WO2010141550A2

WO2010141550A2 - 11-beta hsd1 inhibitors

Info

Publication number: WO2010141550A2
Application number: PCT/US2010/037024
Authority: WO
Inventors: Zhao-Kui Wan; Eva Chenail; Manus Ipek; Huan-Qiu Li; Tarek Suhayl Mansour; Vipin Suri; Jason Shaoyun Xiang; Eddine Saiah
Original assignee: Wyeth Llc
Priority date: 2009-06-04
Filing date: 2010-06-02
Publication date: 2010-12-09
Also published as: WO2010141550A3

Abstract

This invention features a chemical entity E, which is a compound of Formula I, or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide thereof (e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof). Formula I is provided below: formula (I) R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and A can be as defined anywhere herein.

Description

11 -beta HSDl Inhibitors

TECHNICAL FIELD

This invention features compounds that inhibit 11 -beta HSDl.

BACKGROUND

Diabetes is generally characterized by relatively high levels of plasma glucose (hyperglycemia) in the fasting state. Patients having type 2 diabetes (non-insulin dependent diabetes mellitus (NIDDM)) produce insulin (and even exhibit hyperinsulinemia), whilst demonstrating hyperglycemia.

Type 2 diabetics can often develop insulin resistance, in which the effect of insulin in stimulating glucose and lipid metabolism is diminished. Further, patients having insulin resistance, but have not developed type 2 diabetes, are also at risk of developing Syndrome X (metabolic syndrome). Syndrome X is characterized by insulin resistance, along with obesity (e.g., abdominal obesity), hyperinsulinemia, high blood pressure, relatively low HDL and relatively high VLDL.

Glucocorticoids (e.g., Cortisol in humans, corticosterone in rodents) are counter regulatory hormones that oppose the action of insulin. It is established that glucocorticoid activity is controlled at the tissue level by intracellular interconversion of active Cortisol and inactive cortisone by the 11 -beta hydroxysteroid dehydrogenases, llβHSDl, which activates cortisone and llβHSD2, which inactivates Cortisol. Excess levels of glucocorticoids (e.g., Cortisol) can cause metabolic complications. For example, excess Cortisol is associated with disorders including NIDDM, obesity, dyslipidemia, insulin resistance, and hypertension.

It is believed that inhibition of 1 lβHSDl can reduce the effects of excessive amounts of 1 lβ-hydroxysteroids, e.g., Cortisol, and therefore can be useful for the treatment and control of diseases mediated by abnormally high levels of Cortisol and other 1 lβ-hydroxysteroids, e.g., NIDDM, obesity, dyslipidemia, and hypertension. SUMMARY

In one aspect, this invention features a chemical entity E, which is a compound of Formula I, or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide thereof (e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof). Formula I is provided below:

wherein:

R¹ is halo, -CH₃, -CH₂X, -CHX₂, -CF₃, -OCH₃ or -OCF₃;

R² is halo, -CN, -C(O)-NH₂, -C(O)-NH-(C_L3 alkyl), -C(0)-N(d_₃ alkyl)₂, or 5- to 6-membered heteroaryl containing 1-4 ring heteroatoms independently selected from O, N, N(R^2sl) and S, wherein R^2sl is -H, -CH₃ or ethyl, and wherein said heteroaryl is unsubstituted or substituted with one or two substituents R^2s2 independently selected from halo, -CH₃, ethyl, -CF₃, -OH and -OCH₃;

R³ is -H, halo, -CH₃, ethyl, -OH or -OCH₃; one of R⁴ and R⁵ is H, and the other is -CH₃, -CH₂X, -CHX₂, -CF₃ or ethyl;

A is phenyl, or 5- to 6-membered heteroaryl containing 1-3 ring heteroatoms independently selected from O, N, N(R^al) and S, and in which the atom bonded to the sulfonyl sulfur is carbon, wherein R^al is -H, -CH₃ or ethyl; R⁹ is -H, halo, -CH₃, -CH₂X, -CHX₂, -CF₃, ethyl, -OCH₃ or -OCF₃; provided that when A is 5- membered heteroaryl containing 3 ring heteroatoms, then R⁹ is absent;

R⁶ is -CH₃, ethyl, -OH or -OCH₃;

R⁷ is -CH₃, -CH₂X, -CHX₂, -CF₃ or phenyl, wherein said phenyl is unsubstituted or substituted with one or two substituents R^7sl independently selected from halo, -CH₃, ethyl, -CF₃, -OH and -OCH₃; R⁸ is -C(O)-NH₂, -C(O)-NH-(CL₃ alkyl), -C(O)-N(CL₃ alkyl)₂, -NH-C(O)-(CL₃ alkyl), -N(C_L3 alkyl)-C(O)-(C_1-3 alkyl), or 5- to 6-membered heteroaryl containing 1-4 ring heteroatoms independently selected from O, N, N(R^8sl) and S, wherein R^8sl is -H, -CH₃ or ethyl, and wherein said heteroaryl is unsubstituted or substituted with one or two substituents R^8s2 independently selected from halo, -CH₃, ethyl, -CF₃, -OH and -OCH₃; and each instance of X is independently -F, -Cl or -Br; provided that when A is phenyl, then R⁶ and R⁷ cannot both be -CH₃.

In another aspect, this invention features a chemical entity E, which is a compound of Formula I, or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide thereof (e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof), in which: R⁶ is -OH, -CH₃, or ethyl;

R⁷ is -CF₃, -CH₃, or phenyl, wherein said phenyl is unsubstituted or substituted with one or two substituents R^7sl independently selected from halo, -CH₃, ethyl, -CF₃, -OH and -OCH₃; provided that when A is phenyl, then R⁶ and R⁷ cannot both be -CH₃; and R¹, R², R³, R⁴, R⁵, R⁸, and R⁹ can be as defined anywhere herein.

In another aspect, this invention features a chemical entity E, which is a compound of Formula I, or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide thereof (e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof), in which:

R⁶ is -OH;

R⁷ is -CF₃; and

R¹, R², R³, R⁴, R⁵, R⁸, and R⁹ can be as defined anywhere herein. In a further aspect, this invention features a chemical entity E, which is a compound of Formula I, or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide thereof (e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof), in which: R⁶ is -OH;

R⁷ is -CF₃;

R⁸ is -C(O)-NH₂, -C(O)-NH-(C_L3 alkyl), or -C(O)-N(C_L3 alkyl)₂ (e.g., -C(O)-NH₂); and

R¹, R², R³, R⁴, R⁵, and R⁹ can be as defined anywhere herein.

In another aspect, this invention features a chemical entity E, which is a compound of Formula I, or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide thereof (e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof), in which: R⁸ is -C(O)-NH₂, -C(O)-NH-(C_L3 alkyl), or -C(O)-N(C_L3 alkyl)₂ (e.g.,

-C(O)-NH₂); provided that when A is phenyl, then R⁶ and R⁷ cannot both be -CH₃; and

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁹ can be as defined anywhere herein.

In a further aspect, this invention features a chemical entity E, which is a compound of Formula I, or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide thereof (e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof), in which:

A is 5- to 6-membered heteroaryl containing 1-3 ring heteroatoms independently selected from O, N, N(R^al) and S, and in which the atom bonded to the sulfonyl sulfur is carbon, wherein R^al is -H, -CH₃ or ethyl; and

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ can be as defined anywhere herein. In another aspect, this invention features a chemical entity E, which is a compound of Formula I, or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide thereof (e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof), in which:

A is a 5-membered heteroaryl, which has formula (A-I):

in which the carbon atom shown as C in formula (A-I) represents the carbon that is bonded to the sulfonyl sulfur in Formula I; and in which A¹, A², A³, A⁴, and the dotted lines between A¹ and A⁴ and A³ and A⁴ are all defined according to the definitions under (i) below or are all defined according to the definitions under (ii) below:

(i): A¹ is singly bonded to A⁴, and A³ is doubly bonded to A⁴;

AMs O₅ S₅ Or NR"¹; and one of A², A³,and A⁴ is C-C(R⁶)(R⁷)(R⁸), one of A², A³ and A⁴ is C-R⁹, and one of A², A³, and A⁴ is C-H or N; or (ii):

A¹ is doubly bonded to A⁴, and A³ is singly bonded to A⁴;

A³ is O, S, or NR^al; and one of A¹, A², and A⁴ is C-C(R⁶)(R⁷)(R⁸), one of A¹, A², and A⁴ is C-R⁹, and one of A¹, A², and A⁴ is N or C-H; and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ can be as defined anywhere herein.

In some embodiments, the chemical entity E can be a compound of formula (I) (including any subgenus of formula (I) or specific compound of formula (I)). In some embodiments, the chemical entity E can be a salt (e.g., a pharmaceutically acceptable salt) of a compound of formula (I) (including any subgenus of formula (I) or specific compound of formula (I)).

In some embodiments, the chemical entity E can be an N-oxide of a compound of formula (I) (including any subgenus of formula (I) or specific compound of formula (I)).

In some embodiments, the chemical entity E can be a salt (e.g., a pharmaceutically acceptable salt) of an N-oxide of a compound of formula (I) (including any subgenus of formula (I) or specific compound of formula (I)).

In one aspect, this invention features a composition (e.g., a pharmaceutical composition), which includes a chemical entity E as defined anywhere herein and a pharmaceutically acceptable carrier. In some embodiments, the composition can include an effective amount of a chemical entity E as defined anywhere herein. In some embodiments, the composition can further include an additional therapeutic agent. In one aspect, this invention features a dosage form, which includes from about

0.05 milligrams to about 2,000 milligrams (e.g., from about 0.1 milligrams to about 1,000 milligrams, from about 0.1 milligrams to about 500 milligrams, from about 0.1 milligrams to about 250 milligrams, from about 0.1 milligrams to about 100 milligrams, from about 0.1 milligrams to about 50 milligrams, or from about 0.1 milligrams to about 25 milligrams) of a chemical entity E as defined anywhere herein. The dosage form can further include a pharmaceutically acceptable carrier and/or an additional therapeutic agent.

The invention also relates generally to inhibiting 11 -beta HSDl with a chemical entity E as defined anywhere herein. In some embodiments, the methods can include, e.g., contacting an 11-βHSDl in a sample (e.g., a tissue) with a chemical entity E as defined anywhere herein. In other embodiments, the methods can include administering a chemical entity E as defined anywhere herein to a subject (e.g., a mammal, such as a human). Accordingly, in yet another aspect, this invention includes methods of screening for compounds that inhibit 11 -βHSD 1. In one aspect, this invention also features methods for treating (e.g., controlling, relieving, ameliorating, alleviating, or slowing the progression of) or methods for preventing (e.g., delaying the onset of or reducing the risk of developing) a disease or condition that is mediated by excess (e.g., abnormally high) levels or uncontrolled (e.g., resulting in abnormally high) levels of Cortisol and/or other corticosteroids (e.g., 1 lβ- hydroxysteroids), which include administering to a subject in need thereof an effective amount of a chemical entity E as defined anywhere herein.

Examples of such diseases or conditions include, but are not limited to diabetes (e.g., type 1 or type 2 diabetes), Syndrome X, hyperglycemia, low glucose tolerance, insulin resistance, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, hypertension, coronary heart disease, stroke, peripheral vascular disease, Cushing's syndrome, glaucoma, osteoperosis, hyperinsulinemia, tuberculosis, psoriasis, cognitive disorders and dementia (e.g., impairment associated with aging and of neuronal dysfunction, e.g., Alzheimer's disease), depression, viral diseases, inflammatory disorders, immune disorders); or promoting wound healing.

In another aspect, this invention features methods for treating or preventing diabetes (e.g., type I diabetes, type 2 diabetes), which includes administering to a subject (e.g., a subject in need thereof) an effective amount of a chemical entity E as defined anywhere herein.

In a further aspect, this invention features methods for treating or preventing Syndrome X, which includes administering to a subject (e.g., a subject in need thereof) an effective amount of a chemical entity E as defined anywhere herein.

In another aspect, this invention features methods for treating or preventing hyperglycemia, which includes administering to a subject (e.g., a subject in need thereof) an effective amount of a chemical entity E as defined anywhere herein.

In a further aspect, this invention features methods for treating or preventing hyperglycemia, which includes administering to a subject (e.g., a subject in need thereof) an effective amount of a chemical entity E as defined anywhere herein. In another aspect, this invention features methods for treating or preventing obesity, which include administering to a subject (e.g., a subject in need thereof) an effective amount of a chemical entity E as defined anywhere herein.

In a further aspect, this invention features methods for treating or preventing a lipid disorder selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL and high LDL, which include administering to a subject (e.g., a subject in need thereof) an effective amount of a chemical entity E as defined anywhere herein.

In another aspect, this invention features methods for treating or preventing atherosclerosis, which include administering to a subject (e.g., a subject in need thereof) an effective amount of a chemical entity E as defined anywhere herein.

In a further aspect, this invention features methods for treating or preventing a cognitive disorder (e.g., Alzheimer's disease), which include administering to a subject (e.g., a subject in need thereof) an effective amount of a chemical entity E as defined anywhere herein.

In another aspect, this invention features methods for promoting wound healing, which include administering to a subject (e.g., a subject in need thereof) an effective amount of a chemical entity E as defined anywhere herein.

In some embodiments, the subject can be a subject in need thereof (e.g., a subject identified as being in need of such treatment, such as a subject having, or at risk of having, one or more of the diseases or conditions described herein). Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method). In some embodiments, the subject can be a mammal. In certain embodiments, the subject can be a human.

In a further aspect, this invention also relates to methods of making compounds described herein. In embodiments, the methods include taking any one of the intermediate compounds described herein and reacting it with one or more chemical reagents in one or more steps to produce a chemical entity E as defined anywhere herein. In one aspect, this invention relates to a packaged product. The packaged product includes a container, one of the aforementioned compounds in the container, and a legend (e.g., a label or an insert) associated with the container and indicating administration of the compound for treatment and control of the diseases or disorders described herein.

In embodiments, any chemical entity, composition, or method described herein can also include any one or more of the other features delineated in the detailed description and/or in the claims.

The term "mammal" includes organisms, which include mice, rats, cows, sheep, pigs, rabbits, goats, horses, monkeys, dogs, cats, and humans.

"An effective amount" refers to an amount of a compound that confers a therapeutic effect (e.g., treats, e.g., controls, relieves, ameliorates, alleviates, or slows the progression of; or prevents, e.g., delays the onset of or reduces the risk of developing, a disease, disorder, or condition or symptoms thereof) on the treated subject. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). An effective amount of the compound described above may range from about 0.01 mg/kg to about 1000 mg/kg, (e.g., from about 0.1 mg/kg to about 100 mg/kg, from about 1 mg/kg to about 100 mg/kg). Effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents.

The term "halo" or "halogen" refers to any radical of fluorine, chlorine, bromine or iodine.

In general, and unless otherwise indicated, substituent (radical) prefix names are derived from the parent hydride by either (i) replacing the "ane" in the parent hydride with the suffix "yl;" or (ii) replacing the "e" in the parent hydride with the suffix "yl;" (here the atom(s) with the free valence, when specified, is (are) given numbers as low as is consistent with any established numbering of the parent hydride). Accepted contracted names, e.g., furyl, pyridyl, and piperidyl, and trivial names, e.g., phenyl and thienyl are also used herein throughout. Conventional numbering/lettering systems are also adhered to for substituent numbering. The term "Ci_3 alkyl" refers to methyl, ethyl, n-propyl, and ώopropyl.

The term "heteroaryl" refers to an aromatic monocyclic or bicyclic hydrocarbon groups having one or more (e.g., 1-3 or 1-4) heteroatom ring atoms independently selected from O, N, or S (and mono and dioxides thereof, e.g., N→O^~, S(O), SO₂). Any atom can be optionally substituted by one or more substituents. Heteroaryl groups include pyridyl, thienyl, furyl (furanyl), imidazolyl, and pyrrolyl.

The details of one or more embodiments of the invention are set forth in the description below. Other features and advantages of the invention will be apparent from the description and from the claims.

DETAILED DESCRIPTION

This invention features a chemical entity E, which is a compound of Formula I, or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide thereof (e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof). Formula I is provided below:

Here and throughout this specification, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and A can be as defined anywhere herein.

For ease of exposition, it is also understood that where in this specification (including the claims), a group is defined by "as defined anywhere herein" (or the like), the definitions for that particular group include the first occurring and broadest generic definition as well as any sub-generic and specific definitions delineated anywhere in this specification. Variables R¹, R², and R³

In some embodiments, R¹ can be -CH3, -CH₂X, -CHX₂, or -CF3. In some embodiments, R¹ can be -CH₂X, -CHX₂, or -CF3. In some embodiments, R¹ can be -CF₃.

In some embodiments, R¹ can be -CH₂X, Or-CHX₂. In some embodiments, R¹ can be -CH3.

In embodiments, each instance of X can be, independently, -F or -Cl, e.g., -F. In some embodiments, R¹ can be halo (e.g., -F or -Cl). In some embodiments, R¹ can be -OCH₃ or -OCF₃.

In certain embodiments, R¹ can be -CF₃, -F, -Cl, -CH₃, or -OCH₃.

In some embodiments, R² can be: (i) halo;

(ϋ)-CN;

(iii) -C(O)-NH₂; or

(iv) 5- to 6-membered heteroaryl containing 1-4 ring heteroatoms independently selected from O, N, N(R^2sl) and S, in which R^2sl is -H, -CH₃ or ethyl, and in which said heteroaryl is unsubstituted or substituted with one or two substituents R^2s2 independently selected from halo, -CH₃, ethyl, -CF₃, -OH and -OCH₃.

In some embodiments, R² can be:

(i) halo; or (iv) 5- to 6-membered heteroaryl containing 1-4 ring heteroatoms independently selected from O, N, N(R^2sl) and S, in which R^2sl is -H, -CH₃ or ethyl, and in which said heteroaryl is unsubstituted or substituted with one or two substituents R^2s2 independently selected from halo, -CH₃, ethyl, -CF₃, -OH and -OCH₃.

In some embodiments, R² can be halo (e.g., -F). In some embodiments, R² can be 5- to 6-membered heteroaryl containing 1-4 (e.g., 2-3, 2-4, 3-4, 1-3, 1-2, 1, 2, 3, or 4) ring heteroatoms independently selected from O, N, N(R^2sl) and S, in which R^2sl is -H, -CH₃ or ethyl, and in which said heteroaryl is unsubstituted or substituted with one or two substituents R^2s2 independently selected from halo, -CH₃, ethyl, -CF₃, -OH and -OCH₃.

In certain embodiments, each instance of R^2sl can be, independently, -H or -CH₃ (e.g., -H).

In certain embodiments, each instance of R^2s2 can be, independently, -CH₃, ethyl, or -CF₃ (e.g., -CH₃ or ethyl; e.g., -CH₃). In certain embodiments, the 5- to 6-membered heteroaryl can contain 1-3 (e.g., 2-

3, 1, 2, or 3) ring heteroatoms.

In certain embodiments, the 5- to 6-membered heteroaryl can contain 2-4 (e.g., 2- 3, 3-4, 2, 3, or 4) ring heteroatoms.

In certain embodiments, the 5- to 6-membered heteroaryl can contain 3 or 4 ring heteroatoms. In embodiments, the 3 or 4 ring heteroatoms can be independently selected from O, N, and N(R^2sl). In other embodiments, each of the 3 or 4 ring heteroatoms can be independently selected from N and N(R^2sl). For example, one of the 3 or 4 ring heteroatoms can be O or N(R^2sl), and the others can each be N.

In embodiments, the 5- to 6-membered heteroaryl is bonded to the phenyl ring via a ring carbon atom and not via one of the aforementioned ring heteroatoms.

In certain embodiments, R² can be 5- membered heteroaryl containing 1-4 (e.g., 2-3, 2-4, 3-4, 1-3, 1-2, 1, 2, 3, or 4) ring heteroatoms independently selected from O, N, N(R^2sl) and S, in which R^2sl can be as defined anywhere herein; and in which said heteroaryl can be unsubstituted or substituted with one or two substituents R^2s2, in which each instance of R^2s2 can be as defined anywhere herein.

Embodiments can include one or more of the following features. R^2sl can be -H.

R^2s2 can be -CH₃ or ethyl; e.g., -CH₃. The 5- membered heteroaryl can contain 3 ring heteroatoms. In certain embodiments, each of the 3 ring heteroatoms can be independently selected from O, N, and N(R^2sl). In certain embodiments, each of the 3 ring heteroatoms can be independently selected from N and N(R^2sl).

In embodiments, one of the 3 ring heteroatoms can be O, and the others can be N. For example, the 5- membered heteroaryl can be l,2,4-oxadiazol-5-yl (unsubstituted or substituted with, e.g., -CH3) or l,3,4-oxadiazol-2-yl (unsubstituted or substituted with, e.g., -CH₃).

In embodiments, one of the 3 ring heteroatoms can be N(R^2sl), and the others can be N. For example, the 5- membered heteroaryl can be l,2,4-triazol-3-yl (unsubstituted or substituted with, e.g., -CH₃). The 5- membered heteroaryl can contain 4 ring heteroatoms. For example, the 5- membered heteroaryl can be tetrazol-5-yl.

In some embodiments, R² can be -C(O)-NH₂. In some embodiments, R² can be -CN.

In certain embodiments, R² can be -F; -CN; -C(O)-NH₂; l,2,4-oxadiazol-5-yl (unsubstituted or substituted with, e.g., -CH₃); l,3,4-oxadiazol-2-yl (unsubstituted or substituted with, e.g., -CH₃); l,2,4-triazol-3-yl (unsubstituted or substituted with, e.g., - CH₃); or tetrazol-5-yl.

In some embodiments:

R¹ is -CH₂X, -CHX₂, or -CF₃; and

R² is:

(i) halo (e.g., -F); (ϋ)-CN;

(iii) -C(O)-NH₂; or

Embodiments can include one or more of the following features. R¹ can be -CF₃.

X; the ring heteroatom content of the 5- to 6-membered heteroaryl; R^2sl; and R^2s2 can each be, independently, as defined anywhere herein. R² can be -F.

In some embodiments:

R¹ is -CH₂X, -CHX₂, or -CF₃; and

R² is:

(i) halo (e.g., -F); or (iv) 5- to 6-membered heteroaryl containing 1-4 ring heteroatoms independently selected from O, N, N(R^2sl) and S, in which R^2sl is -H, -CH₃ or ethyl, and in which said heteroaryl is unsubstituted or substituted with one or two substituents R^2s2 independently selected from halo, -CH₃, ethyl, -CF₃, -OH and -OCH₃.

X; the ring heteroatom content of the 5- to 6-membered heteroaryl; R^2sl; and R^2s2 can each be, independently, as defined anywhere herein.

R² can -F.

In some embodiments:

R¹ is -CH₂X, -CHX₂, or -CF₃; and

R² is halo (e.g., -F).

Embodiments can include one or more of the following features.

R¹ can be -CF₃. R² can -F.

In some embodiments, R¹ is -CF₃, and R² is -F.

In some embodiments, R³ can be -H. Variables R⁴ and R⁵

In some embodiments, the carbon atom attached to R⁴ and R⁵ can have the R- configuration (such compounds are referred to herein as having "the i?-CR⁴R⁵ configuration"). In some embodiments, the carbon atom attached to R⁴ and R⁵ can have the ^-configuration (such compounds are referred to herein as compounds having "the S- CR⁴R⁵ configuration").

In some embodiments, one of R⁴ and R⁵ can be H, and the other can be -CH3. In certain embodiments, R⁴ can be H, and R⁵ can be -CH3. In other embodiments, R⁴ can be H, and R⁵ can be -CH₃.

Variables A, R⁶, R⁷, R⁸, and R⁹

Variable A

In some embodiments, A can be 5- to 6-membered heteroaryl containing 1-3 (e.g., 1-2, 2-3, 1, 2, or 3) ring heteroatoms independently selected from O, N, N(R^al) and S, and in which the atom bonded to the sulfonyl sulfur is carbon. In certain embodiments, R^al can be -H or -CH₃.

In certain embodiments, the 5- to 6-membered heteroaryl can contain 1 or 2 ring heteroatoms. In certain embodiments, the ring heteroatoms can be independently selected from

N, N(R^al) and S.

In some embodiments, A can be 5-membered heteroaryl containing 1-3 (e.g., 1-2, 2-3, 1, 2, or 3) ring heteroatoms independently selected from O, N, N(R^al) and S, and in which the atom bonded to the sulfonyl sulfur is carbon, and in which R^al can be as defined anywhere herein.

In certain embodiments, the 5-membered heteroaryl can contain 1 ring heteroatom (e.g., S).

In certain embodiments, the 5-membered heteroaryl can contain 2 ring heteroatoms. In embodiments, the 2 ring heteroatoms can be independently selected from N, N(R^al) and S. For example, one of the 2 ring heteroatoms can be N, and the other can be S. As another example, one of the 2 ring heteroatoms can be N, and the other can be

N(R^al). In certain embodiments, the 5- membered heteroaryl can contain 3 ring heteroatoms. For example, one of the 3 ring heteroatoms can be N(R^al) or S, (e.g., N(R^a1)), and the others can each be N.

In certain embodiments, A can be a 5-membered heteroaryl, which has formula

(A-I):

(i):

A¹ is singly bonded to A⁴, and A³ is doubly bonded to A⁴;

AMs O₅ S₅ Or NR"¹; and one of A², A³,and A⁴ is C-C(R⁶)(R⁷)(R⁸), one of A², A³ and A⁴ is C-R⁹, and one of A², A³, and A⁴ is C-H or N; or

(ii):

A¹ is doubly bonded to A⁴, and A³ is singly bonded to A⁴;

A³ is O, S, or NR^al; and one of A¹, A², and A⁴ is C-C(R⁶)(R⁷)(R⁸), one of A¹, A², and A⁴ is C-R⁹, and one of A¹, A², and A⁴ is N or C-H. In certain embodiments, the definitions set forth under (i) {supra) apply, i.e.: A¹ is singly bonded to A⁴, and A³ is doubly bonded to A⁴; A¹ Is O, S, or NR^al; and one of A², A³,and A⁴ is C-C(R⁶)(R⁷)(R⁸), one of A², A³ and A⁴ is C- R⁹, and one of A², A³, and A⁴ is C-H or N.

When the definitions set forth under (i) {supra) apply, it is understood that A is 5- membered heteroaryl, which has formula (A-2):

and the carbon atom shown as C in formula (A-2) represents the carbon that is bonded to the sulfonyl sulfur in Formula I; and

A¹ is O, S, or NR^al; and one of A², A³,and A⁴ is C-C(R⁶)(R⁷)(R⁸), one of A², A³ and A⁴ is C-R⁹, and one of A², A³, and A⁴ is C-H or N.

Embodiments of formula (A-2) can include one or more of the following features.

A¹ can be S.

A⁴ can be C-C(R⁶)(R⁷)(R⁸).

A² canbe C-H. A² can be N. A³ canbe C-R⁹. R⁹ can be -H.

A¹ canbe S,A⁴ canbe C-C(R⁶)(R⁷)(R⁸), andA² canbe C-H orN.

A¹ canbe S,A³ canbe C-C(R⁶)(R⁷)(R⁸), andA² canbe C-H orN.

A¹ canbe S,A⁴ canbe C-C(R⁶)(R⁷)(R⁸),A² can be C-H, andA³ canbe C-R⁹. R⁹ can be -H. A¹ canbe S,A⁴ canbe C-C(R⁶)(R⁷)(R⁸),A² can beN, andA³ canbe C-R⁹. R⁹ can be -H. In certain embodiments, the definitions set forth under (ii) {supra) apply, i.e.: A¹ is doubly bonded to A⁴, and A³ is singly bonded to A⁴; A³ is O, S, or NR^al; and one of A¹, A², and A⁴ is C-C(R⁶)(R⁷)(R⁸), one of A¹, A², and A⁴ is C-R⁹, and one of A¹, A², and A⁴ is N or C-H.

When the definitions set forth under (ii) {supra) apply, it is understood that A is 5- membered heteroaryl, which has formula (A-3):

and the carbon atom shown as C in formula (A-3) represents the carbon that is bonded to the sulfonyl sulfur in Formula I; and

A³ is O, S, or NR^al; and one of A¹, A², and A⁴ is C-C(R⁶)(R⁷)(R⁸), one of A¹, A², and A⁴ is C-R⁹, and one of A¹, A², and A⁴ is N or C-H.

Embodiments of formula (A-3) can include one or more of the following features.

A³ can be NR^al. R^al can be -CH₃.

One of A² and A⁴ can be C-C(R⁶)(R⁷)(R⁸), and one of A² and A⁴ can be C-R⁹. A¹ can be N or C-H (e.g., N).

A³ can be NR^al; one of A² and A⁴ can be C-C(R⁶)(R⁷)(R⁸), and one of A² and A⁴ can be C-R⁹; and A¹ can be N.

In some embodiments, A can be phenyl. In certain embodiments, -C(R⁶)(R⁷)(R⁸) can be attached to the phenyl ring carbon that is meta or para with respect to the phenyl carbon that is attached to the sulfonyl sulfur in Formula I. Variables R⁶. R⁷. and R⁸

In some embodiments, R⁶ can be -OH or -OCH₃. In certain embodiments, R⁶ can be -OH.

In some embodiments, R⁶ can be CH₃ or ethyl. In certain embodiments, R⁶ can be -CH₃.

In certain embodiments, R⁶ can be -OH or -CH₃.

In some embodiments, R⁷ can be -CH₃, -CH₂X, -CHX₂, or -CF₃.

In some embodiments, R⁷ can be -CH₂X, -CHX₂, or -CF₃. In some embodiments, R⁷ can be -CF₃.

In some embodiments, R⁷ can be -CH₂X, Or-CHX₂.

In some embodiments, R⁷ can be -CH₃.

In certain embodiments, each instance of X can be, independently, -F or -Cl, e.g., -F. In some embodiments, R⁷ can be phenyl, wherein said phenyl is unsubstituted or substituted with one or two substituents R^7sl independently selected from halo, -CH₃, ethyl, -CF₃, -OH and -OCH₃. In certain embodiments, R⁷ can be unsubstituted phenyl.

In some embodiments, R⁸ can be -C(O)-NH₂, -C(O)-NH-(d_₃ alkyl), or -C(O)-N(C_L3 alkyl)₂.

In some embodiments, R⁸ can be -C(O)-NH₂.

In some embodiments, R⁸ can be -C(O)-NH-(Ci_₃ alkyl), or -C(O)-N(Ci_₃ alkyl)₂, e.g., -C(O)-NH-(CH₃), or -C(O)-N(CH₃)₂.

In some embodiments, R⁸ can be -NH-C(O)-(Ci_₃ alkyl) or

-N(C_L3 alkyl)-C(O)-(Ci_₃ alkyl). In certain embodiments, R⁸ can be -NH-C(O)-(C_L3 alkyl), e.g., -NH-C(O)-(CH₃).

In some embodiments, R⁸ can be 5- to 6-membered heteroaryl containing 1-4 (e.g., 2-3, 2-4, 3-4, 1-3, 1-2, 1, 2, 3, or 4) ring heteroatoms independently selected from O, N, N(R^2sl) and S, in which R^8sl is -H, -CH₃ or ethyl, and in which said heteroaryl is unsubstituted or substituted with one or two substituents R^8s2 independently selected from halo, -CH₃, ethyl, -CF₃, -OH and -OCH₃.

In certain embodiments, each instance of R^8sl can be, independently, -H or -CH₃ (e.g., -H). In certain embodiments, each instance of R^8s2 can be, independently, -CH₃, ethyl, or -CF₃ (e.g., -CH₃ or ethyl; e.g., -CH₃).

In certain embodiments, the 5- to 6-membered heteroaryl can contain 1-3 (e.g., 2- 3, 1, 2, or 3) ring heteroatoms.

In certain embodiments, the 5- to 6-membered heteroaryl can contain 3 or 4 ring heteroatoms. In embodiments, the 3 or 4 ring heteroatoms can be independently selected from O, N, and N(R^8sl). In other embodiments, each of the 3 or 4 ring heteroatoms can be independently selected from N and N(R^8sl). For example, one of the 3 or 4 ring heteroatoms can be O or N(R^8sl), and the others can each be N.

In embodiments, the 5- to 6-membered heteroaryl is bonded to the quaternary carbon via a ring carbon atom and not via one of the aforementioned ring heteroatoms.

In certain embodiments, R⁸ can be 5- membered heteroaryl containing 1-4 (e.g., 2-3, 2-4, 3-4, 1-3, 1-2, 1, 2, 3, or 4) ring heteroatoms independently selected from O, N, N(R^8sl) and S, in which R^8sl can be as defined anywhere herein; and in which said heteroaryl can be unsubstituted or substituted with one or two substituents R^8s2, in which each instance of R^8s2 can be as defined anywhere herein.

Embodiments can include one or more of the following features. R^8sl can be -H.

R^8s2 can be -CH₃ or ethyl; e.g., -CH₃.

In certain embodiments, the 5- membered heteroaryl can contain 1-3 (e.g., 2-3, 1, 2, or 3) ring heteroatoms.

The 5- membered heteroaryl can contain 3 ring heteroatoms. In certain embodiments, each of the 3 ring heteroatoms can be independently selected from O, N, and N(R^8sl). In certain embodiments, each of the 3 ring heteroatoms can be independently selected from N and N(R^8sl).

In embodiments, one of the 3 ring heteroatoms can be N(R^8sl), and the others can be N. For example, the 5- membered heteroaryl can be l,2,4-triazol-3-yl (unsubstituted or substituted with, e.g., -CH₃). The 5- membered heteroaryl can contain 4 ring heteroatoms. For example, the 5- membered heteroaryl can be tetrazol-5-yl.

In certain embodiments, R⁸ can be -C(O)-NH₂; -C(O)-NH-(CH₃); -C(O)-N(CH₃)₂; -NH-C(O)-(CH₃); or 5-membered heteroaryl containing 1-4 (e.g., 1-3) ring heteroatoms independently selected from O, N, N(R^8sl) and S, wherein said heteroaryl is unsubstituted or substituted with one or two substituents R^8s2 independently selected from halo, -CH₃, ethyl, -CF₃, -OH and -OCH₃ (e.g., l,2,4-triazol-3-yl or 1,2,4- oxadiazol-3-yl, each of which is unsubstituted or substituted with one or two substituents R^8s2 independently selected from halo, -CH₃, ethyl, -CF₃, -OH and -OCH₃).

In some embodiments, the carbon atom attached to R , R , and R can have the R- configuration (referred to herein as "the i?-CR⁶R⁷R⁸ configuration"). In some embodiments, the carbon atom attached to R , R , and R can have the ^-configuration (referred to herein as "the ,S-CR⁶R⁷R⁸ configuration").

Variable R⁹

In some embodiments, R⁹ can be -H, halo (e.g., chloro or bromo), or -CH₃.

In some embodiments, R⁹ can be -H.

In some embodiments, R⁹ can be absent. [1] In some embodiments:

R⁶ is -OH, -CH₃, or ethyl; and

R⁷ is -CF₃, -CH3, or phenyl, wherein said phenyl is unsubstituted or substituted with one or two substituents R^7sl independently selected from halo, -CH₃, ethyl, -CF₃, -OH and -OCH₃.

Embodiments in which R⁶ is -OH, -CH₃, or ethyl; and R⁷ is -CF₃, -CH₃, or phenyl that is unsubstituted or substituted with one or two substituents R^7sl independently selected from halo, -CH₃, ethyl, -CF₃, -OH and -OCH₃ can also include any one or more of the features described herein, including (but not limited) to those delineated below.

R⁶ can be -OH.

R⁷ can be -CF₃.

A can be 5- to 6-membered heteroaryl containing 1-3 (e.g., 1-2, 2-3, 1, 2, or 3) ring heteroatoms independently selected from O, N, N(R^al) and S, and in which the atom bonded to the sulfonyl sulfur is carbon. R^al can be -H or -CH₃. The 5- to 6-membered heteroaryl can contain 1 or 2 ring heteroatoms. The ring heteroatoms can be independently selected from N, N(R^al) and S.

A can be 5-membered heteroaryl containing 1-3 (e.g., 1 or 2) ring heteroatoms independently selected from O, N, N(R^al) and S, and in which the atom bonded to the sulfonyl sulfur is carbon, and in which R^al can be as defined anywhere herein. E.g., A can have formula (A-I):

(A-I) in which the carbon atom shown as C in formula (A-I) represents the carbon that is bonded to the sulfonyl sulfur in Formula I; and in which A¹, A², A³, A⁴, and the dotted lines between A¹ and A⁴ and A³ and A⁴ are all defined according to the definitions under (i) below or are all defined according to the definitions under (ii) below: (i): A¹ is singly bonded to A⁴, and A³ is doubly bonded to A⁴;

(ii):

A¹ is doubly bonded to A⁴, and A³ is singly bonded to A⁴;

In certain embodiments, the definitions set forth under (i) {supra) apply, and A can have formula (A-2):

in which the carbon atom shown as C in formula (A-2) represents the carbon that is bonded to the sulfonyl sulfur in Formula I; and A¹ is O, S, or NR^al; one of A², A³, and A⁴ is C-C(R⁶)(R⁷)(R⁸), one of A², A³ and A⁴ is C-R⁹, and one of A², A³, and A⁴ is C-H or N. Each of A¹, A², A³, and A⁴ can be as defined anywhere herein in (e.g., A¹ can be S, A⁴ can be C-C(R⁶)(R⁷)(R⁸), and A² can be C-H or N).

A can be 5-membered heteroaryl having formula (A-3) as described herein. A can be phenyl. In certain embodiments, -C(R⁶)(R⁷)(R⁸) can be attached to the phenyl ring carbon that is meta ox para with respect to the phenyl carbon that is attached to the sulfonyl sulfur in Formula I. R⁸ can be -C(O)-NH₂, -C(O)-NH-(CH₃), -C(O)-N(CH₃)₂, -NH-C(O)-(CH₃), or

5-membered heteroaryl containing 1-3 ring heteroatoms independently selected from O, N, N(R^8sl) and S, wherein said heteroaryl is unsubstituted or substituted with one or two substituents R^8s2 independently selected from halo, -CH₃, ethyl, -CF₃, -OH and -OCH₃. In certain embodiments, R⁸ can be -C(O)-NH₂. In other embodiments, R⁸ can be l,2,4-triazol-3-yl or l,2,4-oxadiazol-3-yl, each of which is unsubstituted or substituted with one or two substituents R^8s2 independently selected from halo, -CH₃, ethyl, -CF₃, -OH and -OCH₃ (e.g., -CH₃).

The carbon atom attached to R⁴ and R⁵ can have the ^-configuration.

The carbon atom attached to R , R , and R can have the ^-configuration.

R⁹ can be 5 --HH oorr aabbsseenntt..

One of R and R is H, and the other is -CH₃ (e.g., R can be H, and R can be -CH₃).

R¹ and R² can be, independently, as defined as defined anywhere herein. R¹ can be -CF₃.

R² can be -F.

R¹ can be -CF₃, and R² can be -F. R³ can be -H. R¹ can be -CF₃, R² can be -F, and R³ can be -H.

[2] In some embodiments: R⁶ is -OH; and R⁷ is -CF₃.

Embodiments in which R⁶ is -OH, and R⁷ is -CF₃ can also include any one or more of the features described herein, including (but not limited to) those delineated below.

A can be 5- to 6-membered heteroaryl containing 1-3 (e.g., 1-2, 2-3, 1, 2, or 3) ring heteroatoms independently selected from O, N, N(R^al) and S, and in which the atom bonded to the sulfonyl sulfur is carbon. R^al can be -H or -CH₃. The 5- to 6-membered heteroaryl can contain 1 or 2 ring heteroatoms. The ring heteroatoms can be independently selected from N, N(R^al) and S. A can be 5-membered heteroaryl containing 1-3 (e.g., 1 or 2) ring heteroatoms independently selected from O, N, N(R^al) and S, and in which the atom bonded to the sulfonyl sulfur is carbon, and in which R^al can be as defined anywhere herein. E.g., A can have formula (A-I):

(A-I) in which the carbon atom shown as C in formula (A-I) represents the carbon that is bonded to the sulfonyl sulfur in Formula I; and in which A¹, A², A³, A⁴, and the dotted lines between A¹ and A⁴ and A³ and A⁴ are all defined according to the definitions under (i) below or are all defined according to the definitions under (ii) below:

(i):

A¹ is singly bonded to A⁴, and A³ is doubly bonded to A⁴; AMs O₅ S₅ Or NR"¹; and one of A², A³,and A⁴ is C-C(R⁶)(R⁷)(R⁸), one of A², A³ and A⁴ is C-R⁹, and one of A², A³, and A⁴ is C-H or N; or

(ii): A¹ is doubly bonded to A⁴, and A³ is singly bonded to A⁴;

in which the carbon atom shown as C in formula (A-2) represents the carbon that is bonded to the sulfonyl sulfur in Formula I; A¹ is O, S, or NR^al; and one of A², A³,and A⁴ is C-C(R⁶)(R⁷)(R⁸), one of A², A³ and A⁴ is C-R⁹, and one of A², A³, and A⁴ is C-H or N. Each of A¹, A², A³, and A⁴ can be as defined anywhere herein in (e.g., A¹ can be S, A⁴ can be C-C(R⁶XR⁷XR⁸), and A² can be C-H or N).

A can be 5-membered heteroaryl having formula (A-3) as described herein.

A can be phenyl. In certain embodiments, -C(R⁶)(R⁷)(R⁸) can be attached to the phenyl ring carbon that is meta ox para with respect to the phenyl carbon that is attached to the sulfonyl sulfur in Formula I. R⁸ can be -C(O)-NH₂, -C(O)-NH-(CH₃), -C(O)-N(CH₃)₂, -NH-C(O)-(CH₃), or

5-membered heteroaryl containing 1-3 ring heteroatoms independently selected from O,

N, N(R , 8s^sl ) and S, wherein said heteroaryl is unsubstituted or substituted with one or two substituents R ,8s2 independently selected from halo, -CH₃, ethyl, -CF₃, -OH and -OCH₃.

In certain embodiments, R⁸ can be -C(O)-NH₂. In other embodiments, R⁸ can be l,2,4-triazol-3-yl or l,2,4-oxadiazol-3-yl, each of which is unsubstituted or substituted with one or two substituents R^8s2 independently selected from halo, -CH₃, ethyl, -CF₃, -OH and -OCH₃ (e.g., -CH₃).

The carbon atom attached to R⁴ and R⁵ can have the ^-configuration. The carbon atom attached to R⁶, R⁷, and R⁸ can have the ^-configuration. R⁹ can be -H or absent.

One of R⁴ and R⁵ is H, and the other is -CH₃ (e.g., R⁴ can be H, and R⁵ can be -CH₃).

R¹ and R² can be, independently, as defined as defined anywhere herein. R¹ can be -CF₃. R² can be -F.

R¹ can be -CF₃, and R² can be -F.

R³ can be -H.

R¹ canbe -CF₃, R² canbe -F, and R³ can be -H. [3] In some embodiments: R⁶ is -OH; R⁷ is -CF₃; and

R⁸ is -C(O)-NH₂, -C(O)-NH-(CL₃ alkyl), or -C(O)-N(CL₃ alkyl)₂ (e.g., R⁸ is -C(O)-NH₂).

Embodiments in which R⁶ is -OH, R⁷ is -CF₃, and R⁸ is -C(O)-NH₂, -C(O)-NH-(C_L3 alkyl), or -C(O)-N(C_L3 alkyl)₂ (e.g., R⁸ is -C(O)-NH₂) can also include any one or more of the features described herein, including (but not limited to) those delineated below.

(i):

(ii): A¹ is doubly bonded to A⁴, and A³ is singly bonded to A⁴;

in which the carbon atom shown as C in formula (A-2) represents the carbon that is bonded to the sulfonyl sulfur in Formula I; A¹ is O, S, or NR^al; and one of A², A³,and A⁴ is C-C(R⁶)(R⁷)(R⁸), one of A², A³ and A⁴ is C-R⁹, and one of A², A³, and A⁴ is C-H or N. Each of A¹, A², A³, and A⁴ can be as defined anywhere herein in (e.g., A¹ can be S, A⁴ can be C-C(R⁶)(R⁷)(R⁸), and A² can be C-H or N).

A can be 5-membered heteroaryl having formula (A-3) as described herein. A can be phenyl. In certain embodiments, -C(R⁶)(R⁷)(R⁸) can be attached to the phenyl ring carbon that is meta ox para with respect to the phenyl carbon that is attached to the sulfonyl sulfur in Formula I.

The carbon atom attached to R⁴ and R⁵ can have the ^-configuration.

The carbon atom attached to R⁶, R⁷, and R⁸ can have the ^-configuration. R⁹ can be -H or absent.

R¹ and R² can be, independently, as defined as defined anywhere herein.

R¹ can be -CF₃.

R can be -F. R¹ can be -CF₃, and R² can be -F.

R³ can be -H.

R¹ can be -CF₃, R² can be -F, and R³ can be -H.

[4] In some embodiments:

R⁶ is -OH; R⁷ is -CF₃; and one, more than one, or all of the following features is(are) present:

• R⁸ is -C(O)-NH₂.

• A is a 5-membered heteroaryl, which has formula (A-2):

o (A-2)

• in which the carbon atom shown as C in formula (A-2) represents the carbon that is bonded to the sulfonyl sulfur in Formula I; A¹ is O, S, or NR^al; and one of A², A³,and A⁴ is C-C(R⁶)(R⁷)(R⁸), one of A², A³ and A⁴ is C-R⁹, and one of A², A³, and A⁴ is C-H or N. Each of A¹, A², A³, and A⁴ can be as defined anywhere herein in (e.g., A¹ can be S, A⁴ can be C- C(R⁶)(R⁷)(R⁸), and A² can be C-H or N; e.g., A¹ can be S, A⁴ can be C- C(R⁶)(R⁷)(R⁸), and A² can be C-H).

• The carbon atom attached to R⁴ and R⁵ has the ^-configuration. • The carbon atom attached to R , R , and R has the ^-configuration.

• R⁹ is -H or absent.

• R⁴ is H, and R⁵ is -CH₃.

• R¹ is -CF₃.

• R² is -F. • R³ is -H. In some embodiments, the chemical entity E can have formula II (i.e., in which A in formula I is 2-thienyl):

in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ can be as defined anywhere herein.

Embodiments of formula II can include any one or more of the features described herein, including but not limited to those delineated below.

R⁶ can be -OH.

R⁷ can be -CF₃.

R⁸ can be -C(O)-NH₂.

R⁶ can be -OH, and R⁷ can be -CF₃.

R⁶ can be -OH, R⁷ can be -CF₃, and R⁸ can be -C(O)-NH₂.

-CR⁶R⁷R⁸ can be attached to C₅ of the thienyl ring.

The carbon atom attached to R⁴ and R⁵ can have the ^-configuration.

The carbon atom attached to R , R , and R can have the ^-configuration.

R⁹ can be -H.

R⁴ can be H, and R⁵ can be -CH₃.

R¹ and R² can be, independently, as defined as defined anywhere herein.

R¹ can be -CF₃.

R² can be -F.

R³ can be -H.

R¹ can be -CF₃, and R² can be -F.

R¹ can be -CF₃, and R² can be -F, and R³ can be -H.

The chemical entity E can be (2R)-3,3,3-trifluoro-2-[5-({(2R)-4-[4-fluoro-2- (trifluoromethyl)phenyl]-2-methylpiperazin- 1 -yl} sulfonyl)thiophen-2-yl]-2- hydroxypropanamide or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide thereof; (e.g., or a pharmaceutically acceptable salt thereof).

It is understood that the actual electronic structure of some chemical entities cannot be adequately represented by only one canonical form (i.e. Lewis structure).

While not wishing to be bound by theory, the actual structure can instead be some hybrid or weighted average of two or more canonical forms, known collectively as resonance forms or structures. Resonance structures are not discrete chemical entities and exist only on paper. They differ from one another only in the placement or "localization" of the bonding and nonbonding electrons for a particular chemical entity. It can be possible for one resonance structure to contribute to a greater extent to the hybrid than the others. Thus, the written and graphical descriptions of the embodiments of the present invention are made in terms of what the art recognizes as the predominant resonance form for a particular species. The compounds described herein can be synthesized according to methods described herein (or variations thereof) and/or conventional, organic chemical synthesis methods from commercially available starting materials and reagents or from starting materials and reagents that can be prepared according to conventional organic chemical synthesis methods. It is also possible to make use of variants of any of the aforementioned process steps. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the formulae herein will be evident to those skilled in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.

Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. C. Larock, Comprehensive Organic Transformations, 2d.ed., Wiley- VCH Publishers (1999); P. G. M. Wuts and T. W. Greene, Protective Groups in Organic Synthesis, 4th Ed., John Wiley and Sons (2007); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents or Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof. The compounds described herein can be separated from a reaction mixture and further purified by a method such as column chromatography, high- performance liquid chromatography (HPLC), or recrystallization.

The compounds of this invention can be readily prepared according to the following schemes from commercially available starting materials or starting materials which can be prepared using literature procedures. The schemes show the preparation of representative compounds of this invention. It is also possible to make use of variants of these process steps, which in themselves are known to and well within the preparatory skill of the skilled artisan. In the following reaction schemes, R¹ to R⁹, and A are selected from groups defined above (unless otherwise indicated).

In general, the compounds described herein can be prepared according to Scheme

I below.

Scheme I

manipulation

steps

Referring to Scheme I, piperazine 1 (e.g., (R)-2-methyl-piperazine, which can be obtained commercially from Aldrich Chemical Company or synthesized according the procedure described in Xiang, J. et al, Journal Medicinal Chemistry, 2008, 57(14), 4068- 4071) can be coupled to halobenzene 2 (Hal¹ can be Br or I, typically Br) at elevated temperatures and in the presence of a transition metal catalyst (typically a palladium- based catalyst, e.g., Pd₂(dba)₃) to provide N-phenyl piperazine 3. Reaction of intermediate 3 with sulfonyl halide 4 (Hal² is typically chloro; Z is halo, e.g., bromo; or Z is hydrogen) results in the formation sulfonamide 5. In some embodiments, sulfonyl halide 4 can be synthesized by reacting the corresponding thiol with a halogenating reagent, e.g., SO₂CI₂/KNO₃, in a polar aprotic solvent such as acetonitrile. In some embodiments, the process of converting 3 to 5 can also include one or more steps needed to introduce certain R² substituents (e.g., when R² is 5-membered heteroaryl). Metallation of 5 (e.g., by metal-halogen exchange when Z is halo; or by deprotonation with a strong base, e.g., LDA or n-BuLi, when Z is hydrogen) followed by addition of a carbon electrophile (e.g., a ketone, such as 3,3,3-trifluoropyruvate) provides 6, in which E is a substituent precursor (e.g., a tertiary alcohol) to -CR⁶R⁷R⁸ in the final compound 7. In some embodiments, the process of converting 6 to 7 can also include one or more steps needed to introduce certain R² substituents (e.g., when R² is -C(O)NH₂ or 5- membered heteroaryl).

In some embodiments, compounds in which R⁶ is -OH, R⁷ is CF3, and R⁸ is CONH₂, can be prepared according to Scheme II. Scheme II

chiral column separation

11

Referring to Scheme II above, metallation of 5 (cf: Scheme I), followed by addition of 3,3,3-trifluoropyruvate results in the formation of methyl ester 8, which in turn can be transformed into the corresponding amide 9 using, e.g., NH₃ (g). The aforementioned sequence of reactions typically provides a mixture of diastereoisomers 10 and 11, which can be separated using, e.g., chiral column chromatography.

As mentioned above, the process of converting 6 to 7 in Scheme I can also include one or more steps needed to introduce certain R² substituents. By way of example, compounds in which R² is -CN can be partially hydrolyzed to provide amide 13 or can undergo an intermolecular dipolar addition reaction to produce tetrazole 14 (see Scheme III). Scheme III

14

In some embodiments, compounds in which R⁸ is -NH-C(O)-(Ci_3 alkyl) can be prepared according to Scheme IV, which shows for illustrative purposes only the synthesis of compounds in which R⁸ is -NH-C(O)-(CHs).

Scheme IV

15

Referring to Scheme IV, metallation of 5 (cf: Scheme I), followed by addition of a ketone provides a tertiary alcohol intermediate (not shown), which upon exposure to acetonitrile and aqueous sulfuric acid results in the conversion of the hydroxyl group in the tertiary alcohol intermediate to a -NH-C(O)-(CHs) group (see compound 15 in Scheme IV).

In some embodiments, compounds in which R⁸ is 5-membered heteroaryl can be prepared according to Scheme V, which shows for illustrative purposes only the synthesis of compounds in which R⁶ is -OH, R⁷ is CF₃, and R⁸ is 5-membered heteroaryl from compounds in which R⁶ is -OH, R⁷ is CF₃, and R⁸ is CONH₂. Scheme V

NH₂OHHCI, HOAc, dioxane

20

Referring to Scheme V, compound 9 (c/v Scheme I) can be converted to compound 18 using DMF dimethyl acetal. Exposure of compound 18 to hydrazine results in the formation of triazine 19, while reaction of compound 18 with hydroxylamine affords oxadiazole 20. In certain embodiments, the tertiary hydroxyl group in 9 can be protected, e.g., as an ether, e.g., as a silyl ether.

Similar chemistries to those shown in Scheme V can be used to synthesize compounds in which R² is triazinyl or oxadiazolyl. In certain embodiments, compounds in which R² is oxadiazolyl can be prepared according to Scheme VI.

Scheme VI

21 22

1 SOCI₂, DCE

2 NH₂NH₂

23

24 n-BuLι CF₃COCO₂Me

25 26

Referring to Scheme VI, nitrile 21 (Hal is typically -Br) can be hydrolyzed under basic conditions (e.g., 3N NaOH in methanol and water) to carboxylic acid 22, which in turn can be converted to the corresponding hydrazide 23 under conventional conditions. Formation of the oxadiazole ring in 24 can be achieved upon reacting hydrozide 23 with an ortho formate, such as triethylorthoformate, in the presence of a catalytic amount of acid, e.g., PSA. Compounds 25 and 26 can be obtained using the chemistries described in the preceding schemes.

In some embodiments, compounds in which R⁶ is -CH3, R⁷ is -CH₃, and R⁸ is - CONH₂ can be prepared according to Scheme VII. Scheme VII

LiOH, THF/H₂O

30 29

Referring to Scheme VII above, compound 5 (cf. Scheme I) can be coupled with silyl enol ether 27 to form ester 28, which is hydrolyzed to the carboxylic acid 29. Conversion of 29 to the amide 30 can be achieved, e.g., using CDI and NH3.

The compounds of this invention may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of these compounds are expressly included in the present invention.

In some embodiments, a chemical entity E can have the i?-CR⁴CR⁵ configuration and the i?-CR⁶R⁷R⁸ configuration ("a i?-CR⁴CR⁵, i?-CR⁶R⁷R⁸ stereoisomer"). In other embodiments, a chemical entity E can have the i?-CR⁴CR⁵ configuration and the S- CR⁶R⁷R⁸ configuration ("a i?-CR⁴CR⁵, ,S-CR⁶R⁷R⁸ stereoisomer").

In certain embodiments, a i?-CR⁴CR⁵, i?-CR⁶R⁷R⁸ stereoisomer can be present as a mixture with its corresponding i?-CR⁴CR⁵, S-CR⁶R⁷R⁸ stereoisomer. In embodiments, the mixture can contain greater than about 50% of the i?-CR⁴CR⁵, i?-CR⁶R⁷R⁸ stereoisomer (e.g., about 60%, about 70%, about 80%, about 90%, about 95%, about 99%). In these embodiments, the mixture can further include one or more other substances (e.g., one or more pharmaceutically acceptable carriers, biological fluids, cellular culture, or any combination thereof). In still other embodiments, the i?-CR⁴CR⁵, i?-CR⁶R⁷R⁸ stereoisomer can be substantially free of its i?-CR⁴CR⁵, ,S-CR⁶R⁷R⁸ stereoisomer. The i?-CR⁴CR⁵, i?-CR⁶R⁷R⁸ stereoisomer can be in substantially pure form.

The compounds of this invention may also contain linkages (e.g., carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds) wherein bond rotation is restricted about that particular linkage, e.g. restriction resulting from the presence of a ring or double bond. Accordingly, all cis/trans and E/Z isomers and rotational isomers are expressly included in the present invention. The compounds of this invention may also be represented in multiple tautomeric forms, in such instances, the invention expressly includes all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented (e.g., alkylation of a ring system may result in alkylation at multiple sites, the invention expressly includes all such reaction products). All such isomeric forms of such compounds are expressly included in the present invention.

The compounds of this invention include the compounds themselves, as well as their salts and their prodrugs, if applicable. A salt, for example, can be formed between an anion and a positively charged substituent (e.g., amino) on a compound described herein. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate. Likewise, a salt can also be formed between a cation and a negatively charged substituent (e.g., carboxylate) on a compound described herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion. Examples of prodrugs include Ci_6 alkyl esters of carboxylic acid groups, which, upon administration to a subject, are capable of providing active compounds.

Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(alkyl)₄ salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization. Salt forms of the compounds of any of the formulae herein can be amino acid salts of carboxy groups (e.g. L-arginine, -lysine, -histidine salts).

The term "pharmaceutically acceptable carrier" refers to a carrier that may be administered to a subject (e.g., a patient), together with a chemical entity E as defined anywhere herein, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the chemical entity E.

Pharmaceutical compositions described herein can include any one or more of the following: ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein. In general, the chemical entities described herein can be used for treating (e.g., controlling, relieving, ameliorating, alleviating, or slowing the progression of) or methods for preventing (e.g., delaying the onset of or reducing the risk of developing) a disease or condition that is mediated by excess (e.g., abnormally high) levels or uncontrolled (e.g., resulting in abnormally high) levels of Cortisol and/or other corticosteroids (e.g., 11 β- hydroxy steroids. While not wishing to be bound by any theory, it is believed that the chemical entities described herein can reduce the levels of Cortisol and other corticosteroids (e.g., llβ-hydroxysteroids) by inhibiting the reductase activity of llβ- HSDl. The diseases, disorders, conditions or symptoms mediated by excess or uncontrolled amounts of Cortisol and/or other corticosteroids can include diabetes (e.g., type 1 or type 2 diabetes), Syndrome X, hyperglycemia, low glucose tolerance, insulin resistance, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, hypertension, coronary heart disease, stroke, peripheral vascular disease, Cushing's syndrome, glaucoma, osteoperosis, hyperinsulinemia, tuberculosis, psoriasis,cognitive disorders and dementia (e.g., impairment associated with aging and of neuronal dysfunction, e.g., Alzheimer's disease), depression, viral diseases, inflammatory disorders, immune disorders. In some embodiments, the diseases, disorders conditions or symptoms can further include those where insulin resistance is a component. In other embodiments, the chemical entities described herein can be used for promoting wound healing.

In some embodiments, the chemical entities described herein can be coadministered with one or more other threapeutic agents. In certain embodiments, the additional agents may be administered separately, as part of a multiple dose regimen, from the chemical entities described herein (e.g., sequentially, e.g., on different overlapping schedules with the administration of one or more compounds of formula (I)). Alternatively, these agents may be part of a single dosage form, mixed together with the chemical entities described herein in a single composition. In still another embodiment, these agents can be given as a separate dose that is administered at about the same time that one or more chemical entities described herein are administered (e.g., simultaneously with the administration of one or more chemical entities described herein). When the compositions described herein include a combination of a chemical entity E as defined anywhere herein and one or more additional therapeutic or prophylactic agents, both the chemical entity and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.

Other therapeutic agents can include DP-IV inhibitors; insulin sensitizers (e.g., (i) PPAR agonists and (ii) biguanides); insulin and insulin analogues and mimetics; sulfonylureas and other insulin secretagogues; prandial glucose regulators, alpha.- glucosidase inhibitors; glucagon receptor antagonists; GLP-I, GLP-I mimetics, and GLP-I receptor agonists; GIP₅GIP mimetics, and GIP receptor agonists; PACAP,

PACAP mimetics, and PACAP receptor 3 agonists; cholesterol lowering agents (e.g., (i) HMG-CoA reductase inhibitors, (ii) sequestrants, (iii) nicotinyl alcohol, nicotinic acid and salts thereof, (iv) PPAR. alpha, agonists, (v) PPAR. alpha./, gamma, dual agonists, (vi) inhibitors of cholesterol absorption, (vii) acyl CoAxholesterol acyltransferase inhibitors, and (viii) anti-oxidants; PPAR.delta. agonists); antiobesity compounds (e.g., sibutramine and orlisat); an ileal bile acid transporter inhibitor; anti-inflammatory agents excluding glucocorticoids (e.g., aspirin); protein tyrosine phosphatase- IB (PTP-IB) inhibitors; agents that suppress hepatic glucose output (e.g., metformin); agents designed to reduce the absorption of glusoce from the intestine (e.g., acarbose); agents designed to treat the complications of prolonged hyperglycemia (e.g., aldose reductase inhibitors); antidiabetic agents (e.g., glusoce phosphatase inhibitors, glucose -6-phosphatase inhibitors, glucagon receptor antagonists, glucose kinase activators, glycogen phosphorylase inhibitors, fructose 1,6 bisphosphatase inhibitors, glutamine:fructose-6-phosphate amidotransferase inhibitors); antihypertensive agents (e.g., β blockers (e.g., atenolol, inderal), ACE inhibitors (e.g., lisinopril), calcium agonists (e.g., nifedipine), angiotensin receptor antagonists (e.g., candesartan), a agonists and diuretic agents (e.g., furosemide, benzthiazide)); and haemostasis modulators (e.g., antithrombotics, activators of fibrinolysis and antiplatelet agents (e.g., clopidogrel, aspirin), thrombin antogonists, factor Xa inhibitors, factor Vila inhibitors, anticoagulants (e.g., heparin and low molecular weight analogues, hirudin), warfarin). The chemical entities and compositions described herein can, for example, be administered orally, parenterally (e.g., subcutaneously, intracutaneously, intravenously, intramuscularly, intraarticularly, intraarterially, intrasynovially, intrasternally, intrathecally, intralesionally and by intracranial injection or infusion techniques), by inhalation spray, topically, rectally, nasally, buccally, vaginally, via an implanted reservoir, by injection, subdermally, intraperitoneally, transmucosally, or in an ophthalmic preparation, with a dosage ranging from about 0.01 mg/Kg to about 1000 mg/Kg, (e.g., from about 0.01 to about 100 mg/kg, from about 0.1 to about 100 mg/Kg, from about 1 to about 100 mg/Kg, from about 1 to about 10 mg/kg) every 4 to 120 hours, or according to the requirements of the particular drug. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep. 50, 219 (1966). Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970). In certain embodiments, the compositions are administered by oral administration or administration by injection. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations contain from about 20% to about 80% active compound.

Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, condition or symptoms, and the judgment of the treating physician.

Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary.

Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms. The compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.

The compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3- butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

The compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

The compositions of this invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

In some embodiments, topical administration of the compounds and compositions described herein may be presented in the form of an aerosol, a semi-solid pharmaceutical composition, a powder, or a solution. By the term "a semi-solid composition" is meant an ointment, cream, salve, jelly, or other pharmaceutical composition of substantially similar consistency suitable for application to the skin. Examples of semi-solid compositions are given in Chapter 17 of The Theory and Practice of Industrial Pharmacy, Lachman, Lieberman and Kanig, published by Lea and Febiger (1970) and in Remington's Pharmaceutical Sciences, 21st Edition (2005) published by Mack Publishing Company, which is incorporated herein by reference in its entirety.

Topical administration of the compositions of this invention is useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation.

Topically-transdermal patches are also included in this invention. Also within the invention is a patch to deliver active chemotherapeutic combinations herein. A patch includes a material layer (e.g., polymeric, cloth, gauze, bandage) and the compound of the formulae herein as delineated herein. One side of the material layer can have a protective layer adhered to it to resist passage of the compounds or compositions. The patch can additionally include an adhesive to hold the patch in place on a subject. An adhesive is a composition, including those of either natural or synthetic origin, that when contacted with the skin of a subject, temporarily adheres to the skin. It can be water resistant. The adhesive can be placed on the patch to hold it in contact with the skin of the subject for an extended period of time. The adhesive can be made of a tackiness, or adhesive strength, such that it holds the device in place subject to incidental contact, however, upon an affirmative act (e.g., ripping, peeling, or other intentional removal) the adhesive gives way to the external pressure placed on the device or the adhesive itself, and allows for breaking of the adhesion contact. The adhesive can be pressure sensitive, that is, it can allow for positioning of the adhesive (and the device to be adhered to the skin) against the skin by the application of pressure (e.g., pushing, rubbing,) on the adhesive or device.

The compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. A composition having a chemical entity as defined anywhere herein and an additional agent (e.g., a therapeutic agent) can be administered using any of the routes of administration described herein. In some embodiments, a composition having the compound of the formulae herein and an additional agent (e.g., a therapeutic agent) can be administered using an implantable device. Implantable devices and related technology are known in the art and are useful as delivery systems where a continuous, or timed- release delivery of compounds or compositions delineated herein is desired. Additionally, the implantable device delivery system is useful for targeting specific points of compound or composition delivery (e.g., localized sites, organs). Negrin et al, Biomaterials, 22(6): 563 (2001). Timed-release technology involving alternate delivery methods can also be used in this invention. For example, timed-release formulations based on polymer technologies, sustained-release techniques and encapsulation techniques (e.g., polymeric, liposomal) can also be used for delivery of the compounds and compositions delineated herein. The invention will be further described in the following examples. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.

EXAMPLES The title compounds of Examples 1.1, 1.2, and 1.3 were prepared as shown in

Scheme 1 below. Detailed synthesis procedures are provided below.

Scheme 1

Example 1.1

3,3,3-trifluoro-2-r5-({(2R)-4-r4-fluoro-2-(trifluoromethyl)phenyll-2-methylpiperazin- l-yl}sulfonyl)-2-thienyll-2-hvdroxypropanamide Step IA: A mixture of (R)-2-methyl-piperazine (25.0 g, 250 mmol), 2-bromo 5- fluoro benzotrifluoride (55.1 g, 227 mmol), tris(dibenzylidineacetone)dipalldium (0) (2.08g, 2.27 mmol), rac-2,2'-bis(diphenylphosphino)-l,r-binaphthyl (4.24 g, 6.81 mmol) and sodium tert-butoxide (27.3 g, 280 mmol) was mixed and purged with N₂. Anhydrous toluene (500 mL) was added and purged with N₂ again. The resulting mixture was heated in an oil bath at 105 ⁰C under N₂ for 3.5 hours. After cooling, the reaction mixture was concentrated and then filtered through a pad of Celite, washed with Et₂O. The organic layer was concentrated, diluted with Et₂O (500 mL), filtered through a pad of Celite again, and washed with IN aq. HCl (2 x 150 mL). The aqueous layer was basified with NaOH at 0 ⁰C (pH = -10) and then was extracted with Et₂O (3 x 200 mL). The combined organic layer was dried over MgSO₄ and concentrated under vacuum to give (3i?)-l-[4- fluoro-2-(trifluoromethyl)phenyl]-3-methylpiperazine as a brown oil (58.5 g, 98%), which was used without further purification.

Step IB: To a solution of 5-bromothiophene-2-sulfonyl chloride (26.2 g, 100 mmol) and (3R)-l-(4-fluoro-2-(trifluoromethyl)phenyl)-3-methylpiperazine (27.6 g, lOOmmol) in DCM (200 ml) was added Et₃N (41.8 ml, 300 mmol) at room temp. The reaction mixture was stirred at room temperature until completion of the reaction (about 6 hours) and then washed with aq. NaHCO₃. The basic washes were back extracted with dichloromethane (DCM). The combined organic layers were washed with brine and dried over Na₂SO₄. The crude product was purified on a SiO₂ column using hexanes/DCM as the eluent to give (R)-l-(5-bromothiophen-2-ylsulfonyl)-4-(4-fluoro-2- (trifluoromethyl)phenyl)-2-methylpiperazine as a white solid (38 g, 78 mmol, 78 % yield).

Step 1C: To a solution of (R)-l-(5-bromothiophen-2-ylsulfonyl)-4-(4-fluoro-2- (trifluoromethyl)phenyl)-2-methylpiperazine (28.1 g, 57.7 mmol) in anhydrous THF (200 ml) was added Butyllithium (28.8 ml, 57.7 mmol) at -78⁰C. The reaction mixture was Stirred under N₂ for 15 min. and then a solution of methyl 3,3,3-trifluoropyruvate (6.07 ml, 57.7 mmol) in THF (20 mL) was added via a cannula. The reaction mixture was stirred at -78⁰C for 2 h. and then quenched with a 10 mL of 10% aq. HCl. The reaction mixture was dried over MgSO₄ and CombiFlashed with DCM/hexane (15 - 100%) to provide methyl 3,3,3-trifluoro-2-(5-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2- methylpiperazin-l-ylsulfonyl)thiophen-2-yl)-2-hydroxypropanoate as a sticky, light yellow solid (22 g, 39.0 mmol, 67.6 % yield).

Step ID, Method 1: To a solution of methyl 3,3,3-trifluoro-2-(5-((R)-4-(4-fiuoro- 2-(trifluoromethyl)phenyl)-2-methylpiperazin-l-ylsulfonyl)thiophen-2-yl)-2- hydroxypropanoate (21.5 g, 38.1 mmol) in MeOH (200 ml) was added aq. NH₃ (-28-

30%, 50 mL). The reaction mixture was stirred at room temperature o/n and then diluted with ice water (700 mL). The resultant white ppt was collected by filtration, washed with water, and dried in an oven at 60 ⁰C to give the desired product 3,3,3-trifluoro-2-(5-((R)- 4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-l-ylsulfonyl)thiophen-2-yl)-2- hydroxypropanamide (15 g, 27.3 mmol, 71.7 % yield). The aqueous layer was extracted with DCM (4 x 100 mL), and the combined organic layers were concentrated. Purification of the concentrate by column chromatography with EA/DCM (0-40%) gave an additional 1.5 g of product.

Method 2: To a solution of methyl 3,3,3-trifluoro-2-(5-((R)-4-(4-fluoro-2-

(trifluoromethyl)phenyl)-2-methylpiperazin-l-ylsulfonyl)thiophen-2-yl)-2- hydroxypropanoate (200 mg) in MeOH (20 ml) at -78⁰C was bubbled NH₃ gas. The resultant mixture was stirred at room temperature overnight, concentrated, and dissolved in fresh DCM. The organic layer was washed with aq. NaHCO₃ and dried to give 3,3,3- trifluoro-2-(5 -((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin- 1 - ylsulfonyl)thiophen-2-yl)-2-hydroxypropanamide as a white solid (150 mg). It was found that competing hydrolysis of the ester group to the corresponding acid occurred to a greater extent when using Method 1. Thus, in some instances, it may be preferable to use Method 2 when performing step D.

HRMS: calcd for Ci₉Hi₈F₇N₃O₄S₂ + H+, 550.06997; found (ESI-FTMS,

[M+H]¹⁺), 550.07165. Example 1.2

αR)-3,3,3-trifluoro-2-r5-ααR)-4-r4-fluoro-2-(trifluoromethyl)phenyll-2- methylpiperazin-l-yl}sulfonyl)thiophen-2-yll-2-hvdroxypropanamide

13.5 grams of 3,3,3-trifluoro-2-(5-((R)-4-(4-fiuoro-2-(trifluoromethyl)phenyl)-2- methylpiperazin-l-ylsulfonyl)thiophen-2-yl)-2-hydroxypropanamide (prepared according to a procedure similar to that described in Example 1.1) was separated was separated with a chiral column (Chiralpak ADH) in SFC Analytical Instrument; Mobile Phase was 90% CO2 /10%Methanol at flow rate 5mL/min. Early fraction (Retention 4.4min) was collected to give the title compound (5.7g); late fraction was collected to give the diastereomer described in Example 1.3 (6g, retention time 6. lmin).

HRMS: calcd for Ci₉Hi₈F₇N₃O₄S₂ + H+, 550.06997; found (ESI, [M+H]+), 550.0697. Example 1.3

αS)-3,3,3-trifluoro-2-r5-ααR)-4-r4-fluoro-2-qrifluoromethyl)phenyll-2- methylpiperazin-l-yl}sulfonyl)thiophen-2-yll-2-hvdroxypropanamide The title compound was obtained as the late fraction using the separation method described in Example 1.2.

HRMS: calcd for Ci₉Hi₈F₇N₃O₄S₂ + H+, 550.06997; found (ESI, [M+H]+), 550.0701.

Example 1.4

(2R)-2- [2-bromo-5-({(2R)-4- r4-fluoro-2-(trifluoromethyl)phenyll -2-methylpiperazin- l-yl}sulfonyl)-3-thienyll-3,3i3-trifluoro-2-hvdroxypropanamide

The title compound was isolated from the crude reaction mixture that was obtained after performing step D in Example 1.1. The title compound was separated using a chiral column (Chiralpak ADH) in SFC Analytical Instrument. Mobile Phase was 90% CO2 /10%Methanol. (900 mg, 3.76% yield).

HRMS: calcd for Ci₉H_nBrF₇N₃O₄S₂ + H+, 627.98048; found (ESI, [M+H]+), 627.9805.

Example 1.5

2-[5-f{f2R)-4-[4-fluoro-2-ftrifluoromethyl)phenyll-2-methylpiperazin-l- yl} sulfonyl)thiophen-2-yll -2-hydr oxypr opanamide

The title compound was prepared using a procedure analogous to that described in Example 1.1 (235 mg, 54.1% yield), but using 2-oxo-propionic acid ethyl ester instead of methyl 3,3,3-trifluoropyruvate in Step 1C.

HRMS: calcd for Ci₉H_2IF₄N₃O₄S₂ + H+, 496.09824; found (ESI, [M+H]+), 496.0997.

2-[5-f{f2R)-4-[4-fluoro-2-ftrifluoromethyl)phenyll-2-methylpiperazin-l- yl} sulfonyl)thiophen-2-yll -2-hydroxy-2-phenylacetamide

The title compound was prepared using a procedure analogous to that described in Example 1.1 (85 mg, 27.3% yield), but using oxo-phenyl-acetic acid methyl ester instead of methyl 3,3,3-trifluoropyruvate in Step 1C.

Example 2.1

3,3,3-trifluoro-2-r2-α(2R)-4-r4-fluoro-2-(trifluoromethyl)phenyll-2-methylpiperazin- 1-yl} sulfonyl)- 1 ,3-thiazol-5-yll -2-hydroxypropanamide The title compound of Example 2.1 was prepared as shown in Scheme 2 below.

Detailed synthesis procedures are provided below. Scheme 2

Step 2A: To a suspension of 2-mercaptothiazole (1.0 g, 8.53 mmol) with KNO3 (2.15 g, 21.3 mmol) in 17 mL of anhydrous MeCN was added SO₂Cl₂ (1.73 mL, 21.3 mmol) at O⁰C under N₂. The suspension was stirred at O⁰C for lhr, after which time the reaction was determined to be complete by thin layer chromatography (TLC). The reaction mixture was diluted with ether and neutralized with sat. NaHCO₃ solution until a pH=6-7 was attained. The reaction mixture was extracted first with ether, then with EtOAc. The combined organic layers were washed with sat. brine, dried over Na₂SO₄, concentrated down to give thiazole-2-sulfonyl chloride as a brown-yellow color liquid (350 mg), which was used in next step without purification.

Step 2B: To a stirred solution of (3i?)-l-[4-fluoro-2-(trifluoromethyl)phenyl]-3- methylpiperazine (100 mg, 0.38 mmol) and diisopropylethylamine (0.13 mL, 0.76 mmol) in anhydrous dichloromethane (2 mL) was added thiazole-2-sulfonyl chloride (70 mg, 0.38 mmol) at O⁰C. The reaction mixture was stirred at O⁰C for 15 min, then stirred at room temperature for 3 hrs, after which time the reaction was judged complete by TLC. Another batch was prepared using (400 mg) of (3i?)-l-[4-fluoro-2- (trifluoromethyl)phenyl]-3-methylpiperazine. The reaction mixtures were combined, washed with H2O, extracted with DCM. The organic layers were dried over Na₂SO₄ and concentrated to afford a brown oil. The crude product was purified via flash column chromatography, eluting with 20-40% EtOAc/Hexane to yield (2i?)-4-[4-fluoro-2- (trifluoromethyl)phenyl]-2-methyl-l-(l,3-thiazol-2-ylsulfonyl)piperazine in 64% yield (497 mg) as a light yellow solid. Step 2C: To a solution of (2i?)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-l-

(l,3-thiazol-2-ylsulfonyl)piperazine (258 mg, 0.63 mmol) in anhydrous THF (4 ml) was added lithium diisopropyl amide (0.38 ml, 0.76 mmol) at -78⁰C. The reaction mixture was stirred under N₂ for 20 min, the methyl 3,3,3-trifluoropyruvate (0.096 ml, 0.945 mmol) was added. The resultant mixture was stirred at -78⁰C for 15 min, warmed to room temperature, quenched with H2O, and extracted with DCM (3x). The combined organic layers were dried over MgSO₄. The crude product was purified by chromatography (CombiFlash) with 30-50% EtOAc/Hexane to give methyl 3,3,3- trifluoro-2-[2-({(2i?)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-l- yl}sulfonyl)-l,3-thiazol-5-yl]-2-hydroxypropanoate as a yellow solid (229.5 mg, 64.4 % yield).

Step 2D: To a solution of 3,3,3-trifiuoro-2-[2-({(2i?)-4-[4-fluoro-2- (trifluoromethyl)phenyl]-2-methylpiperazin- 1 -yl} sulfonyl)-l ,3-thiazol-5-yl]-2- hydroxypropanoate (213 mg, 0.38 mmol) in MeOH (2 ml) was added aq. NH3 (-28-30%, 1 mL). The reaction mixture was stirred at room temperature for 5 hrs, after which the reaction was determined to be complete by LC/MS. Most of the solvent was removed under reduced pressure. The concentrate was then neutralized with IN HCl solution until a pH=6 was attained. The concentrate was extracted with EtOAc first, then extracted with DCM. The combined organic layers were concentrated and purified via flash column chromatography, eluting with 3-5% MeOH/DCM to yield (25)-3,3,3-trifluoro-2- [5-( {(2i?)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin- 1 - yl}sulfonyl)thiophen-2-yl]-2-hydroxypropanamide as an off-white solid (112 mg, 53.5% yield).

HRMS: calcd for Ci₈Hi₇F₇N₄O₄S₂ + H+, 551.06522; found (ESI, [M+H]+), 551.0639.

Example 2.1 was separated with a chiral column (Chiralpak ADH) in SFC Analytical Instrument. Mobile Phase was 90% CO2 /10%MethanoL. The title compounds of Example 2.2 and 2.3 were isolated in good yield.

Example 2.2

αR)-3,3,3-trifluoro-2-r2-ααR)-4-r4-fluoro-2-(trifluoromethyl)phenyll-2- methylpiperazin- 1-vU sulfonyl)- 1.,3-thiazol-5-yH -2-hvdroxypropanamide

HRMS: calcd for Ci₈Hi₇F₇N₄O₄S₂ + H+, 551.06522; found (ESI, [M+H]+), 551.0650.

Example 2.3

αS)-3,3,3-trifluoro-2-r2-ααR)-4-r4-fluoro-2-(trifluoromethyl)phenyll-2- methylpiperazin- 1-vU sulfonyl)- 1.,3-thiazol-5-yH -2-hvdroxypropanamide

HRMS: calcd for Ci₈Hi₇F₇N₄O₄S₂ H+, 551.06522; found (ESI, [M+H]+), 551.0651.

Example 3.1

3-,3.,3-trifluoro-2-[3-f{f2R)-4-[4-fluoro-2-ftrifluoromethyl)phenyll-2-methylpiperazin- 1-yll sulfonyl)- 1-methyl- IH- 1 ,2,4-triazol-5-yll -2-hydroxypropanamide

The title compound of Example 3.1 was prepared as shown in Scheme 3 below. Detailed synthesis procedures are provided below. Scheme 3

THF

Step 3 A: To a stirred solution of (3i?)-l-[4-fluoro-2-(trifluoromethyl)phenyl]-3- methylpiperazine (1.57 g, 5.97 mmol) and diisopropylethylamine (3.1 rnL, 17.91 mmol) in anhydrous dichloromethane (20 rnL) was added 2H-[l,2,4]triazole-3-sulfonyl chloride (1.0 g, 5.97 mmol) at O⁰C. The mixture was stirred at O⁰C for 30 min, then stirred at room temperature for o/n. The reaction mixture was washed with H₂O and extracted with DCM. The organic layer was dried over Na₂SO₄ and concentrated. The crude product was purified via flash column chromatography, eluting with 3-6% MeOH/DCM to yield (2i?)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-l-(lH-l,2,4-triazol-5- ylsulfonyl)piperazine in 52.3% yield (1.228 g) as a white solid. Step 3B : To a stirred solution of (2i?)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2- methyl-l-(lH-l,2,4-triazol-5-ylsulfonyl)piperazine (695 mg, 1.77 mmol) in 10 mL of anhydrous TΗF was added NaH (77.9 mg, 1.947 mmol) at room temperature. The reaction mixture was heated to reflux for 6 hrs. The reaction mixture was cooled to room temperature, and methyl iodide (MeI) (0.12 mL, 1.947 mmol) was added. The reaction mixture was heated to reflux again for lhr, after which time the reaction was determined to be complete by TLC. The reaction mixture was cooled to room temperature and stirred o/n. The solvent was evaporated to afford a residue that was diluted with DCM, then washed with H2O and sat. brine, dried over MgSO4, and concentrated to afford an orange gum, which was purified via flash column chromatography, eluting with 40-80% EtOAc/Hexane to yield (2i?)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-l-[(l- methyl-lH-l,2,4-triazol-5-yl)sulfonyl]piperazine as a light yellow solid (522 mg, 72.4% yield).

Step 3C: To a solution of (2i?)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-l- [(l-methyl-lH-l,2,4-triazol-5-yl)sulfonyl]piperazine (484 mg, 1.19 mmol) in anhydrous TΗF (7 ml) was added n-Butyllithium (0.52 ml, 1.31 mmol) at -78⁰C. The reaction mixture was stirred under N₂ for 30 min., then methyl 3,3,3-trifluoropyruvate (0.18 ml, 1.785 mmol) was added. Stirring at -78⁰C was continued for 1.5 hrs, then the reaction mixture was warmed to room temperature. The reaction mixture was quenched with H₂O and extracted with DCM (3x). The combined organic layers were dried over MgSO₄. The crude product was purified by chromatography (CombiFlash) with 35-70%

EtOAc/Hexane to give methyl 3,3,3-trifluoro-2-[3-({(2i?)-4-[4-fluoro-2- (trifluoromethyl)phenyl]-2-methylpiperazin-l-yl}sulfonyl)-l-methyl-lH-l,2,4-triazol-5- yl]-2-hydroxypropanoate as a colorless gum (230 mg, 34.3 % yield).

Step 3D: To methyl 3,3,3-trifluoro-2-[3-({(2i?)-4-[4-fluoro-2-

(trifluoromethyl)phenyl]-2-methylpiperazin-l-yl}sulfonyl)-l-methyl-lH-l,2,4-triazol-5- yl]-2-hydroxypropanoate (213.5 mg, 0.379 mmol) was added 3 mL OfNH₃ in MeOH (2.0 M in MeOH, 1.5 mmol). The reaction mixture was stirred at room temperature o/n, after which time the reaction was determined to be complete by TLC. Evaporation of the solvent and purification via flash column chromatography (eluting with 30-50% EtOAc/Hexane) afforded 3,3,3-trifluoio-2-[3-({(2i?)-4-[4-fluoio-2- (trifluoromethyl)phenyl]-2-methylpiperazin-l-yl}sulfonyl)-l-methyl-lH-l,2,4-triazol-5- yl]-2-hydroxypropanamide as a white powder (75.6 mg, 36.4% yield).

ΗRMS: calcd for Ci₈Hi₉F₇N₆O₄S + H+, 549.11495; found (ESI, [M+H]+), 549.1146.

The title compounds of Examples 4.1 and 4.2 were prepared as shown in Scheme 4 below. Detailed synthesis procedures are provided below.

Scheme 4

Example 4.1

αR)-3,3,3-trifluoro-2-r4-ααR)-4-r4-fluoro-2-qrifluoromethyl)phenyll-2- methylpiperazin-l-yl}sulfonyl)-l-methyl-lH-imidazol-5-yll-2-hvdroxypropanamide

Step 4A: To a stirred solution of (3i?)-l-[4-fluoro-2-(trifluoromethyl)phenyl]-3- methylpiperazine (1.038 g, 3.96 mmol) and diisopropylethylamine (1.38 rnL, 7.92 mmol) in anhydrous dichloromethane (15 rnL) was added 1 -methyl- lΗ-imidazole-4-sulfonyl chloride (0.715 g, 3.96 mmol) at O⁰C. The mixture was stirred at O⁰C for 30 min, then stirred at room temperature for o/n. The reaction mixture was washed with H2O, extracted with DCM. The organic layer was dried over Na₂SO₄ and concentrated. The crude product was purified via flash column chromatography, eluting with 2-4% MeOH/DCM to yield (2i?)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-l-[(l- methyl-lH-imidazol-4-yl)sulfonyl]piperazine as a light yellow solid (1.22 g, 75.8% yield).

Step 4B: To a solution of (2i?)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-l- [(I -methyl- lH-imidazol-4-yl)sulfonyl]piperazine (552 mg, 1.36 mmol) in anhydrous

TΗF (7 ml) was added n-Butyllithium (0.60 ml, 1.49 mmol) at -78⁰C. The reaction was stirred at this tempeature under N₂ for 40 min., then methyl 3,3,3-trifluoropyruvate (0.21 ml, 2.04 mmol) was added. The reaction mixture was stirred at -78⁰C for 1 hr, then warmed to room temperature and Quenched with a Η2O. The quenched reaction mixture was extracted with DCM (3x). The combined organic layers were dried over MgSO₄. Evaporation of the solvent and purification by chromatography (CombiFlash) with 40- 80% EtOAc/Hexane afforded methyl 3,3,3-trifluoro-2-[4-({(2i?)-4-[4-fluoro-2- (trifluoromethyl)phenyl]-2-methylpiperazin-l-yl}sulfonyl)-l-methyl-lH-imidazol-5-yl]- 2-hydroxypropanoate as a white solid (330 mg, 43.1 % yield). Step 4C: To a solution of methyl 3,3,3-trifluoro-2-[4-({(2i?)-4-[4-fluoro-2-

(trifluoromethyl)phenyl]-2-methylpiperazin-l-yl}sulfonyl)-l-methyl-lH-imidazol-5-yl]- 2-hydroxypropanoate (230 mg, 0.41 mmol) in 2 mL of MeOH was added aq. NΗ3 (~28-

30%, 2 mL). The reaction mixture was stirred at room temperature for o/n, after which time the reaction was determined to be complete as by TLC. Evaporation of the solvent and purification via preparative HPLC under neutral condition yielded (2i?)-3,3,3- trifluoro-2-[4-({(2i?)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-l- yl}sulfonyl)-l-methyl-lH-imidazol-5-yl]-2-hydroxypropanamide as a white solid (1.7 mg) and (2_lS)-3,3,3-trifluoro-2-[4-({(2i?)-4-[4-fluoro-2-(trifluoromethyl) phenyl]-2- methylpiperazin- 1 -yl} sulfonyl)- 1 -methyl- lH-imidazol-5-yl]-2-hydroxypropanamide as a white solid (12.3 mg). The chiral column and conditions described elsewhere were used to effect separation of the above-described isomers.

ΗRMS: calcd for Ci₉H₂₀F₇N₅O₄S + H+, 548.11970; found (ESI, [M+H]⁺), 548.1195.

Example 4.2

αR)-3,3,3-trifluoro-2-r4-ααR)-4-r4-fluoro-2-qrifluoromethyl)phenyll-2- methylpiperazin-l-yl}sulfonyl)-l-methyl-lH-imidazol-5-yll-2-hvdroxypropanamide The title compound was obtained using the separation method described in

Example 4.1.

ΗRMS: calcd for Ci₉H₂₀F₇N₅O₄S + H+, 548.11970; found (ESI, [M+H]+), 548.1197.

The title compounds of Examples 5.1 and 5.2 were prepared as shown in Scheme

5 below. Detailed synthesis procedures are provided below.

Toluene

Example 5.1

4-r(3R)-4-{r5-α-carbamoyl-2,2,2-trifluoro-l-hvdroxyethyl)-2-thienyllsulfonyl}-3- methylpiperazin-l-yll-3-ftrifluoromethyl)benzamide

Step 5 A: A mixture of (R)-2-methyl-piperazine (6.0 g, 59.9 mmol), 4-chloro-3- trifluoromethyl-benzonitrile (11.2 g, 54.5 mmol), tris(dibenzylidineacetone)dipalldium (0) (0.499 g, 0.545 mmol), rac-2,2'-bis(diphenylphosphino)-l,l '-binaphthyl (1.02 g, 1.635 mmol)and sodium tert-butoxide (6.55 g, 68.12 mmol) was mixed and purged with N₂. Anhydrous toluene (75 mL) was added and the resultant mixture was purged with N₂ again. The resultant mixture was heated in an oil bath at 107 ⁰C under N₂ for 3 hours. After cooling, the reaction mixture was diluted with DCM (200 mL), washed with H₂O (50 mL), and washed with saturated brine (50 mL). The combined organic layers were dried over Na₂SO₄, concentrated under reduced pressure to give a dark brown liquid. The crude product was purified using a SiO₂ gel column, eluting with 5-7% MeOH in DCM to give 4-[(3i?)-3-methylpiperazin-l-yl]-3-(trifluoromethyl)benzonitrile as a brownish red color oil (l 1.2 g, 76.2%). Step 5B: To a stirred solution of 4-[(3i?)-3-methylpiperazin-l-yl]-3- (trifluoromethyl)benzonitrile (2.69 g, 10 mmol) and TEA (4.18 rnL, 30 mmol) in anhydrous dichloromethane (20 mL) was added thiophene-2-sulfonyl chloride (1.92 g, 10 mmol) at O⁰C. The mixture was stirred at O⁰C for 15 min, then stirred at room temperature for o/n, after which time the reaction was determined to be complete by

TLC. The reaction mixture was washed with aq. NaHCO₃, then extracted with DCM. The organic layer was dried over Na₂SO₄ and concentrated. The crude product was purified via flash column chromatography to yield 5-chloro-Λ/-{4-[(6-cyano-2-{3-[4- (dimethylamino)piperidin-l-yl]phenyl}pyrazolo[l,5-a]pyrimidin-7-yl)amino]-2- methoxyphenyl}-l-benzofuran-2-carboxamide in 96% yield (3.98 g) as a white solid.

Step 5C: To a solution of 5-chloro-N-{4-[(6-cyano-2-{3-[4- (dimethylamino)piperidin-l-yl]phenyl}pyrazolo[l,5-a]pyrimidin-7-yl)amino]-2- methoxyphenyl}-l-benzofuran-2-carboxamide (4.15 g, 10 mmol) in anhydrous THF (60 ml) was added freshly made LDA (12 mmol) at -78⁰C. The reaction mixture was stirred under N₂ for 20 min., and then methyl 3,3,3-trifluoropyruvate (2.1 mL, 20 mmol) was added. Stirring at -78⁰C was maintained for 30 min. The reaction mixture was then warmed to room temperature and quenched with a H2O. The quenched reaction mixture was extracted with DCM (3x). The combined organic layers were dried over MgSO₄ and concentrated. The crude product was purified by chromatography (CombiFlash) with EtOAc/Hexane to give methyl 2-[5-( {(2i?)-4-[4-cyano-2-(trifluoromethyl)phenyl]-2- methylpiperazin-l-yl}sulfonyl)-2-thienyl]-3,3,3-trifluoro-2-hydroxypropanoate as a light yellow solid (4.3 g, 78 % yield).

Step 5D: To methyl 2-[5-({(2i?)-4-[4-cyano-2-(trifluoromethyl)phenyl]-2- methylpiperazin- 1 -yl} sulfonyl)-2-thienyl] -3 ,3 ,3 -trifluoro-2-hydroxypropanoate (120 mg, 0.21) was added NH₃ in EtOH (2.0M, 5 mL). The resultant mixture was stirred at room temperature for 2 days. The reaction mixture was then concentrated and purified on a SiO₂ gel column, eluting with MeOH in DCM to give 2-[5-({(2i?)-4-[4-cyano-2- (trifluoromethyl)phenyl]-2-methylpiperazin-l-yl}sulfonyl)-2-thienyl]-3,3,3-trifluoro-2- hydroxypropanamide as a white solid (58 mg, 50% yield). Step 5E: To a solution of 2-[5-({(2i?)-4-[4-cyano-2-(trifluoromethyl)phenyl]-2- methylpiperazin-l-yl}sulfonyl)-2-thienyl]-3,3,3-trifluoro-2-hydroxypropanamide (200 mg, 0.36 mmol) in t-BuOH (2 niL) was added powdered KOH (100 mg, 1.8 mmol) at room temperature. The reaction mixture was heated to 8O⁰C for 15 min., after which the Reaction was determined to be complete by LC/MS. The reaction mixture was diluted with EtOAc, washed with H₂O three times, then washed with sat. brine. The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure to give 4-[(3i?)-4-{[5-(l-carbamoyl-2,2,2-trifluoro-l-hydroxyethyl)-2-thienyl]sulfonyl}-3- methylpiperazin-l-yl]-3-(trifluoromethyl)benzamide as a white solid (160 mg, 77.4% yield).

HRMS: calcd for C₂₀H₂₀F₆N₄O₅S₂ + H+, 575.08521; found (ESI, [M+H]+), 575.0852.

Example 5.2

2-[5-f{f2/?)-4-[4-cvano-2-ftrifluoromethyl)phenyll-2-methylpiperazin-l-yl}sulfonyl)- 2-thienyll-3,3i3-trifluoro-2-hvdroxypropanamide

The title compound was prepared using a procedure similar to that described in Example 5.1, steps 5A-5D (58 mg, 50% yield).

HRMS: calcd for C₂₀Hi₈F₆N₄O₄S₂ + H+, 557.07464; found (ESI, [M+H]+), 557.0749.

Example 6.1

3,3,3-trifluoro-2-hvdroxy-2-r5-({(2R)-2-methyl-4-r4-(3-methyl-l,2,4-oxadiazol-5-yl)- 2-ftrifluoromethyl)phenyllpiperazin-l-yl}sulfonyl)thiophen-2-yllpropanamide The title compound of Example 6.1 was prepared as shown in Scheme 6 below.

Detailed synthesis procedures are provided below. Scheme 6

Step 6A: The starting material, 4-[(3i?)-3-methylpiperazin-l-yl]-3- (trifluoromethyl)benzonitrile, was prepared according to a procedure similar to that described in Example 5.1, step 5 A. To a stirred solution of 4-[(3i?)-3-methylpiperazin-l- yl]-3-(trifluoromethyl)benzonitrile (3.24 g, 12.03 mmol) and diisopropylethylamine (4.19 mL, 24.06 mmol) in anhydrous dichloromethane (30 mL) was added 5-bromo-thiophene- 2-sulfonyl chloride (3.15 g, 12.03 mmol) at O⁰C. The mixture was stirred at O⁰C for 30 min, then stirred at room temperature for o/n. The reaction mixture was washed with H2O and extracted with DCM. The organic layer was dried over Na₂SO₄ and concentrated. The crude product was purified via flash column chromatography, eluting with 30-50% EtOAc/Hexane to yield 4-{(3i?)-4-[(5-bromo-2-thienyl)sulfonyl]-3- methylpiperazin-l-yl}-3-(trifluoromethyl)benzonitrile in 74.5% yield (4.432 g) as a yellow solid.

Step 6B: To 4-{(3i?)-4-[(5-bromo-2-thienyl)sulfonyl]-3-methylpiperazin-l-yl}-3- (trifluoromethyl)benzonitrile (2.51 g, 5.08 mmol) was added a mixture of TFA/H₂SO₄ (15 mL, TFA//H2SO4 = 2/1, v/v) at room temperature. The reaction mixture was stirred at room temperature for over night and then carefully poured onto ice. The aqueous mixture was neutralized with 6 N NaOH solution until pH =5-6 was attained and then extracted with DCM (3x). The combined organic layers were washed with sat. brine, dried over Na₂SO₄, and concentrated to give a tan solid. This solid was re-dissolved in DCM, then hexane was added to form a slurry. The slurry was filtered, washed with hexane, to give 4-{(3i?)-4-[(5-bromo-2-thienyl)sulfonyl]-3-methylpiperazin-l-yl}-3- (trifluoromethyl)benzamide as a tan color solid (2.20 g, 84.8%). Step 6C: To a 50 mL flask containing 4-{(3i?)-4-[(5-bromo-2-thienyl)sulfonyl]-3- methylpiperazin-l-yl}-3-(trifluoromethyl)benzamide was added N,N-dimethylacetamide dimethylacetal (6 mL, 37 mmol). The reaction mixture was stirred at 85⁰C for 20 min., after which time the reaction was determined to be complete by LC/MS. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The crude product was purified via flash column chromatography, eluting with 1-3% MeOH/DCM to yield 4-{(3i?)-4-[(5-bromo-2-thienyl)sulfonyl]-3-methylpiperazin- l-yl}-Λ/-[(lZ)-l-(dimethylamino) ethylidene]-3-(trifluoromethyl)benzamide as a light yellow solid (1.36 g, 100% yield).

Step 6D: To a solution of hydroxy lamine hydrochloride (93.2 mg, 1.34 mmol) in a mixture of 6N NaOH solution (223 μL, 1.34 mmol) and 7 mL of 70% aqueous acetic acid was added 4-{(3i?)-4-[(5-bromo-2-thienyl)sulfonyl]-3-methylpiperazin-l-yl}-Λ/- [(lZ)-l-(dimethylamino) ethylidene]-3-(trifluoromethyl)benzamide (650 mg, 1.12 mmol). The reaction mixture was stirred at room temperature for 1.5 hrs., after which time the reaction was determined to be complete by LC/MS. The reaction mixture was diluted with H₂O, which resulted in the formation of a slurry. Filtration of the slurry gave (2R)- 1 - [(5 -bromo-2-thienyl)sulfonyl]-2-methyl-4-[4-(3 -methyl- 1 ,2,4-oxadiazol-5-yl)-2- (trifluoromethyl)phenyl]piperazine as an off- white solid (532 mg, 86.1% yield).

Step 6E: To a solution of (2i?)-l-[(5-bromo-2-thienyl)sulfonyl]-2-methyl-4-[4-(3- methyl-l,2,4-oxadiazol-5-yl)-2-(trifluoromethyl)phenyl]piperazine (500 mg, 0.91 mmol) in anhydrous THF (10 ml) was added n-butyllithium (0.36 ml, 2.5 M in hexane, 0.91 mmol) at -78⁰C. The reaction mixture was stirred under N₂ for 5 min. and then methyl 3,3,3-trifluoropyruvate (0.20 ml, 1.36 mmol) was added. Stirring at -78⁰C was maintained for 1 hr, then the reaction mixture was warmed to room temperature and diluted with EtOAc. The EtOAc layer was washed with aq. NaHCO3 solution (3x) and dried over Na₂SO₄. Purification by chromatography (CombiFlash) with 10-80%

EtOAc/Hexane afforded methyl 3,3,3-trifluoro-2-hydroxy-2-[5-({(2i?)-2-methyl-4-[4-(3- methyl-l,2,4-oxadiazol-5-yl)-2-(trifluoromethyl)phenyl]piperazin-l- yl}sulfonyl)thiophen-2-yl]propanoate as a yellow solid (200 mg, 35% yield).

Step 6F: To a solution of 3,3,3-trifluoro-2-hydroxy-2-[5-({(2i?)-2-methyl-4-[4-(3- methyl-l,2,4-oxadiazol-5-yl)-2-(trifluoromethyl)phenyl]piperazin-l- yl}sulfonyl)thiophen-2-yl]propanoate (200 mg, 0.31 mmol) in 20 mL of MeOH was bubbled NH3 (g) for 30 seconds at -78⁰C. The reaction mixture was warmed up to room temperature and stirred under empty balloon for o/n., after which the reaction was determined to be complete by LC/MS. The solvent was evaporated, and the residue was washed with aq. NaHCO₃ solution and extracted with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated to yield 3,3,3-trifluoro-2-hydroxy-2-[5-({(2i?)-2- methyl-4-[4-(3 -methyl- 1 ,2,4-oxadiazol-5-yl)-2-(trifluoromethyl)phenyl] piperazin- 1 - yl}sulfonyl)thiophen-2-yl]propanamide as a pale yellow powder (150 mg, 79% yield ).

HRMS: calcd for C₂₂H₂IF₆N₅O₅S₂ + H+, 614.09610; found (ESI, [M+H]+), 614.0957.

αS)-3,3,3-trifluoro-2-hvdroxy-2-r5-ααR)-2-methyl-4-r4-(3-methyl-l,2,4-oxadiazol- 5-yl)-2-ftrifluoromethyl)phenyllpiperazin-l-yl}sulfonyl)-2-thienyllpropanamide

150 mg of 3,3,3-trifluoro-2-hydroxy-2-[5-({(2i?)-2-methyl-4-[4-(3-methyl-l,2,4- oxadiazol-5-yl)-2-(trifluoromethyl)phenyl]piperazin- 1 -yl} sulfonyl)thiophen-2- yl]propanamide (prepared according to a procedure similar to that described in Example 6.1, step 6A-6F) separated with a chiral column (Chiralpak ADH) in SFC Analytical Instrument. Mobile Phase was 90% CO2 /10%Methanol. Early fraction was collected to give the title compound (60 mg); late fraction was collected to give the diastereomer described in Example 6.3 (53 mg).

HRMS: calcd for C₂₂H₂IF₆N₅O₅S₂ + H+, 614.09610; found (ESI, [M+H]+), 614.0963. Example 6.3

αR)-3,3,3-trifluoro-2-hvdroxy-2-r5-ααR)-2-methyl-4-r4-(3-methyl-l,2,4-oxadiazol- 5-yl)-2-ftrifluoromethyl)phenyllpiperazin-l-yl}sulfonyl)-2-thienyllpropanamide The title compound was obtained as the late fraction using the separation method described in Example 6.2.

HRMS: calcd for C₂₂H₂IF₆N₅O₅S₂ + H+, 614.09610; found (ESI, [M+H]+), 614.0958.

Example 7.1

3,3,3-trifluoro-2-hvdroxy-2-r5-ααR)-2-methyl-4-r4-q,3,4-oxadiazol-2-yl)-2- ftrifluoromethyl)phenyllpiperazin-l-yl}sulfonyl)thiophen-2-yllpropanamide

The title compound of Example 7.1 was prepared as shown in Scheme 7 below. Detailed synthesis procedures are provided below.

Scheme 7

Step 7A: The starting material, 4-{(3i?)-4-[(5-bromo-2-thienyl)sulfonyl]-3- methylpiperazin-l-yl}-3-(trifluoromethyl)benzonitrile, was prepared according to a procedure similar to that described in Example 6.1, step 6 A.

To a solution of 4-{(3i?)-4-[(5-bromo-2-thienyl)sulfonyl]-3-methylpiperazin-l- yl}-3-(trifluoromethyl)benzonitrile (1.908 g, 3.86 mmol) in a mixture of MeOH (10 mL) and H₂O (10 mL) was added 3N NaOH (7.72 mL, 23.16 mmol) at room temperature. The reaction mixture was heated to reflux for over night., after which time the reaction was determined to be complete by TLC. The reaction mixture was cooled to room temperature, acidified with 6 N HCl solution until pH =5, and extracted with EtOAc three times. The combined organic layers were washed with sat. brine and dried over Na₂SO₄. Removal of the solvent under reduced pressure afforded 4-{(3i?)-4-[(5-bromo-2- thienyl)sulfonyl]-3-methylpiperazin- 1 -yl} -3-(trifluoromethyl)benzoic acid as a yellow solid (1.737 g, 87.7% yield).

Step 7B: To a solution of 4-{(3i?)-4-[(5-bromo-2-thienyl)sulfonyl]-3- methylpiperazin-l-yl}-3-(trifluoromethyl)benzoic acid (700 mg, 1.36 mmol) in 7 mL of anhydrous 1 ,2-dichloroethane was added SOCl₂ (0.6 mL, 8.18 mmol). The reaction mixture was stirred at room temperature for 2 hours, heated at reflux for 5hrs., and then cooled to room temperature and stirred o/n. The solvent was evaporated to afford a residue, which was taken up in 7 mL of DCM. The DCM mixture was cooled to O⁰C, and NH₂NH₂ (0.26 mL, 8.18 mmol) was added. Stirring was continued at O⁰C for 30 min., after which the reaction was determined to be complete by LC/MS. The solvent was removed under reduced pressure. To the resulting residue was added H2O, and the aqueous mixture was extracted with DCM (3x). The combined organic layers were washed with sat. brine, dried over Na₂SO₄, concentrated, and purified via flash column chromatography, eluting with 2-4% MeOH/DCM to yield 4-{(3i?)-4-[(5-bromo-2- thienyl)sulfonyl]-3-methylpiperazin- 1 -yl} -3-(trifluoromethyl)benzohydrazide as a white solid (548 mg, 76% yield).

Step 7C: To a solution of 4-{(3i?)-4-[(5-bromo-2-thienyl)sulfonyl]-3- methylpiperazin-l-yl}-3-(trifluoromethyl)benzohydrazide (548 mg, 1.04 mmol) in 3 mL of EtOH were added triethylortho formate (5 mL) and a few mg of PSA. The reaction mixture was heated to 8O⁰C for 3 hrs., after which the reaction was determined to be complete by LC/MS. The reaction mixture was cooled to room temperature, and the solvent removed under reduced pressure. The crude product was purified via flash column chromatography, eluting with 30-50% EtOAc/Hexane to yield (2i?)-l-[(5-bromo- 2-thienyl)sulfonyl]-2-methyl-4-[4-(l,3,4-oxadiazol-2-yl)-2- (trifluoromethyl)phenyl]piperazine as a white solid (500 mg, 89.5% yield).

Step 7D: The penultimate compound in Scheme 7 was prepared according to a procedure similar to that described in Example 6.1, step 6E.

Step 7E: The final compound in Scheme 7 was prepared according to a procedure similar to that described in Example 6.1, step 6F (50 mg, 83.4% yield). HRMS: calcd for C₂IHi₉F₆N₅O₅S₂ + H+, 600.08045; found (ESI, [M+H]+),

600.0804.

Example 8.1

3,3,3-trifluoro-2-hvdroxy-2-r5-ααR)-2-methyl-4-r4-qH-tetrazol-5-yl)-2- (ϊrifluoromethyl)phenyllpiperazin-l-yl}sulfonyl)-2-thienyllpropanamide

The title compound of Example 8.1 was prepared as shown in Scheme 8 below. Detailed synthesis procedures are provided below.

Step 8A: The starting material, 2-[5-({(2i?)-4-[4-cyano-2-

(trifluoromethyl)phenyl]-2-methylpiperazin-l-yl}sulfonyl)-2-thienyl]-3,3,3-trifluoro-2- hydroxypropanamide, was prepared according to a procedure similar to that described in Example 5.1, steps 5 A to 5D.

In a microwave vial with 2-[5-({(2i?)-4-[4-cyano-2-(trifluoromethyl)phenyl]-2- methylpiperazin-l-yl}sulfonyl)-2-thienyl]-3,3,3-trifluoro-2-hydroxypropanamide (55 mg, 0.1 mmol) was added a mixture of isopropanol (0.3 mL) and H₂O (0.1 mL). ZnBr₂ (45 mg, 0.2 mmol) and NaN₃ (33 mg, 0.5 mmol) were then added. The resultant mixture was heated to 8O⁰C in oil bath for o/n., after which time the reaction was determined to be complete as by LC/MS. The resultant mixture was cooled to room temperature and concentrated down to remove the isopropanol. The crude product was triturated with cold H₂O to give 3,3,3-trifluoro-2-hydroxy-2-[5-({(2i?)-2-methyl-4-[4-(lH-tetrazol-5-yl)-2- (trifluoromethyl)phenyl]piperazin-l-yl}sulfonyl)-2-thienyl]propanamide as a white powder (68 mg, 100% yield).

ΗRMS: calcd for C₂₀Hi₉F₆N₇O₄S₂ + H+, 600.09169; found (ESI, [M+H]+), 600.0908.

Example 9.1

3,3,3-trifluoro-2-hvdroxy-2-r5-ααR)-2-methyl-4-r4-(4H-l,2,4-triazol-3-yl)-2- ftrifluoromethyl)phenyllpiperazin-l-yl}sulfonyl)-2-thienyllpropanamide

The title compound of Example 9.1 was prepared as shown in Scheme 9 below. Detailed synthesis procedures are provided below.

Step 9A: The starting material, 4-{(3i?)-4-[(5-bromo-2-thienyl)sulfonyl]-3- methylpiperazin-l-yl}-Λ/-[(lZ)-l-(dimethylamino) ethylidene]-3-

(trifluoromethyl)benzamide, was prepared according to a procedure similar to that described in Example 6.1, steps 6A to 6C.

To a solution of hydrazine (0.16 mL, 5.17 mmol) in 25 mL of acetic acid was added 4- {(3i?)-4-[(5-bromo-2-thienyl)sulfonyl]-3-methylpiperazin- 1 -yl} -N-[(IZ)- 1 - (dimethylamino) ethylidene]-3-(trifluoromethyl)benzamide (1.0 g, 1.72 mmol) at room temperature. The reaction mixture was then stirred at room temperature for 10 min., after which time the reaction was determined to be complete by LC/MS. The reaction mixture was concentrated to remove most of the HOAc. The resulting residue was poured into H₂O, which resulted in formation of a solid. The solid was filtered, washed with H₂O, and air dried under suction, to provide (2i?)-l-[(5-bromo-2-thienyl)sulfonyl]-2-methyl-4- [4-(5-methyl-4H-l,2,4-triazol-3-yl)-2-(trifluoromethyl)phenyl]piperazine as a white solid (1.0 g, 94.7% Yield).

Step 9B: The penultimate compound in Scheme 9 was prepared according to a procedure similar to that described in Example 6.1, step 6E. Step 9C: The final compound was prepared according to a procedure similar to that described in Example 6.1, step 6F (58 mg, 94.7% yield).

ΗRMS: calcd for C_2IH₂₀F₆N₆O₄S₂ + H+, 599.09644; found (ESI, [M+H]+), 599.0962. Example 9.2

3,3,3-trifluoro-2-hvdroxy-2-r5-ααR)-2-methyl-4-r4-(5-methyl-4H-l,2,4-triazol-3-yl)- 2-ftrifluoromethyl)phenyllpiperazin-l-yl}sulfonyl)-2-thienyllpropanamide

The title compound was prepared using a procedure analogous to that described in Example 9.1, steps 9A-9C (60 mg, 100% yield), but using 4-{(3R)-4-[(5-bromo-2- thienyl)sulfonyl]-3-methylpiperazin- 1 -yl} -N-[(l E)- (dimethylamino)methylene]-3- (trifluoromethyl)benzamide instead of 4- {(3R)-4-[(5-bromo-2-thienyl)sulfonyl]-3- methylpiperazin- 1 -yl} -N-[( 1 Z)- 1 - (dimethylamino)ethylidene] -3 - (trifluoromethyl)benzamide .

ΗRMS: calcd for C₂₂H₂₂F₆N₆O₄S₂ + H+, 613.11209; found (ESI, [M+H]+), 613.1121.

2,2,2-trifluoro-l-r5-({(2R)-4-r4-fluoro-2-(trifluoromethyl)phenyll-2- methylpiperazin-l-yl}sulfonyl)-2-thienyll-l-(4H-l,2,4-triazol-3-yl)ethanol

The title compound of Example 10.1 was prepared as shown in Scheme 10 below. Detailed synthesis procedures are provided below.

Scheme 10

Step 1OA: The starting material, 3,3,3-trifluoro-2-(5-((R)-4-(4-fluoro-2- (trifluoromethyl)phenyl)-2-methylpiperazin- 1 -ylsulfonyl)thiophen-2-yl)-2- hydroxypropanamide, was prepared according to a procedure similar to that described in Example 1.1, step IA to ID.

To a 50 mL flask containing 3,3,3-trifluoro-2-(5-((R)-4-(4-fluoro-2- (trifluoromethyl)phenyl)-2-methylpiperazin-l-ylsulfonyl)thiophen-2-yl)-2- hydroxypropanamide (76.9 mg, 0.14 mmol) was added N,N-dimethylformamide dimethylacetal (1 mL). The reaction mixture was stirred at room temperature for 20 min., after which time the reaction was determined to be complete by LC/MS. The reaction mixture was concentrated to give N-dimethylaminomethylene-3,3,3-trifluoro-2-{5-[4-(4- fluoro-2-trifluoromethyl-phenyl)-2-methyl-piperazine- 1 -sulfonyl]-thiophen-2-yl} -2- hydroxy-propionamide as a crude oil (96 mg, 100% Yield), which was used in next step directly without purification.

Step 1OB: To a solution of hydrazine (8 uL, 0.28 mmol) in 3 mL of acetic acid was added N-dimethylaminomethylene-3,3,3-trifluoro-2-{5-[4-(4-fluoro-2- trifluoromethyl-phenyl)-2-methyl-piperazine- 1 -sulfonyl]-thiophen-2-yl} -2-hydroxy- propionamide (96 mg, 0.14 mmol) at room temperature. The reaction mixture was then stirred at room temperature for 1 hour., after which time the reaction was determined to be complete by LC/MS. The solvent was evaporated, and the resultant residue diluted with EtOAc. The EtO Ac-diluted residue was washed with aq. NaHCO3 solution and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified on SiO₂ gel column, eluting with 0-8% MeOH in DCM to give 2,2,2-trifluoro-l-[5-({(2i?)-4-[4-fluoro-2- (trifluoromethyl)phenyl]-2-methylpiperazin-l -yl} sulfonyl)-2-thienyl]- 1 -(AH- 1 ,2,4- triazol-3-yl)ethanol as a light yellow solid (60 mg, 75% Yield).

HRMS: calcd for C₂₀Hi₈F₇N₅O₃S₂ + H+, 574.08120; found (ESI, [M+H]+), 574.0808.

Example 11.1

2,2,2-trifluoro-l-[5-f{f2R)-4-[4-fluoro-2-ftrifluoromethyl)phenyll-2-methylpiperazin- l-yllsulfonyl)-2-thienyll-l-(5-methyl-4H-l,2,4-triazol-3-yl)ethanol

The title compound of Example 11.1 was prepared as shown in Scheme 11 below. Detailed synthesis procedures are provided below. Scheme 11

Step 1 IA: The starting material, 3,3,3-trifluoro-2-(5-((R)-4-(4-fluoro-2- (trifluoromethyl)phenyl)-2-methylpiperazin-l-ylsulfonyl)thiophen-2-yl)-2- hydroxypropanamide, was prepared according to a procedure similar to that described in Example 1.1, step IA to ID.

To a solution of 3,3,3-trifluoro-2-(5-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)- 2-methylpiperazin-l-ylsulfonyl)thiophen-2-yl)-2-hydroxypropanamide (2 g, 3.6 mmol) in DCM (40 niL) was added Et3N( 0.61 mL, 4.4 mmol). The reaction mixture was cooled to O⁰C and TBDPSCl (0.93 mL, 3.6 mmol) was added under N₂. The reaction mixture was stirred at room temperature for 3 days., after which time the reaction was determined to be complete by LC/MS. The reaction mixture was washed with aq. NaHCO₃ solution, and the organic layer was dried over Na₂SO₄ and concentrated. The crude product was purified on SiO₂ gel column, eluting with 5-40% EtOAc in Hexane to give 2-(tert-butyl- diphenyl-silanyloxy)-3,3,3-trifluoro-2-{5-[4-(4-fluoro-2-trifluoromethyl-phenyl)-2- methyl-piperazine-l-sulfonyl]-thiophen-2-yl}-propionamide as a white solid (750 mg, 27% yield). Step 1 IB: To 2-(tert-butyl-diphenyl-silanyloxy)-3,3,3-trifiuoro-2-{5-[4-(4-fluoro-

2-trifluoromethyl-phenyl)-2-methyl-piperazine- 1 -sulfonyl]-thiophen-2-yl} -propionamide (500 mg, 0.6 mmol) was added 10 mL of DMA-DMA. The reaction mixture was stirred at room temperature for 30 min., after which time the reaction was determined to be complete by LC/MS. The reaction mixture was concentrated, and the resultant residue dissolved in minimum volume of HOAc. This HO Ac-diluted residue was then treated with a solution of hydrazine (0.05 mL, 1.5 mmol) in 2.5 mL of acetic acid and stirred at room temperature for 1 hr., after which time the reaction was determined to be complete by LC/MS. Addition of H2O resulted in the formation of a precipitate, which was filtered to yield 2,2,2-trifluoro-l-[5-({(2i?)-4-[4-fiuoro-2-(trifluoromethyl)phenyl]-2- methylpiperazin-l-yl}sulfonyl)-2-thienyl]-l-(5-methyl-4H-l,2,4-triazol-3-yl)ethanol as a light yellow solid (70 mg, 20% yield).

The title compounds of Examples 12.1 and 12.2 were prepared as shown in Scheme 12 below. Detailed synthesis procedures are provided below.

Scheme 12

Example 12 .1

4-r(3R)-3-methyl-4-α5-r2,2,2-trifluoro-l-hvdroxy-l-(4H-l,2,4-triazol-3-yl)ethyll-2- thienyl}sulfonyl)piperazin-l-yll-3-ftrifluoromethyl)benzamide

Step 12A-12B: The starting material was prepared according to a procedure similar to that described in Example 5.1, steps 5 A to 5D.

4-[(3R)-3-methyl-4-( {5-[2,2,2-trifiuoro- 1 -hydroxy- 1 -(4H-1 ,2,4-triazol-3- yl)ethyl]-2-thienyl} sulfonyl)piperazin- 1 -yl]-3-(trifluoromethyl)benzonitrile was prepared according to a procedure similar to that described in Example 10.1, steps 1OA to 1OB.

Step 12C: The title compound was prepared according to a procedure similar to that described in Example 5.1, step 5E (80 mg, 72%yield).

ΗRMS: calcd for C₂IH₂₀F₆N₆O₄S₂ + H+, 599.09644; found (ESI, [M+H]+), 599.0964. Example 12.2

4-r(3R)-3-methyl-4-α5-r2,2,2-trifluoro-l-hvdroxy-l-(4H-l,2,4-triazol-3-yl)ethyll-2- thienyl}sulfonyl)piperazin-l-yll-3-(ϊrifluoromethyl)benzonitrile

The title compound was prepared according to a procedure similar to that described in Example 12.1, steps 12A-12B (110 mg, 31%yield).

ΗRMS: calcd for C_2IHi₈F₆N₆O₃S₂ + H+, 581.08587; found (ESI, [M+H]+), 581.0857.

Example 12.3

4-r(3R)-3-methyl-4-α5-r2,2,2-trifluoro-l-hvdroxy-l-(5-methyl-4H-l,2,4-triazol-3- yl)ethyll-2-thienyl}sulfonyl)piperazin-l-yll-3-ftrifluoromethyl)benzonitrile

The title compound was prepared using a procedure analogous to that described in Example 12.1, steps 12A-12B (19 mg, 5%yield), but using N,N-dimethylacetamide dimethyl acetal instead of N,N-dimethylformamide dimethyl acetal.

Example 13.1

4-r(3R)-3-methyl-4-({5-r2,2,2-trifluoro-l-hvdroxy-l-q,2,4-oxadiazol-5-yl)ethyll-2- thienyl}sulfonyl)piperazin-l-yll-3-(ϊrifluoromethyl)benzonitrile

The title compound of Example 13.1 was prepared as shown in Scheme 13 below. Detailed synthesis procedures are provided below. Scheme 13

NH₂OHHCl, HOAc dioxane

Step 13 A: The starting material, 2-{5-[4-(4-Cyano-2-trifluoromethyl-phenyl)-2- methyl-piperazine-l-sulfonyl]-thiophen-2-yl}-N-dimethylaminomethylene-3,3,3- trifluoro-2-hydroxy-propionamide, was prepared according to a procedure similar to that described in Example 12.1, step 12A.

Step 13B: To a solution of hydroxylamine hydrochloride (40 mg, 0.61 mmol) in a mixture of 3N NaOH solution (100 μL, 0.61 mmol) and 6 mL of 70% aqueous acetic acid was added 2- {5-[4-(4-Cyano-2-trifluoromethyl-phenyl)-2-methyl-piperazine- 1 -sulfonyl]- thiophen-2-yl}-N-dimethylaminomethylene-3,3,3-trifluoro-2-hydroxy-propionamide (373.1 mg, 0.61 mmol). The reaction mixture was stirred at room temperature for 10 min., after which time the reaction was determined to be complete by LC/MS. The reaction mixture was then diluted with 3 mL Of H₂O and extracted with DCM. The organic layer was washed with sat.brine, dried over Na₂SO₄, and concentrated. The crude product (without any further purification) was treated with a mixture of acetic acid (3 mL) and 1,4-dioxane (3 mL). The reaction mixture was stirred at 9O⁰C for 2 hours, after which time the reaction was determined to be complete by LC/MS. The reaction mixture was cooled to room temperature, diluted with H₂O, and extracted with DCM (3x). The organic layer was washed with sat. brine, dried over Na₂SO₄, and concentrated. The crude product was purified on SiO₂ gel column to give 4-[(3i?)-3-methyl-4-({5- [2,2,2-trifluoro- 1 -hydroxy- 1 -( 1 ,2,4-oxadiazol-5-yl)ethyl]-2-thienyl} sulfonyl)piperazin- 1 - yl]-3-(trifluoromethyl)benzonitrile_as a white solid (2 mg, 0.56% Yield).

HRMS: calcd for C_2IHi₇F₆N₅O₄S₂ + H+, 582.06989; found (ESI, [M+H]+), 582.0696. Example 14.1

7V-{2,2,2-trifluoro-l-r5-ααR)-4-r4-fluoro-2-(trifluoromethyl)phenyll-2- methylpiperazin-l-yl}sulfonyl)-2-thienyll-l-methylethyl}acetamide

The title compound of Example 14.1 was prepared as shown in Scheme 14 below. Detailed synthesis procedures are provided below.

Scheme 14 H₂O

Step 14A: The starting material, (R)-l-(5-bromothiophen-2-ylsulfonyl)-4-(4- fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazine, was prepared according to procedure similar to that described in Example 1.1, steps IA- IB.

To a solution of (R)-l-(5-bromothiophen-2-ylsulfonyl)-4-(4-fluoro-2- (trifluoromethyl)phenyl)-2-methylpiperazine (4.0 g, 8.23 mmol) in anhydrous THF (30 ml) was added n-Butyllithium (5.4 mL, 8.64 mmol, 1.6 M in Hexane) at -78⁰C. The reaction mixture was stirred under N₂ for 15 min. and then trifluoromethyl ketone (2.7 mL, 30 mmol) was added. Stirring at -78⁰C was continued for 30 min. and then the reaction mixture was warmed to room temperature, quenched with a H2O, and extracted with DCM (3x). The combined organic layers were dried over MgSO₄ and purified by chromatography (CombiFlash) with DCM/Hexane to give l,l,l-trifluoro-2-[5-({(2i?)-4- [4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-l-yl}sulfonyl)-2-thienyl]propan- 2-ol as a white solid (3.89 g, 91 % yield). Step 14B: To a solution of l,l,l-trifluoro-2-[5-({(2i?)-4-[4-fluoro-2- (trifluoromethyl) phenyl] -2-methylpiperazin- 1 -yl} sulfonyl)-2-thienyl]propan-2-ol (100 mg, 0.192mmol) in MeCN (6 mL) was added sulfuric acid (0.4 rnL, 7.5 mmol) dropwise. The reaction mixture was stirred at room temperature o/n and then diluted with EtOAc, washed with H₂O, and sat. brine. Purification by column chromatography (DCM/EtOAc) afforded N-{2,2,2-trifiuoro-l-[5-({(2i?)-4-[4-fiuoro-2-(trifluoromethyl)phenyl]-2- methylpiperazin-l-yl}sulfonyl)-2-thienyl]-l-methylethyl}acetamide as light yellow solid (28 mg, 26% yield).

HRMS: calcd for C_2IH₂₂F₇N₃O₃S₂ + H+, 562.10635; found (ESI, [M+H]+), 562.1065.

The title compounds of Examples 15.1 - 15.6 were prepared as shown in Scheme 15 below. Detailed synthesis procedures are provided below.

Scheme 15

chiral column separation

Example 15.1

3,3,3-trifluoro-2-r3-({(2R)-4-r4-fluoro-2-(trifluoromethyl)phenyll-2-methylpiperazin- l-yl}sulfonyl)phenyll-2-hvdroxypropanamide

Step 15 A: The starting material, (3i?)-l-[4-fluoro-2-(trifluoromethyl)phenyl]-3- methylpiperazine, was prepared according to a procedure similar to that described in Example 1.1, step IA.

To a stirred solution of (3i?)-l-[4-fluoro-2-(trifluoromethyl)phenyl]-3- methylpiperazine (480 mg, 1.83 mmol) and diisopropylethylamine (0.64 mL, 3.66 mmol) in anhydrous dichloromethane (5 mL) was added 3-bromo benzenesulfonyl chloride (467.6 mg, 1.83 mmol). The reaction mixture was stirred at room temperature over night., after which time the reaction was determined to be complete as by TLC.

Purification of the reaction mixture via flash chromatography afforded (2i?)-l-[(3- bromophenyl)sulfonyl] -4- [4-fluoro-2-(trifluoromethyl)phenyl] -2-methylpiperazine in 59.4% yield (524 mg) as a light yellow solid.

Step 15B: To a solution of (2i?)-l-[(3-bromophenyl)sulfonyl]-4-[4-fluoro-2- (trifluoromethyl)phenyl]-2-methylpiperazine (1.0 g, 2.1 mmol) in anhydrous toluene (5 ml) was added Butyllithium (0.84 ml, 2.1 mmol) at -78⁰C. Stirring was continued under N₂ for 15 min. and then methyl 3,3,3-trifluoropyruvate (0.4 ml, 2.5 mmol) was added. The reaction mixture was stirred at -78⁰C for 2 hours and then was quenched with a few mL of 10% aq. HCl and dried over MgSO₄. Purification of the reaction mixture via chromatography (CombiFlash, 10-80% EtOAc/Hexane) afforded methyl 3,3,3-trifluoro- 2-[3-( {(2i?)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin- 1 - yl}sulfonyl)phenyl]-2-hydroxypropanoate as a colorless oil (250 mg, 21.3 % yield).

Step 15C: To a solution of 3,3,3-trifiuoro-2-[3-({(2i?)-4-[4-fiuoro-2- (trifluoromethyl) phenyl]-2-methylpiperazin- 1 -yl} sulfonyl)phenyl]-2-hydroxypropanoate (250 mg, 0.45 mmol) in 10 mL of MeOH was bubbled NH3 (g) for 30 seconds at -78⁰C. The reaction mixture was warmed up room temperature and stirred under empty balloon for o/n., after which time the reaction was determined to be complete by LC/MS. The solvent was evaporated, and the resultant residue washed with aq. NaHCO₃ solution and extracted with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated to yield 3,3,3-trifiuoro-2-[3-({(2i?)-4-[4-fiuoro-2-(trifiuoromethyl) phenyl]-2- methylpiperazin-l-yl}sulfonyl)phenyl]-2-hydroxypropanamide as a white solid (200 mg, 82% yield ).

HRMS: calcd for C₂IH₂₀F₇N₃O₄S + H+, 544.11355; found (ESI, [M+H]+), 544.1137.

Example 15.2

αS)-3,3,3-trifluoro-2-r3-ααR)-4-r4-fluoro-2-(trifluoromethyl)phenyll-2- methylpiperazin-l-yl}sulfonyl)phenyll-2-hvdroxypropanamide 200 mg of 3,3,3-trifluoro-2-[3-({(2i?)-4-[4-fluoro-2-(trifiuoromethyl) phenyl]-2- methylpiperazin-l-yl}sulfonyl)phenyl]-2-hydroxypropanamide (prepared according to a procedure similar to that described in Example 15.1, step 15A- 15 C) was separated with a chiral column (Chiralpak ADH) in SFC Analytical Instrument. Mobile Phase was 90% CO2 /10%Methanol. Early fraction was collected to give the title compound (80 mg); late fraction was collected to give the diastereomer described in Example 15.3 (92 mg).

HRMS: calcd for C₂IH₂₀F₇N₃O₄S + H+, 544.11355; found (ESI, [M+H]+), 544.1136.

Example 15.3

αR)-3,3,3-trifluoro-2-r3-ααR)-4-r4-fluoro-2-(trifluoromethyl)phenyll-2- methylpiperazin-l-yl}sulfonyl)phenyll-2-hvdroxypropanamide

The title compound was obtained as the late fraction using the separation method described in Example 15.2.

HRMS: calcd for C₂IH₂₀F₇N₃O₄S + H+, 544.11355; found (ESI, [M+H]+), 544.1135. Example 15.4

3,3i3-trifluoro-2-[4-f{f2/?)-4-[4-fluoro-2-ftrifluoromethyl)phenyll-2-methylpiperazin- l-yl}sulfonyl)phenyll-2-hvdroxypropanamide The title compound was prepared using a procedure analogous to that described in

Example 15.1, steps 15A-15C (200 mg, 82%yield), but using using 4-bromobenzene sulfonylchloride instead of 3-bromobenzene sulfonylchloride.

HRMS: calcd for C₂IH₂₀F₇N₃O₄S + H+, 544.11355; found (ESI, [M+H]+), 544.1142.

Example 15.5

αS)-3,3,3-trifluoro-2-r4-ααR)-4-r4-fluoro-2-qrifluoromethyl)phenyll-2- methylpiperazin-l-yl}sulfonyl)phenyll-2-hvdroxypropanamide 200 mg of 3,3,3-trifluoro-2-[4-({(2i?)-4-[4-fluoro-2-(trifiuoromethyl) phenyl]-2- methylpiperazin-l-yl}sulfonyl)phenyl]-2-hydroxypropanamide (prepare using a procedure similar to that described in Example 15D) was separated with a chiral column (Chiralpak ADH) in SFC Analytical Instrument. Mobile Phase was 90% CO2 /10%Methanol. Early fraction was collected to give the title compound (55 mg); late fraction was collected to give the diastereomer described in Example 15.6 (65 mg). HRMS: calcd for C_2IH₂₀F₇N₃O₄S + H+, 544.11355; found (ESI, [M+H]+), 544.1134.

Example 15.6

αR)-3,3,3-trifluoro-2-r4-ααR)-4-r4-fluoro-2-qrifluoromethyl)phenyll-2- methylpiperazin-l-yl}sulfonyl)phenyll-2-hvdroxypropanamide

The title compound was obtained as the late fraction using the separation method described in Example 15.5. HRMS: calcd for C₂IH₂₀F₇N₃O₄S + H+, 544.11355; found (ESI, [M+H]+),

544.1137.

Example 17.1

αR)-3,3,3-trifluoro-2-r5-ααR)-4-r4-fluoro-2-(trifluoromethyl)phenyll-2- methylpiperazin-l-yl}sulfonyl)thiophen-3-yll-2-hvdroxypropanamide

The title compound of Example 17.1 was prepared as shown in Scheme 17 below. Detailed synthesis procedures are provided below. Scheme 17

Step 17A: To a solution of (2i?)-2-[2-bromo-5-( {(2i?)-4-[4-fluoro-2- (trifluoromethyl)phenyl]-2-methylpiperazin-l-yl}sulfonyl)-3-thienyl]-3,3,3-trifluoro-2- hydroxypropanamide (300 mg, 0.477 mmol) in MeOH (10 mL) was added palladium 10% dry on carbon powder (30 mg, 0.282 mmol) under N₂. Then the reaction mixture was stirred under 1 atm H₂ at room temperature for over night., after which time the reaction was determined to be complete by LC/MS. The reaction mixture was filtered through a pad of celite, rinsed with EtOAc, and concentrated under reduced pressure. The crude oil was purified via prep HPLC to yield (2i?)-3,3,3-trifluoro-2-[5-({(2i?)-4-[4- fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-l-yl}sulfonyl)thiophen-3-yl]-2- hydroxypropanamide in 71.7% yield (188 mg) as a white solid. HRMS: calcd for Ci₉Hi₈F₇N₃O₄S₂ + H+, 550.06997; found (ESI, [M+H]+), 550.0694.

The title compound of Example 20.1 was prepared using a procedure analogous to that described in Example 1.1, steps IA - ID, but using l-bromo-2-chloro-4- fluorobenzene instead of 2-bromo-5-fluorobenzotrifluoride in step IA.

The title compound of Example 20.2 was prepared using a procedure analogous to that described in Example 1.1, steps IA - ID, but using l-bromo-4-fluoro-2- methylbenzene instead of 2-bromo-5-fluorobenzotrifluoride in step IA. The title compound of Example 20.3 was prepared using a procedure analogous to that described in Example 1.1, steps IA - ID, but using l-bromo-4-fluoro-2- methoxybenzene instead of 2-bromo-5-fluorobenzotrifluoride in step IA.

The title compound of Example 20.4 was prepared using a procedure analogous to that described in Example 1.1, steps IA - ID, but using l-bromo-2,4-difluorobenzene instead of 2-bromo-5-fluorobenzotrifluoride in step IA.

The title compound of Example 21.1 was prepared using a procedure analogous to that described in Example 1.1, steps IA - ID, but using methylamine instead OfNH₃ in step ID.

The title compound of Example 21.2 was prepared using a procedure analogous to that described in Example 1.1, steps IA - ID, but using dimethylamine instead of NH₃ in step ID.

Example 20.1

2-f5-{[f2R)-4-f2-chloro-4-fluorophenyl)-2-methylpiperazin-l-yllsulfonyl}thiophen-2- yl)-3.,3i3-trifluoro-2-hv<iroxvpropanamide MS (LC-ESIMS) m/z 516; MS (LC-ESIMS) m/z 514.

Example 20.2

3,3,3-trifluoro-2-(5-{[(2R)-4-(4-fluoro-2-methylphenyl)-2-methylpiperazin-l- yllsulfonyl}thiophen-2-yl)-2-hvdroxypropanamide

MS (LC-ESIMS) m/z 496.1; MS (LC-ESIMS) m/z 494.1.

Example 20.3

3,3,3-trifluoro-2-(5-{[(2R)-4-(4-fluoro-2-methoxyphenyl)-2-methylpiperazin-l- yllsulfonyl}thiophen-2-yl)-2-hvdroxypropanamide

MS (LC-ESIMS) m/z 512.1; MS (LC-ESIMS) m/z 510.

Example 20.4

2-f5-{[f2R)-4-f2,4-difluorophenyl)-2-methylpiperazin-l-yllsulfonyl}thiophen-2-yl)-

3-,3i3-trifluoro-2-hvdroxypropanamide MS (LC-ESIMS) m/z 500; MS (LC-ESIMS) m/z 498.1.

Example 21.1

3-,3.,3-trifluoro-2-[5-f{f2R)-4-[4-fluoro-2-ftrifluoromethyl)phenyll-2-methylpiperazin- l-yl}sulfonyl)thiophen-2-yll-2-hvdroxy-7V-methylpropanamide

MS (LC-ESIMS) m/z 563.3; MS (LC-ESIMS) m/z 561.5.

Example 21.2

3-,3.,3-trifluoro-2-[5-f{f2R)-4-[4-fluoro-2-ftrifluoromethyl)phenyll-2-methylpiperazin- l-yl}sulfonyl)thiophen-2-yll-2-hvdroxy-7VJV-dimethylpropanamide

HRMS: calcd for C₂IH₂₂F₇N₃O₄S₂ + H+, 578.10127; found (ESI, [M+H]+ Obs'd), 578.1017.

The chemical names and structures of the title compounds of Examples 1.1-21.2 are set forth in the table below.

Example 22

Determination of ICsn against human 1 Ib-HSDl Compounds described herein can be tested in a cell-based assay using a stable

Chinese Hamster Ovary (CHO) cell line expressing human 1 Ib-HSDl. An exemplary procedure is described below.

Cells are plated at 20,000 cells/well in 384 well plates and incubated overnight (12-16 hrs) at 37 °C/5% CO₂. Cells are treated with different concentration of compound in 90 microliter serum-free media and incubated for 30 minutes at 37 °C/5%CO2. 10 microliter of 5 uM cortisone (final concentration 500 nM) is then added to the cells and the plate is incubated at 37 °C/5%CO2 for 120 minutes. 15 microliter of media is withdrawn and amount of Cortisol in the media is measured using the DiscoverX HitHunter Cortisol Assay (DiscoverX corp, CA), following manufacturer's instructions. Briefly, 15 microliter media is transferred to white 384 well assay plate. 5 microliter of anti-cortisol antibody and 10 microliter of ED complex is added to each well of the assay plate. The assay plate is incubated at room temperature for 60 minutes with gentle shaking. Galacton Star, Emerald Green, and chemiluminescence substrate buffer are mixed 1 :5:19. The mixture is then combined in equal parts with EA complex. 20 microliter of the mix is added to each well of the assay plate and the assay plate is incubated at room temperature for another 60 minutes. The plate is read in Envision multilabel plate reader (Perkin Elmer, MA) in the enhanced luminescence mode. Background subtracted data is fitted to y = a + (b/(l+x / IC50)) and IC50 values are calculated using XLFit (IDBS, MA).

The IC50 values that were obtained for the title compounds of Examples 1.1 - 21.2 using the above-described assay are shown in Table 1.

Table 1

A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A chemical entity E, which is a compound of Formula I, or a pharmaceutically acceptable salt thereof:

wherein: R¹ is halo, -CH₃, -CH₂X, -CHX₂, -CF₃, -OCH₃ or -OCF₃;

A is phenyl, or 5- to 6-membered heteroaryl containing 1-3 ring heteroatoms independently selected from O, N, N(R^al) and S, and in which the atom bonded to the sulfonyl sulfur is carbon, wherein R^al is -H, -CH₃ or ethyl;

R⁹ is -H, halo, -CH₃, -CH₂X, -CHX₂, -CF₃, ethyl, -OCH₃ or -OCF₃; provided that when A is 5- membered heteroaryl containing 3 ring heteroatoms, then R⁹ is absent; R⁶ is -CH₃, ethyl, -OH or -OCH₃;

R⁷ is -CH₃, -CH₂X, -CHX₂, -CF₃ or phenyl, wherein said phenyl is unsubstituted or substituted with one or two substituents R^7sl independently selected from halo, -CH₃, ethyl, -CF₃, -OH and -OCH₃; R⁸ -C(O)-NH₂, -C(O)-NH-(C_L3 alkyl), -C(O)-N(C_L3 alkyl)₂, -NH-C(O)-(C_L3 alkyl), -N(C_L3 alkyl)-C(O)-(C_1-3 alkyl), or 5- to 6-membered heteroaryl containing 1-4 ring heteroatoms independently selected from O, N, N(R^8sl) and S, wherein R^8sl is -H, -CH₃ or ethyl, and wherein said heteroaryl is unsubstituted or substituted with one or two substituents R^8s2 independently selected from halo, -CH₃, ethyl, -CF₃, -OH and -OCH₃; and each instance of X is independently -F, -Cl or -Br; provided that when A is phenyl, then R⁶ and R⁷ cannot both be -CH₃.

2. The chemical entity E of claim 1, wherein A is 5- to 6-membered heteroaryl containing 1-3 ring heteroatoms independently selected from O, N, N(R^al) and S, and in which the atom bonded to the sulfonyl sulfur is carbon.

3. The chemical entity E of claim 2, wherein A is a 5-membered heteroaryl, which has formula (A-I):

in which the carbon atom shown as C in formula (A-I) represents the carbon that is bonded to the sulfonyl sulfur in Formula I; and in which A¹, A², A³, A⁴, and the dotted lines between A¹ and A⁴ and A³ and A⁴ are all defined according to the definitions under (i) below or are all defined according to the definitions under (ii) below: (i):

A¹ is singly bonded to A⁴, and A³ is doubly bonded to A⁴; AMs O₅ S, or NR^al; and one of A², A³,and A⁴ is C-C(R⁶)(R⁷)(R⁸), one of A², A³ and A⁴ is C-R⁹, and one of A², A³, and A⁴ is C-H or N; or (ii):

A¹ is doubly bonded to A⁴, and A³ is singly bonded to A⁴;

4. The chemical entity E of claim 3, wherein:

A¹ is singly bonded to A⁴, and A³ is doubly bonded to A⁴; AMs O₅ S₅ Or NR"¹; and one of A², A³,and A⁴ is C-C(R⁶)(R⁷)(R⁸), one of A², A³ and A⁴ is C-R⁹, and one of

A², A³, and A⁴ is C-H or N.

5. The chemical entity E of claim 4, wherein A¹ is S.

6. The chemical entity E of claim 5, wherein A⁴ is C-C(R⁶)(R⁷)(R⁸).

7. The chemical entity E of claim 6, wherein A² is C-H or N.

8. The chemical entity E of claim 3, wherein: A¹ is doubly bonded to A⁴, and A³ is singly bonded to A⁴;

9. The chemical entity E of claim 8, wherein A³ is NR^al .

10. The chemical entity E of claim 1, wherein

R⁶ is -OH, -OCH₃, CH₃ or ethyl; X is, independently, -F or -Cl; R¹ is -CF₃; R² is halo; R³ is -H; R⁷ is -CF₃, -CH₃ or phenyl, wherein said phenyl is unsubstituted or substituted with one or two substituents R^7sl independently selected from halo, -CH₃, ethyl, -CF₃, -OH and -OCH₃; R⁸ is -C(O)-NH₂, -C(O)-NH-(C_L3 alkyl), or -C(0)-N(d_₃ alkyl)₂, -NH-C(O)-(Ci_-3 alkyl) or -N(Ci_-3 alkyl)-C(O)-(Ci_₃ alkyl), 5- to 6-membered heteroaryl containing 1-3 ring heteroatoms independently selected from O, N, N(R^8sl) and S, wherein said heteroaryl is unsubstituted or substituted with one or two substituents R^8s2 independently selected from halo, -CH₃, ethyl, -CF₃, -OH and -OCH₃; R⁹ is -H or halo; one of R⁴ and R⁵ is H, and the other is -CH₃; wherein the carbon atom attached to R⁴ and R⁵ has the ^-configuration.

11. The chemical entity E of claim 10, wherein R⁸ is l,2,4-triazol-3-yl or l,2,4-oxadiazol-3-yl, each of which is unsubstituted or substituted with one or two substituents R^8s2 independently selected from halo, -CH₃, ethyl, -CF₃, -OH and -OCH₃; R⁶ is -OH or -CH_3; R⁴ is H, and R⁵ is -CH₃; R² is -F.

12. The chemical entity E of claim 1, wherein: R⁶ is -OH, -CH₃, or ethyl; and

R⁷ is -CF₃, -CH₃, or phenyl, wherein said phenyl is unsubstituted or substituted with one or two substituents R^7sl independently selected from halo, -CH₃, ethyl, -CF₃, -OH and -OCH₃.

13. The chemical entity E of claim 12, wherein R⁶ is -OH; R⁷ is -CF₃;

A is a 5-membered heteroaryl, which has formula (A-I):

(i):

A¹ is singly bonded to A⁴, and A³ is doubly bonded to A⁴; AMs O₅ S, or NR^al; and one of A², A³,and A⁴ is C-C(R⁶)(R⁷)(R⁸), one of A², A³ and A⁴ is C-R⁹, and one of A², A³, and A⁴ is C-H or N; or

(ii): A¹ is doubly bonded to A⁴, and A³ is singly bonded to A⁴;

14. The chemical entity E of claim 13, wherein:

A¹ is singly bonded to A⁴, and A³ is doubly bonded to A⁴;

15. The chemical entity E of claim 14, wherein A¹ is S, A⁴ is C-C(R⁶)(R⁷)(R⁸), and A² is C-H or N.

16. The chemical entity E of claim 12, wherein R⁸ is -C(O)-NH₂, -C(O)-NH-(CH₃), -C(O)-N(CHs)₂, -NH-C(O)-(CH₃), or 5-membered heteroaryl containing 1-3 ring heteroatoms independently selected from O, N, N(R^8sl) and S, wherein said heteroaryl is unsubstituted or substituted with one or two substituents R^8s2 independently selected from halo, -CH₃, ethyl, -CF₃, -OH and -OCH₃; R⁹ is -H; one of R⁴ and R⁵ is H, and the other is -CH₃; R¹ is -CF₃; R² is -F; and R³ is -H.

17. The chemical entity E of claim 16, wherein R⁸ is l,2,4-triazol-3-yl or l,2,4-oxadiazol-3-yl, each of which is unsubstituted or substituted with one or two substituents R^8s2 independently selected from halo, -CH₃, ethyl, -CF₃, -OH and -OCH₃; R⁴ is H, and R⁵ is -CH₃.

18. The chemical entity E of claim 1, wherein: R⁶ is -OH; and R⁷ is -CF₃.

A is a 5-membered heteroaryl, which has formula (A-2):

in which the carbon atom shown as C in formula (A-I) represents the carbon that is bonded to the sulfonyl sulfur in Formula I;

A¹ is singly bonded to A⁴, and A³ is doubly bonded to A⁴; AMs O₅ S, or NR^al; and one of A², A³,and A⁴ is C-C(R⁶)(R⁷)(R⁸), one of A², A³ and A⁴ is C-R⁹, and one of A², A³, and A⁴ is C-H or N;

R⁸ is -C(O)-NH₂; R⁹ is -H; R¹ is -CF_3; R² is -F; R³ is -H.; R⁴ is H; and R⁵ is -CH₃.

19. The chemical entity E of claim 18, wherein A¹ is S, A⁴ is C-C(R⁶)(R⁷)(R⁸), and A² is C-H or N.

20. The chemical entity E of claim 19, wherein A² is C-H.

21. The chemical entity E of claim 1 , wherein the chemical entity E is selected from:

3,3,3-trifluoro-2-[5-({(2R)-4-[4-fiuoro-2-(trifluoromethyl)phenyl]-2- methylpiperazin-l-yl}sulfonyl)-2-thienyl]-2-hydroxypropanamide;

(2R)-3,3,3-trifluoro-2-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2- methylpiperazin- 1 -yl} sulfonyl)thiophen-2-yl]-2-hydroxypropanamide;

(2S)-3,3,3-trifiuoro-2-[5-({(2R)-4-[4-fiuoro-2-(trifluoromethyl)phenyl]-2- methylpiperazin- 1 -yl} sulfonyl)thiophen-2-yl]-2-hydroxypropanamide;

(2R)-2-[2-bromo-5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2- methylpiperazin-l-yl}sulfonyl)-3-thienyl]-3,3,3-trifluoro-2-hydroxypropanamide; 2-[5-( {(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin- 1 - yl}sulfonyl)thiophen-2-yl]-2-hydroxypropanamide;

2-[5-( {(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin- 1 - yl}sulfonyl)thiophen-2-yl]-2-hydroxy-2-phenylacetamide; 3,3,3-trifluoro-2-[2-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2- methylpiperazin- 1 -yl} sulfonyl)- 1 ,3-thiazol-5-yl]-2-hydroxypropanamide;

(2R)-3,3,3-trifluoro-2-[2-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2- methylpiperazin- 1 -yl} sulfonyl)- 1 ,3-thiazol-5-yl]-2-hydroxypropanamide;

(2S)-3,3,3-trifiuoro-2-[2-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2- methylpiperazin- 1 -yl} sulfonyl)- 1 ,3-thiazol-5-yl]-2-hydroxypropanamide;

3,3,3-trifluoro-2-[3-({(2R)-4-[4-fiuoro-2-(trifluoromethyl)phenyl]-2- methylpiperazin- 1 -yl} sulfonyl)- 1 -methyl- IH-1 ,2,4-triazol-5-yl]-2-hydroxypropanamide;

(2R)-3,3,3-trifluoro-2-[4-({(2R)-4-[4-fluoro-2-(trifiuoromethyl)phenyl]-2- methylpiperazin- 1 -yl} sulfonyl)- 1 -methyl- 1 H-imidazol-5 -yl] -2-hydroxypropanamide; (2R)-3,3,3-trifluoro-2-[4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2- methylpiperazin- 1 -yl} sulfonyl)- 1 -methyl- 1 H-imidazol-5 -yl] -2-hydroxypropanamide;

4-[(3R)-4-{[5-(l-carbamoyl-2,2,2-trifluoro-l-hydroxyethyl)-2-thienyl]sulfonyl}- 3 -methylpiperazin- 1 -yl] -3 -(trifluoromethyl)benzamide;

2-[5-( {(2R)-4-[4-cyano-2-(trifluoromethyl)phenyl]-2-methylpiperazin- 1 - yl}sulfonyl)-2-thienyl]-3,3,3-trifluoro-2-hydroxypropanamide;

3,3,3-trifluoro-2-hydroxy-2-[5-({(2R)-2-methyl-4-[4-(3-methyl-l,2,4-oxadiazol- 5-yl)-2-(trifluoromethyl)phenyl]piperazin- 1 -yl} sulfonyl)thiophen-2-yl]propanamide;

(2S)-3,3,3-trifluoro-2-hydroxy-2-[5-({(2R)-2-methyl-4-[4-(3-methyl-l,2,4- oxadiazol-5-yl)-2-(trifluoromethyl)phenyl]piperazin-l-yl}sulfonyl)-2- thienyl]propanamide;

(2R)-3,3,3-trifiuoro-2-hydroxy-2-[5-({(2R)-2-methyl-4-[4-(3-methyl-l,2,4- oxadiazol-5-yl)-2-(trifluoromethyl)phenyl]piperazin-l-yl}sulfonyl)-2- thienyl]propanamide;

3,3,3-trifluoro-2-hydroxy-2-[5-({(2R)-2-methyl-4-[4-(l,3,4-oxadiazol-2-yl)-2- (trifluoromethyl)phenyl]piperazin- 1 -yl} sulfonyl)thiophen-2-yl]propanamide; 3,3,3-trifluoro-2-hydroxy-2-[5-({(2R)-2-methyl-4-[4-(lH-tetrazol-5-yl)-2- (trifluoromethyl)phenyl]piperazin- 1 -yl} sulfonyl)-2-thienyl]propanamide;

3,3,3-trifluoro-2-hydroxy-2-[5-({(2R)-2-methyl-4-[4-(4H-l,2,4-triazol-3-yl)-2- (trifluoromethyl)phenyl]piperazin- 1 -yl} sulfonyl)-2-thienyl]propanamide; 3,3,3-trifluoro-2-hydroxy-2-[5-({(2R)-2-methyl-4-[4-(5-methyl-4H-l,2,4-triazol-

3-yl)-2-(trifluoromethyl)phenyl]piperazin- 1 -yl} sulfonyl)-2-thienyl]propanamide;

2,2,2-trifluoro-l-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2- methylpiperazin-l-yl}sulfonyl)-2-thienyl]-l-(4H-l,2,4-triazol-3-yl)ethanol;

2,2,2-trifluoro-l-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2- methylpiperazin-l-yl}sulfonyl)-2-thienyl]-l-(5-methyl-4H-l,2,4-triazol-3-yl)ethanol;

4-[(3R)-3-methyl-4-({5-[2,2,2-trifluoro-l-hydroxy-l-(4H-l,2,4-triazol-3- yl)ethyl]-2-thienyl}sulfonyl)piperazin-l-yl]-3-(trifluoromethyl)benzamide;

4-[(3R)-3-methyl-4-({5-[2,2,2-trifluoro-l-hydroxy-l-(4H-l,2,4-triazol-3- yl)ethyl]-2-thienyl} sulfonyl)piperazin- 1 -yl]-3-(trifluoromethyl)benzonitrile; 4-[(3R)-3-methyl-4-({5-[2,2,2-trifluoro-l-hydroxy-l-(5-methyl-4H-l,2,4-triazol-

3-yl)ethyl]-2-thienyl} sulfonyl)piperazin- 1 -yl]-3-(trifluoromethyl)benzonitrile;

4-[(3R)-3-methyl-4-({5-[2,2,2-trifluoro-l-hydroxy-l-(l,2,4-oxadiazol-5-yl)ethyl]- 2-thienyl} sulfonyl)piperazin- 1 -yl]-3-(trifluoromethyl)benzonitrile;

N-{2,2,2-trifluoro-l-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2- methylpiperazin- 1 -yl} sulfonyl)-2-thienyl]- 1 -methylethyl} acetamide;

3,3,3-trifluoro-2-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2- methylpiperazin- 1 -yl} sulfonyl)phenyl]-2-hydroxypropanamide;

(2S)-3,3,3-trifluoro-2-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2- methylpiperazin- 1 -yl} sulfonyl)phenyl]-2-hydroxypropanamide; (2R)-3,3,3-trifluoro-2-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2- methylpiperazin- 1 -yl} sulfonyl)phenyl]-2-hydroxypropanamide;

3,3,3-trifluoro-2-[4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2- methylpiperazin- 1 -yl} sulfonyl)phenyl]-2-hydroxypropanamide;

(2S)-3,3,3-trifluoro-2-[4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2- methylpiperazin- 1 -yl} sulfonyl)phenyl]-2-hydroxypropanamide; (2R)-3,3,3-trifluoro-2-[4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2- methylpiperazin- 1 -yl} sulfonyl)phenyl]-2-hydroxypropanamide;

(2R)-3,3,3-trifluoro-2-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2- methylpiperazin- 1 -yl} sulfonyl)thiophen-3-yl]-2-hydroxypropanamide; 2-(5-{[(2R)-4-(2-chloro-4-fluorophenyl)-2-methylpiperazin-l- yl]sulfonyl}thiophen-2-yl)-3,3,3-trifluoro-2-hydroxypropanamide;

3 ,3 ,3 -trifluoro-2-(5 - { [(2R)-4-(4-fluoro-2-methylphenyl)-2-methylpiperazin- 1 - yl] sulfonyl} thiophen-2-yl)-2-hydroxypropanamide;

3 ,3 ,3 -trifluoro-2-(5 - { [(2R)-4-(4-fluoro-2-methoxyphenyl)-2-methylpiperazin- 1 - yl] sulfonyl} thiophen-2-yl)-2-hydroxypropanamide;

2-(5-{[(2R)-4-(2,4-difluorophenyl)-2-methylpiperazin-l-yl]sulfonyl}thiophen-2- yl)-3,3,3-trifluoro-2-hydroxypropanamide;

3,3,3-trifluoro-2-[5-({(2R)-4-[4-fiuoro-2-(trifluoromethyl)phenyl]-2- methylpiperazin- 1 -yl} sulfonyl)thiophen-2-yl]-2-hydroxy-N-methylpropanamide; and 3,3,3-trifluoro-2-[5-({(2R)-4-[4-fiuoro-2-(trifluoromethyl)phenyl]-2- methylpiperazin- 1 -yl} sulfonyl)thiophen-2-yl]-2-hydroxy-N,N-dimethylpropanamide; or a pharmaceutically acceptable salt thereof.

22. The chemical entity E of claim 1, wherein the chemical entity E is (2R)- 3,3,3-trifluoro-2-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-l- yl}sulfonyl)thiophen-2-yl]-2-hydroxypropanamide; or a pharmaceutically acceptable salt thereof.

23. A composition comprising a chemical entity E as claimed in claim 1 and a pharmaceutically acceptable carrier.

24. A method for treating a disease or condition mediated by excess or uncontrolled amounts of Cortisol and/or other corticosteroids, the method comprising administering to a subject in need thereof an effective amount of a chemical entity E as claimed in claim 1.

25. A method for treating type 2 diabetes, the method comprising administering to a subject in need thereof an effective amount of a chemical entity E as claimed in claim 1.