≦N≦m, with m>n.
Any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed. For example, reference to disubstituent -A-B-, where A≠B, refers herein to such disubstituent with A attached to a first substituted member and B attached to a second substituted member, and it also refers to such disubstituent with A attached to the second substituted member and B attached to the first substituted member.
According to the foregoing interpretive considerations on assignments and nomenclature, it is understood that explicit reference herein to a set implies, where chemically meaningful and unless indicated otherwise, independent reference to embodiments of such set, and reference to each and every one of the possible embodiments of subsets of the set referred to explicitly.
In some embodiments of Formula (I), —NR1R2 is a structure of Formula (II):
wherein:
In other embodiments of Formula (I), R1 and R2 taken together with the nitrogen to which they are attached form azetidine, pyrrolidine, piperidine, piperazine substituted with Ra, morpholine, or thiomorpholine, each unsubstituted or substituted with one, two, or three Rb substituents. In other embodiments, R1 and R2 taken together with the nitrogen to which they are attached form [1,4]diazepane substituted with Ra, azepane, 1,4,5,6-tetrahydro-pyrimidine substituted with Ra, 1,2,3,6-tetrahydropyridine, or piperazinone substituted with Ra, each unsubstituted or substituted with one, two, or three Rb substituents. In other embodiments, R1 and R2 taken together with the nitrogen to which they are attached form piperidine or piperazine substituted with Ra, each unsubstituted or substituted with one, two, or three Rb substituents.
In some embodiments, Ra is H, methyl, isopropyl, acetyl, or tertbutoxycarbonyl. In other embodiments, Ra is phenyl, cyclopropyl, pyridinyl, pyrimidinyl, or pyrazinyl, each optionally substituted. In still other embodiments, Ra is pyrimidin-2-yl, pyrazinyl, phenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-fluorophenyl, 4-fluorophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 2-ethoxyphenyl, 4-acetylphenyl, 2-chlorophenyl, 3-trifluoromethylphenyl, 3-chloropyridin-2-yl, or 3-cyano-pyridin-2-yl.
In some embodiments, each Rb substituent is independently OH, methyl, CF3, dimethylamino, acetamido, tert-butoxycarbamoyl, fluoro, or methoxy. In other embodiments, each Rb substituent is independently carbamoyl, tert-butyl, 1-hydroxy-1-methyl-ethyl, ureido, 2-hydroxy-acetylamino, ethoxycarbamoyl, methanesulfonylamino, pyrrolidine-1-carbonyl, amino, morpholine-4-carbonyl, dimethylaminomethyl, hydroxymethyl, acetylamino-methyl, carboxy, hydroxyethyl, difluoromethyl, piperidine-1-carbonyl, ethanesulfonylamino, 2-hydroxy-propionylamino, cyano, 2-hydroxy-2-methyl-propionylamino, or 2-oxo-2-pyrrolidin-1-yl-ethoxy. In other embodiments, Rb is pyrrolidinyl, 2-oxo-pyrrolidinyl, or piperidinyl, each optionally substituted. In still other embodiments, Rb is pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl, 5-dimethylamino-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-onyl, or 4-4H-benzo[1,4]oxazin-3-onyl. In still other embodiments, Rb is 5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl, morpholin-1-yl, pyrrolidin-2-on-1-yl, 4-hydroxy-2-oxo-pyrrolidin-1-yl, piperidin-1-yl, 5-oxo-1,5-dihydro-[1,2,4]triazol-4-yl, 5-chloro-1-methyl-1,3-dihydro-2H-benzimidazol-2-on-1-yl, or 5-chloro-1,3-dihydro-2H-benzimidazol-2-on-1-yl. In other embodiments, Rb is phenyl, pyridyl, pyrimidinyl, oxadiazolyl, 1H-pyrrolo[2,3-b]pyridin-3-yl, tetrazolyl, pyrimidinyloxy, pyridinyloxy, cyclohexyl, or benzyl, each optionally substituted. In further embodiments, Rb is phenyl, 4-cyanophenyl, 3-cyanophenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3-chlorophenyl, 3-trifluoromethylphenyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, 3-methyl-[1,2,4]oxadiazol-5-yl, 3-chloro-pyridin-2-yl, 1H-pyrrolo[2,3-b]pyridin-3-yl, 3,5-dichloro-pyridin-4-yl, 1-benzyl-1H-tetrazol-5-yl, cyclohexyl, benzyl, hydroxytriazolyl, pyrimidin-2-yloxy, or pyridin-2-yloxy. In other embodiments, two Rb substituents at the same carbon taken together with the carbon to which they are attached form a [1,3]dioxolane or [1,3]dioxane ring, each optionally substituted. In other embodiments, two Rb substituents on adjacent carbons taken together with the monocyclic heterocycloalkyl group to which they are attached form a fused ring system selected from the group consisting of hexahydro-cyclopenta[c]pyrrol-2-yl, 1,3-dihydro-isoindol-2-yl, 2,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl, 1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl, 3,4-dihydro-1H-isoquinolin-2-yl, or octahydro-isoquinolin-2-yl, each optionally substituted.
In some embodiments, R3 is H or OH.
In some embodiments, R4 is H, methyl, ethyl, acetyl, 2-hydroxyacetyl, 2-methoxyacetyl, 2-acetoxyacetyl, propionyl, 2-hydroxy-propionyl, 2-hydroxy-2-methylpropionyl, 2-hydroxy-2-phenyl-acetyl, 2-aminoacetyl, 2-dimethylamino-acetyl, 2-tert-butoxycarbonylamino-acetyl, 2-methylsulfanyl-acetyl, 2-(piperidin-4-yl)-acetyl, 2-(1-tert-butoxycarbonyl-piperidin-4-yl)-acetyl, or methoxyoxalyl. In other embodiments, R4 is aminooxalyl, methylaminooxalyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, isopropylcarbamoyl, sec-butylcarbamoyl, tert-butylcarbamoyl, diethylcarbamoyl, diisopropylcarbamoyl, pyrrolidine-1-carbonyl, morpholine-4-carbonyl, phenylcarbamoyl, cyclohexylcarbamoyl, thiophen-2-ylcarbamoyl, 4-methyl-piperazine-1-carbonyl, or (4-dimethylaminophenyl)carbamoyl. In other embodiments, R4 is ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, trifluoromethanesulfonyl, cyclopropanesulfonyl, benzenesulfonyl, benzylsulfonyl, or dimethylsulfamoyl. In other embodiments, R4 is cyclobutanecarbonyl, 1-amino-cyclopropanecarbonyl, 1-tert-butoxycarbonylamino-cyclopropanecarbonyl, 1H-[1,2,4]triazole-3-carbonyl, 1-methyl-1H-imidazole-2-carbonyl, thiophene-2-carbonyl, furan-2-carbonyl, tetrahydrofuran-2-carbonyl, 1-methylpyrrolidine-2-carbonyl, 1-acetyl-pyrrolidine-2-carbonyl, 1-trifluoroacetyl-pyrrolidine-2-carbonyl, piperidine-3-carbonyl, or 1-tert-butoxycarbonyl-piperidine-3-carbonyl. In other embodiments, R4 is —SO2CH3, —CONH2, or —COCONH2. In other embodiments, R4 is —SO2CH3.
In some embodiments, R5 is chloro or CF3. In other embodiments, R5 is CF3.
In some embodiments, each R6 is H.
In some embodiments, each R7 is H. In other embodiments, both R7 together form a carbonyl.
In some embodiments, R8 is H or methyl.
In some embodiments, R9 is a methyl, ethyl, propyl, isopropyl, sec-butyl, iso-butyl, or tert-butyl group, each unsubstituted or substituted with Re. In other embodiments, R9 is R10, and R10 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, indanyl, and piperidin-4-yl, each unsubstituted or substituted with methyl, OH, methoxy, dimethylamino, tert-butoxycarbonyl, or halo. In other embodiments, R10 is a phenyl group, unsubstituted or substituted with methyl, OH, halo, dimethylamino, phenyl, or benzyloxy. In other embodiments, R10 is a benzyl or phenethyl group.
In some embodiments, R9 is —COR11, and R11 is a methyl, ethyl, or propyl group, each unsubstituted or substituted with Re. In other embodiments, R11 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, indanyl, and piperidin-4-yl, each unsubstituted or substituted with methyl, OH, methoxy, or halo. In other embodiments, R11 is a phenyl group, unsubstituted or substituted with methyl, ethyl, OH, halo, dimethylamino, or tert-butoxycarbonyl.
In some embodiments, Re is OH, methoxy, dimethylamino, diethylamino, or tert-butoxycarbamoyl. In other embodiments, Re is a cyclopropyl, cyclopentyl, cyclohexyl, furanyl, thiophenyl, pyridyl, phenyl, phenoxy, or imidazolyl group, each unsubstituted or substituted with methyl, OH, methoxy, dimethylamino, or halo. In still other embodiments, Re is OH, methoxy, thiophen-2-yl, cyclohexenyl, phenoxy, piperidinyl, pyrrolidinyl, or tert-butoxycarbamoyl.
In some embodiments, R9 is tert-butoxycarbonyl, cyclopentyl, cyclohexyl, benzyl, methyl, 3-methoxypropyl, thiophen-2-ylmethyl, 2-cyclohex-1-enyl-ethyl, 2-phenoxy-ethyl, 2-morpholin-4-yl-ethyl, 1-ethyl-pyrrolidin-2-ylmethyl, 4-biphenyl, indan-2-yl, 3-biphenyl, 9H-fluoren-1-yl, 4-benzyloxy-phenyl, phenethyl, 4-fluorophenyl, or 1-methyl-piperidin-4-yl. In other embodiments, R9 is propyl, isopropyl, isobutyl, cyclopropyl, 1-methyl-3-phenyl-propyl, 3-hydroxy-propyl, 2-(1H-imidazol-4-yl)-ethyl, or 1-(tert-butoxycarbonyl)-piperidin-4-yl. In other embodiments, R9 is benzoyl, phenylacetyl, 1-tert-butoxycarbonyl-piperidine-4-carbonyl, tert-butylcarbamoyl-acetyl, 4-fluorobenzoyl, 4-hydroxybenzoyl, 4-dimethylamino-benzoyl, 4-fluorophenylacetyl, 1-tert-butoxycarbonyl-piperidine-3-carbonyl, 1-tert-butoxycarbonyl-pyrrolidine-3-carbonyl, 4-tert-butylcarbamoyl-1-butyryl, piperidine-3-carbonyl, pyrrolidine-3-carbonyl, piperidine-4-carbonyl, or benzyloxycarbonyl.
In some embodiments, R9 is —SO2R11, —SO2CF3, or —SO2N(C1-4alkyl)2. In further embodiments, R9 is methanesulfonyl, ethanesulfonyl, dimethylsulfamoyl, trifluoromethanesulfonyl, or benzenesulfonyl.
In some embodiments, R8 and R9 taken together with the nitrogen to which they are attached form azetidine, pyrrolidine, piperidine, piperazine substituted with Rh, morpholine, thiomorpholine, 1,1-dioxo-1λ6-thiomorpholine, azepine, diazepine substituted with Rh, 3,6-dihydro-2H-pyridine, or thiazolidine, each unsubstituted or substituted with Ri as described for Formula (I). In other embodiments, R8 and R9 taken together with the nitrogen to which they are attached form pyrrolidine or piperidine, each unsubstituted or substituted with Rh and Ri as described for Formula (I). In other embodiments, R8 and R9 taken together with the nitrogen to which they are attached form piperazine, morpholine, azetidine, oxo-imidazolidin-1-yl, dihydro-pyrimidin-1-yl, or oxo-piperazinyl.
In some embodiments, Rh is H, methyl, isopropyl, acetyl, tertbutoxycarbonyl, phenyl, or phenethyl.
In some embodiments, each Ri substituent is independently: a methyl or ethyl group unsubstituted or substituted with OH or phenyl; tert-butyl; CF3; fluoro; OH; methoxy; dimethylamino; acetylamino; 2-hydroxy-acetylamino; ethoxycarbonylamino; tert-butoxycarbonylamino; piperidin-1-yl; pyrrolidin-1-yl; acetyl; methoxycarbonyl; carbamoyl; dimethylcarbamoyl; diethylcarbamoyl; phenyl; pyridyl; or benzyl; or two adjacent Ri substituents taken together with the carbons to which they are attached form phenyl, cyclopentyl, or cyclohexyl.
In other embodiments, R8 and R9 taken together with the nitrogen to which they are attached form piperidin-1-yl, 4-hydroxy-piperidin-1-yl, octahydro-isoquinolin-2-yl, 4,4-difluoro-piperidin-1-yl, 3-methyl-piperidin-1-yl, 3,5-dimethylpiperidin-1-yl, 4-methyl-piperidin-1-yl, 3,3-difluoro-piperidin-1-yl, octahydro-quinolin-1-yl, 3-hydroxymethyl-piperidin-1-yl, 3,6-dihydro-2H-pyridin-1-yl, 1,1-dioxo-1λ6-thiomorpholin-4-yl, 4-tert-butyl-piperidin-1-yl, 3-fluoro-piperidin-1-yl, 2-methyl-piperidin-1-yl, 4-phenyl-piperidin-1-yl, 2-trifluoromethyl-pyrrolidin-1-yl, morpholin-1-yl, 4-(2-hydroxy-ethyl)-piperidin-1-yl, pyrrolidin-1-yl, 4-phenyl-piperazin-1-yl, 2-methyl-pyrrolidin-1-yl, 4-methylpiperazin-1-yl, 4-dimethylamino-piperidin-1-yl, 2-phenyl-piperidin-1-yl, 4-carbamoyl-piperidin-1-yl, 4-methoxy-piperidin-1-yl, 3-trifluoromethyl-piperidin-1-yl, 2-hydroxymethyl-piperidin-1-yl, 4-trifluoromethyl-piperidin-1-yl, 2-thiazolidin-3-yl, 3-hydroxy-pyrrolidin-1-yl, 3,4-dihydro-1H-isoquinolin-2-yl, 4-methyl-[1,4]diazepan-1-yl, 3-diethylcarbamoyl-piperidin-1-yl, 3-dimethylamino-pyrrolidin-1-yl, 4-phenyl-3,6-dihydro-2H-pyridin-1-yl, [1,4′]bipiperidinyl-1′-yl, 2-azepan-1-yl, 4-benzyl-piperidin-1-yl, 4-phenethyl-piperidin-1-yl, 4-diethylcarbamoyl-piperidin-1-yl, 2-carbamoyl-pyrrolidin-1-yl, 4-fluoro-piperidin-1-yl, 4-isopropyl-piperazin-1-yl, or 4-phenethyl-piperazin-1-yl. In other embodiments, R8 and R9 taken together with the nitrogen to which they are attached form 3-hydroxy-piperidin-1-yl, 4-(acetylamino)-piperidin-1-yl, 3-hydroxymethyl-piperidin-1-yl, 4-(pyrrolidin-1-yl)-piperidin-1-yl, 4-(1-hydroxy-1-methyl-ethyl)-piperidin-1-yl, 4-(2-hydroxy-acetylamino)-piperidin-1-yl, 4-hydroxy-4-(2-pyridinyl)-piperidin-1-yl, 3,3-dimethyl-piperidin-1-yl, 3-phenyl-piperidin-1-yl, 4-ethoxycarbonylamino-piperidin-1-yl, 2-benzyl-piperidin-1-yl, 3-benzyl-piperidin-1-yl, 4-tert-butoxycarbonylamino-piperidin-1-yl, 4-acetyl-piperazin-1-yl, 3-methyl-morpholin-4-yl, 2,6-dimethyl-morpholin-4-yl, 3-hydroxymethyl-morpholin-4-yl, 2-hydroxylmethyl-morpholin-4-yl, 3,3-difluoro-pyrrolidin-1-yl, 3-fluoro-pyrrolidin-1-yl, 3-hydroxymethyl-pyrrolidin-1-yl, azetidinyl, 4-oxo-imidazolidin-1-yl, 5,6-dihydro-4H-pyrimidin-1-yl, 2-methyl-3-oxo-piperazin-1-yl), or hexahydro-cyclopenta[c]pyrrol-2-yl.
In other embodiments, compounds of Formula (I) are selected from compounds of the following Formula (IV):
Other embodiments include combinations of the above variable definitions.
The invention includes also pharmaceutically acceptable salts of the compounds represented by Formula (I), preferably of those described above and of the specific compounds exemplified herein, and methods of treatment using such salts.
A “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented by Formula (I) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S. M. Berge, et al., “Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. A compound of Formula (I) may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.
If the compound of Formula (I) contains a basic nitrogen, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.
If the compound of Formula (I) is an acid, such as a carboxylic acid or sulfonic acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide, any compatible mixture of bases such as those given as examples herein, and any other base and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines, such as benzylamines, pyrrolidines, piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
The invention also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I), pharmaceutical compositions containing such pharmaceutically acceptable prodrugs, and treatment methods employing such pharmaceutically acceptable prodrugs. The term “prodrug” means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula (I)). A “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.
Examples of prodrugs include compounds having an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues, covalently joined through an amide or ester bond to a free amino, hydroxy, or carboxylic acid group of a compound of Formula (I). Examples of amino acid residues include the twenty naturally occurring amino acids, commonly designated by three letter symbols, as well as 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone.
Additional types of prodrugs may be produced, for instance, by derivatizing free carboxyl groups of structures of Formula (I) as amides or alkyl esters. Examples of amides include those derived from ammonia, primary C1-6alkyl amines and secondary di(C1-6alkyl) amines. Secondary amines include 5- or 6-membered heterocycloalkyl or heteroaryl ring moieties. Examples of amides include those that are derived from ammonia, C1-3alkyl primary amines, and di(C1-2alkyl)amines. Examples of esters of the invention include C1-7alkyl, C5-7cycloalkyl, phenyl, and phenyl(C1-6alkyl) esters. Preferred esters include methyl esters. Prodrugs may also be prepared by derivatizing free hydroxy groups using groups including hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, following procedures such as those outlined in Adv. Drug Delivery Rev. 1996, 19, 115. Carbamate derivatives of hydroxy and amino groups may also yield prodrugs. Carbonate derivatives, sulfonate esters, and sulfate esters of hydroxy groups may also provide prodrugs. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group may be an alkyl ester, optionally substituted with one or more ether, amine, or carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, is also useful to yield prodrugs. Prodrugs of this type may be prepared as described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including ether, amine, and carboxylic acid functionalities.
The present invention also relates to pharmaceutically active metabolites of compounds of Formula (I), and uses of such metabolites in the methods of the invention. A “pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula (I) or salt thereof. Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini, et al., J. Med. Chem. 1997, 40, 2011-2016; Shan, et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 224-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen, et al., eds., Harwood Academic Publishers, 1991).
The compounds of Formula (I) and their pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites (collectively, “active agents”) of the present invention are useful in the methods of the invention.
The compounds of Formula (I) and their pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites, whether alone or in combination, (collectively, “active agents”) of the present invention are useful as cathepsin S modulators in the methods of the invention. Such methods for modulating cathepsin S activity comprise exposing cathepsin S to an effective amount of at least one chemical entity selected from compounds of Formula (I), pharmaceutically acceptable salts of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I), and pharmaceutically active metabolites of compounds of Formula (I). Embodiments of this invention inhibit cathepsin S activity.
In some embodiments, the cathepsin S is in a subject with a disease, disorder, or medical condition mediated through modulation of the cathepsin S, such as those described herein. Symptoms or disease states are intended to be included within the scope of “medical conditions, disorders, or diseases.”
Accordingly, the invention relates to methods of using the active agents described herein to treat subjects diagnosed with or suffering from a disease, disorder, or condition mediated through cathepsin S activity, such as an autoimmune disease, an allergic condition, inflammation, a bowel disorder, tissue transplant rejection, pain, neuropathic pain, or cancer. Active agents according to the invention may therefore be used as immunomodulating agents, immunosuppressants, anti-allergy agents, anti-inflammatory agents, analgesics, or anti-cancer agents.
In some embodiments, an active agent of the present invention is administered to treat lupus, asthma, allergic reaction, atopic allergy, hay fever, atopic dermatitis, food allergy, rhinitis (such as allergic rhinitis and the inflammation caused by non-allergic rhinitis), skin immune system disorders (such as psoriasis), uveitis, inflammation, upper airway inflammation, Sjögren's syndrome, arthritis, rheumatoid arthritis, osteoarthritis, type I diabetes, atherosclerosis, multiple sclerosis, coeliac disease, inflammatory bowel disease (IBD), chronic obstructive pulmonary disorder (COPD), tissue transplant rejection, pain, chronic pain (such as pain due to conditions such as cancer, neuropathic pain, rheumatoid arthritis, osteoarthritis and inflammatory conditions), or cancer (and cancer-related processes such as angiogenesis, tumor growth, cell proliferation, and metastasis). In certain embodiments, an active agent of the present invention is administered to treat psoriasis, pain, multiple sclerosis, atherosclerosis, or rheumatoid arthritis.
Thus, the active agents may be used to treat subjects diagnosed with or suffering from a disease, disorder, or condition mediated through cathepsin S activity. The term “treat” or “treating” as used herein is intended to refer to administration of an active agent or composition of the invention to a subject for the purpose of effecting a therapeutic or prophylactic benefit through modulation of cathepsin S activity. Treating includes reversing, ameliorating, alleviating, inhibiting the progress of, lessening the severity of, or preventing a disease, disorder, or condition, or one or more symptoms of such disease, disorder or condition mediated through modulation of cathepsin S activity. The term “subject” refers to a mammalian patient in need of such treatment, such as a human. “Modulators” include both inhibitors and activators, where “inhibitors” refer to compounds that decrease, prevent, inactivate, desensitize or down-regulate cathepsin S expression or activity, and “activators” are compounds that increase, activate, facilitate, sensitize, or up-regulate cathepsin S expression or activity.
In treatment methods according to the invention, an effective amount of at least one active agent according to the invention is administered to a subject suffering from or diagnosed as having such a disease, disorder, or condition. An “effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic or prophylactic benefit in patients in need of such treatment for the designated disease, disorder, or condition. Effective amounts or doses of the active agents of the present invention may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician. An exemplary dose is in the range of from about 0.001 to about 200 mg of active agent per kg of subject's body weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, or about 0.1 to 10 mg/kg daily in single or divided dosage units (e.g., BID, TID, QID). For a 70-kg human, an illustrative range for a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 2.5 g/day.
Once improvement of the patient's disease, disorder, or condition has occurred, the dose may be adjusted for preventative or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
In addition, the active agents of the invention may be used in combination with additional active ingredients in the treatment of the above conditions. The additional active ingredients may be coadministered separately with an active agent of Formula (I) or included with such an agent in a pharmaceutical composition according to the invention. In an exemplary embodiment, additional active ingredients are those that are known or discovered to be effective in the treatment of conditions, disorders, or diseases mediated by cathepsin S activity, such as another cathepsin S modulator or a compound active against another target associated with the particular condition, disorder, or disease. The combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of an agent according to the invention), decrease one or more side effects, or decrease the required dose of the active agent according to the invention.
The active agents of the invention are used, alone or in combination with one or more additional active ingredients, to formulate pharmaceutical compositions of the invention. A pharmaceutical composition of the invention comprises: (a) an effective amount of at least one active agent in accordance with the invention; and (b) a pharmaceutically acceptable excipient.
A “pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a agent and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
Delivery forms of the pharmaceutical compositions containing one or more dosage units of the active agents may be prepared using suitable pharmaceutical excipients and compounding techniques known or that become available to those skilled in the art. The compositions may be administered in the inventive methods by a suitable route of delivery, e.g., oral, parenteral, rectal, topical, or ocular routes, or by inhalation.
The preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories. Preferably, the compositions are formulated for intravenous infusion, topical administration, or oral administration.
For oral administration, the active agents of the invention can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension. To prepare the oral compositions, the active agents may be formulated to yield a dosage of, e.g., from about 0.05 to about 50 mg/kg daily, or from about 0.05 to about 20 mg/kg daily, or from about 0.1 to about 10 mg/kg daily.
Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.
Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
The active agents of this invention may also be administered by non-oral routes. For example, compositions may be formulated for rectal administration as a suppository. For parenteral use, including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the agents of the invention may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose form such as ampules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses range from about 1 to 1000 μg/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
For topical administration, the agents may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering the agents of the invention may utilize a patch formulation to affect transdermal delivery.
Active agents may alternatively be administered in methods of this invention by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.
Exemplary chemical entities useful in methods of the invention will now be described by reference to illustrative synthetic schemes for their general preparation below and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. In addition, artisans will note that the various transformations described in the following Schemes may be performed in a different order than that depicted. Unless otherwise specified, the variables are as defined above in reference to Formula (I).
Abbreviations and acronyms used herein include the following:
Referring to Scheme A, the tetrahydro-pyrazolo-pyridine core structure of Formula (I) may be prepared from commercially available piperidones (X). Installation of the R4 substituent is accomplished through, for example, alkylation, acylation, amide formation, or other suitable methods methods known in the art to provide ketones (XI). Alternatively, an amine protecting group, such as a Boc group, may be installed, and, at a later point in the synthesis, be removed (for example, by treatment with an acid such as HCl or TFA) and replaced with R4. Enamine formation according to general methods gives enamines (XII), which are then reacted with acyl chlorides, ArC(O)Cl, where Ar is a suitably substituted phenyl group, in the presence of a suitable tertiary amine base, to form enamines (XIII) or the corresponding beta-diketones, or a mixture thereof (not isolated). In situ reaction of the enamines with hydrazine generates pyrazoles (XIV).
As shown in Scheme B, where Ar is a suitably substituted group as in Formula (XV), thioethers may be installed by any one of several methods to give compounds of Formula (XVI), including coupling with thiols HSR, where R is a suitable group that is or may be transformed into —CH2C(R7)2N(R8)R9 according to the subsequent Schemes or other standard methods. For example, thiols HSR where R is —CH2CH2N(R8)R9 may be prepared by reaction of amines HN(R8)R9 with thiirane. Where substituent X is iodide or bromide, coupling with thiols HSR is performed in the presence of a palladium catalyst, such as Pd2 dba3, optional additives such as dppf, a suitable base such as TEA, in a polar solvent such as DMF. Where substituent X is F, reaction with thiols HSR is done at elevated temperatures, preferably using microwave irradiation, in a polar solvent such as DMF. Alternatively, where R5 is an electron withdrawing group such as C1 or CF3 and substituent X is F or NO2, displacement with thiols HSR may be accomplished in the presence of a suitable base. Any thioethers may be oxidized to the corresponding sulfoxides or sulfones (not shown) using methods known in the art, such as meta-chloroperbenzoic acid (mCPBA), dimethyldioxirane, or TeO2/H2O2.
The chemistry described in Scheme B may be used with thiols HSR to generate thioether intermediates that are amenable to subsequent conversion into compounds of Formula (I). Examples are shown in Scheme C.
Thioethers (XVIII) may be converted using known methods into compounds of Formula (XIX), as depicted in Scheme C. Where the two R7 substituents are not carbonyl, activation of the hydroxy group and displacement with amines HNR8R9 give amines (XIX). Where the two R7 groups form a carbonyl group, acids (XVIII) may be coupled with amines HR8R9 using general amide coupling procedures. Also useful are aminoethyl derivatives (XX), where PG is a suitable nitrogen protecting group, such as a Boc group. Deprotection of the PG group and subsequent alkylation, amide formation, or reductive amination gives rise to amines or amides (XIX).
Two variations for the installation of the propyl amino chain are shown in Scheme D. One skilled in the art will recognize an amine protecting group, such as a Boc group, may be installed in place of the R4 shown, and, at a later point in the synthesis, be removed (for example, by treatment with an acid such as HCl or TFA) and replaced with R4. Pyrazoles (XXI) are alkylated with optionally protected reagents (XXII), where R3 is H, C1-4alkyl, —OC1-4alkyl, or a protected hydroxyl group, Y is an aldehyde, a protected aldehyde, —CH2—OH, a —CH2— (protected hydroxyl) group, —CH2—Cl, or —CH2NR1R2, and LG is a suitable leaving group, such as a chloride, bromide, iodide, mesylate or tosylate, to give compounds (XXIII). Where Y is a protected aldehyde (such as an acetal) or a —CH2— (protected hydroxyl) group, deprotection of (XXIII) is accomplished under general conditions. Resulting aldehydes are reacted with amines (XXIV) under reductive amination conditions, to provide propyl amines (XXV) where R3 is H, C1-4alkyl, or —OC1-4alkyl. Alcohols are converted to suitable leaving groups (LG), and displaced with amines HNR1R2. Where Y is —CH2NR1R2, the alkylation step leads to compounds (XXV) directly.
Alternatively, pyrazoles (XXI) are reacted with epichlorohydrin or glycidyinosylate, in the presence of a suitable base, to give epoxides (XXVI). Epoxide opening with amines (XXIV), preferably at elevated temperatures, yields propyl amines (XXV) where R3 is OH.
In another embodiment, shown in Scheme E, addition of pyrazoles (XXI) to α,β-unsaturated nitriles (XXVI), in the presence of a suitable base, such as aq. NaOH, generates nitriles (XXVII). Reduction of the nitriles to the corresponding aldehydes (XXIII, not shown) is accomplished with a reducing agent such as DIBAL-H. Reductive amination of aldehydes (XXIII) with amines (XXIV) gives amines (XXV) as described in Scheme D.
Compounds of Formula (I) may be converted to their corresponding salts using methods described in the art. For example, an amine of Formula (I) may be treated with trifluoroacetic acid, HCl, or citric acid in a solvent such as Et2O, CH2Cl2, THF, or MeOH to provide the corresponding salt form.
Compounds prepared according to the schemes described above may be obtained as single enantiomers, diastereomers, or regioisomers, by enantio-, diastero-, or regiospecific synthesis, or by resolution. Compounds prepared according to the schemes above may alternately be obtained as racemic (1:1) or non-racemic (not 1:1) mixtures or as mixtures of diastereomers or regioisomers. Where racemic and non-racemic mixtures of enantiomers are obtained, single enantiomers may be isolated using conventional separation methods known to one skilled in the art, such as chiral chromatography, recrystallization, diastereomeric salt formation, derivatization into diastereomeric adducts, biotransformation, or enzymatic transformation. Where regioisomeric or diastereomeric mixtures are obtained, single isomers may be separated using conventional methods such as chromatography or crystallization.
The following specific examples are provided to further illustrate the invention and various preferred embodiments.
In obtaining the compounds described in the examples below and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated.
Unless otherwise stated, reaction mixtures were magnetically stirred at room temperature (rt). Where solutions are “dried,” they are generally dried over a drying agent such as Na2SO4 or MgSO4. Where mixtures, solutions, and extracts were “concentrated”, they were typically concentrated on a rotary evaporator under reduced pressure.
Microwave reactions were performed on a Personal Chemistry Emrys Optimizer. Individual reactions were heated to the desired temperature and held at that temperature for the allotted time.
Analytical HPLC retention times are reported in minutes, and were obtained on an Agilent HP-1100 instrument with a Phenomenex Luna C-18 (5 uM, 4.6×150 mm) column, with a flow rate of 1 mL/min, detection at 230, 254, and 280 nM, and a gradient of 10 to 100% CH3CN (0.05% TFA)/H2O (0.05% TFA). Alternatively, analytical reversed-phase HPLC was performed on an Agilent 1100 Series instrument using one of the following gradients: 1 to 99% acetonitrile/water (0.05% trifluoroacetic acid) over 5.0 min or 7.0 min with a flow rate of 1 mL/min (Waters XTerra MS C18 (5 μm, 4.6×100 mm) column or Phenomenex Synergi max-RP (4 μm, 4.6×150 mm) column) or 1 to 99% acetonitrile/water (20 mM NH4OH) over 5.0 min or 7.0 min with a flow rate of 1.5 mL/min (Phenomenex Gemeni C18 (5 μm, 3.0×150 mm) column). Analytical reversed-phase LC/MS was performed either on an Agilent 1100 Series instrument using 5 to 99% acetonitrile/water (0.05% trifluoroacetic acid) over 5.0 min or 7.0 min with a flow rate of 0.6 mL/min (Waters XTerra RP18 (5 μm, 3.0×100 mm) column) or on a Waters 2790 instrument using 5 to 99% acetonitrile/water (0.1% formic acid) over 5.0 min with a flow rate of 0.6 mL/min (Waters XTerra RP18 (5 μm, 3.0×100 mm) column).
Preparatory HPLC purifications were typically performed on a Phenomenex Synergi column (4 μm, 21×150 mm), with a flow rate of 25 mL/min, and solvent conditions as described for Analytical HPLC. Alternatively, preparative reversed phase HPLC was performed on a Dionex APS2000 LC/MS or HPLC with a Phenomenex Gemini C18 (5 μm, 30×100 mm) column or a Waters XBridge C18 (5 μm, 30×100 mm) column and variable gradients of acetonitrile/water (20 mM NH4OH) at a flow rate of 30 mL/min. Alternatively, the purification was performed with a Phenomenex Gemini C18 (5 μm, 50×100 mm) column or a Waters XBridge C18 (5 μm, 50×100 mm) column and variable gradients of acetonitrile/water (20 mM NH4OH) at a flow rate of 80 mL/min.
Lyophilization of the mobile phase from preparatory HPLC runs afforded the free base, ammonium salt, or trifluoroacetate salt forms. Hydrochloric acid salts or citric acid salts were prepared by addition of 4 N HCl/1,4-dioxane, 2 M HCl/Et2O, 1.25 M HCl/MeOH, or solid citric acid to solutions of the free base in CH2Cl2, followed by concentration.
Mass spectra (MS) were obtained on an Agilent series 1100 MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated (calcd.) mass corresponds to the exact mass. The MS data presented is the m/z found (typically [M+H]+) for the molecular ion.
Nuclear magnetic resonance (NMR) spectra were obtained on Bruker model DRX spectrometers (400, 500, or 600 MHz). The format of the 1H NMR data below is: chemical shift in ppm downfield of the tetramethylsilane reference (multiplicity, coupling constant J in Hz, integration). All 1H NMR data was acquired in CD3OD solvent unless otherwise indicated. NMR interpretation was performed using MestReC software to assign chemical shift and multiplicity. In cases where 2 adjacent peaks of equal or unequal height were observed, these 2 peaks may be labeled either as a multiplet or as a doublet. In the case of a doublet a coupling constant using this software may be assigned.
Chemical names were generated using ChemDraw Version 6.0.2 (CambridgeSoft, Cambridge, Mass.) or ACD/Name Version 9 (Advanced Chemistry Development, Toronto, Ontario, Canada).
A. 1-Methanesulfonyl-piperidin-4-one. To a solution of 4-piperidone monohydrate hydrochloride (90 g, 586 mmol) in CHCl3 (300 mL) and H2O (300 mL) was added K2CO3 (324 g, 2340 mmol). The slurry was cooled to 0° C. and treated with methylsulfonyl chloride (MsCl; 136 mL, 1760 mmol) by drop-wise addition over a 1 h period (gas evolution was observed). The reaction mixture was allowed to shake for 72 h and was partitioned between CH2Cl2 (500 mL) and saturated (satd.) aq. NaHCO3 (500 mL). The aqueous layer was extracted with CH2Cl2 (3×, 200 mL). The organic layer was washed with 1% KHSO4 (250 mL), dried (Na2SO4), and concentrated to give 1-methanesulfonyl-piperidin-4-one (90.5 g, 87%) as a white solid. MS (ESI): mass calcd. for C6H11NO3S, 177.05; m/z found, 178.1 [M+H]+. 1H NMR (CDCl3): 3.60 (t, J=6.5, 4H), 2.89 (s, 3H), 2.59 (t, J=6.3, 4H).
B. 5-Methanesulfonyl-3-(3-nitro-4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. p-Toluenesulfonic acid (0.12 g, 0.6 mmol) and morpholine (11.7 mL, 140.0 mmol) were added to a solution of 1-methanesulfonyl-piperidin-4-one (22.6 g, 127.6 mmol) in benzene (100 mL). The reaction mixture was heated at reflux in a flask equipped with a condenser and a Dean-Stark trap for 20 h. The reaction mixture was cooled and concentrated to give the enamine, which was used without further purification.
A 0° C. solution of the enamine (31.4 g, 127.6 mmol) in CH2Cl2 (60 mL) was treated with TEA (24.8 mL, 191.4 mmol) followed by drop-wise addition of a solution of 4-trifluoromethyl-3-nitrobenzoyl chloride* (32.3 g, 127.6 mmol) in CH2Cl2 (60 mL). The reaction mixture was allowed to warm to room temperature (rt) and stirred for 18 h. The reaction mixture was poured into H2O (100 mL). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (4×, 50 mL). The combined organic layers were dried (Na2SO4) and concentrated. The resulting oil was taken up in EtOH (200 mL) and treated with hydrazine (12.0 mL, 382.8 mmol) at 0° C. The reaction mixture was allowed to warm to rt and stirred for 18 h before concentration. The resulting material was taken up in CH2Cl2 and filtered. The crude solid was rinsed with additional CH2Cl2, 1 N HCl, and H2O to afford a light yellow solid (18.9 g, 38%). 1H NMR (DMSO-d6): 8.31 (s, 1H), 8.12-8.04 (m, 2H), 4.54 (s, 2H), 3.56-3.50 (m, 2H), 3.00 (s, 3H), 2.89-2.84 (m, 2H). *Prepared by dissolving 4-trifluoromethyl-3-nitrobenzoic acid (30.0 g, 127.6 mmol) in toluene (350 mL) and thionyl chloride (11.2 mL, 153.1 mmol). A catalytic amount of DMF (850 μL) was added, and the mixture was stirred at rt for 15 h before heating to 50° C. for 6 h. After cooling to rt, the reaction mixture was concentrated and the resulting benzoyl chloride was used without further purification.
C. 2-[5-(5-Methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-trifluoromethyl-phenylsulfanyl]-ethanol. To a solution of 5-methanesulfonyl-3-(3-nitro-4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (4.0 g, 10.2 mmol) and K2CO3 (1.7 g, 12.3 mmol) in DMF (34 mL) was added 2-mercaptoethanol (2.9 mL, 40.9 mmol). The reaction mixture was heated to 70° C. for 13 h, cooled to rt, and poured into 1:1 brine/H2O (100 mL). The resulting precipitate was filtered and rinsed with cold H2O to provide an off-white solid (4.32 g, 100%). MS (ESI): mass calcd. for C16H18F3N3O3S2, 421.07; m/z found, 422.1 [M+H]+. 1H NMR (DMSO-d6): 7.81 (s, 1H), 7.77 (d, J=8.2, 1H), 7.52 (d, J=8.2, 1H), 5.10 (br s, 1H), 4.49 (s, 2H), 3.67 (t, J=6.6, 2H), 3.52 (t, J=5.8, 2H), 3.22 (t, J=6.6, 2H), 3.00 (s, 3H), 2.85 (t, J=5.7, 2H).
D. 2-[5-[1-(2-[1,3]Dioxolan-2-yl-ethyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-p]pyridin-3-yl]-2-trifluoromethyl-phenylsulfanyl]-ethanol. To a solution of 2-[5-(5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-trifluoromethyl-phenylsulfanyl]-ethanol (3.0 g, 7.1 mmol) and Cs2CO3 (4.6 g, 14.2 mmol) in DMF (30 mL) was added 2-(2-bromoethyl)-1,3-dioxolane (1.3 mL, 10.7 mmol). The reaction mixture was stirred at rt for 18 h and poured into cold satd. aq. NH4Cl (100 mL). The resulting precipitate was filtered and rinsed with H2O to afford an off-white solid (3.3 g, 93%) that was used without further purification. MS (ESI): mass calcd. for C21H26F3N3O5S2, 521.13; m/z found, 522.1 [M+H]+. 1H NMR (DMSO-d6): 7.76 (s, 1H), 7.55 (d, J=8.5, 1H), 7.08 (br s, 1H), 5.05 (t, J=5.4, 1H), 4.84 (t, J=4.6, 1H), 4.47 (s, 2H), 4.19-4.12 (m, 2H), 3.93-3.90 (m, 2H), 3.80-3.77 (m, 2H), 3.67-3.62 (m, 2H), 3.55-3.50 (m, 2H), 3.18 (t, J=6.6, 2H), 2.99 (s, 3H), 2.89-2.86 (m, 2H).
E. 3-{3-[3-(2-Hydroxy-ethylsulfanyl)-4-trifluoromethyl-phenyl]-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl-propionaldehyde. To a solution of 2-{5-[1-(2-[1,3]dioxolan-2-yl-ethyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-trifluoromethyl-phenylsulfanyl}-ethanol (2.0 g, 3.8 mmol) in acetone (32 mL) was added 1 N HCl (9.0 mL, 9.0 mmol). The reaction mixture was heated to 55° C. for 6 h or until reaction completion as monitored by HPLC. Additional aliquots of 1 N HCl were added if reaction conversion was slow. After concentration, the resulting residue was re-dissolved in 1:1 CH2Cl2/1 N HCl (60 mL) and the layers were separated. The aqueous layer was extracted with CH2Cl2 (3×, 30 mL), and the combined organic layers were dried (Na2SO4) and concentrated to afford a yellow foam that was used without further purification. MS (ESI): mass calcd. for C19H22F3N3O4S2, 477.10; m/z found, 478.3 [M+H]+.
F. 1-[1-(3-{3-[3-(2-Hydroxy-ethylsulfanyl)-4-trifluoromethyl-phenyl]-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-p]pyridin-1-yl}-propyl)-piperidin-4-yl]-pyrrolidin-2-one. To a solution of 3-{3-[3-(2-hydroxy-ethylsulfanyl)-4-trifluoromethyl-phenyl]-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl}propionaldehyde (1.8 g, 3.8 mmol) in CH2Cl2 (20 mL) was added 4-(N-2-pyrrolidinone)piperidine (1.0 g, 5.7 mmol) and glacial acetic acid (0.8 mL, 14 mmol). After stirring for 5 min, NaB(OAc)3H (1.2 g, 5.7 mmol) was added to the reaction mixture. After stirring at rt for 15 h, 1 N NaOH (20 mL) was added to the mixture, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (4×, 20 mL), and the combined organic layers were dried (Na2SO4) and concentrated to afford a yellow oil. Purification (SiO2; 0-10% 1:9 satd. NH3 in MeOH/MeOH in CH2Cl2) provided a yellow foam (1.3 g, 53%), which could be used without further purification. Or, reverse phase HPLC of this yellow foam gave a white powder. MS (ESI): mass calcd. for C28H38F3N5O4S2, 629.23; m/z found, 630.2 [M+H]+. 1H NMR: 7.97 (s, 1H), 7.77 (d, J=8.2, 1H), 7.59 (d, J=8.2, 1H), 4.57 (s, 2H), 4.31-4.28 (m, 2H), 4.14-4.07 (m, 1H), 3.81 (t, J=6.7, 2H), 3.73-3.64 (m, 4H), 3.32-3.22 (m, 6H), 3.17-3.08 (m, 2H), 3.01 (s, 3H), 2.99-2.92 (m, 2H), 2.43-2.32 (m, 4H), 2.10-2.00 (m, 3H), 2.00-1.92 (m, 3H).
The compounds in Examples 2 and 3 were prepared using methods analogous to those described in Example 1.
MS (ESI): mass calcd. for C26H36F3N5O4S2, 603.22; m/z found, 604.5 [M+H]+.
MS (ESI): mass calcd. for C33H43F3N8O4S2, 736.28; m/z found, 737.4 [M+H]+.
A. Methanesulfonic acid 2-[5-(5-methanesulfonyl-1-{3-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-propyl}-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-trifluoromethyl-phenylsulfanyl]-ethyl ester. To a solution of 1-[1-(3-{3-[3-(2-hydroxy-ethylsulfanyl)-4-trifluoromethyl-phenyl]-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl}-propyl)-piperidin-4-yl]-pyrrolidin-2-one (0.2 g, 0.3 mmol) in CH2Cl2 (1.5 mL) was added pyridine (0.05 mL, 0.6 mmol). MsCl (0.04 mL, 0.5 mmol) was slowly added, and the reaction mixture was stirred for 1 h. After pouring the mixture into H2O (5 mL), the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×, 5 mL). The combined organic layers were washed with brine (5 mL), dried (Na2SO4), and concentrated to afford a yellow-brown foam, which was used without further purification. MS (ESI): mass calcd. for C29H40F3N5O6S3, 707.21; m/z found, 708.2 [M+H]+.
B. 1-{1-[3-(3-{3-[2-(4-Hydroxy-piperidin-1-yl)-ethylsulfanyl]-4-trifluoromethyl-phenyl}-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl)-propyl]-piperidin-4-yl}-pyrolidin-2-one. To a solution of methanesulfonic acid 2-[5-(5-methanesulfonyl-1-{3-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-propyl}-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-trifluoromethyl-phenylsulfanyl]-ethyl ester (0.2 g, 0.3 mmol) in 1:3 dichloroethane/EtOH (2 mL) was added 4-hydroxypiperidine (0.6 g, 6 mmol). The reaction mixture was heated to 60° C. for 15 h and concentrated to provide an orange oil. Further purification using reverse phase HPLC led to a yellow solid (148 mg, 56%). MS (ESI): mass calcd. for C33H47F3N6O4S2, 712.31; m/z found, 713.5 [M+H]+. 1H NMR: 7.92-7.90 (m, 1H), 7.78 (d, J=8.2, 1H), 7.68-7.65 (m, 1H), 4.53 (s, 2H), 4.23 (t, J=6.5, 2H), 4.10-4.03 (m, 1H), 3.66-3.58 (m, 5H), 3.48-3.38 (m, 3H), 3.38-3.28 (m, 5H), 3.22-3.18 (m, 2H), 3.10-3.02 (m, 3H), 2.95 (s, 3H), 2.93-2.90 (m, 2H), 2.35-2.30 (m, 4H), 2.11-2.05 (m, 1H), 2.02-1.92 (m, 6H), 1.91-1.84 (m, 3H), 1.72-1.63 (m, 1H).
Examples 5-53 were prepared according to the methods described in Example 4, with the appropriate substituent changes. In the cases where hydrogen chloride salts of the amine reagent were used, TEA (20 equiv) was added to the reaction mixture.
MS (ESI): mass calcd. for C33H47F3N6O3S2, 696.31; m/z found, 697.5 [M+H]+. 1H NMR: 7.94 (s, 1H), 7.83 (d, J=8.2, 1H), 7.73 (d, J=8.2, 1H), 4.56 (s, 2H), 4.26 (t, J=6.5, 2H), 4.15-4.06 (m, 1H), 3.68-3.65 (m, 2H), 3.66-3.64 (m, 2H), 3.59-3.56 (m, 2H), 3.59-3.46 (m, 2H), 3.36-3.32 (m, 4H), 3.31-3.30 (m, 3H), 3.24-3.21 (m, 2H), 3.12-3.08 (m, 2H), 2.96-2.94 (m, 4H), 2.38-2.33 (m, 4H), 2.05-1.98 (m, 4H), 1.96-1.90 (m, 4H), 1.85-1.70 (m, 3H), 1.55-1.43 (m, 1H).
MS (ESI): mass calcd. for C37H53F3N6O3S2, 750.36; m/z found, 751.5 [M+H]+. 1H NMR: 7.85 (s, 1H), 7.75-7.73 (m, 1H), 7.65-7.63 (m, 1H), 4.47 (s, 2H), 4.17 (t, J=6.5, 2H), 4.04-3.96 (m, 1H), 3.60-3.54 (m, 4H), 3.47-3.44 (m, 1H), 3.40-3.36 (m, 2H), 3.32-3.28 (m, 3H), 3.26-3.21 (m, 1H), 3.18-3.10 (m, 3H), 3.04-2.94 (m, 3H), 2.89 (s, 3H), 2.87-2.85 (m, 2H), 2.30-2.24 (m, 4H), 1.98-1.82 (m, 8H), 1.80-1.75 (m, 1H), 1.72-1.66 (m, 1H), 1.65-1.60 (m, 1H), 1.58-1.50 (m, 3H), 1.44-1.35 (m, 2H), 1.30-1.14 (m, 3H).
MS (ESI): mass calcd. for C33H45F5N6O3S2, 732.29; m/z found, 733.4 [M+H]+. 1H NMR: 7.84 (s, 1H), 7.75-7.73 (m, 1H), 7.66-7.64 (m, 1H), 4.47 (s, 2H), 4.17 (t, J=6.5, 2H), 4.03-3.95 (m, 1H), 3.59-3.56 (m, 3H), 3.55-3.53 (m, 2H), 3.42-3.33 (m, 8H), 3.25-3.20 (m, 1H), 3.17-3.12 (m, 2H), 3.05-2.97 (m, 2H), 2.90 (s, 3H), 2.86-2.82 (m, 2H), 2.30-2.30 (m, 8H), 1.96-1.80 (m, 6H).
MS (ESI): mass calcd. for C34H49F3N6O3S2, 710.33; m/z found, 711.5 [M+H]+. 1H NMR: 7.85 (s, 1H), 7.73 (m, 1H), 7.63 (m, 1H), 4.47 (s, 2H), 4.17 (t, J=6.5, 2H), 4.04-3.97 (m, 1H), 3.60-3.55 (m, 4H), 3.51-3.46 (m, 1H), 3.41-3.37 (m, 3H), 3.29-3.22 (m, 4H), 3.15-3.12 (m, 2H), 3.02-1.98 (m, 2H) 2.89 (s, 3H), 2.87-2.84 (m, 2H), 2.79-2.74 (m, 1H), 2.50-2.48 (m, 1H), 2.30-2.22 (m, 4H), 1.96-1.62 (m, 10H), 1.12-1.02 (m, 1H), 0.90-0.89 (m, 3H).
MS (ESI): mass calcd. for C35H51F3N6O3S2, 724.34; m/z found, 725.5 [M+H]+. 1H NMR: 7.85 (s, 1H), 7.73 (d, J=8.1, 1H), 7.62 (d, J=8.1, 1H), 4.47 (s, 2H), 4.18-4.15 (m, 2H), 4.04-3.98 (m, 1H), 3.58-3.55 (m, 4H), 3.42-3.36 (m, 4H), 3.29-3.22 (m, 4H), 3.15-3.10 (m, 2H), 3.02-2.98 (m, 2H), 2.89 (s, 3H), 2.87-2.84 (m, 2H), 2.45-2.51 (m, 2H), 2.28-2.22 (m, 4H), 1.95-1.90 (m, 4H), 1.85-1.77 (m, 4H), 1.75-1.73 (m, 1H), 0.88 (d, J=6.5, 6H), 0.80-0.73 (m, 1H).
MS (ESI): mass calcd. for C34H49F3N6O3S2, 710.33; m/z found, 711.5 [M+H]+. 1H NMR: 7.84 (s, 1H), 7.74 (d, J=8.2, 1H), 7.64 (d, J=8.2, 1H), 4.47 (s, 2H), 4.17 (t, J=6.5, 2H), 4.04-3.97 (m, 1H), 3.59-3.54 (m, 4H), 3.51-3.47 (m, 2H), 3.39-3.36 (m, 2H), 3.28-3.22 (m, 4H), 3.16-3.11 (m, 2H), 3.04-2.97 (m, 2H), 2.89 (s, 3H), 2.87-2.84 (m, 4H), 2.30-2.22 (m, 4H), 1.95-1.87 (m, 4H), 1.85-1.80 (m, 4H), 1.62-1.56 (m, 1H), 1.35-1.28 (m, 2H), 0.92-0.89 (s, 3H).
MS (ESI): mass calcd. for C33H45F5N6O3S2, 732.29; m/z found, 733.4 [M+H]+. 1H NMR: 7.85 (s, 1H), 7.73 (d, J=8.2, 1H), 7.60 (d, J=8.2, 1H), 4.47 (s, 2H), 4.17 (t, J=6.5, 2H), 4.02-3.96 (m, 1H), 3.58-3.52 (m, 5H), 3.36-3.31 (m, 5H), 3.24-3.21 (m, 2H), 3.17-3.12 (m, 2H), 3.08-2.98 (m, 4H), 2.89 (s, 3H), 2.87-2.85 (m, 2H), 2.29-2.22 (m, 4H), 2.03-1.80 (m, 10H).
MS (ESI): mass calcd. for C37H53F3N6O3S2, 750.36; m/z found, 751.5 [M+H]+. 1H NMR: 7.89 (s, 1H), 7.75 (d, J=8.2, 1H), 7.65 (d, J=8.2, 1H), 4.47 (s, 2H), 4.17 (t, J=6.5, 2H), 4.03-3.97 (m, 1H), 3.59-3.49 (m, 4H), 3.50-3.45 (m, 1H), 3.42-3.37 (m, 2H), 3.34-3.30 (m, 1H), 3.27-3.22 (m, 4H), 3.15-3.11 (m, 2H), 3.08-2.98 (m, 3H), 2.90 (s, 3H), 2.87-2.85 (m, 2H), 2.84-2.81 (m, 1H), 2.29-2.22 (m, 4H), 1.96-1.82 (m, 7H), 1.73-1.63 (m, 4H), 1.59-1.57 (m, 1H), 1.44-1.38 (m, 1H), 1.25-1.14 (m, 4H), 1.08-1.02 (m, 1H).
MS (ESI): mass calcd. for C34H49F3N6O4S2, 726.32; m/z found, 727.5 [M+H]+. 1H NMR: 7.86 (s, 1H), 7.74 (d, J=8.2, 1H), 7.64-7.62 (m, 1H), 4.47 (s, 2H), 4.17 (t, J=6.5, 2H), 4.03-3.97 (m, 1H), 3.60-3.49 (m, 6H), 3.46-3.42 (m, 1H), 3.40-3.37 (m, 2H), 3.34-3.28 (m, 3H), 3.26-3.21 (m, 3H), 3.18-3.15 (m, 2H), 3.03-2.98 (m, 2H), 2.89 (s, 3H), 2.87-2.85 (m, 2H), 2.83-2.77 (m, 1H), 2.68-2.63 (m, 1H), 2.29-2.22 (m, 4H), 1.96-1.80 (m, 8H), 1.75-1.64 (m, 2H), 1.21-1.14 (m, 1H).
MS (ESI): mass calcd. for C33H45F3N6O3S2, 694.29; m/z found, 695.4 [M+H]+. 1H NMR: 7.91 (s, 1H), 7.79 (d, J=8.2, 1H), 7.70-7.68 (m, 1H), 5.96-5.91 (m, 1H), 5.72-5.68 (m, 1H), 4.52 (s, 2H), 4.22 (t, J=6.5, 2H), 4.09-4.02 (m, 1H), 3.94-3.83 (m, 1H), 3.64-3.59 (m, 5H), 3.46-3.40 (m, 5H), 3.32-3.27 (m, 3H), 3.20-3.16 (m, 2H), 3.08-3.02 (m, 2H), 2.94 (s, 3H), 2.93-2.89 (m, 2H), 2.51-2.35 (m, 2H), 2.34-2.27 (m, 4H), 2.00-1.95 (m, 4H), 1.90-1.85 (m, 2H).
MS (ESI): mass calcd. for C32H45F3N6O5S3, 746.26; m/z found, 747.4 [M+H]+. 1H NMR: 7.87 (s, 1H), 7.68 (d, J=8.2, 1H), 7.52 (d, J=8.2, 1H), 4.45 (s, 2H), 4.17 (t, J=6.5, 2H), 4.02-3.96 (m, 1H), 3.59-3.53 (m, 4H), 3.21-3.18 (m, 2H), 3.18-3.13 (m, 2H), 3.09-3.05 (m, 5H), 3.04-3.00 (m, 5H), 2.89 (s, 3H), 2.88-2.84 (m, 4H), 2.30-2.21 (m, 5H), 1.95-1.89 (m, 3H), 1.88-1.82 (m, 4H).
MS (ESI): mass calcd. for C37H55F3N6O3S2, 752.37; m/z found, 753.5 [M+H]+. 1H NMR: 7.84 (s, 1H), 7.74 (d, J=8.2, 1H), 7.65 (d, J=8.2, 1H), 4.47 (s, 2H), 4.17 (t, J=6.5, 2H), 4.02-3.98 (m, 1H), 3.60-3.52 (m, 6H), 3.39-3.35 (m, 2H), 3.27-3.21 (m, 3H), 3.15-3.12 (m, 2H), 3.04-2.97 (m, 2H), 2.89 (s, 3H), 2.87-2.83 (m, 3H), 2.30-2.22 (m, 4H), 1.98-1.80 (m, 10H), 1.47-1.39 (m, 2H), 1.30-1.24 (m, 1H), 0.81 (s, 9H).
MS (ESI): mass calcd. for C33H46F4N6O3S2, 714.30; m/z found, 715.5 [M+H]+. 1H NMR: 7.85 (s, 1H), 7.75 (d, J=8.2, 1H), 7.67-7.65 (m, 1H), 4.47 (s, 2H), 4.17 (t, J=6.5, 2H), 4.04-3.96 (m, 1H), 3.77-3.65 (m, 1H), 3.59-3.53 (m, 5H), 3.46-3.45 (m, 1H), 3.41-3.36 (m, 2H), 3.34-3.30 (m, 2H), 3.27-3.23 (m, 3H), 3.16-3.12 (m, 2H), 3.04-2.97 (m, 3H), 2.90 (s, 3H), 2.87-2.85 (m, 2H), 2.30-2.22 (m, 4H), 2.04-1.76 (m, 10H).
MS (ESI): mass calcd. for C34H49F3N6O3S2, 710.33; m/z found, 711.5 [M+H]+. 1H NMR: 7.88 (s, 1H), 7.75 (d, J=8.2, 1H), 7.66-7.63 (m, 1H), 4.47 (s, 2H), 4.17 (t, J=6.5, 2H), 4.04-3.97 (m, 1H), 3.60-3.55 (m, 4H), 3.50-3.40 (m, 3H), 3.37-3.31 (m, 2H), 3.26-3.20 (m, 4H), 3.14-3.11 (m, 2H), 3.04-2.97 (m, 3H), 2.89 (s, 3H), 2.87-2.85 (m, 2H), 2.29-2.22 (m, 4H), 1.95-1.80 (m, 8H), 1.78-1.70 (m, 2H), 1.34-1.32 (m, 1H), 1.20 (d, J=6.5, 3H).
MS (ESI): mass calcd. for C39H51F3N6O3S2, 772.34; m/z found, 773.5 [M+H]+. 1H NMR: 7.87 (s, 1H), 7.76 (d, J=8.2, 1H), 7.68-7.66 (m, 1H), 7.24-7.21 (m, 2H), 7.15-7.12 (m, 3H), 4.49 (s, 2H), 4.19-4.16 (m, 2H), 4.02-3.96 (m, 1H), 3.66-3.60 (m, 2H), 3.60-3.54 (m, 5H), 3.47-3.45 (m, 1H), 3.44-3.40 (m, 2H), 3.37-3.32 (m, 3H), 3.16-3.12 (m, 2H), 3.10-3.05 (m, 2H), 3.04-2.96 (m, 2H), 2.90 (s, 3H), 2.88-2.85 (m, 2H), 2.81-2.76 (m, 1H), 2.29-2.22 (m, 4H), 2.05-2.00 (m, 2H), 1.98-1.82 (m, 7H).
MS (ESI): mass calcd. for C33H44F6N6O3S2, 750.28; m/z found, 751.4 [M+H]+. 1H NMR: 7.79 (s, 1H), 7.67 (d, J=8.2, 1H), 7.50 (d, J=8.2, 1H), 4.44 (s, 2H), 4.17 (t, J=6.4, 2H), 4.02-3.96 (m, 1H), 3.62-3.58 (m, 1H), 3.57-3.50 (m, 3H), 3.30-3.25 (m, 2H), 3.22-3.12 (m, 5H), 3.13-3.06 (m, 1H), 3.03-2.96 (m, 2H), 2.87 (s, 3H), 2.86-2.84 (m, 3H), 2.50-2.45 (m, 1H), 2.28-2.21 (m, 4H), 2.00-1.88 (m, 3H), 1.88-1.70 (m, 7H).
MS (ESI): mass calcd. for C34H49F3N6O4S2, 726.32; m/z found, 727.5 [M+H]+. 1H NMR: 7.91 (s, 1H), 7.80 (d, J=8.2, 1H), 7.69 (d, J=8.2, 1H), 4.54 (s, 2H), 4.23 (t, J=6.5, 2H), 4.11-4.04 (m, 1H), 3.67-3.60 (m, 6H), 3.48-3.44 (m, 2H), 3.42-3.38 (m, 2H), 3.36-3.28 (m, 4H), 3.23-3.17 (m, 2H), 3.10-3.04 (m, 2H), 3.02-2.95 (m, 2H), 2.96 (s, 3H), 2.94-2.90 (m, 2H), 2.36-2.30 (m, 4H), 2.02-1.94 (m, 6H), 1.92-1.86 (m, 2H), 1.75-1.68 (m, 1H), 1.50-1.42 (m, 2H).
MS (ESI): mass calcd. for C32H45F3N6O4S2, 698.29; m/z found, 699.5 [M+H]+. 1H NMR: 7.89 (s, 1H), 7.78 (d, J=8.2, 1H), 7.68 (d, J=8.2, 1H), 4.52 (s, 2H), 4.21 (t, J=6.5, 2H), 4.08-4.02 (m, 1H), 4.05-3.92 (m, 2H), 3.79-3.67 (m, 2H), 3.63-3.60 (m, 4H), 3.54-3.43 (m, 4H), 3.40-3.35 (m, 3H), 3.31-3.28 (m, 2H), 3.20-3.14 (m, 3H), 3.09-3.01 (m, 2H), 2.94 (s, 3H), 2.91-2.89 (m, 2H), 2.35-2.27 (m, 4H), 2.00-1.93 (m, 4H), 1.90-1.85 (m, 2H).
MS (ESI): mass calcd. for C33H47F3N6O3S2, 696.31; m/z found, 697.5 [M+H]+. 1H NMR: 7.87 (s, 1H), 7.73 (d, J=8.2, 1H), 7.59 (d, J=8.2, 1H), 4.45 (s, 2H), 4.16 (t, J=6.5, 2H), 2.05-1.98 (m, 1H), 3.59-3.54 (m, 4H), 3.52-3.45 (m, 1H), 3.30-3.22 (m, 4H), 3.19-3.15 (m, 2H), 3.15-3.11 (m, 2H), 3.15-2.97 (m, 2H), 2.89 (s, 3H), 2.86-2.84 (m, 2H), 2.30-2.24 (m, 4H), 2.02-1.88 (m, 6H), 1.84-1.80 (m, 2H), 1.71-1.68 (m, 2H), 1.58-1.48 (m, 5H).
MS (ESI): mass calcd. for C35H51F3N6O4S2, 740.34; m/z found, 741.5 [M+H]+. 1H NMR: 7.91 (s, 1H), 7.79 (d, J=8.2, 1H), 7.68 (d, J=8.2, 1H), 4.53 (s, 2H), 4.23 (t, J=6.5, 2H), 4.11-4.05 (m, 1H), 3.66-3.61 (m, 4H), 3.61-3.56 (m, 4H), 3.47-3.43 (m, 2H), 3.35-3.29 (m, 4H), 3.22-3.17 (m, 2H), 3.10-3.03 (m, 2H), 2.99-2.96 (m, 2H), 2.96 (s, 3H), 2.94-2.90 (m, 2H), 2.35-2.29 (m, 4H), 2.02-1.94 (m, 6H), 1.91-1.86 (m, 2H), 1.76-1.68 (m, 1H), 1.49-1.38 (m, 4H).
MS (ESI): mass calcd. for C32H45F3N6O3S2, 682.29; m/z found, 683.5 [M+H]+. 1H NMR: 7.85 (s, 1H), 7.73 (d, J=8.2, 1H), 7.62 (d, J=8.2, 1H), 4.46 (s, 2H), 4.16 (t, J=6.5, 2H), 4.04-3.97 (m, 1H), 3.65-3.58 (m, 2H), 3.58-3.53 (m, 4H), 3.39-3.33 (m, 4H), 3.25-3.23 (m, 2H), 3.14-3.11 (m, 2H), 3.02-2.98 (m, 4H), 2.89 (s, 3H), 2.86-2.84 (m, 2H), 2.29-2.21 (m, 4H), 2.08-1.98 (m, 2H), 1.95-1.86 (m, 6H), 1.85-1.79 (m, 2H).
MS (ESI): mass calcd. for C38H50F3N7O3S2, 773.34; m/z found, 774.5 [M+H]+. 1H NMR: 7.97 (s, 1H), 7.85 (d, J=8.2, 1H), 7.75-7.74 (m, 1H), 7.30-7.26 (m, 2H), 7.01-6.99 (m, 2H), 6.94-6.91 (m, 1H), 4.58 (s, 2H), 4.27 (t, J=6.6, 2H), 4.11-4.05 (m, 1H), 3.70-3.62 (m, 6H), 3.57-3.47 (m, 7H), 3.35-3.32 (m, 3H), 3.25-3.20 (m, 3H), 3.12-3.05 (m, 2H), 2.99 (s, 3H), 2.98-2.94 (m, 2H), 2.38-2.31 (m, 4H), 2.05-1.87 (m, 7H).
MS (ESI): mass calcd. for C35H51F3N6O3S2, 724.34; m/z found, 725.5 [M+H]+. 1H NMR (CDCl3): 7.89 (s, 1H), 7.72 (d, J=8.2, 1H), 7.48 (d, J=8.2, 1H), 4.53 (s, 2H), 4.26-4.18 (m, 1H), 4.19-4.13 (m, 2H), 3.71-3.62 (m, 4H), 3.56-3.48 (m, 1H), 3.44-3.27 (m, 4H), 3.22-3.08 (m, 4H), 2.98-2.88 (m, 5H), 2.88-2.83 (m, 2H), 2.76 (s, 3H), 2.44-2.38 (m, 4H), 2.34-2.15 (m, 2H), 2.08-2.00 (m, 3H), 2.00-1.93 (m, 1H), 1.94-1.83 (m, 4H), 1.75-1.68 (m, 1H), 1.44-1.28 (m, 4H), 1.18-1.07 (m, 1H).
MS (ESI): mass calcd. for C33H47F3N6O3S2, 696.31; m/z found, 697.5 [M+H]+. 1H NMR: 7.86 (s, 1H), 7.75 (d, J=8.2, 1H), 7.65 (d, J=8.2, 1H), 4.47 (s, 2H), 4.17 (t, J=6.5, 2H), 4.03-3.97 (m, 1H), 3.71-3.67 (m, 1H), 3.61-3.51 (m, 6H), 3.47-3.45 (m, 1H), 3.44-3.38 (m, 2H), 3.34-3.30 (m, 2H), 3.16-3.10 (m, 3H), 3.03-2.98 (m, 2H), 2.89 (s, 3H), 2.87-2.85 (m, 2H), 2.29-2.19 (m, 5H), 2.05-1.98 (m, 1H), 1.98-1.84 (m, 7H), 1.66-1.60 (m, 1H), 1.32 (s, 3H).
MS (ESI): mass calcd. for C35H45F3N6O3S2, 718.29; m/z found, 719.5 [M+H]+. 1H NMR (CDCl3): 7.90 (s, 1H), 7.68 (d, J=8.2, 1H), 7.39-7.32 (m, 6H), 4.51 (s, 2H), 4.13-4.11 (m, 3H), 4.07 (s, 2H), 3.67-3.63 (m, 2H), 3.62-3.57 (m, 2H), 3.31-3.26 (m, 4H), 3.15-3.10 (m, 4H), 3.01-2.97 (m, 2H), 2.88 (s, 3H), 2.85-2.81 (m, 2H), 2.37-2.33 (m, 2H), 2.43-2.37 (m, 2H), 2.12-2.06 (m, 2H), 2.03-1.97 (m, 2H), 1.78-1.73 (m, 2H).
MS (ESI): mass calcd. for C29H41F3N6O3S2, 642.26; m/z found, 643.4 [M+H]+. 1H NMR: 7.97 (s, 1H), 7.85 (d, J=8.2, 1H), 7.72 (d, J=8.2, 1H), 4.56 (s, 2H), 4.27 (t, J=6.5, 2H), 4.13-4.06 (m, 1H), 3.70-3.63 (m, 4H), 3.40-3.32 (m, 5H), 3.30-3.26 (m, 2H), 3.24-3.20 (m, 2H), 3.13-3.07 (m, 2H), 2.99 (s, 3H), 2.97-2.94 (m, 2H), 2.74 (s, 3H), 2.39-2.32 (m, 4H), 2.06-1.90 (m, 6H).
MS (ESI): mass calcd. for C32H47F3N6O4S2, 700.31; m/z found, 701.5 [M+H]+. 1H NMR (CDCl3): 7.93 (s, 1H), 7.71 (d, J=8.2, 1H), 7.41 (d, J=8.2, 1H), 4.52 (s, 2H), 4.25-4.18 (m, 1H), 4.17-4.12 (m, 2H), 3.66 (t, J=5.6, 4H), 3.52 (t, J=5.5, 2H), 3.42-3.38 (m, 2H), 3.36-3.33 (m, 3H), 3.33 (s, 3H), 3.23-3.18 (m, 2H), 3.17-3.12 (m, 4H), 3.03-2.96 (m, 2H), 2.91 (s, 3H), 2.86-2.82 (m, 2H), 2.45-2.36 (m, 4H), 2.24-2.13 (m, 2H), 2.08-2.00 (m, 2H), 2.00-1.97 (m, 2H), 1.88-1.82 (m, 2H).
MS (ESI): mass calcd. for C33H48F3N7O3S2, 711.32; m/z found, 712.5 [M+H]+. 1H NMR (CDCl3): 7.80 (s, 1H), 7.71 (d, J=8.2, 1H), 7.45 (d, J=8.2, 1H), 4.51 (s, 2H), 4.24-4.16 (m, 3H), 3.69-3.64 (m, 4H), 3.50-3.30 (m, 6H), 3.30-3.22 (m, 6H), 3.15-3.10 (m, 2H), 3.08-3.03 (m, 2H), 2.92 (s, 3H), 2.88-2.84 (m, 4H), 2.82 (s, 3H), 2.40-2.35 (m, 4H), 3.25-3.16 (m, 2H), 2.06-2.00 (m, 2H), 1.88-1.83 (m, 2H).
MS (ESI): mass calcd. for C30H43F3N6O3S2, 656.28; m/z found, 657.4 [M+H]+. 1H NMR: 7.88 (s, 1H), 7.73 (d, J=8.2, 1H), 7.60 (d, J=8.2, 1H), 4.46 (s, 2H), 4.16 (t, J=6.5, 2H), 4.03-3.97 (m, 1H), 3.56 (t, J=5.8, 2H), 3.55-3.51 (m, 2H), 3.39-3.36 (m, 2H), 3.27-3.21 (m, 4H), 3.15-3.08 (m, 2H), 3.01-2.95 (m, 2H), 2.89 (s, 3H), 2.84-2.87 (m, 2H), 2.83 (s, 6H), 2.30-2.22 (m, 4H), 1.96-1.88 (m, 4H), 1.83-1.78 (m, 2H).
MS (ESI): mass calcd. for C35H52F3N7O3S2, 739.35; m/z found, 740.5 [M+H]+. 1H NMR: 7.89 (s, 1H), 7.81 (d, J=8.2, 1H), 7.74 (d, J=8.2, 1H), 4.56 (s, 2H), 4.25 (t, J=6.4, 2H), 4.10-4.04 (m, 1H), 3.80-3.75 (m, 2H), 3.69-3.61 (m, 4H), 3.50-3.45 (m, 3H), 3.40-3.35 (m, 2H), 3.32-3.29 (m, 2H), 3.25-3.20 (m, 2H), 3.12-3.04 (m, 4H), 2.98 (s, 3H), 2.95-2.92 (m, 2H), 2.89 (s, 6H), 2.37-2.30 (m, 6H), 2.10-1.87 (m, 8H).
MS (ESI): mass calcd. for C39H51F3N6O3S2, 772.34; m/z found, 773.5 [M+H]+. 1H NMR: 7.65 (s, 1H), 7.63 (d, J=8.2, 1H), 7.57-7.55 (m, 1H), 7.17-7.16 (m, 2H), 7.14-7.12 (m, 1H), 7.11-7.07 (m, 2H), 4.44 (s, 2H), 4.23-4.19 (m, 2H), 4.12-4.09 (m, 1H), 4.02-3.96 (m, 1H), 3.72-3.63 (m, 2H), 3.59-3.53 (m, 4H), 3.47-3.44 (m, 1H), 3.30-3.28 (m, 2H), 3.18-3.08 (m, 3H), 3.02-2.96 (m, 3H), 2.95 (s, 3H), 2.92-2.55 (m, 3H), 2.30-2.24 (m, 4H), 1.98-1.80 (m, 12H).
MS (ESI): mass calcd. for C34H48F3N7O4S2, 739.32; m/z found, 740.54 [M+H]+.
MS (ESI): mass calcd. for C34H49F3N6O4S2, 726.32; m/z found, 727.5 [M+H]+.
MS (ESI): mass calcd. for C34H46F6N6O3S2, 764.30; m/z found, 767.5 [M+H]+.
MS (ESI): mass calcd. for C34H49F3N6O4S2, 726.32; m/z found, 727.3 [M+H]+.
MS (ESI): mass calcd. for C34H46F6N6O3S2, 764.30; m/z found, 765.4 [M+H]+.
MS (ESI): mass calcd. for C31H43F3N6O3S3, 700.25; m/z found, 701.1 [M+H]+.
MS (ESI): mass calcd. for C33H43F3N6O3S3, 724.25; m/z found, 725.4 [M+H]+.
MS (ESI): mass calcd. for C32H45F3N6O4S2, 698.29; m/z found, 699.5 [M+H]+.
MS (ESI): mass calcd. for C37H47F3N6O3S2, 744.31; m/z found, 745.5 [M+H]+.
MS (ESI): mass calcd. for C34H50F3N7O3S2, 725.34; m/z found, 726.5 [M+H]+.
MS (ESI): mass calcd. for C36H51F3N6O3S2, 736.34; m/z found, 737.5 [M+H]+.
MS (ESI): mass calcd. for C36H47F3N6O4S2, 748.31; m/z found, 749.5 [M+H]+.
MS (ESI): mass calcd. for C34H50F3N7O4S2, 741.33; m/z found, 742.5 [M+H]+.
MS (ESI): mass calcd. for C40H54F3N7O3S2, 801.37; m/z found, 802.5 [M+H]+.
MS (ESI): mass calcd. for C35H52F3N7O3S2, 739.35; m/z found, 740.5 [M+H]+.
MS (ESI): mass calcd. for C36H47F3N6O3S2, 732.21; m/z found, 733.5 [M+H]+.
MS (ESI): mass calcd. for C38H56F3N7O4S2, 795.38; m/z found, 796.5 [M+H]+.
MS (ESI): mass calcd. for C34H50F3N7O3S2, 725.34; m/z found, 726.5 [M+H]+.
A. Methanesulfonic acid 2-[5-[1-(2-[1,3]dioxolan-2-yl-ethyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-trifluoromethyl-phenylsulfanyl]-ethyl ester. To a solution of 2-{5-[1-(2-[1,3]dioxolan-2-yl-ethyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-trifluoromethyl-phenylsulfanyl}-ethanol (1.4 g, 2.7 mmol) in CH2Cl2 (13 mL) was added pyridine (0.5 mL, 6.1 mmol) and MsCl (0.31 mL, 4.0 mmol). The reaction was stirred at rt for 18 h and additional MsCl (0.1 mL) was added to the mixture. After another 24 h, the mixture was poured into H2O (20 mL) and the layers were separated. The aqueous layer was extracted with CH2Cl2 (3×, 10 mL). The combined organic layers were dried (Na2SO4) and concentrated to a light orange solid, which was used without further purification. MS (ESI): mass calcd. for C22H28F3N3O7S3, 599.10; m/z found, 600.3 [M+H]+.
B. 1-(2-[1,3]Dioxolan-2-yl-ethyl)-5-methanesulfonyl-3-[3-(2-piperidin-1-yl-ethylsulfanyl)-4-trifluoromethyl-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine To a solution of methanesulfonic acid 2-{5-[1-(2-[1,3]dioxolan-2-yl-ethyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-trifluoromethyl-phenylsulfanyl}-ethyl ester (1.6 g, 2.7 mmol) in 1:2 dichloroethane/EtOH (15 mL) was added piperidine (5.3 mL, 54.0 mmol). The reaction mixture was heated to 60° C. for 14 h. After concentration, the resulting residue was re-dissolved in 1:1 CH2Cl2/H2O (50 mL). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×, 20 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4) and concentrated to an orange solid, which was used without additional purification. MS (ESI): mass calcd. for C26H35F3N4O4S2, 588.21; m/z found, 589.2 [M+H]+.
C. 5-Methanesulfonyl-3-[3-(2-piperidin-1-yl-ethylsulfanyl)-4-trifluoromethyl-phenyl]-1-(3-piperidin-1-yl-propyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. This compound was prepared using the methods outlined in Example 1, Steps E and F, substituting 1-(2-[1,3]dioxolan-2-yl-ethyl)-5-methanesulfonyl-3-[3-(2-piperidin-1-yl-ethylsulfanyl)-4-trifluoromethyl-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine for 2-{5-[1-(2-[1,3]dioxolan-2-yl-ethyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-trifluoromethyl-phenylsulfanyl}-ethanol and piperidine for 4-(N-2-pyrrolidinone)piperidine. MS (ESI): mass calcd. for C29H42F3N5O2S2, 613.27; m/z found, 614.4 [M+H]+. 1H NMR: 7.83 (s, 1H), 7.72 (d, J=8.2, 1H), 7.63 (d, J=8.2, 1H), 4.47 (s, 2H), 4.15 (t, J=6.7, 2H), 3.57 (t, J=5.8, 2H), 3.50-3.42 (m, 4H), 3.39-3.35 (m, 2H), 3.27-3.23 (m, 2H), 3.10-3.06 (m, 2H), 2.89 (s, 3H), 2.88-2.79 (m, 6H), 2.26-2.20 (m, 2H), 1.87-1.81 (m, 4H), 1.75-1.68 (m, 3H), 1.68-1.59 (m, 3H), 1.44-1.35 (m, 2H).
Examples 55-60 were prepared according to the methods described in Example 54, with the appropriate substituent changes.
MS (ESI): mass calcd. for C33H49F3N6O2S2, 682.33; m/z found, 683.5 [M+H]+. 1H NMR: 7.83 (s, 1H), 7.72 (d, J=8.2, 1H), 7.63 (d, J=8.2, 1H), 4.47 (s, 2H), 4.15 (t, J=6.6, 2H), 3.68-3.62 (m, 2H), 3.59-3.55 (m, 3H), 3.50-3.45 (m, 2H), 3.38-3.34 (m, 3H), 3.27-3.23 (m, 3H), 3.16-3.11 (m, 2H), 3.08-2.94 (m, 4H), 2.90 (s, 3H), 2.89-2.83 (m, 4H), 2.36-2.30 (m, 2H), 2.29-2.22 (m, 2H), 2.11-2.01 (m, 2H), 2.01-1.87 (m, 4H), 1.87-1.81 (m, 2H), 1.75-1.60 (m, 3H), 1.44-1.35 (m, 1H).
MS (ESI): mass calcd. for C30H43F3N6O3S2, 656.28; m/z found, 657.4 [M+H]+. 1H NMR: 7.83 (s, 1H), 7.73 (d, J=8.2, 1H), 7.64 (d, J=8.2, 1H), 4.47 (s, 2H), 4.17 (t, J=6.6, 2H), 3.57 (t, J=5.8, 2H), 3.50-3.40 (m, 3H), 3.39-3.35 (m, 3H), 3.28-3.24 (m, 3H), 3.22-3.20 (m, 4H), 3.19-3.15 (m, 3H), 2.89 (s, 3H), 2.89-2.84 (m, 4H), 2.30-2.24 (m, 2H), 2.03 (s, 3H), 1.87-1.82 (m, 2H), 1.75-1.60 (m, 3H), 1.44-1.36 (m, 1H).
MS (ESI): mass calcd. for C28H40F3N5O2S2, 599.26; m/z found, 600.3 [M+H]+. 1H NMR: 7.92 (s, 1H), 7.79 (d, J=8.2, 1H), 7.66 (d, J=8.2, 1H), 4.56 (s, 2H), 4.25 (t, J=6.7, 2H), 3.74-3.65 (m, 5H), 3.62-3.56 (m, 2H), 3.52-3.47 (m, 2H), 3.38-3.27 (m, 5H), 3.16-3.05 (m, 4H), 2.98-2.93 (m, 2H), 2.38-2.31 (m, 2H), 2.19-2.11 (m, 2H), 2.08-1.90 (m, 4H), 1.85-1.75 (m, 3H), 1.66-1.46 (m, 2H).
MS (ESI): mass calcd. for C28H40F3N5O2S2, 615.25; m/z found, 616.3 [M+H]+. 1H NMR: 7.82 (s, 1H), 7.73 (d, J=8.2, 1H), 7.66-7.62 (m, 1H), 4.47 (s, 2H), 4.46-4.42 (m, 1H), 4.16 (t, J=6.6, 2H), 3.72-3.61 (m, 1H), 3.59-3.56 (m, 3H), 3.50-3.43 (m, 4H), 3.39-3.35 (m, 3H), 3.28-3.23 (m, 3H), 3.14-2.99 (m, 2H), 2.89 (s, 3H), 2.89-2.84 (m, 4H), 2.26-2.19 (m, 2H), 2.04-1.96 (m, 1H), 1.87-1.81 (m, 2H), 1.76-1.69 (m, 1H), 1.69-1.60 (m, 2H), 1.44-1.35 (m, 1H).
MS (ESI): mass calcd. for C28H40F3N5O3S2, 615.25; m/z found, 616.3 [M+H]+. 1H NMR: 7.85 (s, 1H), 7.72 (d, J=8.2, 1H), 7.61 (d, J=8.2, 1H), 4.48 (s, 2H), 4.18 (t, J=6.7, 2H), 3.98-3.93 (m, 2H), 3.73-3.66 (m, 2H), 3.60-3.57 (m, 2H), 3.53-3.48 (m, 2H), 3.46-3.38 (m, 4H), 3.29-3.23 (m, 2H), 3.21-3.16 (m, 2H), 3.10-3.05 (m, 2H), 2.92 (s, 3H), 2.90-2.85 (m, 2H), 2.32-2.26 (m, 2H), 1.88-1.82 (m, 2H), 1.76-1.65 (m, 3H), 1.59-1.53 (m, 1H), 1.53-1.38 (m, 2H).
MS (ESI): mass calcd. for C37H47F3N6O4S2, 760.31; m/z found, 761.3 [M+H]+. 1H NMR: 7.91 (s, 1H), 7.80 (d, J=8.2, 1H), 7.71 (d, J=8.2, 1H), 7.29 (d, J=7.6, 1H), 7.07-6.98 (m, 3H), 4.55 (s, 2H), 4.44 (s, 2H), 4.44-4.37 (m, 1H), 4.26-4.22 (m, 2H), 3.71-3.63 (m, 4H), 3.57-3.51 (m, 2H), 3.46-3.42 (m, 2H), 3.35-3.30 (m, 2H), 3.24-3.19 (m, 2H), 3.18-3.11 (m, 2H), 3.05-2.98 (m, 2H), 2.97 (s, 3H), 2.96-2.91 (m, 4H), 2.37-2.32 (m, 2H), 2.08-2.03 (m, 2H), 1.93-1.88 (m, 2H), 1.82-1.68 (m, 3H), 1.50-1.42 (m, 1H).
A. {2-[5-(5-Methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-trifluoromethyl-phenylsulfanyl]-ethyl}-carbamic acid tert-butyl ester. The title compound was prepared using methods similar to those described in Example 1, Steps A-C, with the appropriate substituent changes. MS (ESI): mass calcd. for C21H27F3N4O4S2, 520.1; m/z found, 465.2 [M-tButyl]+. 1H NMR (acetone-d6): 8.04 (s, 1H), 7.78 (d, J=8.2, 1H), 7.56 (d, J=8.0, 1H), 4.63 (br s, 2H), 3.63 (t, J=5.8, 2H), 3.37-3.35 (m, 2H), 3.28-3.24 (m, 3H), 2.94 (s, 3H), 2.92-2.90 (m, 3H), 1.43 (s, 9H).
B. {2-[5-(5-Methanesulfonyl-1-oxiranylmethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-trifluoromethyl-phenylsulfanyl]-ethyl}-carbamic acid tert-butyl ester. To a stirred solution of {2-[5-(5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-trifluoromethyl-phenylsulfanyl]-ethyl}-carbamic acid tert-butyl ester (450 mg, 0.7 mmol) and epichlorohydrin (656 mg, 7.0 mmol) in DMF (5.0 mL) was added Cs2CO3 (346 mg, 1.1 mmol). The reaction mixture was stirred at rt under N2 for 18 h. To the mixture was added a solution of cold satd. aq. NH4Cl (100 mL) and the product was extracted with CH2Cl2 (3×, 100 mL). The combined extracts were dried (Na2SO4) and concentrated to give a light brown liquid, which was purified through reverse phase HPLC to give the desired product as a white solid (195 mg, 40%). MS (ESI): mass calcd. for C24H31F3N4O5S2, 576.2; m/z found, 521.3 [M-tButyl]+. 1H NMR: 7.89 (s, 1H), 7.73 (d, J=8.2, 1H), 7.54 (d, J=8.2, 1H), 4.57-4.53 (m, 3H), 4.18-4.13 (dd, J=15.2, 5.8, 1H), 3.69-3.57 (m, 2H), 3.37-3.29 (m, 2H), 3.19-3.16 (m, 2H), 2.94 (s, 3H), 2.82 (t, J=4.5, 1H), 2.77 (t, J=6.9, 1H), 2.54-2.52 (m, 1H), 1.49-1.39 (m, 3H), 1.39 (s, 9H).
C. {2-[5-(1-{2-Hydroxy-3-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-propyl}-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-trifluoromethyl-phenylsulfanyl]-ethyl}-carbamic acid tert-butyl ester. To a solution of {2-[5-(5-methanesulfonyl-1-oxiranylmethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-trifluoromethyl-phenylsulfanyl]-ethyl}-carbamic acid tert-butyl ester (816 mg, 1.1 mmol) in EtOH (10.0 mL) was added 1-piperidin-4-yl-pyrrolidin-2-one (238 mg, 1.4 mmol). The reaction mixture was stirred at 90° C. under N2 for 18 h. The reaction mixture was concentrated to give white foam, which was purified (SiO2; 1:9:90 satd. NH3 in MeOH/MeOH/CH2Cl2) to give the desired product as a white solid (768 mg, 88%). MS (ESI): mass calcd. for C33H47F3N6O6S2, 744.3; m/z found, 745.5 [M+H]+. 1H NMR (acetone-d6): 7.91 (s, 1H), 7.75-7.74 (d J=8.2, 1H), 6.23 (s, 1H), 4.61 (br s, 2H), 4.27-4.24 (dd, J=13.4, 3.2, 1H), 4.18-4.12 (m, 2H), 4.09 (t, J=6.7, 1H), 3.82-3.75 (m, 1H), 3.67-3.57 (m, 2H), 3.37-3.32 (m, 4H), 3.22 (t, J=7.0, 2H), 3.09-2.94 (m, 4H), 2.93 (s, 3H), 2.48-2.39 (m, 2H), 2.18 (t, J=8.0, 3H), 2.17-2.14 (m, 1H), 2.12-2.07 (td, J=12.0, 2.2, 1H), 1.96-1.90 (m, 2H), 1.76-1.68 (m, 2H), 1.54-1.51 (m, 2H), 1.37 (s, 9H).
To a stirred solution of {2-[5-(1-{2-hydroxy-3-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-propyl}-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-trifluoromethyl-phenylsulfanyl]-ethyl}-carbamic acid tert-butyl ester (132 mg, 0.17 mmol) in CH2Cl2 (363 μL) was added trifluoroacetic acid (262 mg, 2.3 mmol) and triethylsilane (51 mg, 0.44 mmol). The reaction mixture was stirred at rt for 1.5 h. The reaction mixture was concentrated to give a clear oil, which was purified through reverse phase HPLC to give the desired product as a white solid (76 mg, 57%). MS (ESI): mass calcd. for C28H39F3N6O4S2, 644.2; m/z found, 645.4 [M+H]+. 1H NMR: 7.91 (s, 1H), 7.75-7.74 (d J=8.2, 1H), 6.23 (s, 1H), 4.55 (br s, 2H), 4.51-4.50 (br m, 1H), 4.27-4.19 (m, 2H), 4.17-4.09 (m, 1H), 3.79-3.60 (m, 5H), 3.41 (t, J=6.7, 2H), 3.34 (t, J=7.0, 2H), 3.27-3.10 (m, 6H), 3.01-2.99 (m, 2H), 2.97 (s, 3H), 2.38 (t, J=8.0, 2H), 2.18-2.11 (m, 2H), 2.08-2.00 (m, 3H), 1.94-1.89 (m, 2H).
This compound was prepared using the methods outlined in Example 61, with the appropriate substituent changes. The final product was isolated as a mixture of regioisomers, as determined by NMR. MS (ESI): mass calcd. for C30H40F3N5O6S2, 687.24; m/z found, 688.5 [M+H]+. 1H NMR: 7.93 (s, 1H), 7.83 (d, J=8.3, 2H), 7.75 (d, J=8.2, 1H), 7.66 (d, J=8.3, 1H), 7.50 (d, J=8.0, 1H), 4.55 (s, 2H), 4.48 (br s, 2H), 4.36-4.16 (m, 5H), 4.15-4.06 (m, 6H), 3.98-3.88 (m, 2H), 3.86 (s, 2H), 3.76-3.54 (m, 9H), 3.70 (s, 3H), 3.46-3.36 (m, 5H), 3.27-3.06 (m, 7H), 3.02-2.88 (m, 5H), 2.99 (s, 3H), 2.92 (s, 3H), 2.42-2.34 (m, 5H), 2.18-2.08 (m, 2H), 2.08-1.98 (m, 7H), 1.96-1.84 (m, 4H), 1.15 (t, J=7.1, 3H).
To a solution of [5-(1-{2-hydroxy-3-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-propyl}-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-trifluoromethyl-phenylsulfanyl]-acetic acid ethyl ester (0.41 g, 0.59 mmol) in IPA (0.70 mL) was added a solution of KOH (0.07 g, 1.2 mmol) in H2O (1.3 mL). The reaction mixture stirred for 24 h at rt. IPA was removed under reduced pressure. The aqueous layer was frozen and lyophilized to afford a white powder, which was used without further purification. MS (ESI): mass calcd. for C28H36F3N5O5S2, 659.74; m/z found, 660.5 [M+H]+. 1H NMR: 7.74 (s, 1H), 7.67 (d, J=8.0, 1H), 7.57 (d, J=8.5, 1H), 4.56 (s, 2H), 4.23-4.16 (m, 2H), 4.07-4.01 (m, 1H), 3.94-3.89 (m, 1H), 3.88-3.79 (m, 1H), 3.69 (s, 2H), 3.68-3.58 (m, 2H), 3.44-3.38 (m, 2H), 3.44-3.38 (m, 2H), 3.05-2.99 (m, 2H), 3.01 (s, 3H), 2.48-2.44 (m, 2H), 2.35 (t, J=8.1, 2H), 2.19-2.12 (m, 2H), 2.03-1.96 (m, 2H), 1.81-1.70 (m, 2H), 1.63-1.54 (m, 2H).
To a solution of [5-(1-{2-hydroxy-3-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-propyl}-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-trifluoromethyl-phenylsulfanyl]-acetic acid (0.04 g, 0.06 mmol) in DMF (0.30 mL) was added EDC (0.02 g, 0.09 mmol), HOBt (0.01 g, 0.09 mmol), pyrrolidine (0.01 g, 0.09 mmol) and TEA (0.01 g, 0.18 mmol). The reaction was monitored by HPLC, and additional coupling reagents were added when reaction progress was slow. The product was isolated by reverse phase HPLC to yield a white solid (26.2 mg, 60%). MS (ESI): mass calcd. for C32H43F3N6O5S2, 712.27; m/z found, 713.4 [M+H]+. 1H NMR (CDCl3): 8.02 (s, 1H), 7.64 (d, J=8.3, 1H), 7.61 (d, J=8.6, 1H), 4.63 (s, 2H), 4.18-4.13 (m, 1H), 4.12-4.06 (m, 1H), 4.02-3.93 (m, 2H), 3.71 (s, 2H), 3.69-3.59 (m, 2H), 3.51 (t, J=6.8, 2H), 3.44 (t, J=6.9, 2H), 3.31 (t, J=7.0, 2H), 3.03-2.96 (m, 2H), 2.96 (s, 3H), 2.93 (s, 1H), 2.92-2.83 (m, 2H), 2.86 (s, 1H), 2.47-2.38 (m, 2H), 2.38-2.33 (m, 2H), 2.17-2.08 (m, 1H), 2.02-1.92 (m, 4H), 1.87-1.80 (m, 2H), 1.75-1.69 (m, 1H), 1.67-1.61 (m, 3H).
Examples 66-74 were prepared using methods similar to those described in Example 65, with the appropriate substituent changes.
MS (ESI): mass calcd. for C40H45F3N6O5S2, 810.28; m/z found, 811.5 [M+H]+. 1H NMR (CDCl3): 8.61 (s, 1H), 7.86 (s, 1H), 7.73 (d, J=8.2, 1H), 7.57 (d, J=8.4, 2H), 7.53 (d, J=8.2, 2H), 7.45 (d, J=8.3, 2H), 7.42 (t, J=7.6, 2H), 7.38-7.30 (m, 2H), 4.58-4.46 (m, 3H), 4.26-4.18 (m, 2H), 4.14-4.08 (m, 1H), 4.02-3.86 (m, 2H), 3.64 (t, J=5.8, 2H), 3.62-3.51 (m, 2H), 3.34-3.25 (m, 2H), 3.23-3.17 (m, 1H), 3.16-3.09 (m, 2H), 3.08-2.96 (m, 2H), 2.89 (s, 3H), 2.87-2.80 (m, 1H), 2.41-2.36 (m, 2H), 2.28-2.18 (m, 1H), 2.16-2.06 (m, 1H), 2.04-1.97 (m, 3H), 1.66-1.60 (m, 2H).
MS (ESI): mass calcd. for C36H45F3N6O6S2, 778.28; m/z found, 779.5 [M+H]+. 1H NMR (CDCl3): 7.60 (s, 1H), 7.54 (d, J=8.1, 1H), 7.26-7.24 (m, 1H), 7.23-7.17 (m, 3H), 6.95-6.90 (m, 1H), 6.69-6.65 (m, 2H), 4.62-4.54 (m, 1H), 4.50-4.48 (m, 2H), 4.34-4.08 (m, 3H), 3.90-3.84 (m, 2H), 3.83-3.78 (m, 3H), 3.70-3.60 (m, 5H), 3.42-3.31 (m, 3H), 3.28-3.14 (m, 3H), 3.07-3.00 (m, 1H), 2.97 (s, 3H), 2.92-2.82 (m, 1H), 2.42 (t, J=8.0, 2H), 2.34-2.20 (m, 3H), 2.07-2.02 (m, 2H), 1.90-1.78 (m, 2H).
MS (ESI): mass calcd. for C39H47F3N6O5S2, 800.30; m/z found, 801.4 [M+H]+.
MS (ESI): mass calcd. for C37H45F3N6O5S2, 774.28; m/z found, 775.5 [M+H]+.
MS (ESI): mass calcd. for C40H45F3N6O5S2, 810.28; m/z found, 811.4 [M+H]+.
MS (ESI): mass calcd. for C41H45F3N6O5S2, 822.28; m/z found, 823.4 [M+H]+.
MS (ESI): mass calcd. for C41H47F3N6O6S2, 840.30; m/z found, 841.5 [M+H]+.
MS (ESI): mass calcd. for C35H43F3N6O5S2, 748.27; m/z found, 749.4 [M+H]+.
MS (ESI): mass calcd. for C36H45F3N6O5S2, 762.28; m/z found, 763.5 [M+H]+.
A. [5-(5-Methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-trifluoromethyl-phenylsulfanyl]-acetic acid ethyl ester. This compound was prepared using methods similar to those described in Example 1, Step C, with the appropriate substituent changes. MS (ESI): mass calcd. for C18H20F3N3O4S2, 463.08; m/z found, 464.1 [M+H]+. 1H NMR (CDCl3): 7.85 (s, 1H), 7.67 (d, J=8.2, 1H), 7.48 (d, J=7.9, 1H), 4.58 (s, 2H), 4.17 (dd, J=14.5, 7.4, 2H), 3.68 (s, 2H), 3.65 (t, J=5.8, 2H), 2.95 (s, 3H), 2.94-2.88 (m, 2H), 1.24-1.19 (m, 3H).
B. {5-[1-(2-[1,3]Dioxolan-2-yl-ethyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-trifluoromethyl-phenylsulfanyl]-acetic acid ethyl ester. This compound was prepared using methods similar to those described in Example 1, Step D. MS (ESI): mass calcd. for C23H28F3N3O6S2, 563.14; m/z found, 564.1 [M+H]+. 1H NMR: 7.91 (s, 1H), 7.75 (d, J=8.2, 1H), 7.64 (d, J=8.2, 1H), 4.55 (s, 2H), 4.26-4.21 (m, 2H), 4.15 (dd, J=14.3, 7.1, 1H), 3.99-3.94 (m, 2H), 3.87-3.82 (m, 4H), 3.65 (t, J=5.8, 2H), 3.19-3.14 (m, 1H), 2.97 (s, 3H), 2.94-2.91 (m, 2H), 2.23-2.18 (m, 2H), 2.02-1.97 (m, 1H), 1.17 (t, J=7.1, 3H).
C. {5-[5-Methanesulfonyl-1-(3-oxo-propyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-trifluoromethyl-phenylsulfanyl}-acetic acid ethyl ester. This compound was prepared using methods similar to those described in Example 1, Step E. MS (ESI): mass calcd. for C21H24F3N3O5S2, 519.11; m/z found, 520.1 [M+H]+.
D. [5-(5-Methanesulfonyl-1-[3-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-propyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-trifluoromethyl-phenylsulfanyl]-acetic acid ethyl ester. This compound was prepared using methods similar to those described in Example 1, Step F. MS (ESI): mass calcd. for C30H40F3N5O5S2, 671.24; m/z found, 672.1 [M+H]+. 1H NMR: 8.07 (s, 1H), 7.76 (d, J=8.2, 1H), 7.60 (d, J=8.1, 1H), 4.72-4.33 (m, 4H), 4.56 (s, 2H), 4.30 (d, J=6.3, 3H), 4.19-4.10 (m, 1H), 3.92 (s, 2H), 3.75 (d, J=11.2, 2H), 3.63 (t, J=5.8, 2H), 3.41 (t, J=7.61 (2H), 3.27 (t, J=6.9, 2H), 3.23-3.14 (m, 2H), 2.98-2.93 (m, 2H), 2.95 (s, 3H), 2.54-2.46 (m, 2H), 2.23 (t, J=8.1, 2H), 2.20-2.09 (m, 2H), 1.99-1.91 (m, 2H), 1.86-1.78 (m, 2H).
E. [5-(5-Methanesulfonyl-1-{3-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-propyl}-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-trifluoromethyl-phenylsulfanyl]-acetic acid. This compound was prepared using methods similar to those described in Example 64. MS (ESI): mass calcd. for C28H36F3N5O5S2, 643.21; m/z found, 644.1 [M+H]+. 1H NMR: 7.72 (s, 1H), 7.68 (d, J=8.2, 1H), 7.58 (d, J=8.0, 1H), 4.56 (s, 2H), 4.15 (t, J=6.6, 2H), 3.86-3.79 (m, 1H), 3.70 (s, 2H), 3.65 (t, J=5.8, 2H), 3.41 (t, J=7.0, 2H), 3.04 (s, 3H), 2.98-2.92 (m, 4H), 2.36 (dd, J=15.8, 7.8, 4H), 2.11-2.05 (m, 2H), 2.05-1.97 (m, 4H), 1.74-1.66 (m, 2H), 1.63-1.57 (m, 2H).
F. 1-{1-[3-(3-{3-[2-(3-Hydroxy-pyrrolidin-1-yl)-2-oxo-ethylsulfanyl]-4-trifluoromethyl-phenyl}-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl)-propyl]-piperidin-4-yl}-pyrrolidin-2-one. This compound was prepared using methods similar to those described in Example 65, substituting PyBOP for EDC, HOAt for HOBt, DIPEA for TEA, and 3-pyrrolidinol for pyrrolidine. MS (ESI): mass calcd. for C32H43F3N6O5S2, 712.27; m/z found, 713.4 [M+H]+. 1H NMR: 8.08 (s, 1H), 7.77 (d, J=8.2, 1H), 7.66 (d, J=8.1, 1H), 4.57 (s, 2H), 4.48-4.38 (m, 1H), 4.27 (t, J=6.2, 2H), 4.14-4.06 (m, 1H), 3.94 (s, 1H), 3.91 (s, 1H), 3.76-3.62 (m, 6H), 3.58-3.42 (m, 3H), 3.34 (s, 1H), 3.30-3.24 (m, 3H), 3.16-3.08 (m, 2H), 3.00 (s, 3H), 2.96-2.91 (m, 2H), 2.40-2.30 (m, 4H), 2.12-1.96 (m, 4H), 1.96-1.86 (m, 4H).
Examples 76-91 were prepared using methods similar to those described in Example 75, with the appropriate substituent changes.
MS (ESI): mass calcd. for C33H45F3N6O4S2, 710.29; m/z found, 711.4 [M+H]+. 1H NMR: 7.97 (s, 1H), 7.68 (d, J=8.2, 1H), 7.57 (d, J=8.2, 1H), 4.48 (s, 2H), 4.20-4.14 (m, 2H), 4.04-3.94 (m, 2H), 3.80 (s, 1H), 3.60-3.52 (m, 5H), 3.46-3.28 (m, 2H), 3.20-3.14 (m, 4H), 3.06-2.98 (m, 2H), 3.90 (s, 3H), 2.86-2.82 (m, 2H), 2.30-2.20 (m, 4H), 1.98-1.86 (m, 4H), 1.88-1.78 (m, 5H), 1.64-1.48 (m, 1H), 1.10 (d, J=6.5, 1H), 1.01 (d, J=6.4, 2H).
MS (ESI): mass calcd. for C34H47F3N6O5S2, 740.30; m/z found, 741.4 [M+H]+. 1H NMR: 8.10 (s, 1H), 7.77 (d, J=8.2, 1H), 7.66 (d, J=8.0, 1H), 4.58 (s, 2H), 4.54-4.48 (m, 2H), 4.32-4.24 (m, 2H), 4.14-3.94 (m, 4H), 3.74-3.62 (m, 3H), 3.38 (d, J=6.1, 2H), 3.34 (s, 1H), 3.33-3.29 (m, 4H), 3.30-3.25 (m, 2H), 3.20-3.08 (m, 2H), 3.00 (s, 3H), 2.97-2.92 (m, 2H), 2.69-2.62 (m, 1H), 2.40-2.31 (m, 3H), 2.05-1.98 (m, 2H), 1.97-1.89 (m, 3H), 1.85-1.68 (m, 3H), 1.27-1.15 (m, 1H), 1.12-1.00 (m, 1H).
MS (ESI): mass calcd. for C33H45F3N6O5S2, 726.28; m/z found, 727.4 [M+H]+. 1H NMR: 8.08 (s, 1H), 7.77 (d, J=8.2, 1H), 7.65 (d, J=8.1, 1H), 4.58 (s, 2H), 4.28 (t, J=6.2, 2H), 4.14-3.98 (m, 4H), 3.88-3.82 (m, 2H), 3.72-3.61 (m, 4H), 3.38-3.24 (m, 5H), 3.20-3.08 (m, 3H), 3.00 (s, 3H), 2.96-2.91 (m, 2H), 2.36 (t, J=8.1, 2H), 2.36-2.30 (m, 2H), 2.06-1.99 (m, 2H), 1.96-1.88 (m, 5H), 1.86-1.78 (m, 1H), 1.60-1.52 (m, 1H), 1.46-1.39 (m, 1H).
MS (ESI): mass calcd. for C34H47F3N6O4S2, 724.31; m/z found, 725.4 [M+H]+. 1H NMR: 8.10 (s, 1H), 7.78 (d, J=8.2, 1H), 7.66 (d, J=8.2, 1H), 4.58 (s, 2H), 4.38-4.22 (m, 1H), 4.28 (t, J=6.1, 2H), 4.13-3.92 (m, 4H), 3.89-3.79 (m, 1H), 3.67 (t, J=5.6, 3H), 3.64 (s, 1H), 3.30-3.25 (m, 4H), 3.13-3.09 (m, 2H), 3.00 (s, 3H), 2.95 (t, J=5.6, 2H), 2.78-2.60 (m, 1H), 2.42-2.31 (m, 5H), 2.06-1.98 (m, 3H), 1.96-1.91 (m, 5H), 1.84-1.79 (m, 1H), 1.78-1.66 (m, 1H), 1.63-1.32 (m, 2H), 1.22-1.14 (m, 1H).
MS (ESI): mass calcd. for C37H51F3N6O4S2, 764.34; m/z found, 765.5 [M+H]+. 1H NMR: 8.09 (s, 1H), 7.77 (d, J=8.2, 1H), 7.65 (d, J=8.3, 1H), 4.58 (s, 2H), 4.78 (t, J=6.2, 2H), 4.14-3.98 (m, 4H), 3.94-3.84 (m, 1H), 3.70-3.63 (m, 4H), 3.30-3.24 (m, 3H), 3.18-3.08 (m, 3H), 3.00 (s, 3H), 2.96-2.92 (m, 2H), 2.40-2.31 (m, 4H), 2.06-1.98 (m, 2H), 1.96-1.83 (m, 6H), 1.82-1.66 (m, 2H), 1.65-1.56 (m, 2H), 1.55-1.43 (m, 3H), 1.42-1.33 (m, 3H), 1.31-1.23 (m, 2H).
MS (ESI): mass calcd. for C34H47F3N6O4S2, 724.31; m/z found, 725.4 [M+H]+. 1H NMR: 8.11 (d, J=12.4, 1H), 7.78 (d, J=8.1, 1H), 7.65 (d, J=7.9, 1H), 4.58 (s, 2H), 4.36-4.26 (m, 1H), 4.28 (t, J=6.2, 2H), 4.11-4.05 (m, 1H), 4.04-3.92 (m, 2H), 3.78-3.72 (m, 1H), 3.67 (t, J=5.8, 3H), 3.64 (s, 1H), 3.34 (s, 3H), 3.30-3.26 (m, 2H), 3.26-3.22 (m, 3H), 3.00 (s, 3H), 2.96 (t, J=5.7, 2H), 2.38-2.30 (m, 4H), 2.04-1.96 (m, 2H), 1.94-1.88 (m, 3H), 1.76-1.66 (m, 2H), 1.64-1.54 (m, 3H), 1.33 (d, J=6.9, 2H), 1.12 (d, J=7.0, 2H).
MS (ESI): mass calcd. for C33H44F4N6O4S2, 728.28; m/z found, 729.4 [M+H]+. 1H NMR: 8.07 (s, 0.6H), 8.01 (s, 0.4H), 7.80-7.75 (m, 1H), 7.68-7.62 (m, 1H), 4.84-4.62 (m, 1H), 4.57 (s, 2H), 4.32-4.26 (m, 2H), 4.19-3.91 (m, 5H), 3.80-3.73 (m, 1H), 3.70-3.62 (m, 4H), 3.44-3.36 (m, 2H), 3.30-3.20 (m, 2H), 3.16-3.08 (m, 3H), 2.99 (s, 3H), 2.97-2.91 (m, 2H), 2.42-2.31 (m, 4H), 2.05-1.95 (m, 3H), 1.96-1.84 (m, 5H), 1.82-1.70 (m, 1H), 1.66-1.48 (m, 1H).
MS (ESI): mass calcd. for C33H42F6N6O4S2, 764.26; m/z found, 765.5 [M+H]+. 1H NMR: 8.05-7.98 (m, 1H), 7.72-7.66 (m, 1H), 7.59-7.54 (m, 1H), 4.49 (s, 2H), 4.18 (t, J=6.2, 2H), 4.04-3.94 (m, 1H), 3.63-3.52 (m, 4H), 3.20-3.14 (m, 3H), 3.10-2.99 (m, 2H), 2.91 (s, 3H), 2.85 (t, J=5.7, 2H), 2.30-2.22 (m, 4H), 1.96-1.88 (m, 2H), 1.86-1.78 (m, 4H), 1.78-1.73 (m, 1H), 1.66-1.58 (m, 3H), 1.54-1.44 (m, 2H), 1.34-1.16 (m, 4H).
MS (ESI): mass calcd. for C34H40F4N6O4S2, 736.25; m/z found, 738.0 [M+H]+. 1H NMR (CDCl3): 8.55 (s, 1H), 7.69 (d, J=8.2, 1H), 7.64 (s, 1H), 7.58 (d, J=8.2, 1H), 7.43-7.38 (m, 2H), 6.98 (t, J=8.7, 2H), 4.48 (s, 2H), 4.06 (t, J=6.8, 2H), 3.99-3.91 (m, 1H), 3.90 (s, 2H), 3.62 (t, J=5.8, 2H), 3.33 (t, J=7.0, 2H), 2.93 (s, 3H), 2.91-2.85 (m, 4H), 2.38 (t, J=8.1, 2H), 2.30 (t, J=6.9, 2H), 2.07-1.95 (m, 6H), 1.71-1.62 (m, 4H).
MS (ESI): mass calcd. for C30H41F3N6O4S2, 670.26; m/z found, 672.0 [M+H]+. 1H NMR (CDCl3): 7.96 (s, 1H), 7.70-7.62 (m, 2H), 4.63 (s, 2H), 4.08 (t, J=6.8, 2H), 4.00-3.91 (m, 1H), 3.79 (s, 2H), 3.65 (t, J=5.7, 2H), 3.34 (t, J=7.0, 2H), 3.08 (s, 3H), 2.98 (s, 3H), 2.95 (s, 3H), 2.93-2.86 (m, 4H), 2.39 (t, J=8.1, 2H), 2.32 (t, J=6.8, 2H), 2.10-1.94 (m, 6H), 1.71-1.68 (m, 4H).
MS (ESI): mass calcd. for C29H39F3N6O4S2, 656.2; m/z found, 658.0 [M+H]+. 1H NMR (CDCl3): 7.72 (m, 2H), 7.28 (s, 1H), 6.89-6.82 (m, 1H), 4.45 (s, 2H), 4.08 (t, J=6.8, 2H), 3.99-3.91 (m, 1H), 3.72 (s, 2H), 3.64 (t, J=5.7, 2H), 3.34 (t, J=7.0, 2H), 3.07 (s, 3H), 2.89 (t, J=5.5, 4H), 2.84 (d, J=4.9, 3H), 2.38 (t, J=8.1, 2H), 2.32 (t, J=6.7, 2H), 2.08-1.95 (m, 6H), 1.68-1.61 (m, 4H).
MS (ESI): mass calcd. for C35H50F3N7O4S2, 753.33; m/z found, 754.5 [M+H]+. 1H NMR: 8.05 (s, 1H), 7.77 (d, J=8.2, 1H), 7.69 (d, J=8.0, 1H), 4.71-4.67 (m, 1H), 4.58 (s, 2H), 4.27 (t, J=6.2, 2H), 4.24-4.17 (m, 1H), 4.12-4.04 (m, 1H), 4.07 (s, 2H), 3.72-3.64 (m, 4H), 3.54-3.45 (m, 1H), 3.34 (s, 1H), 3.34-3.31 (m, 2H), 3.30-3.26 (m, 1H), 3.25-3.19 (m, 1H), 3.16-3.08 (m, 2H), 3.00 (s, 3H), 2.97-2.92 (m, 2H), 2.90-2.84 (m, 6H), 2.74-2.64 (m, 1H), 2.42-2.32 (m, 4H), 2.20-2.08 (m, 2H), 2.06-1.98 (m, 2H), 1.98-1.88 (m, 4H), 1.80-1.70 (m, 1H), 1.60-1.50 (m, 1H).
MS (ESI): mass calcd. for C34H48F3N7O4S2, 739.32; m/z found, 740.4 [M+H]+. 1H NMR: 7.96 (s, 0.4H), 7.93 (s, 0.6H), 7.67 (d, J=8.2, 1H), 7.64-7.58 (m, 1H), 4.48 (s, 2H), 4.17 (t, J=6.3, 2H), 4.12-4.07 (m, 1H), 4.05-3.95 (m, 1H), 3.94-3.86 (m, 3H), 3.86-3.76 (m, 1H), 3.75-3.60 (m, 2H), 3.60-3.52 (m, 4H), 3.52-3.45 (m, 1H), 3.42-3.35 (m, 1H), 3.20-3.17 (m, 2H), 3.09-2.98 (m, 2H), 2.92 (s, 2H), 2.90 (s, 1H), 2.87 (s, 3H), 2.86-2.81 (m, 2H), 2.83 (s, 3H), 2.49-2.33 (m, 1H), 2.30-2.21 (m, 2H), 2.27 (t, J=8.1, 2H), 2.21-2.01 (m, 1H), 1.97-1.89 (m, 2H), 1.89-1.76 (m, 4H).
MS (ESI): mass calcd. for C38H54F3N7O4S2, 793.36; m/z found, 794.5 [M+H]+.
MS (ESI): mass calcd. for C34H47F3N6O4S2, 724.31; m/z found, 725.4 [M+H]+.
MS (ESI): mass calcd. for C34H46F3N7O5S2, 753.30; m/z found, 754.4 [M+H]+.
Examples 92 through 109 were prepared using methods similar to those described in Example 75, substituting HATU for PyBOP and the appropriate amine for 3-pyrrolidinol.
MS (ESI): mass calcd. for C32H43F3N6O4S2, 696.27; m/z found, 697.4 [M+H]+. 1H NMR: 8.11 (s, 1H), 7.78 (d, J=8.2, 1H), 7.67 (d, J=8.0, 1H), 4.57 (s, 2H), 4.32-4.27 (m, 2H), 4.13-4.05 (m, 1H), 3.91 (s, 2H), 3.72-3.64 (m, 4H), 3.58-3.54 (m, 2H), 3.45-3.40 (m, 2H), 3.29-3.24 (m, 3H), 3.17-3.08 (m, 2H), 3.00 (s, 3H), 2.98-2.93 (m, 2H), 2.42-2.31 (m, 4H), 2.05-2.01 (m, 2H), 2.01-1.95 (m, 3H), 1.95-1.90 (m, 3H), 1.90-1.84 (m, 3H).
MS (ESI): mass calcd. for C33H45F3N6O4S2, 710.29; m/z found, 711.5 [M+H]+. 1H NMR: 8.10 (s, 1H), 7.78 (d, J=8.0, 1H), 7.66 (d, J=8.3, 1H), 4.58 (s, 2H), 4.32-4.26 (m, 2H), 4.12-4.04 (m, 1H), 3.99 (s, 2H), 3.72-3.66 (m, 3H), 3.56-3.50 (m, 5H), 3.30-3.22 (m, 3H), 3.14-3.08 (m, 2H), 3.00 (s, 3H), 2.96-2.91 (m, 2H), 2.40-2.32 (m, 4H), 2.04-1.98 (m, 2H), 1.96-1.88 (m, 4H), 1.70-1.60 (m, 5H), 1.54-1.48 (m, 2H).
MS (ESI): mass calcd. for C32H43F3N6O5S2, 712.27; m/z found, 713.4 [M+H]+. 1H NMR: 8.07 (s, 1H), 7.78 (d, J=8.2, 1H), 7.68 (d, J=8.1, 1H), 4.58 (s, 2H), 4.23 (t, J=6.3, 2H), 4.12-4.06 (m, 1H), 4.02 (s, 2H), 3.71-3.66 (m, 5H), 3.65-3.62 (m, 4H), 3.62-3.58 (m, 2H), 3.58-3.54 (m, 2H), 3.30-3.25 (m, 3H), 3.17-3.08 (m, 2H), 3.00 (s, 3H), 2.96-2.93 (m, 2H), 2.37 (t, J=8.1, 2H), 2.35-2.31 (m, 2H), 2.06-1.99 (m, 2H), 1.97-1.89 (m, 4H).
MS (ESI): mass calcd. for C34H47F3N6O4S2, 724.31; m/z found, 725.5 [M+H]+. 1H NMR: 8.10 (s, 1H), 7.78 (d, J=8.2, 1H), 7.67 (d, J=8.0, 1H), 4.58 (s, 2H), 4.28 (t, J=6.1, 2H), 4.12-4.04 (m, 1H), 3.99 (s, 2H), 3.70-3.65 (m, 3H), 3.64 (s, 1H), 3.59 (t, J=6.1, 2H), 3.51 (t, J=5.9, 2H), 3.30-3.22 (m, 4H), 3.14-3.08 (m, 2H), 3.00 (s, 3H), 2.96-2.92 (m, 2H), 2.40-2.32 (m, 4H), 2.04-1.98 (m, 2H), 1.96-1.88 (m, 4H), 1.82-1.77 (m, 2H), 1.70-1.64 (m, 2H), 1.62-1.52 (m, 4H).
MS (ESI): mass calcd. for C34H48F3N7O4S2, 739.32; m/z found, 740.5 [M+H]+. 1H NMR: 8.01 (s, 1H), 7.77 (d, J=8.3, 1H), 7.72 (d, J=8.8, 1H), 4.59 (s, 2H), 4.27 (t, J=6.3, 2H), 4.15-4.05 (s, 2H), 3.83-3.76 (m, 2H), 3.72-3.63 (m, 5H), 3.63-3.48 (m, 3H), 3.34 (s, 3H), 3.30-3.25 (m, 2H), 3.19 (s, 1H), 3.16-3.08 (m, 2H), 3.00 (s, 3H), 2.97-2.92 (m, 3H), 2.91 (s, 2H), 2.42-2.32 (m, 4H), 2.32-2.23 (m, 1H), 2.20-2.11 (m, 1H), 2.07-2.00 (m, 3H), 2.00-1.89 (m, 3H).
MS (ESI): mass calcd. for C33H43F3N6O4S2, 708.27; m/z found, 709.4 [M+H]+. 1H NMR: 8.07 (m, 1H), 7.78 (d, J=8.1, 1H), 7.66 (d, J=8.2, 1H), 5.90-5.82 (m, 1H), 5.74-5.64 (m, 1H), 4.58 (s, 2H), 4.28 (t, J=6.2, 2H), 4.11-4.06 (m, 2H), 4.04 (s, 1H), 4.02-3.98 (m, 2H), 3.70-3.61 (m, 6H), 3.28-3.21 (m, 3H), 3.16-2.98 (m, 2H), 3.00 (s, 3H), 2.95 (t, J=5.4, 2H), 2.40-2.31 (m, 5H), 2.28-2.22 (m, 1H), 2.14-2.08 (m, 1H), 2.04-1.98 (m, 2H), 1.96-1.86 (m, 4H).
MS (ESI): mass calcd. for C37H45F3N6O4S2, 758.29; m/z found, 759.4 [M+H]+. 1H NMR: 7.97 (d, J=8.0, 1H), 7.68 (d, J=8.1, 0.6H), 7.61 (d, J=8.1, 0.4H), 7.55 (d, J=8.0, 0.6H), 7.45 (d, J=8.0, 0.4H), 7.12-7.06 (m, 3H), 7.04-6.96 (m, 1H), 4.62 (s, 1H), 4.59 (s, 1H), 4.44 (s, 2H), 4.17 (t, J=6.2, 1H), 4.13 (t, J=6.1, 1H), 4.04-3.94 (m, 3H), 3.72 (t, J=5.9, 1H), 3.65 (t, J=5.9, 1H), 3.60-3.50 (m, 4H), 3.20-3.14 (m, 3H), 3.10 (t, J=7.0, 1H), 3.06-2.92 (m, 2H), 2.89 (d, J=3.1, 3H), 2.87-2.81 (m, 3H), 2.68 (t, J=5.9, 1H), 2.32-2.17 (m, 4H), 1.97-1.86 (m, 2H), 1.85-1.74 (m, 4H).
MS (ESI): mass calcd. for C35H50F3N7O4S2, 753.33; m/z found, 754.5 [M+H]+. 1H NMR: 8.03 (s, 1H), 7.80-7.78 (m, 1H), 7.74-6.98 (m, 1H), 4.63-4.54 (m, 1H), 4.59 (s, 2H), 4.30-4.24 (m, 2H), 4.16-4.06 (m, 2H), 4.04 (s, 1H), 3.74-3.60 (m, 5H), 3.58-3.51 (m, 2H), 3.30-3.24 (m, 2H), 3.24-3.16 (m, 1H), 3.15-3.08 (m, 4H), 3.06-3.00 (m, 5H), 2.98-2.94 (m, 2H), 2.92-2.80 (m, 4H), 2.44-2.31 (m, 4H), 2.08-1.99 (m, 5H), 1.98-1.90 (m, 4H), 1.85-1.79 (m, 1H).
MS (ESI): mass calcd. for C39H49F3N6O4S2, 786.32; m/z found, 788.4 [M+H]+. 1H NMR: 8.09 (s, 1H), 7.79 (d, J=8.2, 1H), 7.66 (d, J=7.9, 1H), 7.30-7.22 (m, 2H), 6.98 (d, J=7.9, 2H), 6.89 (t, J=7.3, 1H), 4.57 (s, 2H), 4.12-4.04 (m, 1H), 4.05 (s, 2H), 3.79-3.72 (m, 4H), 3.68-3.59 (m, 4H), 3.28-3.25 (m, 4H), 3.22-3.18 (m, 2H), 3.16-3.12 (m, 2H), 3.12-3.04 (m, 2H), 2.99 (s, 3H), 2.96-2.90 (m, 2H), 2.35 (t, J=8.1, 2H), 2.34-2.28 (m, 2H), 2.05-1.97 (m, 2H), 1.95-1.86 (m, 5H).
MS (ESI): mass calcd. for C35H49F3N6O4S2, 738.32; m/z found, 739.5 [M+H]+. 1H NMR: 8.11 (s, 0.5H), 8.05 (s, 0.5H), 7.79 (t, J=8.5, 1H), 7.69-7.64 (m, 1H), 4.57 (s, 2H), 4.32-4.22 (m, 1H), 4.27 (t, J=6.2, 2H), 4.13-4.04 (m, 1H), 3.99 (d, J=3.8, 2H), 3.72-3.62 (m, 4H), 3.30-3.24 (m, 4H), 3.17-3.07 (m, 2H), 3.00 (s, 3H), 2.98-2.92 (m, 4H), 2.80 (s, 1H), 2.39-2.31 (m, 4H), 2.05-1.97 (m, 2H), 1.97-1.87 (m, 4H), 1.86-1.74 (m, 2H), 1.74-1.50 (m, 4H), 1.48-1.28 (m, 3H), 1.19-1.09 (m, 1H).
MS (ESI): mass calcd. for C35H43F3N6O4S2, 732.27; m/z found, 733.4 [M+H]+. 1H NMR: 7.99 (s, 1H), 7.78 (d, J=8.2, 1H), 7.62 (d, J=7.9, 1H), 7.16-7.07 (m, 5H), 4.50 (s, 2H), 4.39-4.35 (m, 2H), 4.24 (t, J=6.1, 2H), 4.09-4.01 (m, 1H), 3.85 (s, 2H), 3.63 (t, J=5.8, 2H), 3.59 (d, J=11.8, 2H), 3.28-3.22 (m, 4H), 3.08-3.02 (m, 2H), 2.99 (s, 3H), 2.93 (t, J=5.5, 2H), 2.36 (d, J=8.1, 2H), 2.32-2.22 (m, 2H), 2.05-1.99 (m, 2H), 1.92-1.84 (m, 4H).
MS (ESI): mass calcd. for C33H46F3N7O4S2, 725.30; m/z found, 726.5 [M+H]+. 1H NMR: 8.02 (s, 1H), 7.77 (d, J=8.2, 1H), 7.71 (d, J=8.1, 1H), 4.58 (s, 2H), 4.27 (t, J=6.3, 2H), 4.16-4.05 (m, 2H), 4.12 (s, 2H), 3.72-3.62 (m, 2H), 3.67 (t, J=5.7, 2H), 3.34-3.24 (m, 10H), 3.18-3.06 (m, 3H), 3.00 (s, 3H), 2.98-2.92 (m, 2H), 2.93 (s, 3H), 2.44-2.31 (m, 4H), 2.08-1.86 (m, 6H).
MS (ESI): mass calcd. for C40H51F3N6O4S2, 800.34; m/z found, 801.5 [M+H]+.
MS (ESI): mass calcd. for C41H53F3N6O4S2, 814.35; m/z found, 816.5, 817.5 [M+H]+.
MS (ESI): mass calcd. for C39H47F3N6O4S2, 784.31; m/z found, 785.5 [M+H]+.
MS (ESI): mass calcd. for C38H54F3N7O5S2, 809.36; m/z found, 810.5 [M+H]+.
MS (ESI): mass calcd. for C33H44F3N7O5S2, 739.28; m/z found, 740.2 [M+H]+.
MS (ESI): mass calcd. for C35H50F3N7O4S2, 753.33; m/z found, 754.5 [M+H]+.
A. {5-[1-(2-[1,3]Dioxolan-2-yl-ethyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-trifluoromethyl-phenylsulfanyl]-acetic acid. This compound was prepared using methods similar to those described in Example 64. MS (ESI): mass calcd. for C21H24F3N3O6S2, 535.11; m/z found, 536.1 [M+H]+. 1H NMR: 7.63 (s, 1H), 7.58 (d, J=8.2, 1H), 7.48 (d, J=8.2, 1H), 4.46 (s, 2H), 4.13 (t, J=7.0, 2H), 3.90-3.86 (m, 3H), 3.77-3.73 (m, 3H), 3.61 (s, 1H), 3.55 (t, J=5.8, 2H), 2.92 (s, 3H), 2.82 (t, J=5.7, 2H), 2.13-2.08 (m, 2H).
B. 2-{5-[1-(2-[1,3]Dioxolan-2-yl-ethyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-trifluoromethyl-phenylsulfanyl}-1-morpholin-4-yl-ethanone. This compound was prepared using methods similar to those described in Example 65, substituting HATU for EDC, HOAt for HOBt, DIPEA for TEA, and morpholine for pyrrolidine. MS (ESI): mass calcd. for C25H31F3N4O6S2, 604.16; m/z found, 605.1 [M+H]+.
C. 2-(5-{5-Methanesulfonyl-1-[3-(4-pyrrolidin-1-yl-piperidin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-trifluoromethyl-phenylsulfanyl)-1-morpholin-4-yl-ethanone. This compound was prepared using methods similar to those described in Example 1, Steps E and F, with the appropriate substituent changes. MS (ESI): mass calcd. for C32H45F3N6O4S2, 698.29; m/z found, 699.2 [M+H]+. 1H NMR: 7.95 (s, 1H), 7.75 (d, J=8.3, 1H), 7.65 (d, J=8.3, 1H), 4.58 (s, 2H), 4.15 (t, J=6.7, 2H), 4.00 (s, 2H), 3.69-3.60 (m, 6H), 3.60-3.54 (m, 3H), 2.98-2.89 (m, 5H), 2.97 (s, 3H), 2.64-2.58 (m, 4H), 2.33-2.27 (m, 2H), 2.11-2.03 (m, 3H), 2.00-1.90 (m, 4H), 1.83-1.77 (m, 4H), 1.57-1.46 (m, 2H).
Examples 111-113 were prepared using methods similar to those described in Example 110, with the appropriate substituent changes.
MS (ESI): mass calcd. for C29H37F6N5O4S2, 697.22; m/z found, 698.2 [M+H]+. 1H NMR: 7.94 (d, J=8.8, 1H), 7.76-7.70 (m, 1H), 7.65 (d, J=8.0, 1H), 4.57 (s, 2H), 4.15 (t, J=6.7, 2H), 4.00 (d, J=5.0, 2H), 3.68-3.60 (m, 5H), 3.60-3.52 (m, 3H), 3.12 (s, 1H), 3.02-2.90 (m, 5H), 2.97 (s, 3H), 2.36-2.31 (m, 2H), 2.18-2.00 (m, 3H), 1.99-1.90 (m, 2H), 1.86-1.80 (m, 2H), 1.61-1.50 (m, 2H).
MS (ESI): mass calcd. for C29H39F3N6O5S2, 672.24; m/z found, 673.2 [M+H]+. 1H NMR: 7.96-7.91 (m, 1H), 7.67-7.62 (m, 1H), 7.59-7.53 (m, 1H), 4.48 (s, 2H), 4.17-4.12 (m, 2H), 3.83 (d, J=9.2, 2H), 3.70 (br s, 3H), 3.60-3.56 (m, 3H), 3.56-3.51 (m, 2H), 3.48-3.42 (m, 3H), 3.33-3.26 (m, 1H), 3.18-3.09 (m, 5H), 3.03-2.98 (m, 1H), 2.88 (s, 3H), 2.85-2.80 (m, 3H), 2.32-2.24 (m, 2H), 2.08-1.96 (m, 1H), 2.00 (s, 3H).
MS (ESI): mass calcd. for C33H47F3N6O6S2, 744.30; m/z found, 745.2 [M+H]+. 1H NMR: 7.95 (s, 1H), 7.75 (d, J=8.2, 1H), 7.65 (d, J=8.2, 1H), 4.57 (s, 2H), 4.15 (t, J=6.6, 2H), 4.02-3.96 (m, 1H), 4.00 (s, 1H), 3.69-3.60 (m, 6H), 3.60-3.53 (m, 4H), 3.27-3.23 (m, 1H), 2.97 (s, 3H), 2.96-2.90 (m, 2H), 2.87-2.80 (m, 2H), 2.34 (t, J=7.3, 2H), 2.10-2.00 (m, 4H), 1.84-1.78 (m, 2H), 1.46-1.36 (m, 2H), 1.41 (s, 9H).
Examples 114 through 126 were prepared using methods similar to those described in Example 65, substituting HATU for EDC, HOAt for HOBt, DIPEA for TEA, and the appropriate amine for pyrrolidine.
MS (ESI): mass calcd. for C35H43F3N6O5S2, 748.3; m/z found, 749.4 [M+H]+. 1H NMR: 8.00 (s, 1H), 7.70 (t, J=8.0, 3H), 7.49 (t, J=6.7, 2H), 7.40 (t, J=7.7, 2H), 4.52 (br s, 2H), 4.49 (br s, 1H), 4.23-4.14 (m, 2H), 4.09-4.03 (m, 1H), 3.70-3.58 (m, 6H), 3.35-3.32 (m, 5H), 3.26-3.16 (m, 2H), 3.11-3.06 (m, 1H), 2.97-2.94 (m, 2H), 2.91 (s, 3H), 2.35 (t, J=8.0, 2H), 2.09-1.91 (m, 4H), 1.86-1.83 (m, 2H).
MS (ESI): mass calcd. for C36H45F3N6O5S2, 762.3; m/z found, 763.4 [M+H]+. 1H NMR: 7.93 (s, 1H), 7.74 (d, J=8.2, 1H), 7.56 (d, J=8.0, 1H), 7.28-7.25 (m, 2H), 7.21 (d, J=7.5, 3H), 4.53 (br s, 2H), 4.44 (br s, 1H), 4.23-4.14 (m, 2H), 4.09-4.02 (m, 1H), 3.64-3.58 (m, 4H), 3.47-3.45 (m, 4H), 3.35-3.31 (m, 2H), 3.26-3.23 (m, 1H), 3.22-3.13 (m, 4H), 3.05-3.00 (m, 1H), 2.97-2.95 (m, 2H), 2.91 (s, 3H), 2.36 (t, J=8.0, 2H), 2.04-1.99 (m, 3H), 1.94-1.92 (m, 1H), 1.86-1.83 (m, 2H).
MS (ESI): mass calcd. for C39H56F3N7O7S2, 855.4; m/z found, 856.5 [M+H]+. 1H NMR: 7.88 (s, 1H), 7.72 (d, J=8.2, 1H), 7.56 (d, J=8.0, 1H), 4.54 (br s, 2H), 4.23-4.17 (m, 2H), 4.06-4.03 (m, 3H), 3.87-3.80 (m, 1H), 3.67-3.58 (m, 2H), 3.44-3.39 (m, 4H), 3.33 (m, 3H), 3.20 (t, J=6.7, 2H), 3.05-2.99 (m, 3H), 2.94 (s, 3H), 2.73 (br s, 2H), 2.53-2.45 (m, 2H), 2.35 (t, J=8.0, 2H), 2.21-2.16 (m, 2H), 2.02-1.96 (m, 2H), 1.80-1.73 (m, 2H), 1.69-1.67 (m, 2H), 1.61-1.58 (m, 2H), 1.53-1.45 (m, 2H), 1.43 (s, 9H).
MS (ESI): mass calcd. for C35H50F3N7O7S2, 801.3; m/z found, 802.5 [M+H]+. 1H NMR: 7.90 (s, 1H), 7.73 (d, J=8.2, 1H), 7.57 (d, J=8.2, 1H), 4.55 (br s, 2H), 4.24-4.19 (m, 2H), 4.08-4.04 (m, 1H), 3.88-3.81 (m, 1H), 3.67-3.59 (m, 4H), 3.46-3.39 (m, 4H), 3.33 (s, 1H), 3.19 (t, J=6.9, 2H), 3.06-2.96 (br m, 4H), 2.95 (s, 3H), 2.51-2.49 (m, 2H), 2.35 (t, J=8.1, 2H), 2.23-2.17 (m, 2H), 2.02-1.96 (m, 2H), 1.81-1.73 (m, 2H), 1.62-1.59 (m, 2H), 1.42 (s, 9H).
MS (ESI): mass calcd. for C35H42F4N6O5S2, 766.26; m/z found, 767.4 [M+H]+.
MS (ESI): insufficient ionization.
MS (ESI): mass calcd. for C37H48F3N7O5S2, 791.31; m/z found, 792.5 [M+H]+.
MS (ESI): mass calcd. for C36H44F4N6O5S2, 780.28; m/z found, 781.4 [M+H]+.
MS (ESI): mass calcd. for C39H56F3N7O7S2, 855.36; m/z found, 856.5 [M+H]+.
MS (ESI): mass calcd. for C38H54F3N7O7S2, 841.35; m/z found, 842.5 [M+H]+.
MS (ESI): mass calcd. for C37H54F3N7O7S2, 829.35; m/z found, 830.5 [M+H]+.
MS (ESI): mass calcd. for C34H48F3N7O5S2, 755.31; m/z found, 756.5 [M+H]+.
MS (ESI): insufficient ionization.
This compound was prepared using methods similar to those described in Example 64, with the appropriate substituent changes. MS (ESI): mass calcd. for C34H48F3N7O5S2, 755.3; m/z found, 756.5 [M+H]+. 1H NMR: 7.89 (s, 1H), 7.74 (d, J=8.2, 1H), 7.59 (d, J=8.2, 1H), 4.56 (br s, 2H), 4.48-4.40 (m, 1H), 4.27-4.15 (m, 2H), 4.11-4.03 (m, 1H), 3.69-3.62 (m, 2H), 3.61-3.56 (m, 3H), 3.13-3.08 (m, 1H), 3.04-2.99 (m, 5H), 2.97 (s, 3H), 2.53-2.46 (m, 1H), 2.37 (t, J=8.1, 2H), 2.08-1.93 (m, 7H), 1.88-1.78 (m, 4H).
A. 3-(4-Chloro-3-iodo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. This compound was prepared using the methods outlined in Example 1, Steps A and B, substituting 4-chloro-3-iodobenzoyl chloride for 4-trifluoromethyl-3-nitrobenzoyl chloride. MS (ESI): mass calcd. for C13H13CIIN3O2S, 437.7; m/z found, 438.1 [M+H]+. 1H NMR (DMSO-d6): 8.05 (d, J=1.9, 1H), 7.51 (d, J=8.3, 1H), 7.43 (dd, J=8.4, 1.9 2H), 4.30 (s, 2H), 3.36 (t, J=5.8, 2H), 3.30 (br s, 1H), 2.86 (s, 3H), 2.69 (t, J=5.6, 2H).
B. 3-(4-Chloro-3-iodo-phenyl)-5-methanesulfonyl-1-(3-morpholin-4-yl-propyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. This compound was prepared using the methods outlined in Example 1, substituting 3-(4-chloro-3-iodo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine for 2-[5-(5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-trifluoromethyl-phenylsulfanyl]-ethanol and morpholine for 4-(N-2-pyrrolidinone)piperidine. MS (ESI): mass calcd. for C20H26CIIN4O3S, 564.9; m/z found, 566.2 [M+H]+. 1H NMR (CDCl3): 8.15 (s, 1H), 7.46-7.45 (m, 2H), 4.49 (s, 2H), 4.09 (t, J=6.8, 2H), 3.70 (t, J=4.6, 4H), 3.64 (t, J=5.8, 2H), 2.90 (s, 3H), 2.89 (t, J=5.8, 2H), 2.44-2.39 (bm, 4H), 2.32 (t, J=6.8, 2H), 2.11-2.03 (m, 2H).
C. 3-(3-Benzylsulfanyl-4-chloro-phenyl)-5-methanesulfonyl-1-(3-morpholin-4-yl-propyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. A solution of the above iodoarene (100 mg, 0.177 mmol), tris(dibenzylideneacetone)dipalladium (8.1 mg, 8.9×10−3 mmol), diphenylphosphinoferrocene (19.4 mg, 0.035 mmol) and TEA (50 μL, 0.354 mmol) in degassed DMF was stirred at rt under N2 for 15 min. Benzylmercaptan (23 μL, 0.177 mmol) was added drop-wise and the reaction mixture was heated at 70° C. for 5 h. After 1 N NaOH (5 mL) was added, the two layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×, 5 mL). The combined organic extracts were dried (Na2SO4) and filtered to give a yellow oil. Purification (SiO2; 0-3%1:9 satd. NH3 in MeOH/MeOH in CH2Cl2) afforded the desired product as a clear oil (94 mg, 95%). MS (ESI): mass calcd. for C27H33ClN4O3S2, 561.2; m/z found, 562.5 [M+H]+. 1H NMR (CDCl3): 7.56 (d, J=2.0, 1H), 7.38 (d, J=8.3, 1H), 7.32-7.22 (m, 6H), 4.39 (s, 2H), 4.21 (s, 2H), 4.08 (t, J=6.8, 2H), 3.68 (t, J=4.6, 4H), 3.62 (t, J=5.8, 2H), 2.87-2.84 (m, 2H), 2.86 (s, 3H), 2.41-2.38 (m, 4H), 2.31 (t, J=6.8, 2H), 2.09-2.02 (m, 2H).
Examples 129 through 139 were prepared using methods similar to those described in Example 128, with the appropriate substituent changes.
MS (ESI): mass calcd. for C28H35ClN4O3S2, 575.2; m/z found, 576.3 [M+H]+. 1H NMR (CDCl3): 7.66 (d, J=2.0, 1H), 7.40 (d, J=8.2, 1H), 7.34-7.21 (m, 6H), 4.49 (s, 2H), 4.10 (t, J=6.8, 2H), 3.68 (t, J=4.6, 4H), 3.64 (t, J=5.8, 2H), 3.26-3.22 (m, 2H), 3.03-2.99 (m, 2H), 2.89 (t, J=5.7, 2H), 2.84 (s, 3H), 2.41-2.38 (br m, 4H), 2.32 (t, J=6.8, 2H), 2.10-2.05 (m, 2H).
MS (ESI): mass calcd. for C29H35F3N4O4S2, 624.21; m/z found, 625.5 [M+H]+. 1H NMR (CDCl3): 7.92 (s, 1H), 7.71 (d, J=8.2, 1H), 7.43 (d, J=8.1, 1H), 7.28-7.23 (m, 2H), 6.95 (t, J=7.3, 1H), 6.86 (d, J=8.5, 2H), 4.50 (s, 2H), 4.21 (t, J=7.0, 2H), 4.16 (t, J=6.5, 2H), 3.97-3.87 (m, 4H), 3.64 (t, J=5.7, 2H), 3.49 (s, 1H), 3.48-3.43 (m, 1H), 3.41 (t, J=6.9, 2H), 3.12-3.05 (m, 2H), 2.87-2.82 (m, 2H), 2.85 (s, 3H), 2.81-2.72 (m, 2H), 2.41-2.33 (m, 2H).
MS (ESI): mass calcd. for C25H31ClN4O4S2, 550.15; m/z found, 551.5 [M+H]+. 1H NMR (CDCl3): 7.61 (d, J=1.9, 1H), 7.43-7.34 (m, 3H), 6.29-6.26 (m, 1H), 6.20 (d, J=3.2, 1H), 4.45 (s, 2H), 4.21 (s, 2H), 4.09 (t, J=6.8, 2H), 3.70 (t, J=4.5, 4H), 3.65 (t, J=5.8, 2H), 2.91-2.86 (m, 2H), 2.88 (s, 3H), 2.45-2.38 (m, 4H), 2.33 (t, J=6.7, 2H), 2.11-2.03 (m, 2H).
MS (ESI): mass calcd. for C23H33ClN4O3S2, 512.17; m/z found, 513.5 [M+H]+. 1H NMR: 7.59 (d, J=2.0, 1H), 7.43 (d, J=8.3, 1H), 7.34 (dd, J=8.5, 2.0, 1H), 4.49 (s, 2H), 4.16 (t, J=6.7, 2H), 3.69-3.62 (m, 6H), 3.01 (t, J=7.3, 2H), 2.99 (s, 3H), 2.97-2.93 (m, 2H), 2.42 (br s, 4H), 2.34 (t, J=7.1, 2H), 2.10-2.03 (m, 2H), 1.79-1.70 (m, 2H), 1.09 (t, J=7.4, 3H).
MS (ESI): mass calcd. for C28H35ClN4O4S2, 590.18; m/z found, 591.5 [M+H]+.
MS (ESI): mass calcd. for C33H39ClF3N5O3S2, 709.21; m/z found, 710.6 [M+H]+.
MS (ESI): mass calcd. for C27H32Cl2N4O3S2, 594.13; m/z found, 595.5 [M+H]+.
MS (ESI): mass calcd. for C27H32ClFN4O3S2, 578.16; m/z found, 579.5 [M+H]+.
MS (ESI): mass calcd. for C34H42F3N5O4S2, 705.26; m/z found, 706.6 [M+H]+.
MS (ESI): mass calcd. for C26H33ClN6O3S2, 576.17; m/z found, 577.5 [M+H]+.
MS (ESI): mass calcd. for C23H32Cl2N4O3S2, 546.13; m/z found, 547.4 [M+H]+.
The title compound was prepared using methods analogous to those described for example 153, substituting (S)-(+)-glycidyl nosylate for epichlorohydrin. MS (ESI): mass calcd. for C31H45F4N5O3S2, 675.29; m/z found, 676.3 [M+H]+. 1H NMR: 7.94 (s, 1H), 7.82 (d, J=8.2, 1H), 7.72 (d, J=8.1, 1H), 4.573 (dd, J=17.6, 14.2, 2H), 4.51-4.47 (m, 1H), 4.24 (dd, J=14.5, 4.2, 2H), 4.18 (dd, J=14.4, 6.6, 2H), 3.70-3.41 (m, 11H), 3.36 (d, J=13.3, 2.6, 1H), 3.33-3.24 (m, 2H), 3.24-3.18 (m, 2H), 3.14 (dd, J=12.5, 3.5, 1H), 3.116 (dd, J=12.4, 3.4, 1H), 3.05-2.94 (m, 5H), 2.41-1.85 (m, 4H), 1.76 (ddd, J=14.0, 13.6, 9.9, 1H), 1.71-1.58 (m, 3H), 1.08 (s, 3H), 1.03 (s, 3H).
Examples 141 and 142 were prepared using methods similar to those described in Example 140, with the appropriate substituent changes.
MS (ESI): mass calcd. for C31H43F5N6O4S2, 722.27; m/z found, 723.3 [M+H]+. 1H NMR: 7.95 (s, 1H), 7.81 (d, J=8.2, 1H), 7.70 (d, J=8.0, 1H), 4.57 (dd, J=17.2, 14.0, 2H), 4.53-4.47 (m, 1H), 4.41-4.14 (m, 2H), 4.07-2.92 (m, 22H), 2.41-1.65 (m, 12H).
MS (ESI): mass calcd. for C30H42F5N5O3S2, 679.26; m/z found, 680.3 [M+H]+. 1H NMR: 7.95 (s, 1H), 7.81 (d, J=8.2, 1H), 7.68 (d, J=8.0, 1H), 4.58 (dd, J=17.4, 14.0, 2H), 4.55-4.48 (m, 1H), 4.25 (dd, J=14.4, 4.0, 2H), 4.19 (dd, J=14.5, 6.7, 2H), 4.01-2.80 (m, 21H), 2.28-1.36 (m, 9H), 1.25-0.88 (m, 3H).
To a solution of 3-(3-benzylsulfanyl-4-chloro-phenyl)-5-methanesulfonyl-1-(3-morpholin-4-yl-propyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (0.05 g, 0.07 mmol) in DMF (0.30 mL) was added tellurium dioxide (0.01 g, 0.07 mmol), 30% hydrogen peroxide (0.02 mL, 0.05 mmol), and a catalytic amount of concentrated HCl. After stirring for 16 h at rt, H2O was added to the reaction mixture. The aqueous layer was extracted with CH2Cl2 (3×, 20 mL), and the combined organic layers were dried (Na2SO4) and concentrated to afford a bright yellow solid. Purification (SiO2; 0-8% 1:9 satd. NH3 in MeOH/MeOH in CH2Cl2) provided a yellow oil (0.03 g, 75%), and reverse phase HPLC (C18; 20 mM NH4OH/H2O/CH3CN) yielded the desired compound as a white powder. MS (ESI): mass calcd. for C27H33ClN4O4S2, 576.16; m/z found, 577.5 [M+H]+. 1H NMR (CDCl3): 7.70 (dd, J=8.3, 2.2, 1H), 7.58 (d, J=2.1, 1H), 7.41 (d, J=8.3, 1H), 7.29-7.25 (m, 3H), 7.13-7.08 (m, 2H), 4.38-4.27 (m, 3H), 4.11-4.03 (m, 3H), 3.74-3.66 (m, 5H), 3.55-3.48 (m, 1H), 2.89 (s, 3H), 2.88-2.83 (m, 2H), 2.43-2.36 (m, 4H), 2.92 (t, J=6.8, 2H), 2.08-2.01 (m, 2H).
Unless otherwise specified, the compounds in Examples 144-614 were prepared as free base, hydrochloride salt, trifluoroacetic acid salt, or citric acid salt forms.
Examples 144-148 were prepared according to the methods described in Example 4, with the appropriate substituent changes.
MS (ESI): mass calcd. for C32H47F3N6O3S2, 684.31; m/z found, 685.3 [M+H]+. 1H NMR: 7.88 (s, 1H), 7.76 (d, J=8.2, 1H), 7.63-7.59 (m, 1H), 4.46 (s, 2H), 4.21-4.14 (m, 2H), 4.04-3.96 (m, 1H), 3.62-3.52 (m, 4H), 3.48-3.44 (m, 2H), 3.30-3.08 (m, 6H), 3.05-2.96 (m, 2H), 2.89 (s, 3H), 2.88-2.84 (m, 2H), 2.31-2.20 (m, 4H), 1.98-1.80 (m, 6H), 1.26 (s, 9H).
MS (ESI): mass calcd. for C29H42F3N5O3S2, 629.27; m/z found, 630.2 [M+H]+. 1H NMR: 7.94 (brs, 1H), 7.75-7.67 (m, 1H), 7.62-7.54 (m, 1H), 4.61-4.38 (m, 2H), 4.24-4.11 (m, 2H), 4.02-3.72 (m, 4H), 3.68-3.33 (m, 10H), 3.16-2.71 (m, 8H), 2.40-2.21 (m, 2H), 1.89-1.65 (m, 5H), 1.49-1.14 (m, 6H).
MS (ESI): mass calcd. for C30H44F3N5O3S2, 643.28; m/z found, 644.3 [M+H]+. 1H NMR: 7.91 (brs, 1H), 7.75-7.67 (m, 1H), 7.61-7.55 (m, 1H), 4.58-4.43 (m, 2H), 4.24-4.13 (m, 2H), 3.93-3.83 (m, 2H), 3.66-3.37 (m, 8H), 3.35-3.00 (m, 3H), 2.98-2.79 (m, 7H), 2.70-2.56 (m, 2H), 2.38-2.27 (m, 2H), 1.90-1.64 (m, 5H), 1.49-1.36 (m, 1H), 1.22-1.05 (m, 7H).
MS (ESI): mass calcd. for C29H42F3N5O4S2, 645.26; m/z found, 646.2 [M+H]+. 1H NMR: 7.91 (br s, 1H), 7.74-7.67 (m, 1H), 7.60-7.54 (m, 1H), 4.59-4.43 (m, 2H), 4.24-4.14 (m, 2H), 4.06-3.98 (m, 1H), 3.88-3.75 (m, 2H), 3.67-3.29 (m, 12H), 3.15-2.74 (m, 10H), 2.44-2.18 (m, 2H), 1.90-1.65 (m, 5H), 1.47-1.38 (m, 1H), 1.30-1.13 (m, 1H).
MS (ESI): mass calcd. for C29H42F3N5O4S2, 645.26; m/z found, 646.2 [M+H]+. 1H NMR: 7.95 (br s, 1H), 7.78-7.69 (m, 1H), 7.64-7.58 (m, 1H), 4.63-4.40 (m, 2H), 4.28-4.14 (m, 2H), 4.04-3.34 (m, 14H), 3.17-2.73 (m, 9H), 2.43-2.21 (m, 2H), 1.92-1.68 (m, 5H), 1.52-1.37 (m, 2H), 1.35-1.15 (m, 2H).
Examples 149-152 were prepared according to the methods described in Example 54, with the appropriate substituent changes.
MS (ESI): mass calcd. for C38H52F3N9O3S2, 803.36; m/z found, 804.3 [M+H]+. 1H NMR: 7.91 (s, 1H), 7.72 (d, J=8.2, 1H), 7.53 (d, J=8.2, 1H), 7.27-7.23 (m, 1H), 6.31 (d, J=8.6, 1H), 4.56 (s, 2H), 4.33-4.23 (m, 1H), 4.21-4.16 (m, 2H), 3.69-3.64 (m, 3H), 3.56-3.53 (m, 1H), 3.24-3.19 (m, 2H), 3.09-2.97 (m, 10H), 2.96 (s, 3H), 2.83-2.72 (m, 2H), 2.66-2.60 (m, 2H), 2.47 (br s, 4H), 2.41-2.35 (m, 2H), 2.15-2.06 (m, 4H), 1.73-1.66 (m, 2H), 1.61-1.37 (m, 7H).
MS (ESI): mass calcd. for C32H47F3N6O4S2, 700.31; m/z found, 701.3 [M+H]+. 1H NMR: 7.93 (s, 1H), 7.82-7.79 (m, 1H), 7.72-7.66 (m, 1H), 4.57 (s, 2H), 4.32-4.18 (m, 2H), 4.16-4.02 (m, 2H), 3.75-3.55 (m, 7H), 3.54-3.42 (m, 3H), 3.41-3.31 (m, 3H), 3.29-3.15 (m, 3H), 3.13-2.90 (m, 5H), 2.43-2.28 (m, 2H), 2.21-2.10 (m, 2H), 2.09-1.99 (m, 1H), 1.98-1.88 (m, 2H), 1.88-1.69 (m, 5H), 1.58-1.42 (m, 1H), 1.31-1.15 (m, 3H).
MS (ESI): mass calcd. for C27H40F3N5O2S2, 587.26; m/z found, 588.3 [M+H]+. 1H NMR: 7.97 (s, 1H), 7.83 (d, J=8.2, 1H), 7.72-7.68 (m, 1H), 4.57 (s, 2H), 4.31-4.21 (m, 2H), 3.74-3.65 (m, 2H), 3.61-3.51 (m, 2H), 3.43-3.25 (m, 4H), 3.23-3.15 (m, 2H), 3.09-2.88 (m, 9H), 2.42-2.29 (m, 2H), 2.00-1.89 (m, 2H), 1.87-1.63 (m, 5H), 1.58-1.42 (m, 1H), 1.01 (t, J=7.4, 3H).
MS (ESI): mass calcd. for C33H49F3N6O3S2, 698.33; m/z found, 699.3 [M+H]+. 1H NMR: 7.86 (s, 1H), 7.74 (d, J=8.3, 1H), 7.63-7.59 (m, 1H), 4.46 (s, 2H), 4.20-4.12 (m, 2H), 3.64-3.49 (m, 4H), 3.49-3.38 (m, 4H), 3.33-3.04 (m, 6H), 2.99-2.82 (m, 10H), 2.32-2.19 (m, 2H), 1.97-1.76 (m, 4H), 1.65-1.55 (m, 4H), 1.54-1.47 (m, 2H), 1.46-1.40 (m, 2H), 0.90 (t, J=7.4, 3H).
A. 2-Piperidin-1-yl-ethanethiol. To a stirring solution of piperidine (3.3 mL, 34 mmol) in toluene (18 mL) was added ethylene sulfide. A reflux condenser was attached, the flask was purged with N2, and the mixture was heated at reflux for 4 h. The mixture was cooled to rt and concentrated to afford the title compound (3.3 g, 58%), which was used immediately without further purification.
B. 5-Methanesulfonyl-3-[3-(2-piperidin-1-yl-ethylsulfanyl)-4-trifluoromethyl-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. This compound was prepared using methods similar to those described in Example 1, Step C, substituting 2-piperidin-1-yl-ethanethiol for 2-mercaptoethanol.
C. 1-[5-(Methylsulfonyl)-3-{3-[(2-piperidin-1-ylethyl)sulfanyl]-4-(trifluoromethyl)phenyl}-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl]-3-piperidin-1-ylpropan-2-ol. This compound was prepared using methods similar to those described in Example 61, Steps B and C, substituting piperidine for 1-piperidin-4-yl-pyrrolidin-2-one. Purification was conducted using reverse phase HPLC. MS (ESI): mass calcd. for C29H42F3N5O3S2, 629.27; m/z found, 630.2 [M+H]+. 1H NMR (CDCl3): 7.83 (s, 1H), 7.66 (d, J=8.1, 1H), 7.38 (d, J=8.0, 1H), 4.59 (d, J=14.5, 1H), 4.53 (d, J=14.4, 1H), 4.18 (dd, J=14.1, 2.7, 1H), 4.13-4.07 (m, 1H), 3.99 (dd, J=14.0, 6.9, 1H), 3.75-3.69 (m, 1H), 3.68-3.60 (m, 1H), 3.17 (dd, J=8.9, 6.7, 2H), 3.14-3.07 (m, 1H), 2.96-2.89 (m, 1H), 2.87 (s, 3H), 2.65-2.61 (m, 2H), 2.61-2.51 (m, 2H), 2.51-2.37 (m, 5H), 2.37-2.26 (m, 2H), 1.61-1.50 (m, 10H), 1.48-1.39 (m, 4H).
Examples 154-189 were prepared using methods similar to those described in Example 153, with the appropriate substituent changes.
MS (ESI): mass calcd. for C38H52F3N9O4S2, 819.35; m/z found, 820.3 [M+H]+. 1H NMR: 8.01 (s, 1H), 7.81 (d, J=7.8, 1H), 7.70 (d, J=6.8, 1H), 7.62 (d, J=7.7, 1H), 7.31 (d, J=7.7, 1H), 4.81-4.73 (m, 1H), 4.73-4.66 (m, 1H), 4.65-4.56 (m, 2H), 4.35-4.17 (m, 2H), 3.87 (d, J=29.1, 2H), 3.74-3.66 (m, 2H), 3.67-3.53 (m, 5H), 3.51-3.40 (m, 6H), 3.40-3.33 (m, 8H), 3.19-2.90 (m, 10H), 2.19-2.01 (m, 2H), 1.98-1.89 (m, 2H), 1.88-1.77 (m, 3H), 1.57-1.44 (m, 1H).
MS (ESI): mass calcd. for C34H45F3N6O3S2, 706.29; m/z found, 707.3 [M+H]+. 1H NMR: 8.80 (s, 1H), 8.63 (s, 1H), 8.11-8.04 (m, 1H), 8.03-7.98 (m, 2H), 7.84-7.76 (m, 1H), 7.73-7.65 (m, 1H), 4.71-4.62 (m, 1H), 4.62-4.55 (m, 1H), 4.41-4.11 (m, 2H), 3.96-3.76 (m, 2H), 3.76-3.39 (m, 10H), 3.38-3.31 (m, 4H), 3.12-2.82 (m, 6H), 2.44-2.20 (m, 4H), 2.19-2.07 (m, 1H), 1.99-1.88 (m, 2H), 1.88-1.76 (m, 2H), 1.58-1.44 (m, 1H), 1.44-1.23 (m, 2H).
MS (ESI): mass calcd. for C35H44F3N7O3S2, 731.29; m/z found, 732.2 [M+H]+. 1H NMR: 7.95 (s, 1H), 7.83 (d, J=8.3, 1H), 7.75 (d, J=8.1, 1H), 7.69 (d, J=7.7, 1H), 7.64 (dd, J=8.3, 7.6, 1H), 7.24-7.19 (m, 2H), 4.64-4.51 (m, 3H), 4.29 (dd, J=14.4, 4.1, 1H), 4.22 (dd, J=14.5, 6.5, 1H), 3.72-3.62 (m, 5H), 3.61-3.54 (m, 4H), 3.52-3.44 (m, 5H), 3.40-3.33 (m, 4H), 3.06-3.01 (m, 3H), 3.00-2.98 (m, 5H), 1.99-1.88 (m, 2H), 1.87-1.67 (m, 3H), 1.55-1.42 (m, 1H).
MS (ESI): mass calcd. for C33H47F3N6O4S2, 712.31; m/z found, 713.3 [M+H]+. 1H NMR: 7.99 (s, 1H), 7.80 (d, J=7.7, 1H), 7.72-7.65 (m, 1H), 4.65-4.45 (m, 3H), 4.31-4.05 (m, 4H), 3.83-3.62 (m, 4H), 3.62-3.51 (m, 5H), 3.44-3.39 (m, 2H), 3.38-3.32 (m, 3H), 3.05-2.91 (m, 8H), 2.37 (t, J=7.9, 2H), 2.22-2.10 (m, 1H), 2.10-1.98 (m, 3H), 1.98-1.87 (m, 4H), 1.86-1.76 (m, 4H), 1.56-1.45 (m, 1H).
MS (ESI): mass calcd. for C35H51F3N6O5S2, 756.33; m/z found, 757.3 [M+H]+. 1H NMR: 7.96 (s, 1H), 7.84 (d, J=8.3, 1H), 7.73 (d, J=8.2, 1H), 4.63-4.46 (m, 3H), 4.27 (dd, J=14.3, 3.3, 2H), 4.20 (dd, J=14.4, 6.5, 2H), 3.79-3.34 (m, 18H), 3.29-3.04 (m, 3H), 3.05-2.95 (m, 5H), 2.97-2.80 (m, 2H), 2.80-2.72 (m, 1H), 2.09-1.94 (m, 7H), 1.91 (dd, J=13.7, 6.8, 2H), 1.87-1.75 (m, 2H), 1.29 (d, J=12.4, 1H).
MS (ESI): mass calcd. for C31H45F3N6O3S2, 670.29; m/z found, 671.3 [M+H]+. 1H NMR: 8.08-7.94 (m, 1H), 7.80 (d, J=7.5, 1H), 7.67 (d, J=7.5, 1H), 4.71-4.61 (m, 1H), 4.61-4.50 (m, 2H), 4.32-4.21 (m, 2H), 3.98-3.73 (m, 7H), 3.72-3.49 (m, 7H), 3.37-3.31 (m, 3H), 3.08-2.92 (m, 8H), 1.93 (d, J=11.9, 2H), 1.82 (d, J=10.7, 3H), 1.57-1.43 (m, 1H), 1.28-1.21 (m, 3H), 1.04-0.96 (m, 2H), 0.95-0.86 (m, 1H).
MS (ESI): mass calcd. for C28H40F3N5O4S2, 631.25; m/z found, 632.2 [M+H]+. 1H NMR (CDCl3): 7.83 (s, 1H), 7.66 (d, J=8.2, 1H), 7.38 (d, J=8.2, 1H), 4.55 (q, J=14.3, 2H), 4.20 (dd, J=14.0, 2.9, 1H), 4.17-4.12 (m, 1H), 4.01 (dd, J=14.0, 6.8, 1H), 3.77-3.59 (m, 7H), 3.18-3.13 (m, 2H), 3.10-3.03 (m, 1H), 2.97-2.89 (m, 1H), 2.88 (s, 3H), 2.69-2.58 (m, 4H), 2.51-2.35 (m, 8H), 1.59-1.55 (m, 4H), 1.46-1.37 (m, 2H).
MS (ESI): mass calcd. for C28H40F3N5O3S2, 615.25; m/z found, 616.2 [M+H]+. 1H NMR (CDCl3): 7.83 (s, 1H), 7.66 (d, J=8.2, 1H), 7.39 (d, J=8.1, 1H), 4.56 (q, J=14.5, 2H), 4.20 (dd, J=13.9, 2.8, 1H), 4.12-4.06 (m, 1H), 4.02 (dd, J=13.9, 7.0, 1H), 3.74-3.69 (m, 1H), 3.69-3.60 (m, 1H), 3.16 (dd, J=8.8, 6.8, 2H), 3.10-3.04 (m, 1H), 2.96-2.89 (m, 1H), 2.87 (s, 3H), 2.68-2.58 (m, 5H), 2.53-2.47 (m, 2H), 2.44 (dd, J=11.9, 4.3, 5H), 1.78 (t, J=6.3, 4H), 1.70-1.62 (m, 3H), 1.59-1.54 (m, 4H).
MS (ESI): mass calcd. for C31H47F3N6O3S2, 672.31; m/z found, 673.3 [M+H]+. 1H NMR (CDCl3): 7.83 (s, 1H), 7.66 (d, J=8.2, 1H), 7.38 (d, J=8.3, 1H), 4.58 (d, J=15.4, 1H), 4.53 (d, J=14.5, 1H), 4.18 (dd, J=14.0, 2.7, 1H), 4.13-4.06 (m, 1H), 4.00 (dd, J=14.0, 7.0, 1H), 3.76-3.67 (m, 1H), 3.67-3.61 (m, 1H), 3.19-3.13 (m, 2H), 3.00-2.93 (m, 2H), 2.88-2.86 (m, 3H), 2.85-2.81 (m, 1H), 2.65-2.62 (m, 2H), 2.48-2.34 (m, 5H), 2.27-2.26 (m, 5H), 2.13-2.05 (m, 1H), 2.04-1.96 (m, 1H), 1.86-1.78 (m, 3H), 1.76-1.62 (m, 7H), 1.60-1.54 (m, 5H).
MS (ESI): mass calcd. for C29H43F3N6O3S2, 644.28; m/z found, 645.2 [M+H]+. 1H NMR (CDCl3): 7.83 (s, 1H), 7.66 (d, J=8.2, 1H), 7.38 (d, J=8.0, 1H), 4.58 (d, J=14.4, 1H), 4.53 (d, J=14.5, 1H), 4.19 (dd, J=14.1, 2.9, 1H), 4.16-4.09 (m, 1H), 4.00 (dd, J=14.1, 7.0, 1H), 3.85-3.73 (m, 1H), 3.73-3.69 (m, 1H), 3.68-3.61 (m, 1H), 3.18-3.14 (m, 2H), 3.11-3.05 (m, 1H), 2.96-2.89 (m, 1H), 2.87 (s, 3H), 2.74-2.58 (m, 5H), 2.54-2.34 (m, 11H), 2.28 (s, 3H), 1.59-1.55 (m, 4H), 1.46-1.37 (m, 2H).
MS (ESI): mass calcd. for C29H42F3N5O5S2, 661.26; m/z found, 662.3 [M+H]+. 1H NMR: 7.94 (s, 1H), 7.85-7.81 (m, 1H), 7.76-7.72 (m, 1H), 4.62-4.54 (m, 2H), 4.51-4.46 (m, 1H), 4.27-4.10 (m, 3H), 3.85-3.73 (m, 2H), 3.71-3.44 (m, 13H), 3.22-3.09 (m, 2H), 3.08-2.93 (m, 8H), 1.98-1.67 (m, 5H), 1.58-1.48 (m, 1H).
MS (ESI): mass calcd. for C33H47F3N6O6S2, 744.30; m/z found, 745.3 [M+H]+. 1H NMR: 7.94 (s, 1H), 7.85-7.82 (m, 1H), 7.76-7.73 (m, 1H), 4.62-4.53 (m, 2H), 4.52-4.45 (m, 1H), 4.29-4.08 (m, 4H), 3.86-3.38 (m, 17H), 3.29-3.08 (m, 4H), 3.06-2.96 (m, 6H), 2.42-2.35 (m, 2H), 2.18-1.88 (m, 6H).
MS (ESI): mass calcd. for C29H41F3N6O4S2, 658.26; m/z found, 659.2 [M+H]+. 1H NMR: 8.02 (s, 1H), 7.82 (d, J=8.2, 1H), 7.66 (d, J=8.1, 1H), 4.65-4.49 (m, 3H), 4.30-4.14 (m, 2H), 3.93-3.84 (m, 1H), 3.72-3.27 (m, 13H), 3.24-3.15 (m, 1H), 3.12-2.95 (m, 7H), 2.03-1.72 (m, 5H), 1.61-1.49 (m, 4H).
MS (ESI): mass calcd. for C33H46F3N7O5S2, 741.30; m/z found, 742.3 [M+H]+. 1H NMR: 8.01 (s, 1H), 7.85-7.81 (m, 1H), 7.69-7.65 (m, 1H), 4.59 (s, 2H), 4.54-4.48 (m, 1H), 4.31-4.08 (m, 3H), 3.88-3.59 (m, 5H), 3.56-3.37 (m, 9H), 3.30-3.11 (m, 5H), 3.05-2.95 (m, 5H), 2.40 (t, J=8.1, 2H), 2.18-1.90 (m, 6H), 1.50 (t, J=7.0, 3H).
MS (ESI): mass calcd. for C34H44F3N7O4S2, 735.28; m/z found, 736.3 [M+H]+. 1H NMR: 8.62-8.58 (m, 1H), 8.06-7.98 (m, 2H), 7.82 (d, J=8.2, 1H), 7.67 (d, J=8.1, 1H), 7.57-7.46 (m, 2H), 4.64-4.51 (m, 3H), 4.31-4.17 (m, 2H), 3.91-3.74 (m, 3H), 3.72-3.60 (m, 2H), 3.59-3.53 (m, 1H), 3.53-3.26 (m, 10H), 3.24-3.13 (m, 2H), 3.05-2.97 (m, 5H), 2.28-2.05 (m, 4H), 1.55-1.47 (m, 3H).
MS (ESI): mass calcd. for C29H42F3N5O4S2, 645.26; m/z found, 646.2 [M+H]+. 1H NMR: 7.93 (d, J=11.3, 1H), 7.82 (d, J=8.2, 1H), 7.76-7.69 (m, 1H), 4.61-4.53 (m, 2H), 4.52-4.46 (m, 1H), 4.27-4.14 (m, 2H), 4.10-4.06 (m, 0.5H), 3.83-3.75 (m, 0.5H), 3.71-3.51 (m, 5H), 3.51-3.30 (m, 7H), 3.22-3.15 (m, 1H), 3.11-2.92 (m, 8H), 2.17-2.09 (m, 1H), 2.02-1.65 (m, 8H), 1.58-1.45 (m, 1H).
MS (ESI): mass calcd. for C33H47F3N6O5S2, 728.30; m/z found, 729.3 [M+H]+. 1H NMR: 7.97-7.91 (m, 1H), 7.84-7.81 (m, 1H), 7.78-7.71 (m, 1H), 4.59-4.56 (m, 2H), 4.52-4.46 (m, 1H), 4.29-4.05 (m, 4H), 3.84-3.56 (m, 5H), 3.51-3.29 (m, 9H), 3.28-3.03 (m, 4H), 3.02-2.94 (m, 5H), 2.39 (t, J=8.1, 2H), 2.17-2.09 (m, 2H), 2.08-2.00 (m, 3H), 1.99-1.88 (m, 4H), 1.74-1.64 (m, 1H).
MS (ESI): mass calcd. for C35H44F3N7O4S2, 747.28; m/z found, 748.2 [M+H]+. 1H NMR: 8.00-7.91 (m, 1H), 7.86-7.82 (m, 1H), 7.79-7.73 (m, 1H), 7.71-7.68 (m, 1H), 7.66-7.62 (m, 1H), 7.27-7.18 (m, 2H), 4.64-4.51 (m, 3H), 4.33-4.20 (m, 2H), 3.88-3.26 (m, 20H), 3.12-2.92 (m, 6H), 2.20-2.07 (m, 1H), 2.02-1.87 (m, 2H), 1.75-1.61 (m, 1H).
MS (ESI): mass calcd. for C34H45F3N6O4S2, 722.29; m/z found, 723.3 [M+H]+. 1H NMR: 8.69-8.61 (m, 1H), 8.19-8.11 (m, 1H), 7.98-7.90 (m, 1H), 7.85-7.80 (m, 1H), 7.77-7.70 (m, 1H), 7.67-7.57 (m, 2H), 4.64-4.50 (m, 3H), 4.32-4.18 (m, 2H), 4.11-4.05 (m, 0.5H), 3.86-3.74 (m, 2.5H), 3.72-3.60 (m, 3H), 3.54-3.16 (m, 11H), 3.13-2.93 (m, 6H), 2.31-2.07 (m, 5H), 2.01-1.88 (m, 2H), 1.77-1.62 (m, 1H).
MS (ESI): mass calcd. for C38H52F3N9O5S2, 835.35; m/z found, 836.3 [M+H]+. 1H NMR: 8.02-7.71 (m, 3H), 7.38-7.29 (m, 1H), 6.46-6.31 (m, 1H), 4.76-4.49 (m, 4H), 4.36-4.19 (m, 2H), 3.89-3.58 (m, 6H), 3.56-3.19 (m, 12H), 3.16-2.94 (m, 15H), 2.24-1.86 (m, 5H), 1.81-1.58 (m, 1H).
MS (ESI): mass calcd. for C28H40F3N5O4S2, 631.25; m/z found, 632.2 [M+H]+. 1H NMR: 8.01 (s, 1H), 7.86-7.81 (m, 1H), 7.74-7.68 (m, 1H), 4.69-4.54 (m, 3H), 4.33-4.15 (m, 2H), 4.11-4.01 (m, 2H), 3.93-3.82 (m, 2H), 3.75-3.54 (m, 8H), 3.53-3.33 (m, 3H), 3.27-3.17 (m, 3H), 3.16-2.96 (m, 7H), 2.05-1.74 (m, 5H), 1.63-1.49 (m, 1H).
MS (ESI): mass calcd. for C29H42F3N5O4S2, 645.26; m/z found, 646.3 [M+H]+. 1H NMR: 7.94 (s, 1H), 7.87-7.82 (m, 1H), 7.79-7.74 (m, 1H), 4.60 (s, 2H), 4.54-4.47 (m, 1H), 4.30-4.15 (m, 2H), 3.92 (br s, 4H), 3.74-3.38 (m, 10H), 3.32-3.16 (m, 4H), 3.12-2.91 (m, 7H), 1.99-1.81 (m, 2H), 1.77-1.65 (m, 1H), 1.60-1.37 (m, 2H), 1.06-0.95 (m, 3H).
MS (ESI): mass calcd. for C30H44F3N5O4S2, 659.28; m/z found, 660.3 [M+H]+. 1H NMR: 7.93 (s, 1H), 7.85-7.81 (m, 1H), 7.77-7.73 (m, 1H), 4.61-4.55 (m, 2H), 4.51-4.46 (m, 1H), 4.28-4.15 (m, 2H), 4.13-3.72 (m, 4H), 3.74-3.58 (m, 2H), 3.53-3.40 (m, 7H), 3.39-3.28 (m, 3H), 3.26-3.07 (m, 4H), 3.04-2.94 (m, 5H), 1.84-1.53 (m, 4H), 1.13-0.99 (m, 6H).
MS (ESI): mass calcd. for C28H39F4N5O4S2, 649.24; m/z found, 650.2 [M+H]+. 1H NMR: 7.93 (s, 1H), 7.84-7.81 (m, 1H), 7.76-7.73 (m, 1H), 4.59-4.56 (m, 2H), 4.55-4.47 (m, 1H), 4.27-4.15 (m, 2H), 4.11-3.73 (m, 3H), 3.72-3.60 (m, 3H), 3.59-3.33 (m, 9H), 3.28-3.18 (m, 3H), 3.03-2.95 (m, 5H), 2.33-1.92 (m, 4H).
MS (ESI): mass calcd. for C32H48F3N5O4S2, 687.31; m/z found, 688.3 [M+H]+. 1H NMR: 7.83 (s, 1H), 7.75-7.72 (m, 1H), 7.67-7.65 (m, 1H), 4.54-4.45 (m, 2H), 4.43-4.36 (m, 1H), 4.18-4.04 (m, 2H), 4.03-3.64 (m, 4H), 3.64-3.50 (m, 5H), 3.48-3.04 (m, 10H), 3.00-2.78 (m, 6H), 1.97-1.79 (m, 2H), 1.60-1.39 (m, 2H), 1.34-1.23 (m, 1H), 0.81 (s, 9H).
MS (ESI): mass calcd. for C27H38F3N5O5S2, 633.22; m/z found, 634.2 [M+H]+. 1H NMR: 7.92 (s, 1H), 7.72 (d, J=8.2, 1H), 7.58 (d, J=8.1, 1H), 4.60-4.44 (m, 3H), 4.24-4.09 (m, 2H), 4.01-3.87 (m, 4H), 3.84-3.67 (m, 4H), 3.65-3.41 (m, 9H), 3.39-3.29 (m, 3H), 3.29-3.07 (m, 4H), 3.00-2.84 (m, 5H).
MS (ESI): mass calcd. for C37H50F3N9O5S2, 821.33; m/z found, 822.3 [M+H]+. 1H NMR: 8.04 (s, 1H), 7.87-7.80 (m, 1H), 7.75-7.62 (m, 2H), 7.40-7.35 (m, 1H), 4.84-4.70 (m, 2H), 4.69-4.58 (m, 2H), 4.41-4.21 (m, 2H), 4.13-4.00 (m, 2H), 3.97-3.80 (m, 4H), 3.78-3.54 (m, 8H), 3.52-3.29 (m, 11H), 3.28-3.20 (m, 3H), 3.19-2.95 (m, 8H), 2.20-2.03 (m, 2H).
MS (ESI): mass calcd. for C32H45F3N6O5S2, 714.28; m/z found, 715.2 [M+H]+. 1H NMR: 7.84 (s, 1H), 7.75-7.71 (m, 1H), 7.67-7.64 (m, 1H), 4.54-4.44 (m, 2H), 4.44-4.35 (m, 1H), 4.19-3.98 (m, 4H), 3.66-3.50 (m, 6H), 3.48-3.44 (m, 2H), 3.41-3.29 (m, 8H), 3.26-2.98 (m, 5H), 2.94-2.86 (m, 5H), 2.29 (t, J=8.1, 2H), 2.08-1.98 (m, 1H), 1.98-1.90 (m, 3H), 1.88-1.77 (m, 2H).
MS (ESI): mass calcd. for C33H43F3N6O4S2, 708.27; m/z found, 709.2 [M+H]+. 1H NMR: 8.86-8.81 (m, 1H), 8.70-8.63 (m, 1H), 8.10 (d, J=8.2, 1H), 8.07-8.01 (m, 2H), 7.87-7.81 (m, 1H), 7.73-7.68 (m, 1H), 4.74-4.67 (m, 1H), 4.66-4.59 (m, 2H), 4.37-4.25 (m, 2H), 4.09-4.03 (m, 2H), 3.94-3.83 (m, 3H), 3.74-3.39 (m, 12H), 3.36 (s, 3H), 3.28-3.19 (m, 2H), 3.09-3.00 (m, 5H), 2.43-2.23 (m, 4H).
MS (ESI): mass calcd. for C34H42F3N7O4S2, 733.27; m/z found, 734.2 [M+H]+. 1H NMR: 7.96 (s, 1H), 7.87-7.83 (m, 1H), 7.79-7.76 (m, 1H), 7.72-7.69 (m, 1H), 7.67-7.63 (m, 1H), 7.27-7.19 (m, 2H), 4.64-4.52 (m, 3H), 4.33-4.21 (m, 2H), 4.15-3.77 (m, 5H), 3.75-3.60 (m, 7H), 3.53-3.30 (m, 12H), 3.07-2.97 (m, 5H).
MS (ESI): mass calcd. for C28H40F3N5O3S2, 615.25; m/z found, 616.2 [M+H]+. 1H NMR: 7.94 (s, 1H), 7.83 (d, J=8.3, 1H), 7.74 (d, J=8.1, 1H), 4.57 (d, J=2.5, 2H), 4.52-4.46 (m, 1H), 4.27-4.14 (m, 2H), 3.79-3.61 (m, 4H), 3.60-3.53 (m, 2H), 3.50-3.41 (m, 4H), 3.36-3.32 (m, 1H), 3.21-3.15 (m, 1H), 3.15-3.02 (m, 3H), 3.02-2.99 (m, 2H), 2.98 (s, 3H), 2.97-2.92 (m, 1H), 2.24-2.08 (m, 2H), 2.07-1.98 (m, 2H), 1.97-1.87 (m, 2H), 1.86-1.71 (m, 3H), 1.60-1.47 (m, 1H).
MS (ESI): mass calcd. for C38H52F3N7O3S2, 775.3; m/z found, 776.3 [M+H]+. 1H NMR: 8.60 (d, J=5.1, 1H), 8.04 (t, J=7.2, 1H), 7.90 (s, 1H), 7.82 (d, J=8.3, 1H), 7.78 (d, J=8.2, 1H), 7.54 (d, J=7.9, 1H), 7.52-7.47 (m, 1H), 4.65-4.45 (m, 3H), 4.28 (dd, J=14.4, 4.0, 1H), 4.21 (dd, J=14.4, 6.5, 1H), 3.86-3.73 (m, 4H), 3.73-3.62 (m, 4H), 3.49 (dd, J=10.3, 5.3, 2H), 3.47-3.35 (m, 4H), 3.35-2.89 (m, 15H), 2.43 (d, J=13.5, 2H), 2.35-1.83 (m, 10H).
MS (ESI): mass calcd. for C35H46F3N7O4S2, 749.3; m/z found, 750.3 [M+H]+. 1H NMR: 8.68 (d, J=5.3, 1H), 8.23 (t, J=6.6, 1H), 7.92 (s, 1H), 7.81 (d, J=8.3, 1H), 7.75-7.69 (m, 2H), 7.69-7.62 (m, 1H), 4.72-4.43 (m, 3H), 4.28 (dd, J=14.4, 3.6, 1H), 4.20 (dd, J=14.4, 6.8, 1H), 4.12-3.09 (m, 22H), 3.09-2.91 (m, 5H), 2.49-1.97 (m, 7H).
MS (ESI): mass calcd. for C30H43F3N6O4S2, 672.2; m/z found, 673.2 [M+H]+. 1H NMR: 7.93 (s, 1H), 7.83 (d, J=8.3, 1H), 7.74 (d, J=8.2, 1H), 4.64-4.55 (m, 2H), 4.50 (ddd, J=13.7, 6.7, 3.8, 1H), 4.26 (dd, J=14.4, 4.0, 1H), 4.18 (J=14.4, 6.8, 1H), 3.84 (s, 3H), 3.74-3.14 (m, 18H), 3.13-2.91 (m, 7H), 2.15 (s, 1H), 2.05-1.66 (m, 5H), 1.62-1.47 (m, 1H).
MS (ESI): mass calcd. for C29H41F4N5O3S2, 647.2; m/z found, 648.2 [M+H]+. 1H NMR: 7.93 (s, 1H), 7.81 (d, J=8.3, 1H), 7.71 (d, J=8.2, 1H), 4.61-4.53 (m, 2H), 4.52-4.46 (m, 1H), 4.24 (dd, J=14.5, 4.1, 1H), 4.17 (dd, J=14.4, 6.8, 1H), 3.80-2.85 (m, 23H), 2.39-1.41 (m, 10H).
MS (ESI): mass calcd. for C34H44F4N6O3S2, 724.2; m/z found, 725.2 [M+H]+. 1H NMR: 8.68-8.63 (m, 1H), 8.17 (t, J=7.3, 1H), 7.94 (s, 1H), 7.83 (d, J=8.3, 1H), 7.74 (d, J=8.2, 1H), 7.66 (d, J=8.0, 1H), 7.64-7.59 (m, 1H), 4.64-4.50 (m, 3H), 4.28 (dd, J=14.4, 3.9, 1H), 4.21 (dd, J=14.4, 6.6, 1H), 3.80 (t, J=14.1, 2H), 3.72-3.61 (m, 2H), 3.62-2.95 (m, 20H), 2.45-1.84 (m, 9H).
The title compound was prepared using methods analogous to those described for Example 234. MS (ESI): mass calcd. for C30H43F4N5O3S2, 661.2; m/z found, 662.2 [M+H]+. 1H NMR: 7.97-7.91 (m, 1H), 7.81 (d, J=8.2, 1H), 7.68 (d, J=8.1, 1H), 4.70-4.55 (m, 2H), 4.50 (ddd, J=13.7, 6.8, 4.0, 1H), 4.23 (dd, J=14.4, 4.1, 1H), 4.16 (dd, J=14.4, 6.8, 1H), 3.74-3.65 (m, 2H), 3.65-2.91 (m, 19H), 2.40-1.69 (m, 10H), 1.58-1.45 (m, 1H), 1.33 (t, J=7.4, 3H).
Examples 191-195 were prepared using methods similar to those described in Example 153, with the appropriate substituent changes.
MS (ESI): mass calcd. for C33H44F3N7O5S2, 739.2; m/z found, 740.2 [M+H]+. 1H NMR: 8.70-8.55 (m, 2H), 7.95 (s, 1H), 7.82 (d, J=8.1, 1H), 7.79-7.64 (m, 1H), 7.14 (s, 1H), 4.67-4.46 (m, 3H), 4.32-4.12 (m, 3H), 3.90-2.60 (m, 23H), 2.55-1.92 (m, 6H), 1.84 (d, J=12.4, 1H), 1.75 (d, J=14.0, 1H), 1.66 (t, J=12.4, 1H).
MS (ESI): mass calcd. for C34H45F3N6O5S2, 738.2; m/z found, 739.2 [M+H]+. 1H NMR: 8.63 (d, J=4.4, 1H), 8.13 (s, 1H), 8.02-7.93 (m, 1H), 7.86 (d, J=7.9, 1H), 7.82 (d, J=8.1, 1H), 7.78-7.67 (m, 1H), 7.57 (s, 1H), 4.74-4.45 (m, 3H), 4.38-4.09 (m, 3H), 4.00-3.24 (m, 18H), 3.23-2.95 (m, 7H), 2.69-2.48 (m, 2H), 2.20 (s, 1H), 2.05-1.95 (m, 1H), 1.85 (d, J=12.7, 1H), 1.76 (d, J=14.5, 1H), 1.71-1.61 (m, 1H).
MS (ESI): mass calcd. for C31H45F4N5O4S2, 691.2; m/z found, 692.2 [M+H]+. 1H NMR: 8.01 (s, 1H), 7.81 (s, 1H), 7.67 (s, 1H), 5.49 (s, 1H), 4.61 (s, 3H), 4.40-4.13 (m, 2H), 3.84-2.81 (m, 23H), 2.44-2.12 (m, 4H), 2.11-1.87 (m, 3H), 1.87-1.24 (m, 6H).
MS (ESI): mass calcd. for C30H42F4N6O4S2, 690.2; m/z found, 691.2 [M+H]+. 1H NMR: 7.95 (s, 1H), 7.84 (d, J=8.3, 1H), 7.7 (d, J=8.2, 1H), 4.67-4.44 (m, 3H), 4.26 (dd, J=14.3, 4.1, 1H), 4.19 (dd, J=14.4, 6.6, 1H), 3.85-2.89 (m, 26H), 2.36-1.85 (m, 8H).
MS (ESI): mass calcd. for C31H44F4N6O5S2, 720.2; m/z found, 721.2 [M+H]+. 1H NMR: 7.95 (s, 1H), 7.83 (d, J=8.3, 1H), 7.73 (d, J=8.1, 1H), 4.66-4.47 (m, 3H), 4.31-4.16 (m, 2H), 3.99 (s, 3H), 3.81-2.95 (m, 25H), 2.38-1.79 (m, 8H).
Examples 196-214 were prepared using methods analogous to those described in Example 140, substituting the appropriate amines and using (R)-(−)-glycidyl nosylate or (S)-(+)-glycidyl nosylate as needed.
MS (ESI): mass calcd. for C33H47F3N6O6S2, 744.30; m/z found, 745.3 [M+H]+. 1H NMR: 7.96 (s, 1H), 7.87-7.83 (m, 1H), 7.77-7.74 (m, 1H), 4.62-4.57 (m, 2H), 4.55-4.47 (m, 1H), 4.31-4.07 (m, 4H), 3.89-3.40 (m, 18H), 3.30-3.09 (m, 3H), 3.07-2.94 (m, 6H), 2.46-2.35 (m, 2H), 2.21-1.88 (m, 6H).
MS (ESI): mass calcd. for C34H50F3N5O4S2, 713.33; m/z found, 714.3 [M+H]+. 1H NMR: 7.97-7.91 (m, 1H), 7.82 (d, J=8.2, 1H), 7.72 (d, J=8.1, 1H), 4.61-4.47 (m, 3H), 4.24 (dd, J=14.4, 4.0, 1H), 4.17 (dd, J=14.4, 6.8, 1H), 3.72-3.54 (m, 3H), 3.53-3.45 (m, 3H), 3.44-3.31 (m, 6H), 3.28-3.18 (m, 3H), 3.06-2.92 (m, 6H), 2.08-1.87 (m, 2H), 1.87-1.56 (m, 9H), 1.54-1.29 (m, 5H), 1.29-1.15 (m, 4H), 1.08-0.96 (m, 1H).
MS (ESI): mass calcd. for C29H41F4N5O3S2, 647.2; m/z found, 648.2 [M+H]+. 1H NMR: 7.93 (s, 1H), 7.81 (d, J=8.3, 1H), 7.71 (d, J=8.2, 1H), 4.63-4.53 (m, 2H), 4.53-4.46 (m, 1H), 4.23 (dd, J=14.4, 4.1, 1H), 4.17 (dd, J=14.4, 6.7, 1H), 3.80-3.23 (m, 15H), 3.18 (dd, J=13.3, 10.8, 1H), 3.13-2.90 (m, 7H), 2.44-1.65 (m, 9H), 1.62-1.42 (m, 1H).
MS (ESI): mass calcd. for C29H41F4N5O3S2, 647.2; m/z found, 648.2 [M+H]+. 1H NMR: 7.93 (s, 1H), 7.81 (d, J=8.3, 1H), 7.70 (d, J=8.1, 1H), 4.60-4.53 (m, 2H), 4.52-4.46 (m, 1H), 4.23 (dd, J=14.4, 4.0, 1H), 4.17 (dd, J=14.4, 6.7, 1H), 3.75-3.24 (m, 16H), 3.18 (dd, J=13.3, 10.8, 1H), 3.11-2.90 (m, 7H), 2.35-1.66 (m, 9H), 1.56-1.47 (m, 1H).
MS (ESI): mass calcd. for C30H43F4N5O3S2, 661.2; m/z found, 662.2 [M+H]+. 1H NMR: 7.93 (s, 1H), 7.81 (d, J=8.2, 1H), 7.71 (d, J=8.1, 1H), 4.62-4.53 (m, 2H), 4.52-4.46 (m, 1H), 4.23 (dd, J=14.5, 4.1, 1H), 4.17 (dd, J=14.4, 6.7, 1H), 3.73-3.37 (m, 12H), 3.37-3.23 (m, 7H), 3.20 (dd, J=13.2, 10.7, 1H), 2.42-1.95 (m, 4H), 1.94-1.83 (m, 2H), 1.76-1.57 (m, 1H), 1.52 (ddd, J=16.0, 13.9, 4.0, 1H), 1.43 (ddd, J=15.9, 14.2, 4.0, 1H), 0.99 (d, J=6.5, 3H).
MS (ESI): mass calcd. for C33H47F4N5O3S2, 701.3; m/z found, 702.3 [M+H]+. 1H NMR: 7.93 (s, 1H), 7.83 (d, J=8.2, 1H), 7.74 (d, J=7.2, 1H), 4.73-4.41 (m, 3H), 4.29-4.21 (m, 1H), 4.18 (dd, J=14.4, 6.5, 1H), 3.83-2.95 (m, 24H), 2.61-0.87 (m, 15H).
MS (ESI): mass calcd. for C32H42F4N8O3S2, 726.2; m/z found, 727.2 [M+H]+. 1H NMR: 8.32 (s, 1H), 8.18 (dd, J=2.6, 1.5, 1H), 7.94 (s, 1H), 7.93 (d, J=2.6, 1H), 7.82 (d, J=8.3, 1H), 7.73 (d, J=8.0, 1H), 4.67-4.51 (m, 3H), 4.27 (dd, J=14.5, 4.2, 1H), 4.21 (dd, J=14.5, 6.5, 1H), 3.78-3.19 (m, 21H), 3.08-2.94 (m, 6H), 2.46-1.79 (m, 4H).
MS (ESI): mass calcd. for C34H42Cl2F4N6O3S2, 792.2; m/z found, 793.2 [M+H]+. 1H NMR: 8.34 (s, 2H), 7.85 (s, 1H), 7.72 (d, J=8.3, 1H), 7.63 (d, J=8.1, 1H), 4.59-4.43 (m, 3H), 4.19 (dd, J=14.4, 4.2, 1H), 4.12 (dd, J=14.5, 6.5, 1H), 3.86-2.81 (m, 28H), 2.36-1.76 (m, 4H).
MS (ESI): mass calcd. for C29H39F4N5O3S2, 645.2; m/z found, 646.2 [M+H]+. 1H NMR: 7.93 (s, 1H), 7.82 (d, J=8.2, 1H), 7.72 (d, J=8.2, 1H), 5.99 (d, J=10.4, 1H), 5.74 (d, J=10.4, 1H), 4.62-4.47 (m, 3H), 4.26 (dd, J=14.4, 4.1, 1H), 4.19 (dd, J=14.5, 6.7, 1H), 4.01-3.08 (m, 18H), 3.07-2.94 (m, 5H), 2.69-1.81 (m, 6H).
MS (ESI): mass calcd. for C33H49F4N5O3S2, 703.3; m/z found, 704.3 [M+H]+. 1H NMR: 7.94 (s, 1H), 7.81 (d, J=8.3, 1H), 7.71 (d, J=8.1, 1H), 4.62-4.46 (m, 3H), 4.24 (dd, J=14.4, 4.1, 1H), 4.17 (dd, J=14.5, 6.6, 1H), 3.78-3.09 (m, 16H), 3.06-2.88 (m, 7H), 2.46-1.76 (m, 6H), 1.64 (dq, J=13.8, 4.0, 1H), 1.55 (dq, J=13.6, 3.9, 1H), 1.36 (tt, J=12.4, 2.9, 1H), 0.90 (s, 9H).
MS (ESI): mass calcd. for C29H41F4N5O3S2, 647.2; m/z found, 648.2 [M+H]+. 1H NMR: 7.84 (s, 1H), 7.71 (d, J=8.3, 1H), 7.61 (d, J=8.3, 1H), 4.51-4.44 (m, 2H), 4.40 (ddd, J=13.7, 6.8, 3.8, 1H), 4.14 (dd, J=14.4, 4.1, 1H), 4.07 (dd, J=14.5, 6.8, 1H), 3.81-2.79 (m, 23H), 2.04-1.94 (m, 2H), 1.88-1.59 (m, 7H), 1.49-1.36 (m, 1H).
MS (ESI): mass calcd. for C34H44F4N6O3S2, 724.2; m/z found, 725.2 [M+H]+. 1H NMR: 8.71 (d, J=5.4, 1H), 8.32 (t, J=6.5, 1H), 7.95 (s, 1H), 7.83-7.70 (m, 4H), 4.65-4.48 (m, 2H), 4.28 (dd, J=14.4, 3.8, 1H), 4.21 (dd, J=14.4, 6.7, 1H), 3.90-2.93 (m, 26H), 2.41-1.64 (m, 8H).
MS (ESI): mass calcd. for C29H40F5N5O3S2, 665.2; m/z found, 666.2 [M+H]+. 1H NMR: 7.96 (s, 1H), 7.82 (d, J=8.2, 1H), 7.69 (d, J=8.1, 1H), 4.79-4.47 (m, 3H), 4.25 (dd, J=14.4, 4.1, 1H), 4.18 (dd, J=14.5, 6.8, 1H), 3.98-2.89 (m, 22H), 2.40-1.48 (m, 10H).
MS (ESI): mass calcd. for C31H43F5N6O5S2, 738.2; m/z found, 739.2 [M+H]+. 1H NMR: 7.94 (s, 1H), 7.81 (d, J=8.2, 1H), 7.69 (d, J=7.8, 1H), 4.71-4.45 (m, 3H), 4.31-4.16 (m, 2H), 3.97 (s, 3H), 3.89-2.93 (m, 23H), 2.26-1.77 (m, 8H).
MS (ESI): mass calcd. for C34H43F5N6O3S2, 742.2; m/z found, 743.3 [M+H]+. 1H NMR: 8.57 (d, J=4.4, 1H), 8.06-7.92 (m, 2H), 7.82 (d, J=8.1, 1H), 7.72 (d, J=8.0, 1H), 7.49 (d, J=7.8, 1H), 7.47-7.42 (m, 1H), 4.69-4.49 (m, 3H), 4.28 (dd, J=14.2, 3.9, 1H), 4.21 (dd, J=14.4, 6.7, 1H), 4.00-2.93 (m, 22H), 2.38-1.94 (m, 9H).
MS (ESI): mass calcd. for C29H40F5N5O3S2, 665.3; m/z found, 666.3 [M+H]+. 1H NMR: 7.93 (s, 1H), 7.81 (d, J=8.3, 1H), 7.72 (d, J=8.0, 1H), 4.63-4.54 (m, 2H), 4.49 (ddd, J=13.6, 6.8, 3.9, 1H), 4.24 (dd, J=14.4, 4.1, 1H), 4.17 (dd, J=14.4, 6.7, 1H), 3.74-3.28 (m, 14H), 3.18 (dd, J=13.3, 10.8, 1H), 3.10-2.94 (m, 7H), 2.41-2.29 (m, 4H), 1.97-1.70 (m, 5H), 1.58-1.48 (m, 1H).
MS (ESI): mass calcd. for C34H43F5N6O3S2, 742.3; m/z found, 743.3 [M+H]+. 1H NMR: 8.70 (dd, J=5.4, 0.9, 1H), 8.28 (t, J=7.1, 1H), 7.94 (s, 1H), 7.82 (d, J=8.3, 1H), 7.78-7.67 (m, 3H), 4.62-4.49 (m, 3H), 4.28 (dd, J=14.4, 4.0, 1H), 4.21 (dd, J=14.4, 6.6, 1H), 3.88-3.18 (m, 18H), 3.06-2.95 (m, 5H), 2.41-2.09 (m, 8H).
MS (ESI): mass calcd. for C33H48F5N5O3S2, 721.3; m/z found, 722.3 [M+H]+. 1H NMR: 7.93 (s, 1H), 7.82 (d, J=8.3, 1H), 7.73 (d, J=8.2, 1H), 4.57 (d, J=3.5, 2H), 4.52-4.47 (m, 1H), 3.73-3.35 (m, 10H), 3.31 (td, J=3.3, 1.6, 1.6, 5H), 3.26 (dd, J=13.2, 2.9, 1H), 3.20 (dd, J=13.2, 10.6, 1H), 3.06-2.88 (m, 7H), 2.40-2.30 (m, 4H), 2.00-1.90 (m, 2H), 1.64 (ddd, J=17.0, 13.5, 4.0, 1H), 1.54 (dq, J=13.7, 3.9, 1H), 1.36 (tt, J=12.0, 2.8, 1H), 0.95-0.83 (m, 9H).
MS (ESI): mass calcd. for C35H50F5N5O3S2, 747.3; m/z found, 748.3 [M+H]+. 1H NMR: 7.93 (s, 1H), 7.82 (d, J=8.2, 1H), 7.72 (d, J=8.1, 1H), 4.57 (d, J=4.0, 2H), 4.51-4.44 (m, 1H), 4.24 (dd, J=14.5, 4.1, 1H), 4.18 (dd, J=14.4, 6.5, 1H), 3.72-2.81 (m, 23H), 2.41-2.27 (m, 4H), 2.03-1.90 (m, 2H), 1.87-0.87 (m, 13H).
A. 2-[5-(5-Methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-trifluoromethyl-phenylsulfanyl]-ethanol. This compound was prepared as described in Example 1, Step C. MS (ESI): mass calcd. for C16H18F3N3O3S2, 421.07; m/z found, 422.1 [M+H]+.
B. (2S)-1-{3-[3-(2-Hydroxy-ethylsulfanyl)-4-trifluoromethyl-phenyl]-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl}-3-piperidin-1-yl-propan-2-ol. This compound was prepared using methods similar to those described in Example 153, Step C. MS (ESI): mass calcd. for C24H33F3N4O4S2, 562.2; m/z found, 563.2 [M+H]+.
C. (2S)-1-{3-[3-{[2-(5,6-Dihydropyrimidin-1(4H)-yl)ethyl]sulfanyl}-4-(trifluoromethyl)phenyl]-5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl]-3-piperidin-1-ylpropan-2-ol. This compound was prepared using methods similar to those described in Example 4, Step A, with the appropriate substituent changes and replacing MsCl with p-toluenesulfonic acid (1.01 equiv.) and pyridine with both 4-(dimethylamino)-pyridine (0.32 equiv.) and TEA (0.14 equiv.). MS (ESI): mass calcd. for C31H39F3N4O6S3, 716.2; m/z found, 717.2 [M+H]+.
D. (2S)-1-{3-[3-{[2-(5,6-Dihydropyrimidin-1(4H)-yl)ethyl]sulfanyl}-4-(trifluoromethyl)phenyl]-5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl]-3-piperidin-1-ylpropan-2-ol. To a stirring solution of (2S)-1-{3-[3-{[2-(5,6-dihydropyrimidin-1(4H)-yl)ethyl]sulfanyl}-4-(trifluoromethyl)phenyl]-5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl}-3-piperidin-1-ylpropan-2-ol (0.060 mmol) in 20% DCE/EtOH (v/v, 0.2 M) was added 1,4,5,6-tetrahydro-pyrimidine (5.0 eq) and TEA (10 eq). The reaction vessel was sealed and heated at 80° C. for 36 h. After cooling to rt the final compound was isolated via preparative HPLC. MS (ESI): mass calcd. for C28H39F3N6O3S2, 628.3; m/z found, 629.2 [M+H]+. 1H NMR: 7.95 (d, J=18.8, 1H), 7.81 (d, J=8.2, 1H), 7.66 (d, J=8.0, 1H), 4.62-4.46 (m, 3H), 4.24 (dd, J=14.4, 4.1, 1H), 4.17 (dd, J=14.4, 6.8, 1H), 3.82-2.91 (m, 23H), 2.08-1.71 (m, 8H), 1.58-1.48 (m, 1H).
Examples 216-227 were prepared using methods similar to those described in Example 215, with the appropriate substituent changes.
MS (ESI): mass calcd. for C31H44F3N5O3S2, 655.2; m/z found, 656.2 [M+H]+. 1H NMR: 7.93 (s, 1H), 7.82 (d, J=8.3, 1H), 7.73 (d, J=8.2, 1H), 4.63-4.45 (m, 3H), 4.24 (dd, J=14.4, 4.1, 1H), 4.17 (dd, J=14.4, 6.7, 1H), 3.96-3.85 (m, 1H), 3.71-2.81 (m, 21H), 2.70-2.57 (m, 1H), 2.02-1.43 (m, 13H).
MS (ESI): mass calcd. for C30H44F3N5O4S2, 659.2; m/z found, 660.2 [M+H]+. 1H NMR: 7.94 (s, 1H), 7.82 (d, J=8.3, 1H), 7.72 (d, J=7.9, 1H), 4.62-4.54 (m, 2H), 4.52-4.47 (m, 1H), 4.24 (dd, J=14.4, 4.1, 1H), 4.17 (dd, J=14.4, 6.7, 1H), 3.71-2.84 (m, 27H), 1.97-1.65 (m, 9H).
MS (ESI): mass calcd. for C30H43F3N6O4S2, 672.2; m/z found, 673.2 [M+H]+. 1H NMR: 7.94 (s, 1H), 7.83 (d, J=8.3, 1H), 7.73 (d, J=8.0, 1H), 4.61-4.54 (m, 2H), 4.52-4.47 (m, 1H), 4.24 (dd, J=14.4, 4.0, 1H), 4.17 (dd, J=14.4, 6.8, 1H), 3.73-2.88 (m, 26H), 2.13-1.73 (m, 9H).
MS (ESI): mass calcd. for C33H50F3N5O3S2, 685.3; m/z found, 686.3 [M+H]+. 1H NMR: 7.93 (s, 1H), 7.83 (d, J=8.2, 1H), 7.74 (d, J=7.8, 1H), 4.61-4.55 (m, 2H), 4.53-4.47 (m, 1H), 4.24 (dd, J=14.4, 4.1, 1H), 4.17 (dd, J=14.4, 6.7, 1H), 3.74-2.88 (m, 33H), 2.04-1.26 (m, 9H).
MS (ESI): mass calcd. for C31H45F3N6O4S2, 686.3; m/z found, 687.3 [M+H]+. 1H NMR: 7.93 (s, 1H), 7.83 (d, J=8.2, 1H), 7.74 (d, J=7.8, 1H), 4.62-4.46 (m, 3H), 4.24 (dd, J=14.4, 4.1, 1H), 4.17 (dd, J=14.4, 6.7, 1H), 3.76-2.87 (m, 27H), 2.04-1.19 (m, 10H).
MS (ESI): mass calcd. for C31H45F3N6O5S2, 702.3; m/z found, 703.3 [M+H]+. 1H NMR: 7.93 (s, 1H), 7.83 (d, J=8.3, 1H), 7.73 (d, J=8.0, 1H), 4.62-4.47 (m, 3H), 4.24 (dd, J=14.3, 3.9, 1H), 4.17 (dd, J=14.4, 7.1, 1H), 3.97 (s, 3H), 3.72-2.94 (m, 24H), 2.19-1.47 (m, 10H).
MS (ESI): mass calcd. for C34H45F3N6O4S2, 722.3; m/z found, 723.2 [M+H]+. 1H NMR: 8.64 (d, J=5.5, 1H), 8.25-8.15 (m, 1H), 7.97 (s, 1H), 7.91 (d, J=8.1, 1H), 7.83 (d, J=8.3, 1H), 7.72 (d, J=8.2, 1H), 7.65-7.60 (m, 1H), 4.62-4.54 (m, 2H), 4.53-4.48 (m, 1H), 4.24 (dd, J=14.5, 4.1, 1H), 4.17 (dd, J=14.4, 6.7, 1H), 3.76-2.92 (m, 24H), 2.56 (dt, J=14.5, 4.1, 2H), 2.06-1.44 (m, 8H).
MS (ESI): mass calcd. for C28H40F3N5O5S2, 647.2; m/z found, 648.2 [M+H]+. 1H NMR: 7.87 (s, 1H), 7.73 (d, J=8.2, 1H), 7.63 (d, J=8.0, 1H), 4.52-4.40 (m, 3H), 4.15 (dd, J=14.4, 4.1, 1H), 4.09 (dd, J=14.5, 6.6, 1H), 4.04-2.85 (m, 29H), 1.19 (d, J=1.4, 3H).
MS (ESI): mass calcd. for C30H42F3N5O4S2, 657.3; m/z found, 658.3 [M+H]+. 1H NMR: 7.89-7.78 (m, 1H), 7.72 (d, J=8.3, 1H), 7.65-7.62 (m, 1H), 4.52-4.39 (m, 3H), 4.16 (dd, J=14.5, 4.1, 1H), 4.09 (dd, J=14.5, 6.6, 1H), 4.02-2.70 (m, 29H), 2.55 (s, 1H), 1.98-1.12 (m, 5H).
MS (ESI): mass calcd. for C29H42F3N5O5S2, 661.2; m/z found, 662.5 [M+H]+. 1H NMR: 7.96 (s, 1H), 7.84 (d, J=8.2, 1H), 7.75 (d, J=8.5, 1H), 4.64-4.51 (m, 3H), 4.30-4.19 (m, 2H), 4.16-2.93 (m, 28H), 1.83 (d, J=1.7, 3H), 1.30 (s, 3H).
MS (ESI): mass calcd. for C29H41F3N6O5S2, 674.3; m/z found, 675.3 [M+H]+. 1H NMR: 7.84 (s, 1H), 7.73 (d, J=8.3, 1H), 7.63 (d, J=7.4, 1H), 4.52-4.41 (m, 3H), 4.16 (dd, J=14.4, 4.1, 1H), 4.09 (dd, J=14.5, 6.7, 1H), 4.03-2.84 (m, 28H), 2.43 (s, 1H), 2.11-1.75 (m, 4H).
MS (ESI): mass calcd. for C31H46F3N5O5S2, 689.3; m/z found, 690.3 [M+H]+. 1H NMR: 7.84 (s, 1H), 7.72 (d, J=8.2, 1H), 7.63 (d, J=8.1, 1H), 4.54-4.40 (m, 3H), 4.16 (dd, J=14.4, 4.2, 1H), 4.09 (dd, J=14.5, 6.6, 1H), 4.01-2.80 (m, 28H), 1.94 (d, J=10.8, 1H), 1.56-1.45 (m, 3H), 1.07 (s, 6H).
A. 1-{2-Hydroxy-3-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-propyl}-3-[3-(2-piperidin-1-yl-ethylsulfanyl)-4-trifluoromethyl-phenyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester. This compound was prepared from 3-(3-nitro-4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester using methods similar to those described in Example 153, Steps A-C, substituting 1-piperidin-4-yl-pyrrolidin-2-one for piperidine. MS (ESI): mass calcd. for C37H53F3N6O4S, 734.38; m/z found, 735.3 [M+H]+. 1H NMR: 7.88-7.79 (m, 1H), 7.70-7.59 (m, 1H), 7.46 (s, 1H), 4.74-4.57 (m, 2H), 4.19-4.08 (m, 2H), 4.00 (dd, J=13.3, 6.7, 2H), 3.88-3.64 (m, 3H), 3.34 (t, J=7.0, 2H), 3.18-3.14 (m, 2H), 3.00 (d, J=11.4, 1H), 2.88 (d, J=10.6, 2H), 2.82-2.71 (m, 1H), 2.68-2.60 (m, 2H), 2.49-2.33 (m, 9H), 2.17-2.07 (m, 1H), 2.04-1.98 (m, 2H), 1.78-1.52 (m, 17H), 1.46-1.38 (m, 2H).
B. To a solution of 1-{2-hydroxy-3-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-propyl}-3-[3-(2-piperidin-1-yl-ethylsulfanyl)-4-trifluoromethyl-phenyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.74 mmol) in CH2Cl2 (10 mL) was added HCl (4 M in 1,4-dioxane; 10 mL). The mixture was stirred for 1.5 h, concentrated, and the residue was suspended in MeOH. Dowex 550A basic resin (300 mg) was added and the mixture was stirred for 1 h. Filtration and concentration afforded a quantitative yield of the title compound. MS (ESI): mass calcd. for C32H45F3N6O2S, 634.33; m/z found, 635.3 [M+H]+. 1H NMR: 8.02 (s, 1H), 7.82 (d, J=8.2, 1H), 7.64 (d, J=8.2, 1H), 4.64-4.53 (m, 3H), 4.29 (dd, J=14.5, 4.4, 1H), 4.24 (dd, J=14.4, 6.6, 1H), 4.19-4.09 (m, 1H), 3.76 (t, J=11.0, 2H), 3.67-3.64 (m, 6H), 3.63-3.53 (m, 6H), 3.46-3.40 (m, 2H), 3.39-3.35 (m, 1H), 3.24-3.16 (m, 3H), 2.98 (dt, J=12.4, 3.0, 2H), 2.39 (t, J=8.1, 2H), 2.23-2.12 (m, 1H), 2.12-2.00 (m, 3H), 1.98-1.77 (m, 7H), 1.56-1.43 (m, 1H).
Examples 229-232 were prepared using methods similar to those described in Example 228, with the appropriate substituent changes.
MS (ESI): mass calcd. for C37H50F3N9O2S, 741.38; m/z found, 742.3 [M+H]+. 1H NMR: 8.02 (s, 1H), 7.82 (d, J=8.2, 1H), 7.65 (dd, J=12.0, 8.1, 2H), 7.35 (d, J=8.2, 1H), 4.83-4.68 (m, 2H), 4.63-4.55 (m, 2H), 4.37-4.23 (m, 2H), 3.97-3.80 (m, 2H), 3.66-3.64 (m, 9H), 3.63-3.55 (m, 5H), 3.48-3.41 (m, 4H), 3.40-3.32 (m, 6H), 3.29-3.21 (m, 2H), 3.20-3.06 (m, 2H), 3.07-2.89 (m, 2H), 2.11 (t, J=10.9, 2H), 1.96-1.76 (m, 5H).
MS (ESI): mass calcd. for C33H43F3N6OS, 628.32; m/z found, 629.3 [M+H]+. 1H NMR: 8.82 (d, J=5.6, 1H), 8.65 (t, J=7.8, 1H), 8.10 (d, J=8.1, 1H), 8.06-7.95 (m, 2H), 7.82 (d, J=8.1, 1H), 7.66 (d, J=7.8, 1H), 4.74-4.66 (m, 1H), 4.59 (s, 2H), 4.36-4.25 (m, 2H), 3.95-3.84 (m, 2H), 3.71-3.35 (m, 12H), 3.32-3.28 (m, 3H), 3.28-3.23 (m, 2H), 3.06-2.94 (m, 2H), 2.43-2.19 (m, 4H), 1.98-1.77 (m, 5H), 1.58-1.45 (m, 1H).
MS (ESI): mass calcd. for C32H47F3N6OS, 620.35; m/z found, 621.3 [M+H]+. 1H NMR: 8.02 (s, 1H), 7.83 (d, J=8.2, 1H), 7.66 (d, J=8.0, 1H), 4.69-4.55 (m, 3H), 4.36-4.22 (m, 2H), 3.86 (d, J=11.8, 2H), 3.78-3.68 (m, 4H), 3.66-3.56 (m, 9H), 3.44 (d, J=12.9, 1H), 3.28-3.14 (m, 6H), 3.07-2.92 (m, 2H), 2.46 (t, J=14.3, 2H), 2.38-2.12 (m, 5H), 2.11-2.00 (m, 2H), 1.98-1.78 (m, 5H), 1.59-1.47 (m, 1H).
MS (ESI): mass calcd. for C33H42F4N6OS, 646.3; m/z found, 647.3 [M+H]+. 1H NMR: 8.69 (d, J=5.4, 1H), 8.25 (s, 1H), 7.99 (s, 1H), 7.83 (d, J=8.2, 1H), 7.74 (dd, J=7.7, 3.9, 1H), 7.69 (s, 1H), 7.65 (d, J=8.2, 1H), 4.59 (s, 1H), 4.56-4.49 (m, 2H), 4.27 (ddd, J=21.4, 14.4, 5.3, 2H), 3.83 (dd, J=16.2, 14.9, 2H), 3.61 (t, J=6.3, 2H), 3.59-3.27 (m, 17H), 3.22 (dd, J=12.0, 5.9, 2H), 2.44-1.86 (m, 8H).
This compound was prepared using methods analogous to those described in Example 228, substituting (S)-(+)-glycidyl nosylate for epichlorohydrin. MS (ESI): mass calcd. for C33H42F4N6OS, 646.31; m/z found, 647.3 [M+H]+. 1H NMR: 8.80 (d, J=5.5, 1H), 8.52 (t, J=7.9, 1H), 8.00 (s, 1H), 7.96 (d, J=7.5, 1H), 7.93-7.90 (m, 1H), 7.82 (d, J=8.3, 1H), 7.65 (d, J=8.2, 1H), 4.97-4.89 (m, 1H), 4.65-4.57 (m, 1H), 4.53 (s, 2H), 4.31 (dd, J=14.4, 3.4, 1H), 4.23 (dd, J=14.4, 6.9, 1H), 3.86 (t, J=11.3, 2H), 3.61 (t, J=6.3, 3H), 3.58-3.49 (m, 4H), 3.48-3.36 (m, 5H), 3.36-3.32 (m, 2H), 3.29-3.17 (m, 5H), 2.39-1.96 (m, 8H).
To a solution of benzenesulfonyl chloride (0.011 mL, 0.087 mmol) in CH2Cl2 (1 mL) was added 1-{1-[2-hydroxy-3-(3-{3-[(2-piperidin-1-ylethyl)sulfanyl]-4-(trifluoromethyl)phenyl}-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)propyl]piperidin-4-yl}pyrrolidin-2-one (50 mg, 0.079 mmol). The mixture was stirred for 15 h, concentrated, dissolved in DMF, and purified using reverse phase HPLC. MS (ESI): mass calcd. for C38H49F3N6O4S2, 774.32; m/z found, 775.3 [M+H]+. 1H NMR: 8.10-8.01 (m, 1H), 7.89 (d, J=6.2, 2H), 7.86-7.81 (m, 1H), 7.71-7.65 (m, 1H), 7.65-7.55 (m, 3H), 4.59 (s, 1H), 4.52-4.40 (m, 2H), 4.30-4.06 (m, 3H), 3.75 (s, 2H), 3.65-3.50 (m, 6H), 3.44 (s, 2H), 3.40-3.31 (m, 3H), 3.29-3.10 (m, 3H), 3.10-2.81 (m, 4H), 2.40 (t, J=7.0, 2H), 2.26-1.99 (m, 4H), 1.98-1.76 (m, 8H), 1.56-1.45 (m, 1H).
Examples 235-237 were prepared using methods similar to those described in Example 234, with the appropriate substituent changes.
MS (ESI): mass calcd. for C34H49F3N6O4S2, 726.32; m/z found, 727.3 [M+H]+. 1H NMR: 8.08-8.04 (m, 1H), 7.84 (s, 1H), 7.72-7.62 (m, 1H), 4.66 (s, 3H), 4.33 (d, J=40.1, 2H), 4.24-4.10 (m, 1H), 3.84-3.69 (m, 4H), 3.68-3.54 (m, 5H), 3.51-3.43 (m, 3H), 3.43-3.32 (m, 3H), 3.26-3.13 (m, 3H), 3.09-2.92 (m, 4H), 2.47-2.38 (m, 2H), 2.31-2.09 (m, 2H), 2.10-2.00 (m, 2H), 2.01-1.75 (m, 7H), 1.57-1.45 (m, 1H), 1.38-1.30 (m, 4H).
MS (ESI): mass calcd. for C30H44F3N5O3S2, 643.28; m/z found, 644.3 [M+H]+. 1H NMR: 8.06-7.90 (m, 1H), 7.81 (d, J=8.2, 1H), 7.67 (d, J=8.1, 1H), 4.65-4.60 (m, 2H), 4.59-4.52 (m, 1H), 4.25 (dd, J=14.4, 3.9, 1H), 4.18 (dd, J=14.3, 6.7, 1H), 3.74-3.67 (m, 2H), 3.64-3.51 (m, 6H), 3.38-3.32 (m, 4H), 3.18 (dd, J=14.6, 7.3, 3H), 3.09 (t, J=10.0, 1H), 3.04-2.93 (m, 5H), 2.00-1.72 (m, 10H), 1.58-1.45 (m, 2H), 1.34 (t, J=7.3, 3H).
MS (ESI): mass calcd. for C39H51F3N6O4S2, 788.34; m/z found, 789.3 [M+H]+. 1H NMR: 7.96 (s, 1H), 7.81 (d, J=7.3, 1H), 7.59 (d, J=6.4, 1H), 7.48-7.40 (m, 2H), 7.37-7.33 (m, 3H), 4.62 (s, 1H), 4.53-4.44 (m, 4H), 4.34-4.10 (m, 3H), 3.80-3.70 (m, 2H), 3.64-3.51 (m, 7H), 3.46-3.40 (m, 2H), 3.40-3.31 (m, 3H), 3.29-3.14 (m, 2H), 3.04-2.93 (m, 2H), 2.87-2.81 (m, 2H), 2.41 (t, J=7.6, 2H), 2.25-2.15 (m, 1H), 2.16-2.08 (m, 1H), 2.08-2.00 (m, 2H), 1.99-1.76 (m, 7H), 1.56-1.42 (m, 1H).
A mixture of 1-(3-{3-[(2-morpholin-4-ylethyl)sulfanyl]-4-(trifluoromethyl)phenyl}-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-piperidin-1-ylpropan-2-ol (50 mg, 0.09 mmol) (prepared analogously to Example 228), glycolic acid (27 mg, 0.36 mmol), HATU (69 mg, 0.18 mmol), HOAt (0.5 M in DMF; 0.35 mL), and DIPEA (0.05 mL, 0.27 mmol) was stirred at 70° C. for 16 h at which time the solution was cooled to rt and filtered. The filtrate was concentrated and purified using preparatory HPLC. MS (ESI): mass calcd. for C29H40F3N5O4S, 611.28; m/z found, 612.3 [M+H]+. 1H NMR (mixture of rotamers): 8.05-7.98 (m, 0.3H), 7.96-7.92 (m, 0.7H), 7.87-7.77 (m, 1.7H), 7.74-7.68 (m, 0.3H), 4.77-4.64 (m, 1H), 4.55-4.46 (m, 1H), 4.42-4.28 (m, 2H), 4.28-4.14 (m, 2H), 4.12-3.69 (m, 6H), 3.69-3.39 (m, 8H), 3.40-3.13 (m, 5H), 3.12-2.83 (m, 4H), 2.02-1.66 (m, 5H), 1.62-1.47 (m, 1H).
The compounds in Examples 239-241 were prepared using methods similar to those in Example 238.
MS (ESI): mass calcd. for C30H42F3N5O3S, 609.30; m/z found, 610.3 [M+H]+. 1H NMR: 7.93 (d, J=11.8, 1H), 7.74 (d, J=8.0, 1H), 7.61-7.53 (m, 1H), 4.83 (d, J=1.9, 1H), 4.70-4.68 (m, 1H), 4.37-4.29 (m, 2H), 4.23-4.14 (m, 2H), 4.08-3.99 (m, 1H), 3.99-3.88 (m, 1H), 3.84-3.68 (m, 1H), 3.28-3.18 (m, 2H), 3.02-2.89 (m, 2H), 2.88-2.80 (m, 1H), 2.68-2.60 (m, 2H), 2.56-2.34 (m, 9H), 1.65-1.54 (m, 8H), 1.51-1.41 (m, 4H), 1.36-1.25 (m, 1H), 0.94-0.83 (m, 1H).
MS (ESI): mass calcd. for C34H47F3N6O4S, 692.33; m/z found, 693.3 [M+H]+. 1H NMR: 7.97 (d, J=18.4, 1H), 7.75 (d, J=8.3, 1H), 7.65-7.55 (m, 1H), 4.81 (s, 1H), 4.47-4.40 (m, 1H), 4.36 (s, 1.3H), 4.32 (s, 0.7H), 4.22 (dd, J=14.2, 3.6, 1H), 4.13-3.99 (m, 2H), 3.74 (t, J=5.6, 1H), 3.57 (d, J=10.2, 1H), 3.54-3.46 (m, 3H), 3.43 (t, J=7.1, 2H), 3.24-3.02 (m, 7H), 3.02-2.73 (m, 5H), 2.68 (d, J=15.2, 2H), 2.59 (d, J=15.2, 2H), 2.36 (t, J=8.1, 2H), 2.15-1.96 (m, 4H), 1.84-1.71 (m, 6H), 1.59 (s, 2H).
MS (ESI): mass calcd. for C33H43F5N6O4S, 714.2; m/z found, 715.2 [M+H]+. 1H NMR: 8.15-7.95 (m, 1H), 7.81 (d, J=4.5, 1H), 7.75-7.60 (m, 1H), 5.49 (s, 1H), 4.66-3.08 (m, 27H), 2.95 (d, J=52.1, 2H), 2.69 (s, 2H), 2.39 (t, J=7.4, 2H), 2.31-1.79 (m, 6H).
A. 4-(2-{1-(2-Hydroxy-3-piperidin-1-yl-propyl)-3-[3-(2-morpholin-4-yl-ethylsulfanyl)-4-trifluoromethyl-phenyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-2-oxo-ethyl)-piperidine-1-carboxylic acid tert-butyl ester. This compound was prepared using methods analogous to those described in Example 238, with the appropriate substituent changes. The crude product was used without purification. MS (ESI): mass calcd. for C39H57F3N6O5S, 778.41; m/z found, 779.4 [M+H]+.
B. 1-[3-{3-[(2-Morpholin-4-ylethyl)sulfanyl]-4-(trifluoromethyl)phenyl}-5-(piperidin-4-ylacetyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl]-3-piperidin-1-ylpropan-2-ol. To a solution of 4-(2-{1-(2-hydroxy-3-piperidin-1-yl-propyl)-3-[3-(2-morpholin-4-yl-ethylsulfanyl)-4-trifluoromethyl-phenyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-2-oxo-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.039 mmol) in CH2Cl2 (2 mL) was added TFA (1 mL). The solution was stirred for 3 h and blown dry under a stream of N2. Purification using reverse phase HPLC provided the title compound (16 mg, 61%). MS (ESI): mass calcd. for C34H49F3N6O3S, 678.35; m/z found, 679.3 [M+H]+. 1H NMR (mixture of rotamers): 8.10-8.06 (m, 0.25H), 7.97-7.93 (m, 0.75H), 7.86-7.81 (m, 1H), 7.80-7.75 (m, 0.75H), 7.67-7.63 (m, 0.25H), 4.91-4.72 (m, 2H), 4.56-4.47 (m, 1H), 4.28-4.12 (m, 2H), 4.12-3.65 (m, 6H), 3.66-3.25 (m, 12H), 3.24-3.13 (m, 2H), 3.12-2.81 (m, 6H), 2.60-2.46 (m, 2H), 2.23-2.10 (m, 1H), 2.08-1.69 (m, 7H), 1.62-1.37 (m, 3H).
Examples 243-247 were prepared using methods similar to those described in Example 234, substituting the appropriate acid chloride for the sulfonyl chloride.
MS (ESI): mass calcd. for C30H40F3N5O5S, 639.27; m/z found, 640.3 [M+H]+. 1H NMR (mixture of rotamers): 8.00-7.92 (m, 1H), 7.88-7.77 (m, 1.8H), 7.67-7.62 (m, 0.2H), 4.89-4.74 (m, 1H), 4.56-4.45 (m, 1H), 4.31-4.14 (m, 2H), 4.13-3.71 (m, 9H), 3.69-3.41 (m, 8H), 3.39-3.27 (m, 3H), 3.26-2.91 (m, 6H), 2.02-1.66 (m, 5H), 1.62-1.48 (m, 1H).
MS (ESI): mass calcd. for C35H47F3N6O5S, 720.33; m/z found, 721.3 [M+H]+. 1H NMR: 7.96 (s, 0.2H), 7.93 (s, 0.8H), 7.85-7.77 (m, 2H), 4.49 (s, 1H), 4.29-4.21 (m, 1H), 4.19 (dd, J=14.4, 6.4, 1H), 4.16-4.07 (m, 1H), 3.94-3.84 (m, 3H), 3.84-3.78 (m, 2H), 3.71 (t, J=15.1, 2H), 3.59 (d, J=11.4, 2H), 3.51-3.43 (m, 3H), 3.43-3.39 (m, 2H), 3.37-3.37 (m, 2H), 3.36-3.32 (m, 3H), 3.28-3.18 (m, 2H), 3.13 (t, J=12.9, 1H), 3.05-2.90 (m, 4H), 2.39 (t, J=8.1, 2H), 2.19-2.08 (m, 1H), 2.04 (td, J=15.1, 7.5, 3H), 1.99-1.86 (m, 4H), 1.87-1.67 (m, 3H), 1.57-1.42 (m, 1H).
MS (ESI): mass calcd. for C30H42F3N5O2S, 593.30; m/z found, 594.3 [M+H]+. 1H NMR: 8.07-7.90 (m, 1H), 7.84-7.81 (m, 1H), 7.78-7.65 (m, 1H), 4.95-4.93 (m, 1H), 4.87-4.76 (m, 2H), 4.53-4.45 (m, 1H), 4.23 (dd, J=14.4, 4.1, 1H), 4.17 (dd, J=14.4, 6.7, 1H), 4.00-3.82 (m, 2H), 3.62-3.52 (m, 4H), 3.50-3.45 (m, 2H), 3.39-3.32 (m, 3H), 3.18 (dd, J=13.3, 10.8, 1H), 3.08-3.01 (m, 1H), 3.01-2.82 (m, 5H), 2.24-2.16 (m, 3H), 1.97-1.70 (m, 10H), 1.57-1.44 (m, 2H).
MS (ESI): mass calcd. for C34H47F3N6O3S, 676.34; m/z found, 677.3 [M+H]+. 1H NMR: 8.20-8.06 (m, 1H), 7.87 (d, J=7.2, 1H), 7.72 (d, J=7.1, 1H), 4.96-4.83 (m, 2H), 4.77-4.65 (m, 1H), 4.52-4.39 (m, 1H), 4.40-4.29 (m, 1H), 4.25-4.12 (m, 1H), 4.09-3.93 (m, 2H), 3.87-3.73 (m, 2H), 3.72-3.55 (m, 4H), 3.46-3.17 (m, 9H), 3.16-2.92 (m, 4H), 2.50-2.40 (m, 2H), 2.30-2.26 (m, 3H), 2.21-2.11 (m, 1H), 2.12-2.01 (m, 2H), 2.00-1.78 (m, 7H), 1.59-1.42 (m, 1H).
MS (ESI): mass calcd. for C37H47F3N6O4S, 728.33; m/z found, 729.3 [M+H]+. 1H NMR: 8.14-8.06 (m, 1H), 7.86 (d, J=7.1, 1H), 7.79-7.66 (m, 2H), 7.15 (d, J=2.2, 1H), 6.66-6.60 (m, 1H), 4.73-4.65 (m, 1H), 4.48-4.26 (m, 2H), 4.25-4.10 (m, 3H), 3.85-3.73 (m, 2H), 3.69-3.57 (m, 5H), 3.51-3.44 (m, 3H), 3.42-3.33 (m, 3H), 3.27-3.19 (m, 2H), 3.19-3.07 (m, 2H), 3.06-2.97 (m, 2H), 2.43 (t, J=7.3, 2H), 2.29-2.00 (m, 5H), 1.99-1.78 (m, 8H), 1.57-1.46 (m, 1H).
To a solution of 1-{3-[3-(2-piperidin-1-yl-ethylsulfanyl)-4-trifluoromethyl-phenyl]-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl}-3-(3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-yl)-propan-2-ol (34 mg, 0.050 mmol) in acetonitrile (0.32 mL) was added formaldehyde (37% solution in H2O; 0.054 mL, 0.27 mmol) and NaCNBH3 (7 mg, 0.1 mmol). The reaction mixture was stirred for 4 h, filtered, diluted with DMF and purified using reverse phase HPLC to provide the title compound (29 mg, 91%). MS (ESI): mass calcd. for C34H45F3N6OS, 642.33; m/z found, 643.3 [M+H]+. 1H NMR: 8.71-8.68 (m, 1H), 8.27 (t, J=6.4, 1H), 7.99 (s, 1H), 7.83 (d, J=8.2, 1H), 7.75 (d, J=8.0, 1H), 7.72-7.67 (m, 1H), 7.64 (d, J=8.2, 1H), 4.82-4.67 (m, 1H), 4.65-4.54 (m, 2H), 4.54-4.38 (m, 1H), 4.31 (dd, J=14.4, 3.4, 1H), 4.23 (dd, J=14.4, 7.0, 1H), 3.91-3.75 (m, 3H), 3.57 (d, J=11.7, 3H), 3.48 (dd, J=9.3, 6.5, 3H), 3.45-3.39 (m, 1H), 3.38-3.31 (m, 6H), 3.27-3.20 (m, 1H), 3.11 (s, 3H), 2.96 (t, J=11.7, 2H), 2.33-2.11 (m, 4H), 1.92 (d, J=14.2, 2H), 1.86-1.70 (m, 3H), 1.55-1.40 (m, 1H).
A mixture of N-[1-((2S)-2-hydroxy-3-{3-[3-(2-pyrrolidin-1-yl-ethylsulfanyl)-4-trifluoromethyl-phenyl]-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl}-propyl)-piperidin-4-yl]-acetamide 74.9 mg, 0.14 mmol) (prepared analogously to Example 233), oxamic acid (52 mg, 0.58 mmol), HATU (110 mg, 0.29 mmol), HOAt (0.5 M in DMF; 0.6 mL), and DIPEA (0.075 mL, 0.43 mmol) was stirred at 70° C. for 24.5 h at which time the solution was cooled to rt, and filtered. The filtrate was concentrated and purified using preparatory HPLC. MS (ESI): mass calcd. for C31H42F3N7O4S, 665.30; m/z found, 666.3 [M+H]+. 1H NMR: 8.05-7.64 (m, 3H), 5.01 (d, J=3.9, 1H), 4.87-4.79 (m, 2H), 4.53-4.45 (m, 1H), 4.23 (dd, J=14.5, 4.3, 1H), 4.17 (dd, J=13.6, 6.9, 1H), 4.04-3.84 (m, 3H), 3.80-3.70 (m, 2H), 3.70-3.61 (m, 2H), 3.55-3.40 (m, 5H), 3.37-3.32 (m, 1H), 3.27-3.05 (m, 5H), 3.05-2.98 (m, 1H), 2.97-2.90 (m, 1H), 2.22-2.05 (m, 4H), 2.06-1.95 (m, 4H), 1.93 (s, 3H), 1.82 (dd, J=24.8, 12.5, 1H), 1.74 (dd, J=25.3, 12.6, 1H).
The compounds in Examples 250-251 were prepared using methods similar to those described for Example 249.
MS (ESI): mass calcd. for C30H40F4N6O3S, 640.28; m/z found, 641.2 [M+H]+. 1H NMR: 7.95-7.81 (m, 1H), 7.72 (dd, J=11.5, 8.3, 1H), 7.59 (dd, J=29.9, 8.0, 1H), 4.95-4.89 (m, 2H), 4.78 (d, J=6.0, 2H), 4.56-4.42 (m, 1H), 4.19 (dd, J=14.4, 3.8, 1H), 4.12 (dd, J=14.0, 6.9, 1H), 3.93-3.83 (m, 2H), 3.68-3.57 (m, 1H), 3.58-3.44 (m, 6H), 3.37-3.26 (m, 3H), 3.16-3.05 (m, 2H), 3.05-2.83 (m, 4H), 2.27-2.17 (m, 1H), 2.16-2.01 (m, 3H), 2.00-1.88 (m, 1H), 1.88-1.64 (m, 5H), 1.52-1.38 (m, 1H), 1.26-1.14 (m, 1H).
MS (ESI): mass calcd. for C30H41F4N5O3S, 627.29; m/z found, 628.3 [M+H]+. 1H NMR: 8.04-7.88 (m, 1H), 7.82 (d, J=8.3, 1H), 7.79-7.65 (m, 1H), 4.88-4.77 (m, 2H), 4.53-4.43 (m, 1H), 4.39-4.28 (m, 2H), 4.23 (dd, J=14.4, 4.2, 1H), 4.16 (dd, J=14.4, 6.7, 1H), 3.83-3.71 (m, 2H), 3.62-3.47 (m, 6H), 3.47-3.37 (m, 3H), 3.34-3.31 (m, 1H), 3.17 (dd, J=13.3, 10.8, 2H), 3.11-3.00 (m, 2H), 3.00-2.92 (m, 3H), 2.91-2.83 (m, 1H), 2.32-1.98 (m, 4H), 1.96-1.72 (m, 6H), 1.57-1.47 (m, 1H).
To a solution of (2S)-1-(3-{3-[2-(4-fluoro-piperidin-1-yl)-ethylsulfanyl]-4-trifluoromethyl-phenyl}-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl)-3-piperidin-1-yl-propan-2-ol (64 mg, 0.112 mmol) (prepared analogously to Example 233) in CH2Cl2 (0.94 mL) was added methylisocyanate (7.6, 0.134 mmol). After 3 h, the mixture was concentrated, dissolved in DMF, and filtered. The filtrate was concentrated and purified using preparatory HPLC to afford the citric acid salt (6.5 mg, 0.008 mmol). MS (ESI): mass calcd. for C30H42F4N6O2S, 626.30; m/z found, 627.3 [M+H]+. 1H NMR: 7.99 (s, 1H), 7.75 (d, J=8.2, 1H), 7.60 (d, J=8.2, 1H), 4.79 (d, J=48.6, 1H), 4.63 (s, 2H), 4.55-4.48 (m, 1H), 4.21 (dd, J=14.4, 4.0, 2H), 4.12 (dd, J=14.3, 7.0, 2H), 3.75 (dd, J=10.4, 5.4, 2H), 3.48-3.38 (m, 2H), 3.14 (dd, J=13.2, 10.5, 2H), 3.10-2.97 (m, 5H), 2.92-2.76 (m, 2H), 2.75-2.68 (m, 5H), 2.67-2.58 (m, 3H), 2.18-2.02 (m, 2H), 2.02-1.91 (m, 2H), 1.92-1.76 (m, 4H), 1.68-1.57 (m, 2H).
Examples 253-254 were prepared using methods similar to those described in Example 110, with the appropriate substituent changes.
MS (ESI): mass calcd. for C28H38F3N5O4S2, 629.23; m/z found, 630.2 [M+H]+. 1H NMR (CDCl3): 7.93 (s, 1H), 7.69 (t, J=8.4, 1H), 7.53 (t, J=7.2, 1H), 4.59 (s, 2H), 4.16 (t, J=6.4, 2H), 3.82 (s, 2H), 3.72-3.69 (m, 1H), 3.66 (t, J=5.7, 2H), 3.63-3.57 (m, 2H), 3.18-3.12 (m, 2H), 3.10 (s, 1H), 2.97 (s, 2H), 2.96 (d, J=3.5, 2H), 2.86 (t, J=5.4, 2H), 2.79-2.59 (m, 7H), 2.46-2.34 (m, 2H), 2.04-1.91 (m, 2H), 1.91-1.82 (m, 3H), 1.48-1.32 (m, 1H).
MS (ESI): mass calcd. for C27H36F3N5O5S2, 631.21; m/z found, 632.2 [M+H]+. 1H NMR: 7.95 (d, J=11.3, 1H), 7.75 (t, J=7.7, 1H), 7.66 (d, J=8.0, 1H), 4.58 (d, J=3.0, 2H), 4.18 (t, J=6.6, 2H), 4.01 (d, J=6.0, 2H), 3.72-3.62 (m, 8H), 3.60-3.55 (m, 2H), 3.17-3.09 (m, 2H), 2.98 (s, 3H), 2.96-2.95 (m, 2H), 2.95 (s, 2H), 2.47-2.38 (m, 4H), 2.37-2.32 (m, 2H), 2.13-2.05 (m, 2H).
A. [5-(5-Methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-trifluoromethyl-phenylsulfanyl]-acetic acid ethyl ester. This compound was prepared using methods similar to those described in Example 1, Steps A-C, with the appropriate substituent changes. MS (ESI): mass calcd. for C18H20F3N3O4S2, 463.08; m/z found, 464.1 [M+H]+. 1H NMR (CDCl3): 7.87 (s, 1H), 7.70 (d, J=8.2, 1H), 7.52 (d, J=8.1, 1H), 4.59 (s, 2H), 4.20-4.14 (m, 2H), 3.72-3.65 (m, 4H), 2.98-2.91 (m, 6H), 1.23-1.19 (m, 3H).
B. 2-[5-(5-Methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-trifluoromethyl-phenylsulfanyl]-1-pyrrolidin-1-yl-ethanone. A solution of [5-(5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-trifluoromethyl-phenylsulfanyl]-acetic acid ethyl ester (110 mg, 0.24 mmol) in pyrrolidine (1 mL, 12 mmol) was heated at 220° C. in a microwave reactor for 40 min. The reaction mixture was poured into a solution of cold satd. aq. NH4Cl. The resultant precipitate was collected by filtration (90 mg, 69%) and used without further purification. 1H NMR (DMSO-d6): 7.84-7.72 (m, 2H), 7.63-7.60 (m, 1H), 4.53 (s, 2H), 4.13 (s, 2H), 3.59-3.47 (m, 4H), 3.41-3.29 (m, 2H), 3.01 (s, 3H), 2.85 (t, J=5.5, 2H), 1.96-1.85 (m, 2H), 1.82-1.76 (m, 2H).
C. 1-[5-(Methylsulfonyl)-3-[3-[(2-oxo-2-pyrrolidin-1-ylethyl)sulfanyl]-4-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl]-3-piperidin-1-ylpropan-2-ol. This compound was prepared using methods similar to those described in Example 61, Steps B and C, with the appropriate substituent changes. MS (ESI): mass calcd. for C28H38F3N5O4S2, 629.23; m/z found, 630.2 [M+H]+. 1H NMR: 8.06 (s, 1H), 7.76 (d, J=8.2, 1H), 7.67 (d, J=8.1, 1H), 4.61-4.54 (m, 2H), 4.53-4.43 (m, 1H), 4.27-4.11 (m, 2H), 3.92-3.86 (m, 2H), 3.70-3.59 (m, 2H), 3.58-3.50 (m, 4H), 3.41 (t, J=6.9, 2H), 3.24-3.13 (m, 1H), 3.12-3.01 (m, 1H), 3.01-2.97 (m, 1H), 2.99 (s, 3H), 2.95-2.88 (m, 2H), 2.00-1.90 (m, 4H), 1.90-1.81 (m, 4H), 1.81-1.67 (m, 2H), 1.59-1.42 (m, 1H).
Examples 256-262 were prepared using methods similar to those described in Example 255, with the appropriate substituent changes.
MS (ESI): mass calcd. for C33H41F3N6O4S2, 706.26; m/z found, 707.2 [M+H]+. 1H NMR: 8.65-8.63 (m, 1H), 8.16-8.11 (m, 1H), 8.07 (s, 1H), 7.76 (d, J=8.2, 1H), 7.68 (d, J=8.2, 1H), 7.62 (d, J=7.9, 1H), 7.60-7.57 (m, 1H), 4.59 (s, 1H), 4.57-4.46 (m, 1H), 4.37-4.12 (m, 2H), 4.01-3.86 (m, 2H), 3.85-3.72 (m, 2H), 3.72-3.57 (m, 3H), 3.54 (t, J=6.8, 2H), 3.41 (t, J=7.0, 2H), 3.38-3.32 (m, 2H), 3.29-3.13 (m, 3H), 3.01-2.99 (m, 1H), 2.99 (s, 3H), 2.94-2.89 (m, 1H), 2.29-2.06 (m, 4H), 2.03-1.91 (m, 2H), 1.91-1.82 (m, 2H).
MS (ESI): mass calcd. for C33H45F3N6O5S2, 726.28; m/z found, 727.2 [M+H]+. 1H NMR: 8.05 (s, 1H), 7.75 (d, J=8.2, 1H), 7.67 (d, J=8.0, 1H), 4.58 (s, 2H), 4.54-4.46 (m, 1H), 4.30-4.13 (m, 2H), 3.89 (s, 2H), 3.75-3.61 (m, 4H), 3.59-3.51 (m, 4H), 3.46-3.37 (m, 4H), 3.29-3.21 (m, 1H), 3.20-3.12 (m, 1H), 3.11-3.03 (m, 1H), 2.99 (s, 3H), 2.98-2.96 (m, 2H), 2.90-2.79 (m, 1H), 2.12-1.91 (m, 8H), 1.92-1.76 (m, 4H).
MS (ESI): mass calcd. for C34H43F3N6O4S2, 720.27; m/z found, 721.2 [M+H]+. 1H NMR: 8.65-8.60 (m, 1H), 8.10 (s, 1H), 8.06 (t, J=7.7, 1H), 7.78 (d, J=8.2, 1H), 7.68 (d, J=8.1, 1H), 7.60-7.48 (m, 2H), 4.62 (s, 2H), 4.59-4.47 (m, 1H), 4.41-4.03 (m, 3H), 4.00 (s, 2H), 3.86-3.75 (m, 2H), 3.73-3.64 (m, 2H), 3.63-3.47 (m, 5H), 3.46-3.38 (m, 1H), 3.25-3.12 (m, 2H), 3.03-3.01 (m, 1H), 3.01 (s, 3H), 2.96-2.89 (m, 1H), 2.37-2.03 (m, 4H), 1.79-1.58 (m, 4H), 1.58-1.48 (m, 2H).
MS (ESI): mass calcd. for C34H47F3N6O5S2, 740.30; m/z found, 741.3 [M+H]+. 1H NMR: 8.07 (s, 1H), 7.76 (d, J=8.2, 1H), 7.65 (d, J=7.4, 1H), 4.59 (s, 2H), 4.55-4.42 (m, 1H), 4.37-4.07 (m, 2H), 4.05-3.89 (m, 2H), 3.77-3.61 (m, 4H), 3.60-3.45 (m, 8H), 3.45-3.36 (m, 2H), 3.26-3.03 (m, 2H), 2.99 (s, 3H), 2.98-2.75 (m, 3H), 2.10-1.94 (m, 5H), 1.93-1.76 (m, 3H), 1.75-1.57 (m, 4H), 1.51 (s, 2H).
MS (ESI): mass calcd. for C32H45F3N6O6S2, 730.28; m/z found, 731.2 [M+H]+. 1H NMR: 8.04 (s, 1H), 7.77 (d, J=8.3, 1H), 7.67 (d, J=8.3, 1H), 4.59 (s, 2H), 4.56-4.46 (m, 1H), 4.30-4.14 (m, 2H), 4.00 (s, 2H), 3.99-3.86 (m, 4H), 3.83 (d, J=11.7, 2H), 3.71-3.64 (m, 3H), 3.64-3.60 (m, 3H), 3.60-3.53 (m, 4H), 3.53-3.44 (m, 1H), 3.44-3.27 (m, 5H), 3.27-3.08 (m, 3H), 2.99 (s, 3H), 2.98-2.95 (m, 2H), 2.43 (t, J=14.4, 2H), 2.23-1.98 (m, 2H).
MS (ESI): mass calcd. for C33H41F3N6O5S2, 722.25; m/z found, 723.2 [M+H]+. 1H NMR: 8.70-8.66 (m, 1H), 8.20 (t, J=7.2, 1H), 8.06 (s, 1H), 7.78 (d, J=8.2, 1H), 7.74-7.62 (m, 3H), 4.62 (s, 2H), 4.60-4.53 (m, 1H), 4.34-4.19 (m, 2H), 4.02 (s, 2H), 3.89-3.76 (m, 2H), 3.74-3.52 (m, 10H), 3.50-3.38 (m, 2H), 3.32-3.15 (m, 3H), 3.03-3.01 (m, 2H), 3.01 (s, 3H), 2.42-1.98 (m, 4H).
MS (ESI): mass calcd. for C33H45F3N6O6S2, 742.28; m/z found, 743.4 [M+H]+. 1H NMR: 8.09-8.03 (m, 1H), 7.76 (d, J=8.2, 1H), 7.65 (d, J=8.2, 1H), 4.58 (s, 2H), 4.54-4.45 (m, 1H), 4.31-4.14 (m, 2H), 4.00 (s, 2H), 3.78-3.65 (m, 5H), 3.65-3.61 (m, 4H), 3.60-3.57 (m, 2H), 3.57-3.53 (m, 2H), 3.54-3.43 (m, 2H), 3.43-3.28 (m, 4H), 3.28-3.15 (m, 2H), 3.16-3.07 (m, 1H), 3.06-2.94 (m, 8H), 2.33-2.15 (m, 2H), 2.16-2.00 (m, 1H), 1.95-1.70 (m, 1H).
A. (5-{1-[2-Hydroxy-3-(4-morpholin-4-yl-piperidin-1-yl)-propyl]-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-trifluoromethyl-phenylsulfanyl)-acetic acid ethyl ester. This compound was prepared using methods similar to those described in Example 63, using the appropriate substituent changes. MS (ESI): mass calcd. for C30H42F3N5O6S2, 689.25; m/z found, 690.3 [M+H]+. 1H NMR: 7.97 (s, 1H), 7.78 (d, J=8.3, 1H), 7.69 (d, J=8.2, 1H), 4.58 (s, 2H), 4.53-4.45 (m, 1H), 4.30-4.20 (m, 2H), 4.19-4.14 (m, 2H), 3.95-3.82 (m, 4H), 3.79-3.61 (m, 4H), 3.27-3.03 (m, 8H), 3.01 (s, 3H), 2.43-2.22 (m, 2H), 2.12-1.86 (m, 4H), 1.18 (t, J=7.1, 3H).
B. 1-[5-(Methylsulfonyl)-3-{3-[(2-oxo-2-pyrrolidin-1-ylethyl)sulfanyl]-4-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl]-3-(4-morpholin-4-ylpiperidin-1-yl)propan-2-ol. This compound was prepared using methods similar to those described in Example 255, Step B, using the appropriate substituent changes. MS (ESI): mass calcd. for C32H45F3N6O5S2, 714.28; m/z found, 715.2 [M+H]+. 1H NMR: 8.07 (s, 1H), 7.76 (d, J=8.2, 1H), 7.66 (d, J=7.8, 1H), 4.59 (s, 2H), 4.53-4.47 (m, 1H), 4.30-4.17 (m, 2H), 3.98 (s, 2H), 3.97-3.87 (m, 4H), 3.87-3.76 (m, 3H), 3.72-3.58 (m, 2H), 3.56-3.50 (m, 4H), 3.50-3.44 (m, 2H), 3.26-3.07 (m, 3H), 3.01-2.99 (m, 1H), 2.99 (s, 3H), 2.98-2.96 (m, 2H), 2.49-2.36 (m, 2H), 2.19-2.01 (m, 2H), 1.71-1.57 (m, 4H), 1.56-1.48 (m, 2H).
This compound was prepared using methods similar to those described in Example 263, with the appropriate substituent changes. MS (ESI): mass calcd. for C33H47F3N6O5S2, 728.30; m/z found, 729.3 [M+H]+. 1H NMR: 8.07 (s, 1H), 7.76 (d, J=8.2, 1H), 7.67 (d, J=8.0, 1H), 4.58 (s, 2H), 4.54-4.47 (m, 1H), 4.29-4.17 (m, 2H), 3.99-3.91 (m, 3H), 3.89 (d, J=9.0, 2H), 3.87-3.76 (m, 3H), 3.71-3.59 (m, 2H), 3.53 (t, J=6.8, 2H), 3.51-3.43 (m, 2H), 3.41 (t, J=7.0, 2H), 3.39-3.32 (m, 3H), 3.30-3.28 (m, 2H), 3.28-3.09 (m, 3H), 2.99 (s, 3H), 2.98-2.96 (m, 2H), 2.51-2.31 (m, 2H), 2.21-1.99 (m, 3H), 1.97-1.92 (m, 2H), 1.89-1.82 (m, 2H).
Examples 265-271 were prepared using methods similar to those described in Example 228, with the appropriate substituent changes.
MS (ESI): mass calcd. for C27H36F3N5O3S, 567.25; m/z found, 568.3 [M+H]+. 1H NMR: 8.09 (s, 1H), 7.79 (d, J=8.2, 1H), 7.67 (d, J=8.1, 1H), 4.58-4.51 (m, 3H), 4.33-4.18 (m, 2H), 4.01 (s, 2H), 3.74-3.53 (m, 12H), 3.42-3.32 (m, 2H), 3.28-3.16 (m, 3H), 3.12-2.95 (m, 2H), 2.01-1.72 (m, 5H), 1.62-1.48 (m, 1H).
MS (ESI): mass calcd. for C34H42F3N5O4S, 673.29; m/z found, 674.3 [M+H]+. 1H NMR: 8.10 (s, 1H), 7.81-7.63 (m, 2H), 7.26-7.18 (m, 1H), 7.16-7.12 (m, 1H), 6.99-6.89 (m, 2H), 4.58 (s, 3H), 4.34-4.19 (m, 2H), 4.00 (s, 2H), 3.83 (s, 3H), 3.80-3.45 (m, 12H), 3.45-3.11 (m, 7H), 2.14-1.89 (m, 4H).
MS (ESI): mass calcd. for C31H41F3N6O4S, 650.29; m/z found, 651.3 [M+H]+. 1H NMR: 8.09 (s, 1H), 7.78 (d, J=7.9, 1H), 7.65 (d, J=7.9, 1H), 4.64-4.46 (m, 3H), 4.28 (dd, J=25.9, 13.2, 2H), 4.17-4.10 (m, 1H), 4.02 (s, 2H), 3.81-3.72 (m, 2H), 3.71-3.68 (m, 2H), 3.65-3.58 (m, 6H), 3.57-3.52 (m, 3H), 3.44 (t, J=6.6, 2H), 3.41-3.36 (m, 1H), 3.29-3.12 (m, 4H), 2.39 (t, J=7.9, 2H), 2.24-2.08 (m, 2H), 2.08-2.00 (m, 4H), 1.98-1.88 (m, 2H).
MS (ESI): mass calcd. for C32H39F3N6O3S, 644.28; m/z found, 645.2 [M+H]+. 1H NMR: 8.62-8.57 (m, 1H), 8.09 (s, 1H), 8.07-7.97 (m, 1H), 7.78 (d, J=8.2, 1H), 7.66 (d, J=8.3, 1H), 7.57-7.44 (m, 2H), 4.63-4.59 (m, 1H), 4.59 (s, 2H), 4.35-4.28 (m, 1H), 4.27-4.21 (m, 1H), 4.00 (s, 2H), 3.86-3.75 (m, 2H), 3.71-3.67 (m, 2H), 3.66-3.57 (m, 6H), 3.57-3.51 (m, 3H), 3.48-3.39 (m, 1H), 3.38-3.34 (m, 1H), 3.24-3.13 (m, 4H), 2.45-2.06 (m, 4H).
MS (ESI): mass calcd. for C31H44F3N5O2S, 607.32; m/z found, 608.3 [M+H]+. 1H NMR: 8.09 (s, 1H), 7.80-7.74 (m, 1H), 7.68-7.64 (m, 1H), 4.63-4.48 (m, 3H), 4.30-4.17 (m, 2H), 3.89 (s, 2H), 3.74-3.55 (m, 6H), 3.43-3.37 (m, 2H), 3.35-3.29 (m, 1H), 3.27-3.17 (m, 3H), 3.09-2.91 (m, 2H), 2.02-1.81 (m, 6H), 1.70-1.49 (m, 2H), 1.41-1.33 (m, 1H), 0.90 (s, 9H).
MS (ESI): mass calcd. for C31H41F3N6O3S, 634.29; m/z found, 635.3 [M+H]+. 1H NMR: 8.09 (s, 1H), 7.77 (d, J=8.2, 1H), 7.66 (d, J=8.2, 1H), 4.61-4.55 (m, 1H), 4.57 (s, 2H), 4.34-4.22 (m, 2H), 4.18-4.09 (m, 1H), 3.92 (s, 2H), 3.81-3.71 (m, 2H), 3.62-3.56 (m, 4H), 3.49-3.36 (m, 5H), 3.28-3.15 (m, 4H), 2.39 (t, J=8.1, 2H), 2.24-2.08 (m, 2H), 2.08-2.00 (m, 2H), 1.99-1.94 (m, 3H), 1.94-1.91 (m, 1H), 1.91-1.84 (m, 3H).
MS (ESI): mass calcd. for C32H39F3N6O2S, 628.28; m/z found, 629.3 [M+H]+. 1H NMR: 8.83 (d, J=5.4, 1H), 8.61-8.53 (m, 1H), 8.07 (s, 1H), 8.01 (d, J=8.1, 1H), 7.99-7.94 (m, 1H), 7.76 (d, J=8.3, 1H), 7.67 (d, J=8.2, 1H), 4.64-4.58 (m, 1H), 4.57 (s, 2H), 4.38-4.18 (m, 2H), 3.90 (s, 3H), 3.88-3.84 (m, 1H), 3.65-3.59 (m, 2H), 3.57 (t, J=6.8, 2H), 3.54-3.43 (m, 2H), 3.41 (t, J=6.9, 2H), 3.39-3.33 (m, 2H), 3.30-3.25 (m, 1H), 3.22 (t, J=6.1, 2H), 2.47-2.15 (m, 4H), 2.01-1.92 (m, 2H), 1.90-1.83 (m, 2H).
This compound was prepared using methods similar to those described in Example 228, substituting 20% TFA in CH2Cl2 for 4 M HCl in 1,4-dioxane. MS (ESI): mass calcd. for C27H36F3N5O2S, 551.25; m/z found, 552.3 [M+H]+. 1H NMR: 8.13-8.02 (m, 1H), 7.84-7.72 (m, 1H), 7.71-7.62 (m, 1H), 4.67-4.46 (m, 3H), 4.36-4.15 (m, 2H), 3.97-3.79 (m, 2H), 3.72-3.50 (m, 6H), 3.48-3.36 (m, 3H), 3.27-3.14 (m, 3H), 3.13-2.94 (m, 2H), 2.13-1.66 (m, 9H), 1.65-1.46 (m, 1H).
Examples 273-276 were prepared using methods similar to those described in Example 238, with the appropriate substituent changes.
MS (ESI): mass calcd. for C29H38F3N5O5S, 625.25; m/z found, 626.2 [M+H]+. 1H NMR: 8.11-8.05 (m, 1H), 7.82-7.75 (m, 1H), 7.73-7.68 (m, 1H), 4.88-4.73 (m, 1H), 4.55-4.45 (m, 1H), 4.40-4.33 (m, 2H), 4.27-4.14 (m, 2H), 4.08-3.90 (m, 3H), 3.83-3.49 (m, 12H), 3.27-3.16 (m, 1H), 3.14-2.85 (m, 4H), 2.04-1.69 (m, 5H), 1.62-1.46 (m, 1H).
MS (ESI): mass calcd. for C34H41F3N6O5S, 702.28; m/z found, 703.3 [M+H]+. 1H NMR: 8.65-8.57 (m, 1H), 8.11-8.01 (m, 2H), 7.81-7.67 (m, 2H), 7.57-7.49 (m, 2H), 4.86-4.71 (m, 1H), 4.58-4.50 (m, 1H), 4.39-4.32 (m, 2H), 4.29-4.18 (m, 2H), 4.03 (s, 3H), 3.87-3.49 (m, 12H), 3.44-3.25 (m, 3H), 3.24-3.11 (m, 2H), 2.99-2.88 (m, 2H), 2.28-2.02 (m, 4H).
MS (ESI): mass calcd. for C36H44F3N5O6S, 731.30; m/z found, 732.3 [M+H]+. 1H NMR: 8.10 (d, J=13.8, 1H), 7.80-7.75 (m, 1H), 7.72-7.68 (m, 1H), 7.25-7.18 (m, 1H), 7.14-7.11 (m, 1H), 6.98-6.95 (m, 1H), 6.94-6.89 (m, 1H), 4.90-4.83 (m, 1H), 4.79-4.74 (m, 1H), 4.56-4.49 (m, 1H), 4.38-4.32 (m, 2H), 4.28-4.17 (m, 2H), 4.03 (s, 3H), 3.83 (s, 3H), 3.80-3.46 (m, 11H), 3.44-3.11 (m, 5H), 3.00-2.83 (m, 2H), 2.10-1.89 (m, 4H).
MS (ESI): mass calcd. for C35H44F4N6O3S, 704.31; m/z found, 705.3 [M+H]+. 1H NMR: 8.66-8.60 (m, 1H), 8.15-8.10 (m, 1H), 8.03-7.90 (m, 1H), 7.82 (d, J=8.3, 1H), 7.78 (d, J=7.9, 1H), 7.62 (d, J=7.9, 1H), 7.60-7.55 (m, 1H), 5.04-4.94 (m, 1H), 4.90-4.78 (m, 2H), 4.71 (s, 1H), 4.60-4.49 (m, 1H), 4.38 (s, 2H), 4.33-4.15 (m, 3H), 4.06-3.88 (m, 1H), 3.86-3.70 (m, 4H), 3.64-3.34 (m, 8H), 3.28-3.10 (m, 4H), 3.03-2.83 (m, 2H), 2.45-1.88 (m, 8H).
Examples 277-280 were prepared using methods similar to those described in Example 243, with the appropriate substituent changes.
MS (ESI): mass calcd. for C36H44F3N5O5S, 715.30; m/z found, 716.3 [M+H]+. 1H NMR: 8.15-8.06 (m, 1H), 7.80-7.75 (m, 1H), 7.71-7.67 (m, 1H), 7.25-7.18 (m, 1H), 7.14-7.11 (m, 1H), 6.98-6.94 (m, 1H), 6.93-6.90 (m, 1H), 4.85-4.80 (m, 1H), 4.58-4.48 (m, 1H), 4.29-4.17 (m, 2H), 4.02 (s, 2H), 4.01-3.93 (m, 1H), 3.93-3.84 (m, 2H), 3.83 (s, 3H), 3.78-3.73 (m, 1H), 3.71-3.65 (m, 3H), 3.64-3.58 (m, 4H), 3.57-3.51 (m, 2H), 3.43-3.32 (m, 2H), 3.28-3.12 (m, 3H), 3.00-2.95 (m, 1H), 2.90-2.86 (m, 1H), 2.25-2.17 (m, 3H), 2.10-2.00 (m, 3H), 2.00-1.91 (m, 1H).
MS (ESI): mass calcd. for C33H46F3N5O3S, 649.33; m/z found, 650.46 [M+H]+. 1H NMR: 8.14-8.03 (m, 1H), 7.79-7.74 (m, 1H), 7.72-7.65 (m, 1H), 4.86-4.78 (m, 2H), 4.53-4.43 (m, 1H), 4.27-4.12 (m, 2H), 4.01-3.81 (m, 4H), 3.73-3.51 (m, 4H), 3.43-3.16 (m, 4H), 3.11-2.99 (m, 1H), 2.98-2.82 (m, 3H), 2.26-2.17 (m, 3H), 2.02-1.79 (m, 6H), 1.69-1.43 (m, 2H), 1.42-1.31 (m, 1H), 0.90 (s, 9H).
MS (ESI): mass calcd. for C29H38F3N5O3S, 593.26; m/z found, 594.3 [M+H]+. 1H NMR: 8.13 (s, 0.4H), 8.07 (s, 0.06H), 7.78 (d, J=8.3, 1H), 7.71 (t, J=8.4, 1H), 4.85-4.77 (m, 2H), 4.54-4.45 (m, 1H), 4.28-4.13 (m, 2H), 4.02-3.82 (m, 4H), 3.65-3.51 (m, 4H), 3.44-3.37 (m, 3H), 3.26-3.15 (m, 1H), 3.14-3.04 (m, 1H), 3.03-2.93 (m, 2H), 2.87 (t, J=5.7, 1H), 2.23 (d, J=9.3, 3H), 2.03-1.92 (m, 3H), 1.92-1.79 (m, 5H), 1.79-1.69 (m, 1H), 1.61-1.46 (m, 1H).
MS (ESI): mass calcd. for C30H40F3N5O3S, 607.28; m/z found, 608.3 [M+H]+. 1H NMR: 8.11 (s, 0.4H), 8.04 (s, 0.6H), 7.76 (d, J=8.3, 1H), 7.69 (t, J=7.7, 1H), 4.86-4.77 (m, 2H), 4.54-4.40 (m, 1H), 4.28-4.10 (m, 2H), 4.01-3.80 (m, 4H), 3.69-3.48 (m, 4H), 3.45-3.35 (m, 2H) 3.29-3.17 (m, 2H), 3.13-3.02 (m, 1H), 3.02-2.91 (m, 2H), 2.85 (t, J=5.6, 1H), 2.21 (d, J=7.6, 3H), 2.01-1.91 (m, 3H), 1.91-1.80 (m, 3H), 1.75-1.59 (m, 1H), 1.58-1.31 (m, 2H), 1.14-0.92 (m, 3H).
To a solution of 1-(2-hydroxy-3-{3-[3-(2-oxo-2-pyrrolidin-1-yl-ethylsulfanyl)-4-trifluoromethyl-phenyl]-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl}-propyl)-piperidine-4-carboxylic acid amide (16 mg, 0.025 mmol) in acetonitrile (0.30 mL) was added TEA (0.007 mL, 0.05 mmol), acetaldehyde (0.006 mL, 0.13 mmol) and NaCNBH3 (4 mg, 0.05 mmol). The mixture was stirred under N2 for 36 h, quenched with MeOH (1 mL), filtered, and concentrated. The residue was purified by reverse phase HPLC, yielding the title compound as a white powder (5 mg, 31%). MS (ESI): mass calcd. for C33H45F3N6O3S, 662.32; m/z found, 663.4 [M+H]+. 1H NMR: 8.12 (s, 1H), 7.77 (d, J=8.3, 1H), 7.68 (d, J=8.2, 1H), 4.85-4.74 (m, 1H), 4.59-4.48 (m, 2H), 4.34-4.18 (m, 2H), 4.17-4.07 (m, 1H), 3.90 (s, 3H), 3.80-3.67 (m, 2H), 3.59 (t, J=6.8, 2H), 3.53-3.35 (m, 8H), 3.29-3.23 (m, 3H), 3.22-3.09 (m, 2H), 2.39 (t, J=8.1, 2H), 2.21-2.10 (m, 1H), 2.08-2.01 (m, 3H), 2.00-1.92 (m, 4H), 1.91-1.83 (m, 3H), 1.48 (t, J=7.3, 3H).
This compound was prepared using methods similar to those described in Example 281 with the appropriate substituent changes. MS (ESI): mass calcd. for C34H43F3N6O2S, 656.31; m/z found, 657.4 [M+H]+. 1H NMR: 8.65-8.62 (m, 1H), 8.17-8.06 (m, 2H), 7.77 (d, J=8.3, 1H), 7.69 (d, J=8.6, 1H), 7.62 (d, J=8.0, 1H), 7.60-7.55 (m, 1H), 4.86-4.73 (m, 1H), 4.64-4.46 (m, 2H), 4.36-4.17 (m, 2H), 3.97-3.88 (m, 3H), 3.87-3.74 (m, 2H), 3.66-3.52 (m, 3H), 3.52-3.33 (m, 7H), 3.28-3.12 (m, 4H), 2.38-2.07 (m, 4H), 2.03-1.92 (m, 2H), 1.91-1.82 (m, 2H), 1.48 (t, J=7.3, 3H).
The compounds in Table 1 (Examples 283-896) were prepared using methods analogous to those described in the preceding examples.
Recombinant human cathepsin S (CatS) was expressed in the baculovirus system and purified in one step with a thiopropyl-sepharose column. 10-L yielded ˜700 mg of CatS and N-terminal sequencing confirmed identity. The assay is run in 150 mM sodium acetate pH 5.0 containing 1.5 mM DTT and 150 mM NaCl. The substrate for the assay is: Z-Valine-Valine-Arginine-AMC (catalog #I-1540, Bachem). The Km for the substrate is around 5 μM but the presence of substrate inhibition makes kinetic analysis difficult. With 10 μM substrate the assay rate is linear over the range of 1-8 ng CatS in 100 μL reaction. Using 2 ng/well of CatS, the production of product is linear and yields ˜7-fold signal after 20 min with only 20% loss of substrate. Measurements are taken every min for 20 min. The rate is calculated from the slope of the increase in fluorescence and the percent inhibition is calculated from this.
Results for the compounds tested in this assay are presented in Tables 2, 3, and 4 as an average of results obtained. Compounds were tested in free base, hydrochloride salt, trifluoroacetic acid salt, or citrate salt forms.
While the invention has been illustrated by reference to examples, it is understood that the invention is intended not to be limited to the foregoing detailed description.
This application claims the benefit of U.S. provisional patent application Ser. No. 60/889,976, filed Feb. 15, 2007 which is incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 60889976 | Feb 2007 | US |
