WO2019195775A1

WO2019195775A1 - Tolperisone analogs and methods of use

Info

Publication number: WO2019195775A1
Application number: PCT/US2019/026136
Authority: WO
Inventors: Glenn F. Short, Iii; Robert B. Perni
Original assignee: Flex Pharma, Inc.
Priority date: 2018-04-06
Filing date: 2019-04-05
Publication date: 2019-10-10

Abstract

The present invention is, in part, directed to tolperisone analogs (e.g., compounds of formula (I), (I-a), (I-b), (II), (Il-a), (III), (Ill-a), (ΙΙΙ-b), (III-c), (IV), (IV-a), (V), or (V-a)) and methods of use thereof for the treatment of various conditions including elevated muscle tone and tension (e.g., spasticity, muscle spasm). In one aspect, the tolperisone analogs disclosed herein have an additional substituent at the α-position, which blocks the generation of a β- elimination product.

Description

TOLPERISONE ANALOGS AND METHODS OF USE

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority to, and the benefits of U.S. Provisional Patent Application Serial No. 62/654,007, filed April 6, 2018, and to U.S. Provisional Patent

Application Serial No. 62/753,237, filed October 31, 2018, both of which are incorporated herein by reference in their entireties.

BACKGROUND

Tolperisone is a voltage -gated sodium and calcium ion channel blocker and a centrally- acting muscle relaxant that has been used for the symptomatic treatment of conditions such as spasticity and muscle spasm. Tolperisone is known to exhibit membrane-stabilizing effects in the central and peripheral nervous system. Tolperisone and similar structurally related muscle relaxants (e.g., eperisone, inaperisone, and lanperisone) undergo b-elimination at basic pH. For example, during the synthesis of tolperisone, a small amount of the b-elimination product, 4- MMPPO (2-methyl- 1 -(4- methylphenyl)-3-(-piperidinyl)-l-propanone) is generated. 4-MMPPO is known to be genotoxic, that is, capable of causing genetic mutation and potentially contributing to the development of tumors.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a compound of formula (I):

pharmaceutically acceptable salt thereof, wherein:

R is selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and halide, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more halides; each of R₂ and R _¾ is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, and halide, wherein the alkyl, alkeynyl, alkynyl, or cycloalkyl is optionally substituted with one or more halides; or

R₂ and R₃ can be taken together to form a cycloalkyl or heterocyclyl; R₄ is selected from the group consisting of: -N(R_a)₂, -ORj,, -SR_C, heterocyclyl, heteroaryl, and aryl, wherein the heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more substituents independently selected from the group consisting of: alkyl, -N(R_a)₂, -OR_b, and -SR_C; n is 0, 1, 2, or 3; each of R_a, ¾, and R_c is independently an alkyl or aryl, wherein the alkyl or aryl is optionally substituted with one or more substituents independently selected from the group consisting of: alkyl, -N(R_d)₂, -OR_e, and -SR_f; and each of R _|, R_e, and R_f is alkyl or aryl; wherein the compound is not a compound selected from:

pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of formula (I-a):

pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In some embodiments, the compound is a compound of formula (I-b):

pharmaceutically acceptable salt thereof, wherein the variables as defined herein.

In another aspect, the present invention provides a compound of formula (II):

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In some embodiments, the compound is a compound of formula (Il-a):

In another aspect, the present invention provides a compound of formula (III):

In some embodiments, the compound is a compound of formula (Ill-a):

In some embodiments, the compound is a compound of formula (Ill-b):

In some embodiments, the compound is a compound of formula (III-c):

In another aspect, the present invention provides a compound of formula (IV):

In some embodiments, the compound is a compound of formula (IV-a):

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 38.

In another aspect, the present invention provides a compound of formula (V):

In some embodiments, the compound is a compound of formula (V-a):

In another aspect, the present invention provides a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of formula (I), (I-a), (I-b), (II), (Il-a), (III), (III-a), (Ill-b), (III-c), (IV), (IV-a), (V), or (V-a)) and a pharmaceutically acceptable excipient. The aspects and embodiments of the invention will now be exemplified in a non-limiting manner with reference to the detailed description, the examples and accompanying figures.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 ; Shows Voltage-gated Sodium Ion Channel Inhibition by Tolperisone.

FIG. 2 ; Shows Voltage-gated Sodium Ion Channel Inhibition by Example 1. FIG. 3 ; Shows Inhibition of the Group II Flexor Reflex Recordings in Rats by Example

2 in Comparison to Saline Vehicle.

FIG. 4 ; Shows Summary Time course of Flexor Reflex Responses in Rats mediated by Group II afferents after administration of vehicle, tolperisone-HCl, the compound of Example 2 and diazepam. Tolperisone-HCl, and the compound of Example 2 were administered at 10 mg/kg, iv. Diazepam was administered at 2.5mg/kg iv. **, *** P < 0.01 and 0.001, compared to saline vehicle group, one-way ANOVA. n =3 for diazepam group, n=8 for other groups. DETAILED DESCRIPTION OF THE INVENTION

The present invention, in part, provides compounds (e.g., a compound of formula (I), (I- a), (I-b), (II), (Il-a), (III), (III-a), (Ill-b), (III-c), (IV), (IV-a), (V), or (V-a)) and methods of use thereof for the treatment of various conditions, for example, elevated muscle tone and tension (e.g., spasticity, muscle spasm). In some embodiments, the compounds disclosed herein (e.g., a compound of formula (I), (I-a), (I-b), (II), (Il-a), (III), (III-a), (Ill-b), (III-c), (IV), (IV-a), (V), or (V-a)) are voltage gated sodium and calcium ion channel blockers. In one aspect, the present invention provides compounds that are structurally related to tolperisone. In some embodiments, the tolperisone analogs disclosed herein (e.g., a compound of formula (I), (I-a), (I-b), (II), (Il-a), (III), (III-a), (Ill-b), (III-c), (IV), (IV-a), (V), or (V-a)) have an additional substituent at the ex position (e.g., alkyl, fluoride), which blocks the generation of a b-elimination product.

Generally, 4-MMPPO, the b-elimination product of tolperisone, is known to be genotoxic.

Moreover, 4-MMPPO may be the cause of anaphylaxis and hypersensitivity reactions observed in humans treated with tolperisone. In one aspect of the invention, the compounds disclosed herein (e.g., a compound of formula (I), (I-a), (I-b), (II), (Il-a), (III), (III-a), (Ill-b), (III-c), (IV), (IV-a), (V), or (V-a)) completely eliminate formation of b-elimination products like 4-MMPPO and prevent genotoxic side effects and hypersensitive reactions in patients. In some

embodiments, the present invention provides pharmaceutical compositions comprising a compound of the present invention. In some embodiments, methods for the treatment of conditions such as elevated muscle tone and tension, for example, muscle spasm and spasticity (e.g., hyperreflexia, inhibition of spinal reflexes, inhibition of monosynaptic spinal reflexes) are disclosed herein.

Compounds

In one aspect, the present invention provides a compound of formula (I):

pharmaceutically acceptable salt thereof, wherein:

R₂ and R₃ can be taken together to form a cycloalkyl or heterocyclyl; R₄ is selected from the group consisting of: -N(R_a)₂, -OR_b, -SR_C, heterocyclyl, heteroaryl, and aryl, wherein the heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more substituents independently selected from the group consisting of: alkyl, -N(R_a)₂, -OR_b, and -SR_C; n is 0, 1, 2, or 3; each of R_a, R_b, and R_c is independently an alkyl or aryl, wherein the alkyl or aryl is optionally substituted with one or more substituents independently selected from the group consisting of: alkyl, -N(R_d)₂, -OR_e, and -SR_f; and each of R_lb R_e, and R_f is alkyl or aryl; wherein the compound is not a compound selected from:

pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of formula (I-a):

pharmaceutically acceptable salt thereof, wherein:

R is selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and halide, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more halides; each of R₂ and R₃ is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, and halide, wherein the alkyl, alkeynyl, alkynyl, or cycloalkyl is optionally substituted with one or more halides; or R and R₃ can be taken together to form a cycloalkyl;

R₄ is selected from the group consisting of: -N(R_a)₂, -OR_b, -SR_C, heterocyclyl, heteroaryl, and aryl, wherein the heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more substituents independently selected from the group consisting of: alkyl, -N(R_a)₂, -OR_b, and -SR_C; each of R_a, R_b, and R_c is independently an alkyl or aryl, wherein the alkyl or aryl is optionally substituted with one or more substituents independently selected from the group consisting of: alkyl, -N(R_d)₂, -OR_e, and -SR_f; each of R _|, R_e, and R_f is alkyl or aryl; and n is 0, 1, 2, or 3; wherein the compound is not a compound selected from:

pharmaceutically acceptable salt thereof.

In some embodiments, R is alkyl or halogen, wherein the alkyl is substituted with 1, 2, or 3 halogens. In some embodiments, Rj is selected from the group consisting of methyl, ethyl, F, CF3,

CH2CF3, and CF2CF3.

In some embodiments, R is selected from the group consisting of methyl, F, CF3, and CH2CF3.

In some embodiments, one of R₂ and R₃ is halide and the other is alkyl. In some embodiments, one of R₂ and R₃ is fluoride.

In some embodiments, one of R₂ and R₃ is fluoride and the other is methyl.

In some embodiments, R₂ and R₃ are taken together to form a cycloalkyl.

In some embodiments, R₂ and R₃ are taken together to form a cyclopropyl or cyclobutyl. In some embodiments, R₂ and R₃ are alkyl.

In some embodiments, R₂ and R₃ are methyl.

In some embodiments, R₄ is -N(R_a)₂ or heterocyclyl.

In some embodiments, R₄ is selected from the group consisting of:

In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1. In some embodiments, n is 1 and R is at the para-position of the phenyl.

In some embodiments, the compound is a compound of formula (I-b):

In another aspect, the present invention provides a compound of formula (II):

pharmaceutically acceptable salt thereof, wherein:

R ] is selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, and halogen, wherein alkyl, alkenyl, alkynyl, and cycloalkyl, are optionally substituted with one or more halogen;

R₃ is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, and halogen, wherein the alkyl, alkeynyl, alkynyl, and cycloalkyl are optionally substituted with one or more halogen; R4 is selected from the group consisting of: -N(R_a)2, -OR_b, -SR_C, and heterocyclyl; each of R_a, ¾, and R_c is independently an alkyl; and n is 0, 1, 2, or 3.

In some embodiments, the compound is a compound of formula (Il-a):

In some embodiments, R is alkyl or halogen, wherein the alkyl is substituted with 1, 2, or 3 halogens.

In some embodiments, Ri is selected from the group consisting of methyl, ethyl, F, CF₃, CH2CF₃, and CF₂CF₃.

In some embodiments, R is selected from the group consisting of methyl, F, CF₃, and CH2CF₃.

In some embodiments, R₃ is alkyl.

In some embodiments, R₃ is methyl. In some embodiments, R₄ is -N(R_a)2 or heterocyclyl.

In some embodiments, R₄ is selected from the group consisting of:

In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1. In some embodiments, n is 1 and R is at the para-position of the phenyl. In another aspect, the present invention provides a compound of formula (III):

pharmaceutically acceptable salt thereof, wherein:

R is selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, and halogen, wherein alkyl, alkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more halogen;

R₄ is selected from the group consisting of: -N(R_a)₂, -OR,, -SR_C, and heterocyclyl;

R₆ is independently, for each occurrence, selected from the group consisting of: -CH₂-, - NR_a-, -0-, and -S-; each of R_a, R_b, and R_c is independently an alkyl; m is 2, 3, 4, or 5; and n is 0, 1, 2, or 3.

In some embodiments, the compound is a compound of formula (Ill-a):

In some embodiments, the compound is a compound of formula (Ill-b):

R₄ is selected from the group consisting of: -N(R_a)₂, -0¾, -SR_C, and heterocyclyl; each of R_a, R_b, and R_c is independently an alkyl; m is 2 or 3; and n is 0, 1, 2, or 3.

In some embodiments, the compound is a compound of formula (III-c):

In some embodiments, Ri is selected from the group consisting of methyl, ethyl, F, CF₃, CH₂CF₃, and CF₂CF₃. In some embodiments, R is selected from the group consisting of methyl, F, CF₃, and

CH₂CF₃.

In some embodiments, R₄ is -N(R_a)₂ or heterocyclyl.

In some embodiments, R₄ is selected from the group consisting of:

In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1. In some embodiments, n is 1 and R is at the para- position of the phenyl.

In another aspect, the present invention provides a compound of formula (IV):

pharmaceutically acceptable salt thereof, wherein:

Ri is selected from the group consisting of: alkyl, alkenyl, alkynyl, and cycloalkyl; wherein the alkyl is substituted with one or more halogen; wherein the alkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more halogen;

R and R are independently alkyl; R₄ is selected from the group consisting of: -N(R_a)₂, -ORj,, -SR_C, and heterocyclyl; each of R_a, R_b, and R_c is independently an alkyl; and n is 0, 1, 2, or 3.

In some embodiments, the compound is a compound of formula (IV-a):

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein. In some embodiments, R is alkyl substituted with 1, 2, or 3 halogens.

In some embodiments, Ri is CF3 or CH₂CF3.

In some embodiments, R and R are methyl.

In some embodiments, R is -N(R or heterocyclyl. In some embodiments, R₄ is selected from the group consisting of:

In another aspect, the present invention provides a compound of formula (V):

pharmaceutically acceptable salt thereof, wherein:

R₂ and R₃ are independently alkyl;

R₄ is selected from the group consisting of: -N(R_a)₂, -OR_b, -SR_C, and heterocyclyl; wherein the heterocyclyl is not piperidinyl or pyrrolidinyl; each of R_a, R_b, and R_c is independently an alkyl; and n is 0, 1, 2, or 3.

In some embodiments, the compound is a compound of formula (V-a):

pharmaceutically acceptable salt thereof, wherein the variables are as defined herein. In some embodiments, R is alkyl substituted with 1, 2, or 3 halogens.

In some embodiments, R is selected from the group consisting of: methyl, ethyl, F, CF_¾,

CH₂CF₃, and CF2CF3.

In some embodiments, R₂ and R₃ are methyl.

In some embodiments, R4 is -N(R_a)2 or heterocyclyl, wherein the heterocyclyl is not piperidinyl or pyrrolidinyl.

In some embodiments, R4 is selected from the group consisting of:

In some embodiments, the compound is selected from the group consisting of:

, and a pharmaceutically acceptable salt thereof.

Methods of Synthesizing Compounds of the Invention

Exemplary general synthetic protocols for preparation of compounds disclosed herein (e.g., a compound of formula (I), (I-a), (I-b), (II), (Il-a), (III), (III-a), (Ill-b), (III-c), (IV), (IV-a), (V), or (V-a)) are presented in Schemes 1 through 3. The schemes and accompanying description of synthetic procedures are given for the purpose of illustrating the invention, and should not be construed as limiting the scope of the invention.

Scheme 1. Synthesis of fluorinated analogues

formaldehyde

or

₄

wherein R , R _¾, R4 and n are as defined above for the compounds of formula (I).

Fluorinated analogs are prepared generally following the procedure depicted in Scheme 1. Depending on the structures of the variables, slight modifications (e.g., installation and removal of a protecting group) may be required. Exemplary synthetic schemes of aryl starting materials and fluorinated piperidine analogs are provided below.

Scheme lb. Synthesis of aryl starting materials

Aryl starting materials are prepared by simple modifications of commercially available materials. Two examples for synthesizing aryl starting materials are shown above. Scheme lc. Synthesis of fluorinated piperazine analogues

Fluorinated piperazine analogs are prepared generally following the procedure depicted in Scheme lc. Depending on the structures of the variables, slight modifications may be necessary.

Scheme 2: Synthesis of dialkyl analogues

R-i = alkyl, alkenyl, alkynyl, cycloalkyl, halide R_2, R₃ = alkyl, alkenyl, alkynyl, cycloalkyl, and halide

(e.g.,CH₃, CH₃CH₂ F, CF₃, CF₃CH₂) R₄ = -N(R_a)₂, heterocyclyl

n = 0, 1 , 2, or 3 R_a = alkyl, aryl, or heteroaryl

Dialkyl analogs are prepared generally following the procedure depicted in Scheme 2.

Depending the structure of the variables, slight modifications may be required. Starting materials are commercially available or prepared by simple modifications of commercially available materials.

Scheme 3: Synthesis of spiro-analogues

Spiro-analogs are prepared by the procedure depicted in Scheme 3. Starting materials for the synthetic sequence shown above are commercially available where m = 2 or 3. Pharmaceutical Compositions

In one aspect, the invention provides a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of formula (I), (I-a), (I-b), (II), (Il-a), (III), (Ill-a), (III-b), (III-c), (IV), (IV-a), (V), or (V-a)); also referred to as the“active ingredient”) and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the

pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a

prophylactically effective amount of the active ingredient.

The pharmaceutical compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.

Oral dosage forms include tablets, lozenges, capsules, syrups, oral suspensions, emulsions, granules, and pellets. For example, tablets can be made by compression or molding, optionally with one or more accessory ingredients or additives. Compressed tablets are prepared, for example, by compressing in a suitable tableting machine, the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) and/or surface-active or dispersing agent.

Molded tablets are made, for example, by molding in a suitable tableting machine, a mixture of powdered compounds moistened with an inert liquid diluent. The tablets may optionally be coated or scored, and may be formulated so as to provide slow or controlled release of the active ingredients, using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with a coating, such as a thin film, sugar coating, or an enteric coating to provide release in parts of the gut other than the stomach. Processes, equipment, and toll manufacturers for tablet and capsule making are well-known in the art.

Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.

When used to prevent the onset of a condition or disorder such as elevated muscle tone and tension (e.g., spasticity and muscle spasm), the compounds provided herein will be administered to a subject at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Subjects at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.

The pharmaceutical compositions provided herein can also be administered chronically (“chronic administration”). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc, or may be continued indefinitely, for example, for the rest of the subject’s life. In certain embodiments, the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time.

The pharmaceutical compositions of the present invention may be further delivered using a variety of dosing methods. For example, in certain embodiments, the pharmaceutical composition may be given as a bolus, e.g., in order to raise the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the systemic levels of the active ingredient desired throughout the body, e.g., an intramuscular or subcutaneous bolus dose allows a slow release of the active ingredient, while a bolus delivered directly to the veins (e.g., through an IV drip) allows a much faster delivery which quickly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, e.g., by IV drip, to provide maintenance of a steady-state concentration of the active ingredient in the subject’s body. Furthermore, in still yet other embodiments, the pharmaceutical composition may be administered as first as a bolus dose, followed by continuous infusion.

The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term“unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form.

Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

The above-described components for orally administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing

Company, Easton, Pennsylvania, which is incorporated herein by reference.

The compounds disclosed herein (e.g., a compound of formula (I), (I-a), (I-b), (II), (Il-a), (III), (III-a), (Ill-b), (III-c), (IV), (IV-a), (V), or (V-a)) can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.

The present invention also relates to the pharmaceutically acceptable acid addition salt of a compound of the present invention. The acid which may be used to prepare the pharmaceutically acceptable salt is that which for s a non-toxic acid addition salt, i.e., a salt containing pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient.

Pharmaceutically acceptable excipients include any and all diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, preservatives, lubricants and the like, as suited to the particular dosage form desired, e.g., injection. General considerations in the formulation and/or manufacture of pharmaceutical compositions agents can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21^st Edition (Lippincott Williams & Wilkins, 2005).

Exemplary excipients include, without limitation, polyethylene glycol (PEG), hydrogenated castor oil (HCO), cremophors (polyethoxylated castor oil), carbohydrates, starches (e.g., corn starch), inorganic salts, antimicrobial agents, antioxidants, binders/fillers, surfactants, lubricants (e.g., calcium or magnesium stearate), glidants such as talc, disintegrants, diluents, buffers, acids, bases, film coats, combinations thereof, and the like.

A composition of the invention may include one or more carbohydrates such as a sugar, a derivatized sugar such as an alditol, aldonic acid, an esterified sugar, and/or a sugar polymer. Specific carbohydrate excipients include, for example: monosaccharides, such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), pyranosyl sorbitol, myoinositol, and the like.

Also suitable for use in the compositions of the invention are potato and corn-based starches such as sodium starch glycolate and directly compressible modified starch.

Further representative excipients include inorganic salts or buffers such as citric acid, sodium chloride, potassium chloride, sodium sulfate, potassium nitrate, sodium phosphate monobasic, sodium phosphate dibasic, and combinations thereof.

A composition of the present invention may also include an antimicrobial agent, e.g., for preventing or deterring microbial growth. Non-limiting examples of antimicrobial agents suitable for the present invention include benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, thimersol, and combinations thereof. A composition as provided herein may also contain one or more antioxidants.

Antioxidants are used to prevent oxidation, thereby preventing the deterioration of the tolperisone or other components of the preparation. Suitable antioxidants for use in the present invention include, for example, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, and combinations thereof.

Additional excipients include surfactants such as polysorbates, e.g., "Tween 20" and "Tween 80," and pluronics such as F68 and F88 (both of which are available from BASF,

Mount Olive, N.J.), sorbitan esters, lipids (e.g., phospholipids such as lecithin and other phosphatidylcholines, and phosphatidylethanolamines), fatty acids and fatty esters, steroids such as cholesterol, and chelating agents, such as EDTA, zinc and other such suitable cations.

Further, as described previously, a composition of the invention may optionally include one or more acids. Non-limiting examples of acids that can be used include those acids selected from the group consisting of hydrochloric acid, acetic acid, phosphoric acid, citric acid, succinic acid, adipic acid, propionic acid, toluenesulfonic acid, methanesulfonic acid, malic acid, lactic acid, formic acid, trichloroacetic acid, nitric acid, perchloric acid, phosphoric acid, sulfuric acid, fumaric acid, and combinations thereof.

The amount of any individual excipient in the composition will vary depending on the role of the excipient, the dosage requirements of the active agent (e.g., a compound of formula (I)), and particular needs of the composition. Typically, the optimal amount of any individual excipient is determined through routine experimentation, i.e., by preparing compositions containing varying amounts of the excipient (ranging from low to high), examining the stability and other parameters, and then determining the range at which optimal performance is attained with no significant adverse effects.

Generally, however, the excipient will be present in the composition in an amount of about 1% to about 99% by weight, preferably from about 5% to about 98% by weight, more preferably from about 15 to about 95% by weight of the excipient. In general, the amount of excipient present in a tolperisone composition of the invention is selected from the following: at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or even 95% by weight.

A formulation for oral administration may, for example, contain from about 50 to about 750 mg of a compound disclosed herein (e.g., a compound of formula (I), (I-a), (I-b), (II), (Il-a), (III), (III-a), (Ill-b), (III-c), (IV), (IV-a), (V), or (V-a)), for example, from about 100 to about 500 mg of a compound disclosed herein (e.g., a compound of formula (I), (I-a), (I-b), (II), (Il-a), (III), (Ill-a), (Ill-b), (III-c), (IV), (IV-a), (V), or (V-a)). For example, formulations for oral administration may, in certain instances, contain any one of the following amounts of a compound disclosed herein (e.g., a compound of formula (I), (I-a), (I-b), (II), (Il-a), (III), (Ill-a), (Ill-b), (III-c), (IV), (IV-a), (V), or (V-a)): 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg of a compound disclosed herein (e.g., a compound of formula (I), (I-a), (I-b), (II), (Il-a), (III), (III-a), (Ill-b), (III-c), (IV), (IV-a), (V), or (V-a)).

The foregoing pharmaceutical excipients along with other excipients are described in "Remington: The Science & Practice of Pharmacy", l9.sup.th ed., Williams & Williams,

(1995), the "Physician's Desk Reference", 52.sup.nd ed., Medical Economics, Montvale, N.J. (1998), and Kibbe, A. H., Handbook of Pharmaceutical Excipients, 3.sup.rd Edition, American Pharmaceutical Association, Washington, D.C., 2000.

Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, response of the individual patient, the severity of the patient’s symptoms, and the like.

The compositions are presented in unit dosage forms to facilitate accurate dosing. The term“unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampules or syringes of the liquid compositions. In such compositions, the compound is usually a minor component (from about 0.1% to about 50% by weight or preferably from about 1% to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.

Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. General considerations in the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 2l^st ed., Lippincott Williams & Wilkins, 2005. Dosage

The compositions of the present invention are formulated into acceptable dosage forms by conventional methods known to those of skill in the art. Actual dosage levels of the active ingredients in the compositions of the present invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, without being toxic to the subject. The selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, the route of administration, the time of administration, the rate of absorption of the particular agent being employed, the duration of the treatment, other drugs, substances, and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and like factors well known in the medical arts. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the composition required. For example, the physician or veterinarian can start doses of the substances of the invention employed in the composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, a suitable daily dose of a composition of the invention will be that amount of the substance which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Preferably, the effective daily dose of a therapeutic composition may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.

The frequency of treatment may also vary. The subject can be treated one or more times per day (e.g., once, twice, three, four or more times) or every so-many hours (e.g., about every 2, 4, 6, 8, 12, or 24 hours). The composition can be administered 1, 2, or 3 times per 24 hours.

The time course of treatment may be of varying duration, e.g., for two, three, four, five, six, seven, eight, nine, ten, or more days, two weeks, 1 month, 2 months, 4 months, 6 months, 8 months, 10 months, or more than one year. For example, the treatment can be twice a day for three days, twice a day for seven days, twice a day for ten days. Treatment cycles can be repeated at intervals, for example weekly, bimonthly or monthly, which are separated by periods in which no treatment is given. The treatment can be a single treatment or can last as long as the life span of the subject (e.g., many years).

A therapeutic amount of a compound disclosed herein (e.g., a compound of formula (I), (I-a), (I-b), (II), (Il-a), (III), (III-a), (Ill-b), (III-c), (IV), (IV-a), (V), or (V-a)) can be empirically determined and will vary with the particular condition being treated, the subject, and the like. The actual dose to be administered will vary depending upon the age, weight, and general condition of the subject as well as the severity of the condition being treated, the judgment of the health care professional, and particular dosage form being administered.

A therapeutically effective amount of tolperisone can be determined by those skilled in the art, and will be adjusted to the requirements of each particular case. Generally, a

therapeutically effective amount of tolperisone for an adult will range from a total daily dosage of between about 10 and 3000 mg/day, preferably, in an amount between 25-2000 mg/day, more preferably, in an amount between about 50-1800 mg/day. Typical dosage ranges for adults include total daily dosage ranges from about 150-1000 mg/day, preferably from about 150 to about 750 mg/day, from about 150 to about 400 mg/day, administered as either a single dosage or as multiple dosages. Preferred in certain embodiments are divided dosages over the course of a day, e.g., a recommended daily dose divided into five doses, or four doses, or three doses, or two doses. Preferred dosage amounts include dosages from about 50 mg to 450 mg twice daily or three times daily. That is to say, dosage amounts may be selected from 50 mg/day, 100 mg/day, 150 mg/day, 200 mg/day, 250 mg/day, 300 mg/day, 350 mg/day, 400 mg/day, 450 mg/day, 500 mg/day or more.

Depending upon the dosage amount and precise condition to be treated, administration can be one, two, or three times daily for a time course of one day to several days, weeks, months, and even years, and may even be for the life of the patient. Illustrative dosing regimes will last a period of at least about a day, a week, from about 1-4 weeks, from 1-3 months, from 1-6 months, from 1-50 weeks, from 1-12 months, or longer. Dosage amounts for children ranging in age from 3 months to 18 years in age range from about 1-25 mg/kg/day, preferably from about 2-15 mg/day, in from about 2-4 divided doses, preferably 3 doses. Exemplary recommended dosage ranges for children Include 5-10 mg/kg/day and from 2-4 mg/kg/day, in 2-3 divided doses.

With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg/kg of the compound provided herein, with preferred doses each providing from about 0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg.

Methods of Treatment

In one aspect, the present invention provides a method of treating diseases or conditions (e.g., elevated muscle tone and tension) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-a), (I-b), (II), (Il-a), (III), (III-a), (Ill-b), (III-c), (IV), (IV-a), (V), or (V-a)) or a pharmaceutical composition disclosed herein. In another aspect, the present invention provides the use in the manufacture of a medicament of a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-a), (I-b), (II), (Il-a), (III), (III-a), (Ill-b), (III-c), (IV), (IV-a), (V), or (V-a)) or a pharmaceutical composition disclosed herein for treating diseases or conditions (e.g., elevated muscle tone and tension) in a subject in need thereof, comprising administering to the subject.

In another aspect, the present invention provides the use of a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-a), (I-b), (II), (Il-a), (III), (III-a), (Ill-b), (III-c), (IV), (IV-a), (V), or (V-a)) or a pharmaceutical composition disclosed herein for treating diseases or conditions (e.g., elevated muscle tone and tension) in a subject in need thereof, comprising administering to the subject.

The compounds disclosed herein (e.g., a compound of formula (I), (I-a), (I-b), (II), (Il-a), (III), (III-a), (Ill-b), (III-c), (IV), (IV-a), (V), or (V-a)) are a centrally-acting muscle relaxant that acts on the central nervous system and is used mainly for the treatment of elevated muscle tone and tension, as well as for certain circulatory problems in the extremities. For example, the compounds disclosed herein (e.g., a compound of formula (I), (I-a), (I-b), (II), (Il-a), (III), (Ill-a), (Ill-b), (III-c), (IV), (IV-a), (V), or (V-a)) may be used in the treatment of pathologically increased tone of the cross-striated muscle caused by neurological diseases (damage of the pyramidal tract, multiple sclerosis, myelopathy, encephalomyelitis), for example, post-stroke spasticity, and of spastic paralysis and other encephalopathies manifested with muscular dystonia. Tolperisone has been found to reduce experimental hypertonia and decerebration rigidity, as well as inhibit reticulospinal reflex facilitation without affecting cortical functions. It also improves peripheral blood flow.

The compounds disclosed herein (e.g., a compound of formula (I), (I-a), (I-b), (II), (Il-a), (III), (III-a), (Ill-b), (III-c), (IV), (IV-a), (V), or (V-a)) are useful in treating a number of conditions. For example, the compound disclosed herein (e.g., a compound of formula (I), (I-a), (I-b), (II), (Il-a), (III), (III-a), (Ill-b), (III-c), (IV), (IV-a), (V), or (V-a)) may be administered to a subject suffering from one of more of the following conditions including: muscle spasm, spasticity (e.g., hyperreflexia, inhibition of spinal reflexes, inhibition of monosynaptic spinal reflexes) or spastic syndromes, muscle soreness, myotonia, dysmenorrhea, climacteric complaints, lockjaw, neurolatyrism, osteoarthritis or rheumatoid arthritis (when administered in combination with a non-steroidal anti-inflammatory drug), rheumatic diseases, fibromyalgia syndrome, occupational and sport-related stress, back pain, spasticity caused by neurological diseases, multiple sclerosis, myelopathy, encephalomyelitis, stroke, muscular hypertension, muscular contracture, spinal automatism, obliterative vascular diseases (e.g., obliterative arteriosclerosis, diabetic angiopathy, obliterative thromboangitis, Raynaud's disease, diffuse scleroderma), disorders due to injured innervation of the vessels (acrocyanosis, intermittent angioneurotic dysbasis), neuropathic pain, and in individual cases, post-thrombotic venous and lymphatic circulation disorders, diabetic neuropathy, post-herpetic neuralgia, and crural ulcer, spondylosis, spondylarthrosis, cervical and lumbar syndromes, arthrosis of the large joints, obliterating atherosclerosis of the extremity vessels. Subjects to whom tolperisone may be administered include both children (aged three months to 18 years), and adults (18 years and older).

EXAMPLES

GENERAL EXPERMENTAL

Unless otherwise noted, all materials/reagents were obtained from commercial suppliers and used without further purification. Reactions were monitored by LC-MS and/or thin layer chromatography (TLC) on silica gel 60 F254 (0.2mm) pre-coated aluminum foil or glass-backed and visualized using UV light.

^JH NMR (400 MHz) spectra were recorded on Bruker spectrometers at ambient temperature with TMS or the chloroform residual solvent peak as the internal standard. The line positions or multiples are given in ppm (d) and the coupling constants (J) are given as absolute values in hertz (Hz). The multiplicities in ¹ H NMR spectra are abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br or broad (broadened).

Preparative HPLC purifications were performed on a Shimadzu LC-6AD instrument using Shim-pack PREP-DDS(H)KIT columns. The mobile phases were water (with 0.1% HC(¾H) and acetonitrile; all reagents used were of HPLC grade. The flow rate was 10 ml/min.

LC-MS determinations were performed on a Shimadzu LCMS-2020 instrument equipped with LC-20AD or 30AD pumps, SPD-M20A PDA and Alltech 3300 ELSD pumps; Mobile Phase: A: Water (0.1% Formic acid), B:CAN; 5 minute run; ColummSepax BR-C18 4.6*50 mm, 3 mpi; Flow Rate: 1.0ml/min; Oven Temperature: 40°C; Gradient: 20% B for 0.2 min, increase to 70% B within 1.8 min, 70% B for 2.8 min, back to 20% B within 0.2 min, 20% B for 2 min).

Preparative TLC was performed on WhatmanLK6F Silica Gel 60A size 20x20 cm plates with a thickness of 1000 pm or equivalent. Example 1. Synthesis of 2-Fluoro-2-methyl-l-(4-methylphenyl)-3-(l-piperidinyl)-l- propanone

reflux, 78h

Step 1: Preparation of Tolperisone, 2-methyl-l-(4-methylphenyl)-3-(l-piperidinyl)-l-propanone To a solution of l-(4-methylphenyl)propan-l-one (1.0 g, 6.76 mmol) in methanol (5 mL) was added piperidine (976 mg, 11.5 mmol) and paraformaldehyde (264 mg, 8.79 mmol) at room temperature, followed by the addition of hydrochloric acid in dioxane (4M, 3.5 mL). The reaction mixture was then refluxed for 78 hours. TLC analysis showed the reaction to be complete. The mixture was cooled to room temperature and concentrated. The residue was dissolved into dichloromethane (100 mL) and washed with water (60 mL). The organic layer was collected, washed with brine (60 mL), dried over anhydrous sodium sulfate, and

concentrated under reduced pressure to give crude residue which was purified by silica gel flash column chromatography (eluted with 2% methanol in dichloromethane) to afford 2-methyl-l- (4- methylphenyl)-3-(l-piperidinyl)-l-propanone (150 mg, 7%) as a light yellow solid. ¹ H NMR (400 MHz, CDCL): d 1.18 (d, J = 9.2 Hz, 3H), 1.35-1.41 (m, 2H), 1.50-1.55 (m, 4H), 2.42-2.45 (m, 8H), 2.86-2.91 (m, 1H), 3.74-3.79 (m, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.89 (d, J = 8.4 Hz, 2H). C₁₆H₂₃NO; MW: 245.36; LCMS: (ES+): m/z 246.4 [M+H] ⁺. t_R = 1.852 min;

Step 2: Preparation of 2-Fluoro-2-methyl-l-(4-methylphenyl)-3-(l-piperidinyl)-l- propanone A solution of lithium bis(trimethylsilyl)amide (LiHMDS) (1M in THF, 0.734 mL) was added dropwise to a solution of 2-methyl-l-(4-methylphenyl)-3-(l-piperidinyl)-l-propanone (120 mg, 0.49 mmol) in anhydrous THF (4 mL) at -65°C under a nitrogen atmosphere. The resulting mixture was warmed to 0°C and stirred for 1 hour. The reaction mixture was then cooled to -40°C and a solution of N-fluorobenzenesulfonimide (NFSI) (185 mg, 0.59 mmol) in anhydrous THF (2 mL) was added dropwise. The resulting mixture was allowed to warm to room temperature slowly and stirred about 1.5 h. TLC showed the reaction was complete. The reaction mixture was quenched with aqueous ammonium chloride and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (eluted with 20% ethyl acetate in hexane) to afford 2-fluoro-2-methyl-l-(4-methylphenyl)-3-(l-piperidinyl)-l-propanone (50 mg, 39%) as a colorless oil. ^JH NMR (400 MHz, CDCl₃): d 1.31-1.35 (m, 2H), 1.41-1.44 (m, 4H), 1.57 (d, J = 21.6 Hz, 3H), 2.41 (s, 3H), 2.43-2.47 (m, 2H), 2.53-2.58 (m, 2H), 2.70-2.78 (m, 1H), 2.91-3.03 (m, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.91-7.93 (m, 2H). 19F NMR (376 MHz, CDCl₃) d -152.90 (s). C_I6H₂₂FNO; MW: 263.35; LCMS: (ES+): m/z 264.4 [M+H] ⁺. t_R = 1.822 min.

Alternative Synthetic Scheme for Example 1:

GL

Experimental: Step 1: Synthesis of Tolperisone, 2-methyl-l-(4-methylphenyl)-3-(l-piperidinyl)-l- propanone

A mixture of l-(p-tolyl)propan-l-one (1.0 g, 6.7 mmol), piperidine hydrogen chloride (0.98 g,

8.1 mmol) and methanesulfonic acid (64 mg, 0.67 mmol) in l,3-dioxolane (4.7 mL) was heated to 80°C in sealed tube for 24 hours. TLC showed the reaction was complete. The mixture was cooled to room temperature and concentrated. The residue was diluted with 1.0 M HC1 (30 mL) and washed with ethyl acetate (4 X 50 mL). The water layer was adjusted to pH 8-9 with saturated sodium carbonate and extracted with ethyl acetate (80 mL). The organic layer was washed with water, brine (60 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 2-methyl-3-(piperidin-l-yl)-l-(p-tolyl)propan- l-one (1.6 g, 91%) as a light yellow oil. LCMS: (ES⁺): m/z 246.4 [M+H] ⁺. t_R = 1.85 min; ' HNMR (400 MHz, CDCl₃): d 1.18 (d, / = 9.2 Hz, 3H), 1.35-1.41 (m, 2H), 1.50-1.55 (m, 4H), 2.42-2.45 (m, 8H), 2.86-2.91 (m, 1H), 3.74-3.79 (m, 1H), 7.27 (d, / = 8.0 Hz, 2H), 7.89 (d, / = 8.4 Hz, 2H).

Step 2: Synthesis of Example 1, 2-fluoro-2-methyl-3-(piperidin-l-yl)-l-(p-tolyl)propan-l-one

Example 1

A solution of Lithium bis(trimethylsilyl)-amide (1M in THF, 2.45 mL) was added dropwise into a solution of 2-methyl-3-(piperidin-l-yl)-l-(p-tolyl)propan-l-one (430 mg, 1.75 mmol) in anhydrous THF (6 mL) at -60°C under a nitrogen atmosphere. The mixture was warmed to room temperature and stirred for 1 hour. The mixture was cooled to -40°C and N-fluorobenzene- sulfonimide (0.63 g, 2.11 mmol) in anhydrous THF (3 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature over about 1.5 hour. TLC showed the reaction was complete. The reaction mixture was quenched with aqueous solution of ammonium chloride and extracted with ethyl acetate (80 mL). The organic layer was washed with brine (50 ml), dried over sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (eluted with 10% ethyl acetate in cyclohexane) to afford 2-fluoro-2-methyl-3-(piperidin-l-yl)- l-(p-tolyl)propan-l-one (243 mg, 52%) as a colorless oil. LCMS: (ES⁺): m/z 264.4 [M+H]⁺. t_R = 1.822 min; ' H NMR (400 MHz, CDCI₃): d 1.31-1.35 (m, 2H), 1.41-1.44 (m, 4H), 1.57 (d, / = 21.6 Hz, 3H), 2.41 (s, 3H), 2.43- 2.47 (m, 2H), 2.53-2.58 (m, 2H), 2.70-2.78 (m, 1H), 2.91-3.03 (m, 1H), 7.24 (d, / = 8.0 Hz, 2H), 7.91-7.93 (m, 2H).

Step 3: Synthesis of Tolperisone HCl, 2-methyl-3-(piperidin-l-yl)-l-(p-tolyl)propan-l-one hydrochloride

Tolperisone.HCl

A solution of 2-methyl-3-(piperidin-l-yl)-l-(p-tolyl)propan-l-one (150 mg, 0.61 mmol) in 4M HC1 in dioxane (2 mL) and dioxane (3 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to afford 2-methyl-3-(piperidin-l-yl)-l- (p- tolyl)propan-l-one hydrochloride (130 mg, 76%) as a white solid. LCMS: (ES⁺): m/z 246.1 [M+H] ⁺. t_R = 1.99 min;

1.36 (m, 3H), 1.70-1.85 (m, 4H), 2.04-2.10 (m, 1H), 2.22-2.28 (m, 1H), 2.42-2.46 (m, 4H), 2.73-2.75 (m, 1H), 3.02-3.11 (m, 2H), 3.49-3.52 (m, 1H), 3.77-3.79 (m, 1H), 4.59-4.63 (m, 1H), 7.32 (d, / = 8.0 Hz, 2H), 8.00 (m, 2H), 12.15 (br, 1H). Step 4: Synthesis of Example 2, 2-fluoro-2-methyl-3-(piperidin-l-yl)-l-(p-tolyl)propan-l-one hydrochloride

Example 2

A solution of 2-fluoro-2-methyl-3-(piperidin-l-yl)-l-(p-tolyl)propan-l-one (100 mg, 0.38 mmol) in 4M HC1 in dioxane (2 mL) and dioxane (3 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, the residue was washed with ether and the cake was dried in vacuo to afford 2-fluoro-2-methyl-3-(piperidin-l-yl)- l-(p-tolyl)propan-l- one hydrochloride (88 mg, yield 76%) as a pale-yellow solid LCMS: (ES⁺): m/z 264.1 [M+H] ⁺. t_R = 2.06 min; ^JH NMR (400 MHz, CDCE): d 1.32-1.39 (m, 1H), 1.76-1.80 (m, 3H), 1.92 (d, / = 21.6 Hz, 3H), 2.20-2.27 (m, 1H), 2.44-2.49 (m, 4H), 2.73-2.85 (m, 2H), 3.49-3.81 (m, 3H), 3.84- 3.89 (m, 1H), 7.30 (d, J = 8.0 Hz, 2H), 8.03 (d, / = 8.0 Hz, 2H), 12.35 (br, 1H).

SYNTHESIS OF EXAMPLE 3

Synthetic Scheme

HCI, reflux

Experimental: Step 1 : Synthesis of intermediate 2-methyl-3-(pyrrolidin- 1 -yl)- 1 -(p-tolyl)propan- 1 -one

To a solution of l-(p-tolyl)propan-l-one (1.0 g, 6.8 mmol) in methanol (5 mL) were added pyrrolidine (976 mg, 11.5 mmol) and paraformaldehyde (264 mg, 8.8 mmol) at room temperature, followed by the addition of HC1 in dioxane (4M, 3.5 mL). The resulting mixture was refluxed for 78 hours. TFC showed the reaction was complete. The reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in dichloromethane (100 mL) and washed with water (60 mL). The organic layer was collected, washed with brine (60 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified via silica gel flash column chromatography (eluted with 2% methanol in dichloromethane) to afford 2-methyl-3-(pyrrolidin-l-yl)-l-(p-tolyl)propan-l-one (150 mg, yield 9.5%) as a light yellow solid. FCMS: (ES⁺): m/z 232.1 [M+H] ⁺. t_R = 1.98 min;

^JH NMR (400 MHz, CDCl₃): d 1.22 (d, 7 = 6.8 Hz, 3H), 1.71-1.74 (m, 4H), 2.41 (s, 3H), 2.49- 2.50 (m, 4H), 2.57-2.62 (m, 1H), 2.88-2.93 (m, 1H), 3.68-3.73 (m, 1H), 7.22-7.26 (m, 2H), 7.894 (d, 7 = 8.0 Hz, 2H).

Step 2: Synthesis of Example 3, 2-fluoro-2-methyl-3-(pyrrolidin-l-yl)-l-(p-tolyl)propan-l-one

Example 3

To a solution of 2-methyl-3-(pyrrolidin-l-yl)-l-(p-tolyl)propan-l-one (120 mg, 0.52 mmol) in anhydrous THF (4 mL) at -65°C under nitrogen atmosphere was added dropwise lithium bis(trimethylsilyl) amide in THF (1M, 0.78 mL). After stirring at 0°C for 1 hour, the resulting mixture was cooled to -40°C, followed by the dropwise addition of N-fluoro- benzenesulfonimide (197 mg, 0.62 mmol) in anhydrous THF (2 mL). The resulting mixture was stirred at room temperature for 1.5 hour. TFC showed the reaction was complete. The reaction was quenched with aqueous ammonium chloride and extracted with ethyl acetate (50 ml). The organic layer was washed with brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified via silica gel flash column

chromatography (eluted with 20% ethyl acetate in hexane) to afford 2-fluoro-2-methyl-3- (pyrrolidin-l-yl)-l-(p-tolyl)propan-l-one (40 mg, 31%) as a colorless oil. FCMS: (ES⁺): m/z 250.1 [M+H] ⁺. t_R = 1.98 min; ^JH NMR (400 MHz, CDCl₃): d 1.63 (d, 7 = 21.6 Hz, 3H), 1.67- 1.70 (m, 4H), 2.40 (s, 3H), 2.59-2.63 (m, 4H), 2.90-2.99 (m, 1H), 3.11-3.22 (m, 1H), 7.22-7.26 (m, 2H), 7.91-7.94 (m, 2H). SYNTHESIS OF EXAMPLE 4

Synthetic Scheme

HCI, reflux

Experimental:

Step 1: Synthesis of intermediate 3-(azepan-l-yl)-2-methyl-l-(p-tolyl)propan- l-one

To a solution of l-(p-tolyl)propan-l-one (1.0 g, 6.8 mmol) in ethanol (6 mL) at room temperature was added azepane (0.87 g, 8.8 mmol) and paraformaldehyde (0.26 g, 8.8 mmol), followed by the addition of HC1 in dioxane (4M, 4 mL). The resulting mixture was refluxed for 78 hours. TLC showed the reaction was complete. The reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in water (50 mL) and washed with ethyl acetate (3 X 60 mL) to remove most of the impurities. The aqueous layer was adjusted to pH 8-9 with saturated aqueous sodium carbonate and extracted with ethyl acetate (80 mL). The organic layer was washed with water, brine (60 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 3-(azepan-l-yl)-2-methyl-l-(p-tolyl)propan- l-one

(0.5 g, 29%) as a colorless oil. LCMS: (ES⁺): m/z 260.1 [M+H] ⁺. t_R = 2.07 min; ' H NMR (400 MHz, CDCI₃): d 1.16 (J = 6.8 Hz, 3H), 1.50-1.54 (m, 8H), 2.41 (s, 3H), 2.51-2.56 (m, 1H), 2.61- 2.64 (m, 4H), 2.96-3.01 (m, 1H), 3.64-3.69 (m, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.88 (dd, J = 8.0 Hz, 2H).

Step 2: Synthesis of Example 4, 3-(azepan-l-yl)-2-fluoro-2-methyl-l-(p-tolyl)propan-l-one

Example 4

To a solution of 3-(azepan-l-yl)-2-methyl-l-(p-tolyl)propan-l-one (259 mg, 1.0 mmol) in anhydrous THF (4 mL) at -65°C under nitrogen atmosphere was added dropwise a solution of lithium bis(trimethylsilyl)amide in THF (1M, 1.4 mL). After stirring at 0°C for 1 hour, the resulting mixture was cooled to -40°C, followed by the dropwise addition of N- fluorohenzenesulfonimide (378 mg, 1.2 mmol) in anhydrous THF (2 mL). The resulting mixture was stirred at room temperature for 1.0 hour. TLC showed the reaction was complete. The reaction was quenched with aqueous ammonium chloride and extracted with ethyl acetate (50 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified via silica gel flash column chromatography (eluted with 10% ethyl acetate in hexane) to afford 3-(azepan-l- yl)-2-fluoro-2-methyl-l-(p-tolyl)propan-l-one (100 mg, 36%) as a colorless oil. LCMS: (ES⁺): m/z 278.1 [M+H] ⁺. t_R = 2.19 min;

NMR (400 MHz, CDCl₃): d 1.45-1.60 (m, 11H), 2.41 (s, 3H), 2.72-2.78 (m, 4H), 2.92-3.00 (m, 1H), 3.17-3.28 (m, 1H), 7.23 (d, J = 8.0Hz, 2H), 7.93 (dd, J = 8.0Hz, 2H). SYNTHESIS OF EXAMPLE 5 Synthetic Scheme

HCI, reflux

Experimental: Step 1: Synthesis of intermediate 3-(dimethylamino)-2-methyl-l-(p-tolyl)propan-l-one

To a solution of l-(p-tolyl)propan-l-one (2.0 g, 13.5 mmol) in methanol (10 mL) at room temperature in a sealed tube was added dimethyl amine hydrochloride (1.87 g, 23 mmol) and paraformaldehyde (0.53 g, 17.6 mmol), followed by the addition of HC1 in dioxane (4M, 8 mL). The resulting mixture was stirred at 65-70°C for 78 hours. TLC showed the reaction was complete. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with water (50 mL) and washed with ethyl acetate (3 X 50 mL) to remove most of the impurities. The aqueous layer was adjusted to pH 9 with saturated aqueous sodium carbonate and extracted with ethyl acetate (80 mL). The organic layer was washed with water (60 mL), brine (60 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified via silica gel flash column chromatography (eluted with 2% methanol in dichloromethane) to afford 3-(dimethylamino)-2- methyl- l-(p-tolyl)propan-l- one (0.8 g, 29%) as a colorless oil. LCMS: (ES⁺): m/z 206.2 [M+H] ⁺. t_R = 1.72 min; ¹ H NMR (400 MHz, CDCI₃): d 1.20 (d, J = 6.8 Hz, 3H), 2.23 (s, 6H), 2.32-2.36 (m, 1H), 2.41 (s, 3H), 2.75-2.80 (m, 1H), 3.64-3.69 (m, 1H), 7.26 (d, J = 7.6 Hz, 2H), 7.89 (d, J = 8.4 Hz, 2H).

Step 2: Synthesis of Example 5, [3-(dimethylamino)-2-fluoro-2- methyl- l-(p-tolyl)propan-l- one]

Example 5

To a solution of 3-(dimethylamino)-2-methyl-l-(p-tolyl)propan-l-one (205 mg, 1.0 mmol) in anhydrous THF (6 mL) at -65°C under nitrogen atmosphere was added dropwise lithium bis(trimethylsilyl) amide in THF (1M, 1.3 mL). After stirring at 0°C for 1 hour, the resulting mixture was cooled to -40°C, followed by dropwise addition of N-fluorohenzenesulfonimide (378 mg, 1.2 mmol) in anhydrous THF (2 mL). The resulting mixture was stirred at room temperature for 1.0 hour. TFC showed the reaction was complete. The reaction was quenched with aqueous ammonium chloride and extracted with ethyl acetate (50 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified via silica gel flash column chromatography (eluted with 20% ethyl acetate in hexane) to afford 3-(di-methylamino)-2- fluoro-2-methyl-l-(p- tolyl)propan-l-one (57 mg, 25%) as a colorless oil. FCMS: (ES⁺): m/z 224.2 [M+H] ⁺. t_R = 1.84 min; NMR (400 MHz, CDCF): d 1.61 (d, J = 21.6 Hz, 3H), 2.30 (s, 6H), 2.41 (s, 3H), 2.69- 2.77 (m, 1H), 2.96-3.06 (m, 1H), 7.25 (d, J = 8.0Hz, 2H), 7.94 (d, J = 7.2Hz, 2H).

SYNTHESIS OF EXAMPLE 6 Synthetic Scheme:

Experimental:

Step 1: Synthesis of Intermediate 2-methyl-3-(piperidin-l-yl)-l-(4-(tri- fluoromethyl)- phenyl)propan-l-one

A mixture of l-(4-(trifluoromethyl)phenyl)propan-l-one (1.5 g, 7.4 mmol), piperidine hydrochloride (1.08 g, 8.9 mmol), and methanesulfonic acid (71 mg, 0.74 mmol) in 1,3- dioxolane (6 mL) was stirred at 90°C in sealed tube for 40 hours. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was diluted with hydrochloric acid (0.3M, 50 mL) and washed with ethyl acetate (4 X 50 mL) to remove most of the impurities. The aqueous layer was adjusted to pH 10 with saturated aqueous sodium carbonate and extracted with ethyl acetate (80 mL). The organic layer was washed with water, brine (60 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 2-methyl-3-(piperidin-l-yl)-l-(4-(trifluoro- methyl)phenyl)propan-l-one (1.8 g, 81%) as a colorless oil. LCMS: (ES⁺): m/z 300.3 [M+H] ⁺. t_R = 2.06 min; ' H NMR (400 MHz, CDCI₃): d 1.20 (d, J = 6.8 Hz, 3H), 1.35-1.38 (m, 2H), 1.43-1.48 (m, 4H), 2.33-2.41 (m, 5H), 2.77-2.82 (m, 1H), 3.69-3.73 (m, 1H), 7.73 (d, J = 8.0 Hz, 2H), 8.06 (d, J = 8.0 Hz, 2H).

Step 2: Synthesis of Example 6, 2-fluoro-2-methyl-3-(piperidin-l-yl)-l-(4-(trifluoromethyl)- phenyl)propan-l-one

Example 6

To a solution of 2-methyl-3-(piperidin-l-yl)-l-(4-(trifluoromethyl)phenyl)propan-l- one (1.56 g, 5.21 mmol) in dry THF (25 mL) at -65°C under nitrogen atmosphere was added dropwise LiHMDS (1.0 M in hexane, 7.3 mL, 7.3 mmol). The resulting mixture was warmed to 0°C and stirred for 1 hour. The reaction mixture was then cooled to -40°C (internal temperature), followed by the dropwise addition of a solution of NFSI (1.97 g, 6.26 mmol) in dry THF (10 mL). The resulting mixture was slowly warmed to room temperature, and stirred overnight. The reaction was quenched carefully with hydrochloric acid (2.0 N), and concentrated to remove THF. The aqueous residue was extracted with cyclohexane/EtOAc (3/1) and basified with aqueous sodium hydroxide (2.0 N) to pH >9. The resulting mixture was extracted with EtOAc. The organic phase was washed with brine, dried over Na₂S04 and concentrated under reduced pressure to give a residue which was purified via silica gel flash column chromatography (eluent: cyclohexane/EtOAc = 20/1) to afford the title compound as a light yellow liquid (1.06 g, 64%). LCMS (ES⁺) calcd for CI₆H₁₉F₄NO: 317.1 ; found: 3l 8. l [M+H] t_R = 2.17 min;

NMR (400 MHz, CDCI3): d 1.31-1.35 (m, 2H), 1.39-1.44 (s, 4H), 1.56 (d, J = 21.6 Hz, 3H), 2.38-2.43 (m, 2H), 2.56-2.61 (m, 2H), 2.71-2.79 (m, 1H), 2.91-3.03 (m, 1H), 7.70 (d, J = 8.4 Hz, 2H), 8.07 (d, J = 8.0 Hz, 2H).

Step 3: Synthesis of Example 6.HC1 2-fluoro-2-methyl-3-(piperidin-l-yl)-l-(4-(trifluoro- methyl)phenyl)propan- l-one hydrochloride

Example 6.HC1

To a solution of 2-fluoro-2-methyl-3-(piperidin- l-yl)- l-(4-(trifluoromethyl)phenyl)- propan- l- one (1.06 g, 3.34 mmol) in DCM (15 mL) was added HC1 in methanol (4.0 N, 0.9 mL, 3.6 mmol) at room temperature. The resulting mixture was stirred at ambient temperature for 30 min. The solvent was removed under reduced pressure, the residue triturated with diethyl ether and dried to afford the title compound as a light yellow solid (721 mg, 60%). LCMS (ES⁺) calcd for Ci6H₁₉F₄NO: 317.1 ; found: 3l 8.3[M+H] ; ^JH NMR (400 MHz, CDCl₃) d 8.19 (d, / = 8.0 Hz, 2H), 7.74 (d, / = 8.4 Hz, 2H), 3.86-3.47 (m, 1H), 3.47-2.54 (m, 5H), 1.98-1.38 (m, 9H). SYNTHESIS OF EXAMPLE 7

Synthetic Scheme:

reflux / 36 h

Experimental:

Step 1: synthesis of intermediate l-(4-ethylphenyl)-2-methyl-3-(piperidin-l-yl)propan- l-one

To a solution of l-(4-ethylphenyl)propan- l-one (1.0 g, 6.17 mmol) in ethanol (6 mL) at room temperature in sealed tube was added pyrrolidine (0.68 g, 8.02 mmol) and paraformaldehyde (0.24 g, 8.02 mmol), followed by the addition of HC1 in dioxane (4 M, 4 mL). The resulting mixture refluxed for 36 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with water (50 mL) and washed with ethyl acetate (3 X 50 mL). The aqueous layer was adjusted to pH 8-9 with saturated sodium carbonate solution and extracted with ethyl acetate (50 mL). The organic layer was washed with water, brine (60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford l-(4- ethylphenyl)-2-methyl-3-(piperidin-l-yl)propan- l-one (0.46 g, 29%) as a colorless oil. LCMS: (ES⁺): m/z 260.2 [M+H] ⁺. t_R = 1.94 min; ^JH NMR (400 MHz, CDCl₃): d 1.18 (d, J = 6.8 Hz, 3H), 1.27 (t, J = 7.6 Hz, 3H), 1.35-1.39 (m, 2H), 1.47-1.52 (m, 4H), 2.36-2.41 (m, 5H), 2.71 (q, 2H), 2.79-2.84 (m, 1H), 3.68-3.73 (m, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.0 Hz, 2H). Step 2: Synthesis of Example 7, l-(4-ethylphenyl)-2-fluoro-2-methyl-3-(piperidin-l-yl)- propan- l-one

Example 7

To a solution of l-(4-ethylphenyl)-2-methyl-3-(piperidin-l-yl)propan-l-one (200 mg, 0.77 mmol) in anhydrous THF (6 mL) at -65°C under a nitrogen atmosphere was added dropwise a solution of lithium bis(trimethylsilyl) amide in THF (1M, 1.0 mL). The resulting mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was then cooled to -

40°C, followed by dropwise addition of a solution of N-fluorobenzenesulfonimide (292 mg, 0.93 mmol) in anhydrous THF (2 mL). The resulting mixture was stirred at room temperature for 1.0 hour. TLC showed the reaction was complete. The reaction was quenched with aqueous ammonium chloride and extracted with ethyl acetate (50 mL). The organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified via silica gel flash column chromatography (eluted with 10% ethyl acetate in hexane) to afford l-(4-ethylphenyl)-2-fluoro-2-methyl-3-(piperidin-l-yl)- propan-l-one (100 mg, 47%) as a colorless oil. LCMS: (ES⁺): m/z 278.1 [M+H] ⁺. t_R = 2.11 min;

,

A solution of 4-fluorobenzoic acid (2.0 g, 14.3 mmol) and DMF (20 mg, catalytic) in thionyl chloride (6 mL) was stirred at 80°C for 2 hours. The reaction mixture was concentrated under reduced pressure to afford 4-fluorobenzoyl chloride (2.26 g, 99%) as light-yellow oil, which was used in next step without further purification.

Step 2: Synthesis of intermediate 4-fluoro-N-methoxy-N-methylbenzamide

To a solution of N,O-dimethylhydroxylamine hydrochloride (1.39 g, 14.3 mmol) and N,N- diisopropylethylamine (3.40 mg, 28.5 mmol) in dichloromethane was added slowly a solution of 4-fluorobenzoyl chloride (2.26 g, 14.3 mmol) in dichloromethane at 0-5°C over 20 minutes. The resulting mixture was stirred at 5-l0°C for 40 minutes. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (80 mL) and extracted with ethyl acetate (80 mL). The organic layer was washed with water (80 mL), brine (80 ml), dried over sodium sulfate and concentrated under reduced pressure to afford 4-fluoro-N-methoxy-N- methylbenzamide (2.44 g, 93%) as a pale-yellow solid, which was used in next step without further purification. LCMS: (ES⁺): m/z 184.0 [M+H] ⁺. t_R = 2.36 min; ¹ H NMR (400 MHz, CDCI₃): d 3.36 (s, 3H), 3.54 (s, 3H), 7.09 (t, J = 8.4 Hz, 2H), 7.72-7.76 (m, 2H).

Step 3: Synthesis of intermediate l-(4-fluorophenyl)-2-methylpropan-l-one

To a solution of 4-fluoro-N-methoxy-N-methylbenzamide (1.5 g, 8.2 mmol) in THF (25 mL) at 0-5°C under nitrogen was added dropwise isopropyl magnesium bromide (1.0 M in THF, 16.5 mL, 16.5 mmol) over 20 minutes. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with aqueous ammonium chloride and extracted with ethyl acetate (50 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified via silica gel flash column chromatography (eluted with 7% ethyl acetate in hexane) to afford l-(4-fluorophenyl)-2-methylpropan-l-one (150 mg, 11%) as pale-yellow solid. ¹ H NMR

(400 MHz, CDCI₃): d 1.22 (d, J = 6.8 Hz, 6H)„ 3.48-3.55 (m, 1H), 7.11-7.16 (m, 2H), 7.97-8.00 (m, 2H). Step 4: synthesis of Example 8, l-(4-fluorophenyl)-2,2-dimethyl-3-(piperidin-l-yl)- propan- 1- one

Example 8

A mixture of l-(4-fluorophenyl)-2-methylpropan-l-one (150 mg, 0.90 mmol), piperidine hydrochloride (131 mg, 1.08 mmol) and methanesulfonic acid (9 mg, 0.09 mmol) in 1,3- dioxolane (2 mL) was stirred at 90°C in sealed tube for 24 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was diluted with hydrochloric acid (0.3 M 50 mL) and washed with ethyl acetate (4 X 50 mL) to remove most of impurities. The aqueous layer was adjusted to pH 9 with saturated sodium carbonate and extracted with ethyl acetate (50 mL). The organic layer was washed with water, brine (60 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a residue which was purified through silica gel flash column chromatography (eluted with 30% ethyl acetate in hexane) to affordl-(4-fluorophenyl)-2,2-dimethyl-3-(piperidin-l-yl)- propan-l-one (30 mg, 13%) as a colorless oil. LCMS: (ES⁺): m/z 264.2 [M+H] ⁺. t_R = 1.94 min; ^JH NMR (400 MHz, CDCl₃): d 1.27 (s, 6H), 1.33-1.37 (m, 2H), 1.44-1.49 (m, 4H), 2.37 (m, d, J = 5.2 Hz, 4H), 2.60 (s, 2H), 7.04-7.09 (m, 2H), 7.80-7.84 (m, 2H).

SYNTHESIS OF EXAMPLE 9

Synthetic Scheme:

Experimental

Step 1: Synthesis of intermediate N-methoxy-N-methyl-4-(trifluoromethyl)-benzamide

To a solution of 4-(trifluoromethyl)benzoic acid (5.00 g, 26.3 mmol), HOBt (5.33 g, 39.4 mmol), and N,O-dimethylhydroxylamine HC1 salt (5.13 g, 52.6 mmol) in DCM (130 mL) at 0°C was added TEA (11.0 mL, 78.9 mmol) and EDCI (6.45 g, 41.55 mmol), respectively. The resulting suspension was gradually warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with dilute hydrochloric acid (1N), saturated aq. NaHCOi and brine sequentially. The organic phase was dried over Na SCL and concentrated under reduced pressure to give a residue which was purified via silica gel flash column chromatography (eluent: cyclohexane/EtOAc = 15/1 ~ 2/1) to afford the title compound as a light yellow liquid (5.86g, 95%). LCMS (ES⁺) calcd for C₁₀H₁₀F₃NO₂: 233.1; found:

234.0[

7.79 (d, / = 8.4 Hz, 2H), 7.67 (d, / = 8.0 Hz, 2H), 3.54 (s, 3H), 3.38 (s, 3H).

Step 2: Synthesis of intermediate 2-methyl-l-(4-(trifluoromethyl)phenyl)-propan- l-one

To a solution of N-methoxy-N-methyl-4-(trifluoromethyl)benzamide (2.0 g, 8.6 mmol) in dry THF (40 mL) at -l0°C (internal temperature) under nitrogen atmosphere was added dropwise isopropyl magnesium chloride (1.0 M, 12.85 mL, 12.85 mmol). The resulting mixture was warmed slowly to room temperature and stirred overnight. The reaction was quenched with dilute hydrochloric acid (0.5 N) with ice water bath cooling and extracted with ethyl acetate. The organic phase was washed with water, brine, dried over Na SCb and concentrated under reduced pressure to give a residue which was purified via silica gel flash column chromato- graphy

(cyclohexane/EtOAc = 100/1) to afford the title compound as a light yellow liquid (273 mg, 14%). NMR (400 MHz, CDCl₃) d 8.05 (d, J= 8.0 Hz, 2H), 7.73 (d, / = 8.4 Hz, 2H), 3.60- 3.50 (m, 1H), 1.24 (d, J= 6.8 Hz, 6H). Step 3: Synthesis of Example 9, 2,2-dimethyl-3-(piperidin-l-yl)-l-(4-(trifluoromethyl)phenyl)- propan-l-one

A mixture of 2-methyl- l-(4-(trifluoromethyl)phenyl)propan-l -one (273 mg, 1.26 mmol), piperidine HC1 salt (184 mg, 1.51 mmol) and methanesulfonic acid (catalytic amount, 2 drops) in l,3-dioxalane (5 mL) was stirred at 90°C under nitrogen overnight until a clear light brown solution was obtained. The resulting mixture was acidified with dilute hydrochloric acid (1.0 N) and extracted with cyclohexane/EtOAc (3/1, 3X) to remove most of the impurities. The aqueous solution was basified with aqueous NaOH (4.0 N) and extracted with ethyl acetate. The organic phase was washed with water, brine, dried over Na S0₄ and concentrated under reduced pressure to give a residue, which was purified via preparative TLC (eluent: cyclo- hexane/EtOAc = 20/1) to afford the title compound as a light yellow solid (120 mg, 30%). LCMS (ES⁺) calcd for C17H22F3NO: 313.2; found:

7.81 (d, / = 8.0 Hz, 2H), 7.66 (d, / = 8.0 Hz, 2H), 2.67-2.58 (m, 2H), 2.50-2.35 (m, 4H), 1.57-1.45 (m, 4H), 1.42- 1.34 (m, 2H), 1.30-1.25 (m, 6H).

In Vitro Testing

Sodium ion channel subtype testing

The compounds of the invention were profiled for inhibition of voltage-gated sodium ion channels. The compounds were either assayed against Navl.2/1.3/1.5/1.7/1.8 (5 Nav sub-types) or Navl.2/Navl.8 (2 Nav sub-types) as 5 pt concentration-response relationships (n=4, each data point) on PatchXpress automated patch clamp electrophysiological platform.

The compounds were dissolved in DMSO at 300X the highest test concentration. The compounds were tested as 5 pt concentration response curves (n=4 each data point) at V0.5 inactivation potential on a PatchXpress automated patch clamp system. V0.5 inactivation was determined from the steady-state inactivation curve on each cell run and analyzed by custom scripts. Concentrations were selected to cover the range of <20% to >80% inhibition when possible, dependent upon activity, solubility and DMSO not exceeding 0.3%. Specifically, the following electrophysiological protocol was used.

The holding potential (Vhold) was set to -120 mV. Peak sodium current amplitude was monitored for stability by custom PatchXpress scripts. Once stable, the mid-point voltage of steady state inactivation was determined for each cell using a series of 5 second conditioning steps to increasingly depolarized voltages (-120 to -40 mV) that precedes a 20 ms test pulse to 0 mV to establish magnitude of inactivation. The holding command potential was set to a voltage that produces -50% inactivation (Vhalf - set automatically via PatchXpress scripts). From this holding potential, a 2 ms voltage step to holding potential followed by a 20 ms depolarizing step to 0 mV and then 2 s at the holding potential was applied at a frequency of 0.1 Hz until current amplitude is steady (automatically determined by PatchXpress scripts), at which time test compound was added. The effect of each test compound on Nav current amplitude was monitored using the voltage protocol described above, and washed out after reaching steady state as determined by PatchXpress stability scripts.

The assay summary for Navl.2 and Navl.8 is shown in Table 1 as follows: Table 1:

The results of the testing for Tolperisone (Human Navl.2, 1.3, 1.5, 1.7 and 1.8) are shown in Figure 1 and in Table 2. The results of the testing for the compound of Example 1 (Human Navl.2, 1.3, 1.5, 1.7 and 1.8) are shown in Figure 2 and in Table 2.

Table 2:

The results of testing for compounds of Examples 3-9 (Human Nav 1.2 and 1.8) are shown in Table 3.

Table 3:

Tolperisone is a sodium (Nav) and calcium (Cav) ion channel blocker and it inhibits both central and peripheral Nav channels. It is thought that the ability of tolperisone to inhibit both central and peripheral Nav channels is important to efficacy. As can be seen from the data above, the compounds of theExamples 1 to 9 also exhibit the ability to inhibit Nav channels. In Vivo Testing - In Vivo Assessment of the Group II flexor spinal reflex in rats

The in vivo biological activity of the compound of Example 2 was compared to the biological activity of tolperisone by assessing the group II flexor spinal reflex in rats. This model allows for the identification of compounds which may act as central muscle relaxants.

The following procedure was employed.

Adult male Sprague-Dawley rats, weighing 350-450 g, were used. They were housed in groups of 4 in an air-conditioned room on a 12-hour light/dark cycle. Food and water were available ad libitum. All procedures in this study were undertaken in compliance with the UK Animals (Scientific Procedures) Act 1986.

Naive rats were anaesthetised with urethane (1.2 - 1.6 g/kg, i.p.), followed by regular top- ups (200-400 mg/kg, iv) if needed. The left carotid artery and a jugular vein were cannulated for blood pressure monitoring and drug dosing, respectively. The animal was then mounted on a ST- 7 stereotaxic frame on a thermal blanket system to maintain the body temperature within a physiological range. Two needle electrodes were inserted into the left forepaw and right hind- paw, respectively, for ECG/heart rate monitoring. The left sciatic nerve was exposed, followed by section of sural nerve and tibial nerve. The proximal cut end of tibial nerve was placed on a pair of silver wire electrodes for stimulation (0.1 Hz, 0.05 ms, 2 times of threshold intensity). A silver ball electrode was placed on the ipsilateral anterior tibial muscle to record the Group II afferent fibre-mediated flexor reflex. An indifferent needle electrode was inserted in the nearby tissue. The flexor reflex responses were amplified via a Neurolog system and displayed on a screen, with an online average and real time amplitude monitoring using CED Spike 8 software. A baseline recording was carried out for a period of 20 min, followed by 40 min recording after vehicle or compound dosing.

Tolperisone HC1 and compound of Example 2 HC1 were dissolved in vehicle (normal saline) to 10 mg/ml, immediately before the injection. The vehicle and test compounds were administered intravenously. Each group n=8. Diazepam injection (Hameln Pharmaceuticals, UK) was administered i.v. at 2.5 mg/kg.

At the end of each experiment, a blood sample was collected via a cardiac puncture. Approximately 1 ml of blood was withdrawn and placed in an EDTA vial, well shaken, before being centrifuged at 3000 rpm for 5 mins. 100 mΐ of plasma was placed into an Eppendorf vial and snap-frozen on dry ice. Subsequently the samples were stored in a -20°C freezer before being dispatched to the client. The raw data were saved on a PC and further analysed offline using Spike 8 software.

The waveforms over 100 sec (10 waveforms) were averaged at each time point. The peak-to- peak amplitudes were measured. Changes in flexor reflex amplitude, calculated as a percentage of control and expressed as mean ± S.E.M, were calculated. One-way ANOVA was used to compare the different treatment groups at each observation time point. Paired Student’s t- test was used to compare the values before and after dosing in the same treatment group. All statistical analysis was performed using SPSS software with P < 0.05 taken to indicate statistical significance.

Results

Effects of vehicle on Group II afferent-mediated flexor reflex

The effects of vehicle on Group II afferent-mediated flexor reflex was examined in 8 rats. Following vehicle dosing, the amplitude of the waveform fluctuated within a small range.

Following vehicle dosing, the waveform amplitudes were 101.5 ± 2.0%, 100.5 ± 2.4%, 97.7 ± 2.5% and 102.1 ± 3.6% of the control (100.0%) at the 10, 20, 30 and 40 min time points. There were no significant differences (P > 0.05, paired Students t-test) between the amplitudes of waveforms at different time points following dosing compared to control. See Figures 3 and 4.

Effects of diazepam on Group II afferent-mediated flexor reflex

The effects of diazepam, employed as a positive control in this study, were investigated in 3 rats. Following dosing, the waveform was significantly reduced, from control level

(100.0%) to 60.3 ± 8.6%, 56.5 ± 6.1%, 46.8 ± 6.3% and 44.6 ± 3.1% at 10, 20, 30 and 40 min time points (P < 0.05 to 0.01, compared to pre-dosing control, paired Student’s t- test and compared to vehicle group at the same time points, P < 0.01 to 0.001, one-way ANOVA). Refer to Figure 4 for comparison with vehicle group.

Effects of tolperisone.HCl on Group II afferent-mediated flexor reflex

In 8 rats, the effects of tolperisone.HCl were observed. Following compound

administration, the reflex waveform was significantly reduced from control level of 100% to 45.6 ± 8.6%, 54.1 ± 7.8%, 63.7 ± 9.2% and 66.4 ± 9.0%, respectively, at 10, 20, 30 and 40 min post-dosing. An example is shown in Figure 4. At all time-points, P < 0.01 to 0.001, compared to pre-dosing control level, paired Student’s t- test. In addition, when compared to vehicle at the same observation time points, P < 0.01 to 0.001, one-way ANOVA. See Figure 4. Effects of the compound of Example 2 on Group II afferent-mediated flexor reflex

In another group of 8 rats, the effects of the compound of Example 2 were examined. Following dosing, the amplitude of the reflex waveform was significantly reduced from the control level (100.0%) to 41.8 ± 8.7%, 50.7 ± 8.6%, 48.5 ± 10.1% and 45.6 ± 9.2%, respectively, at 10, 20, 30 and 40 min post-dosing (P < 0.01 to 0.001, when compared to pre-dosing level, paired Student’s Z- test. In addition, when compared to vehicle group, P < 0.001 for all time points, one-way ANOVA). See Figure 4.

Both compounds, administered intravenously (i.v.) at dose of 10 mg/kg, significantly reduced Group II afferent-mediated flexor reflex. Tolperisone.HCl reduced the flexor reflex to 45.6% of control, and Compound of Example 2 to 41.8% of control. Both compounds showed a peak effect 10 min following dosing. The reduction of the waveform by Tolperisone started to recover after 20 min following dosing and reached 66.4% of control at 40 min after dosing. The effect of the compound of Example 2, in contrast, persisted through the whole 40 min

observation period. Finally, diazepam, at a dose of 2.5 mg/kg, i.v., decreased the flexor reflex. This latter result is in line with previously published papers. These results suggest that

Tolperisone.HCl and the compound of Example 2, both inhibit Group II afferent-mediated flexor reflex and are potentially useful in treating various conditions including elevated muscle tone and tension (e.g., spasticity, muscle spasm).

It is surprising (and unanticipated) that the compound of Example 2 demonstrates an inhibition profile most similar to diazepam given the transient nature of group II flexor reflex inhibition of tolperisone.

4-MMPPO SENSITIZATION STUDY

4-MMPPO is a known genotoxic agent which is based on the prior art and arises as a degradation product of tolperisone through the beta elimination reaction outlined below.

A study was undertaken to determine whether 4-MMPPO was a possible driver of hypersensitivity reactions in humans (a known common adverse event associated with this class of drugs) as mentioned by the European Medicines Agency (2013),“Assessment report for tolperisone-containing medicinal products” EMA/753061/2012. The EMA has said that“the risk of hypersensitivity reactions is more significant than previously identified.”

A Direct Peptide Reactivity Assay (DPRA) was undertaken to determine if 4-MMPPO could potentially haptenize proteins and contribute to hypersensitivity in humans. To determine whether 4-MMPPO could potentially serve as a sensitizing agent, the DPRA assessed whether 4- MMPPO could modify Cys and Lys containing peptides to mimic the binding of epidermal proteins which serve as the molecular initiating event on the Adverse Outcome Pathway and hypersensitivity. A positive signal in the DPRA assay is a strong indicator of hypersensitivity and is currently accepted/validated by the EURL-ECVAM (EU Reference Laboratory for Alternatives to Animal Testing ) as part of an integrated approach to test and differentiate between sensitizers and non-sensitizers for hazard classification and labelling.

The objective of this study was to determine the sensitization potential of 2-methyl- l-p- tolyl-propenone (4-MMPPO), based on the depletion of cysteine and/or lysine peptides following 24 + 2 hours of incubation at 25 ± 2.5°C.

EXPERIMENTAL DESIGN

DPRA is an in chemico method which quantifies the remaining concentration of cysteine or lysine-containing peptide following 24 + 2 hours of incubation with the test chemical at a temperature of 25 + 2.5°C. Relative peptide concentration was measured by high performance liquid chromatography (HPLC) with gradient elution and ultraviolet (UV) detection at 220 nm. Cysteine and lysine peptide percent depletion values were calculated and used in a prediction model which allowed the assigning of the test chemical to one of four reactivity classes used to support the discrimination between sensitizers and non-sensitizers. The photometric analysis of the appropriate peptide in each standard and sample was performed using an Agilent Series 1260 HPLC equipped with an Agilent Series 1200 variable wavelength detector, Agilent Series 1200 autosampler and Agilent Series 1200 autosampler thermostat. Chromatographic separations were achieved using an Agilent Zorbax SB-C18 analytical column (100 mm x 2.1 mm, 3.5-pm particle size) with a Phenomenex SecurityGuard Cl 8 cartridge (4 mm x 2.0 mm).

The methods used for the DPRA analysis of 2-methyl- l-p-tolyl-propenone were performed in accordance to the DB-ALM protocol No. 154 (2). In summary, the DPRA methodology consisted of combining test substance with either cysteine or lysine-containing peptides in a 25:75 (acetonitrile (ACN): buffer) solution at ratios of 1 : 10 and 1 :50, respectively, and incubating these solutions for 24 + 2 hours at 25 ± 2.5°C. The buffers used for the cysteine and lysine assays were 100 mM sodium phosphate (pH 7.5) and 100 mM ammonium acetate (pH 10.2), respectively. For each peptide assay, a calibration curve was generated for the analytical sequence using appropriate peptide calibration standards prepared in either 20:80 ACN:pH 7.5 phosphate buffer (for cysteine) or 20:80 ACN:pH 10.2 ammonium acetate buffer (for lysine) dilution solvent. The complete set of calibration standards was analyzed at the beginning of the analytical sequence. A linear regression equation was generated for each peptide assay using the peak area responses versus the respective concentrations of the calibration standards. Examples of cysteine and lysine calibration curves are presented in Figures 1 and 2, respectively. The concentration of the cysteine and lysine peptides were determined in the appropriate reference control samples by substituting the peak area responses into the appropriate linear regression equation. Three sets of reference controls were prepared at 0.500 mM of either cysteine or lysine in the appropriate ACN:buffer solution. A co-elution sample was also prepared for each peptide assay containing only the respective buffer with test substance to ensure that test substance peaks did not overlap with each respective peptide peak. One set of reference controls was to verify system suitability, another to verify the stability of the peptide through the duration of analysis, and the remainder to verify that the solvent does not impact the depletion of the respective peptide. Positive control samples, prepared with cinnamic aldehyde in the sample manner as test substance samples, were prepared and the peptide depletion results for each peptide assay were compared to known tolerance values to ensure accuracy of the DPRA prediction.

RESULTS AND DISCUSSION

The HPLC/UV system suitability assay is considered to be valid if the following conditions are met: a.) the calibration curve should have an r²>0.99; b.) the mean peptide concentration of reference controls (Set A) should be 0.50 ± 0.05 mM and the coefficient of variation (CV) of peptide peak areas for the nine reference controls B and C in ACN should be < 15.0%; c.) the mean percent depletion values of the three positive control replicates should be between 60.8% and 100% with a standard deviation (SD) as of < 14.9% for the cysteine peptide and between 40.2% and 69.0% with an SD of < 11.6% for the lysine peptide. The test chemical data should be considered to be valid if the following criteria are met: a.) the mean peptide concentration of the reference controls (Set C) for the appropriate solvent used should be 0.50 ± 0.05 mM; b.) the SD for the percent depletion values of the three test substance replicates should be < 14.9% for the cysteine peptide and < 11.6% for the lysine peptide. Negative depletion is considered as“0%” when calculating the mean. The system suitability for the reference cysteine peptide assay sequence passed all guideline acceptance criteria (1). The system suitability for the reference lysine peptide assay sequence passed all guideline acceptance criteria (1).

The percent cysteine depletion values for the positive control sample replicates ranged from 67.7 to 68.4%. The percent lysine depletion values for the positive control sample replicates ranged from 46.4 to 53.5%. The mean percent cysteine and lysine depletion values for the respective positive control samples were 68.8 ± 1.4% (N = 3; CV = 2.01%) and 50.2 ± 3.6% (N = 3; CV = 7.15%), respectively. The mean percent cysteine and lysine depletion values for the respective positive control samples were in the range allowed by the OECD guideline (1). Precipitate was not present in the cysteine positive control samples upon initial preparation (i.e.

0 hours) and following approximately 24 hours of incubation. Precipitate was not present in the lysine positive control samples upon initial preparation (i.e. 0 hours) but was present following approximately 24 hours of incubation

The 4-MMPPO (also known as 2-methyl- l-p-tolyl-propenone) test substance co-elution samples demonstrated the test substance did not elute at a similar chromatographic retention time as cysteine or lysine. The percent cysteine depletion values for the 2-methyl- l-p-tolyl- propenone sample replicates were 100%. The percent lysine depletion values for the 2-methyl- l-p-tolyl-propenone sample replicates ranged from 48.4 to 49.7%. The mean percent cysteine depletion for the test substance assay samples was 100 ± 0.0% (N = 3; CV = 0.0%). The mean percent lysine depletion for the test substance assay samples was 49.1 ± 0.7% (N = 3; CV = 1.37%). Precipitate was not present in the cysteine or lysine test substance assay samples upon initial preparation of test substance solutions (i.e. 0 hours) and following approximately 24 hours of incubation.

A cysteine l:l0/lysine 1:50 prediction model was used for the assignment of a reactivity class to the test substance (1). Based on the cysteine l:l0/lysine 1:50 prediction model, the 4- MMPPO (also known as 2-methyl- l-p-tolyl-propenone) test substance would be classified as having high reactivity and a positive DPRA prediction. The overall cysteine and lysine results for the test substance are presented in Table 4. Table 4

CONCLUSIONS

DPRA testing was performed on 4-MMPPO (2-methyl- l-p-tolyl-propenone), using both cysteine and lysine-containing peptides. The cysteine and lysine peptide assay sequence passed all guideline acceptance criteria (1). The 4-MMPPO test material was prepared at a concentration of approximately 100 mM.

The mean percent cysteine and lysine depletion values for 4-MMPPO were 100 ± 0.0% (N = 3; CV = 0.0%) and 49.1 ± 0.7% (N = 3; CV = 1.37%), respectively. The test substance did not co-elute with either the cysteine or lysine-containing peptides. Precipitate was not present in either cysteine or lysine test substance assay samples upon initial preparation of the test substance solutions (i.e., 0 hours) and after approximately 24 hours of incubation. Since both the cysteine and lysine assays were valid for the test substance, the OECD cysteine l: l0/lysine 1 :50 prediction model (exhibited below) was used for the assignment of a reactivity class to the test substance (1).

OECD Cysteine l :l0/lysine 1 :50 Prediction Model

Based on the cysteine l:lO/lysine 1:50 prediction model, 4-MMPPO would be classified as high reactivity and a positive DPRA prediction.

Definitions

The use of the words "a" or "an" when used in conjunction with the term "comprising" herein may mean "one," but are also consistent with the meaning of "one or more," "at least one," and "one or more than one."

The term“administering” and“administration” refers to a mode of delivery. A daily dosage can be divided into one, two, three or more doses in a suitable form to be administered one, two, three or more times throughout a time period. In preferred embodiments of the present invention, compositions and solutions are administered orally.

The terms“analog” or“related analogs” as used herein in regard to a compound or compounds refer to a substance that has a similar chemical structure to another compound, but differs from it with respect to a certain component or components.

“Muscle spasm” as used herein refers to an involuntary contraction or a muscle, or even a few fibers of a muscle. In some embodiments, the magnitude or duration of a spasm is less than that of a cramp.

As used herein, the terms“prevent” or“preventing” as used in the context of a disorder or disease, refer to administration of an agent to a subject such that the onset of at least one symptom of the disorder or disease is delayed as compared to what would be seen in the absence of administration of said agent. As compared with an equivalent untreated control, such prevention is at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100%, as measured by any standard technique.

The term“spasticity” as referred to herein is the uncontrolled tightening or contracting of the muscles that is common in individuals with spinal cord injuries and a variety of nervous system diseases. In some embodiments, spasticity refers to a velocity-dependent increase in the tonic stretch reflex (muscle tone) with exaggerated tendon jerks, clonus, and spasms, resulting from the hyper excitability of the stretch reflex.

The term“subject” as used herein refers to a mammal, including, but not limited to, a human or non-human mammal, such as a bovine, equine, canine, ovine, or feline mammal. In some embodiments, the term subject refers to a human (e.g., a human male or female).

“Treat” or "treating” as used herein refers to administering a composition for therapeutic purposes or administering treatment to a subject already suffering from a disorder to improve the subject's condition. By "treating a condition or disorder" or "alleviating a condition or disorder" is meant that the condition or disorder (e.g., an unwanted or abnormal muscle contraction) and the symptoms associated with the condition or disorder are, e.g., prevented, alleviated, reduced, cured, or placed in a state of remission. As compared with an equivalent untreated control, such alleviation or degree of treatment is at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100%, as measured by any standard technique.

In general, the“effective amount” of a compound refers to an amount sufficient to elicit the desired biological response, e.g., to treat a CNS-related disorder, is sufficient to induce anesthesia or sedation. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment.

As used herein, and unless otherwise specified, a“therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term

“therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

Chemical definitions

Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5^th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and

Carruthers, Some Modem Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example“Ci_₆ alkyl” is intended to encompass, , C\ C_¾, C₄, C₅, C₆, _

The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.

“Alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“Ci_2o alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“Ci_i₂ alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C_j_8 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C_j_6 alkyl”, also referred to herein as“lower alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“Ci_s alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C_j^ alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“ _₃ alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“Ci_₂ alkyl”). In some

embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C_2-6 alkyl”). Examples of _6 alkyl groups include methyl (Ci), ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl (C₄), tert-butyl (C₄), sec-butyl (C₄), iso butyl (C₄), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C₆). Additional examples of alkyl groups include n-heptyl (C₇), n-octyl (C₈) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e. , unsubstituted (an“unsubstituted alkyl”) or substituted (a“substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents,

1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted Ci_io alkyl (e.g., -CH₃). In certain embodiments, the alkyl group is substituted Ci_io alkyl. Common alkyl abbreviations include Me (-CH₃), Et (-CH₂CH₃), iPr (-CH(CH₃)₂), nPr (- CH₂CH₂CH₃), n-Bu (-CH₂CH₂CH₂CH₃), or i-Bu (-CH₂CH(CH₃)₂).

“Alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds (“C₂_ 20 alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂_io alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C₂_g alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C₂_6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C₂_s alkenyl”). In some

embodiments, an alkenyl group has 2 to 4 carbon atoms (“C_2-4 alkenyl”). In some

embodiments, an alkenyl group has 2 to 3 carbon atoms (“C_2-3 alkenyl”). In some

embodiments, an alkenyl group has 2 carbon atoms (“C₂ alkenyl”). The one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C 4 alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1- butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like. Examples of C₂_6 alkenyl groups include the aforementioned C 4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C₆), and the like. Additional examples of alkenyl include heptenyl (C₇), octenyl (C₈), octatrienyl (C₈), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an“unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C₂_io alkenyl. In certain embodiments, the alkenyl group is substituted C₂_io alkenyl.

“Alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds (“C_2-2o alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C₂_io alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C_2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C_2-6 alkynyl”).

In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C₂_s alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C_2-4 alkynyl”). In some

embodiments, an alkynyl group has 2 to 3 carbon atoms (“C_2-3 alkynyl”). In some

embodiments, an alkynyl group has 2 carbon atoms (“C₂ alkynyl”). The one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C_2-4 alkynyl groups include, without limitation, ethynyl (C₂), 1-propynyl (C₃), 2- propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), and the like. Examples of C_2-6 alkenyl groups include the aforementioned C_2-4 alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and the like. Additional examples of alkynyl include heptynyl (C₇), octynyl (C₈), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an“unsubstituted alkynyl”) or substituted (a“substituted alkynyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C₂_io alkynyl. In certain embodiments, the alkynyl group is substituted C_2-io alkynyl.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C_6-14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1- naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄ aryl”; e.g., anthracyl).“Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an“unsubstituted aryl”) or substituted (a“substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted C_6-i4 aryl. In certain embodiments, the aryl group is substituted CVi₄ aryl.

In certain embodiments, an aryl group substituted with one or more of groups selected from halo, Ci-C₈ alkyl, -Cs haloalkyl, cyano, hydroxy, -Cs alkoxy, and amino.

“Heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system ( e.g ., having 6 or 10 p electrons shared in a cyclic array) having ring carbon atoms and 1^1 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a“substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.

Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.

Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl,

benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

“Halo” or“halogen,” independently or as part of another substituent, mean, unless otherwise stated, a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom. The term “halide” by itself or as part of another substituent, refers to a fluoride, chloride, bromide, or iodide atom. In certain embodiments, the halo group is either fluorine or chlorine.

Carbocyclyl” or“carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms C'C io carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C_3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C_3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C₃_6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5_io carbocyclyl”). Exemplary C_3-6 carbocyclyl groups include, without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like. Exemplary C_3-8 carbocyclyl groups include, without limitation, the aforementioned C_3-6 carbocyclyl groups as well as cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃_io carbocyclyl groups include, without limitation, the aforementioned C_3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1 //-indcnyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system

(“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated.“Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an“unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C₃_io carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C₃_io carbocyclyl.

“Cycloalkyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C₃_io cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C_3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C_3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“Cs_6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“Cs_io cycloalkyl”). Examples of Cs_6 cycloalkyl groups include cyclopentyl

(C5) and cyclohexyl (C5). Examples of C_3-6 cycloalkyl groups include the aforementioned Cs_6 cycloalkyl groups as well as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C_3-8 cycloalkyl groups include the aforementioned C_3-6 cycloalkyl groups as well as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwise specified, each instance of a cycloalkyl group is

independently unsubstituted (an“unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C _io cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C _ io cycloalkyl.

“Heterocyclyl” or“heterocyclic” refers to a radical of a 3- to 10-membered non aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an“unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4- membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.

Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

Alkyl, alkenyl, alkynyl, carbocyclyl, and heterocyclyl groups, as defined herein, are optionally substituted (e.g.,“substituted” or“unsubstituted” alkyl,“substituted” or

“unsubstituted” alkenyl,“substituted” or“unsubstituted” alkynyl,“substituted” or

“unsubstituted” carbocyclyl,“substituted” or“unsubstituted” heterocyclyl). In general, the term “substituted”, whether preceded by the term“optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a“substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term“substituted” is contemplated to include substitution with ah permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -N0₂, -N₃, -S0₂H, -SO3H, -OH, -OR^*1, -ON(R^bb)₂, -N(R^bb)₂, -N(R^bb)₃ ⁺X , -N(OR^cc)R^bb, -SH, - SR^aa, -SSR^CC, -C(=0)R^aa, -C0₂H, -CHO, -C(OR^cc)₂, -C0₂R^aa, -0C(=0)R^aa, -0C0₂R^aa, - C(=0)N(R^bb)₂, -0C(=0)N(R^bb)₂, -NR^bbC(=0)R^aa, -NR^bbC0₂R^aa, -NR^bbC(=0)N(R^bb)₂, - C(=NR^bb)R^aa, -C(=NR^bb)OR^aa, -OC(=NR^bb)R^aa, -OC(=NR^bb)OR^aa, -C(=NR^bb)N(R^bb)₂, - OC(=NR^bb)N(R^bb)₂, -NR^bbC(=NR^bb)N(R^bb)₂, -C(=0)NR^bbS0₂R^aa, -NR^bbS0₂R^aa, -S0₂N(R^bb)₂, -SO R³³, -S0₂0R^aa, -0S0₂R^aa, -S(=0)R^aa, -0S(=0)R^aa, -Si(R^aa)₃, -OSi(R^aa)₃ -C(=S)N(R^bb)₂,

Ci_io alkyl, Ci_io perhaloalkyl, C₂_io alkenyl, C₂_io alkynyl, C₃_io carbocyclyl, 3-14 membered heterocyclyl, C₆-i4 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R groups;

or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(R^bb)₂, =NNR^bbC(=0)R^aa, =NNR^bbC(=0)OR^aa, =NNR^bbS(=0)₂R^aa, =NR^bb, or =NOR^cc; each instance of R³²¹ is, independently, selected from Ci_io alkyl, Ci_io perhaloalkyl, C₂_io alkenyl, C₂_io alkynyl, C₃_io carbocyclyl, 3-14 membered heterocyclyl, C₆-i₄ aryl, and 5-14 membered heteroaryl, or two R^aa groups are joined to form a 3-14 membered heterocyclyl or 5- 14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups;

each instance of R^bb is, independently, selected from hydrogen, -OH, -OR³³, -N(R^CC)₂, - CN, -C(=0)R³³, -C(=0)N(R^cc)₂, -C0₂R³³, -S0₂R³³, -C(=NR^CC)0R³³, -C(=NR^CC)N(R^cc)₂, - S0₂N(R^cc)₂, -S0₂R^cc, -S0₂OR^cc, -S0R³³, -C(=S)N(R^cc)₂, -C(=0)SR^cc, -C(=S)SR^cc, - P(=0)₂R³³, -P(=0)(R³³)₂, -P(=0)₂N(R^cc)₂, -P(=0)(NR^cc)₂, Ci-io alkyl, C,_,„ perhaloalkyl, C_2-10 alkenyl, C_2-io alkynyl, C_3-io carbocyclyl, 3-14 membered heterocyclyl, CVi₄ aryl, and 5-14 membered heteroaryl, or two R^bb groups are joined to form a 3-14 membered heterocyclyl or 5- 14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups; each instance of R^cc is, independently, selected from hydrogen, Ci_io alkyl, Ci_io perhaloalkyl, C₂-io alkenyl, C₂-io alkynyl, C3_io carbocyclyl, 3-14 membered heterocyclyl, C₆-i4 aryl, and 5-14 membered heteroaryl, or two R^cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups;

each instance of R^dd is, independently, selected from halogen, -CN, -N0₂, -N₃, -S0₂H, -S0₃H, -OH, -OR^ee, -ON(R^ff)₂, -N(R^ff)₂, -N(R^ff)₃ ⁺X , -N(OR^ee)R^ff, -SH, -SR^ee, -SSR^ee, - C(=0)R^ee, -C0₂H, -C0₂R^ee, -OC(=0)R^ee, -OC0₂R^ee, -C(=0)N(R^ff)₂, -OC(=0)N(R^ff)₂, - NR^ffC(=0)R^ee, -NR^ffC0₂R^ee, -NR^ffC(=0)N(R^ff)₂, -C(=NR^ff)OR^ee, -OC(=NR^ff)R^ee, - OC(=NR^ff)OR^ee, -C(=NR^ff)N (R^ff)₂ , -OC(=NR^ff)N(R^ff)₂, -NR^ffC(=NR^ff)N(R^ff)₂,-NR^ffS0₂R^ee, - S0₂N(R^ff)₂, -S0₂R^ee, -S0₂OR^ee, -OS0₂R^ee, -S(=0)R^ee, -Si(R^ee)₃, -OSi(R^ee)₃, -C(=S)N(R^ff)₂, - C(=0)SR^ee, -C(=S)SR^ee, -SC(=S)SR^ee, -P(=0)₂R^ee, -P(=0)(R^ee)₂, -OP(=0)(R^ee)₂, - OP(=0)(OR^ee)₂, Ci_₆ alkyl, Ci_₆ perhaloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C₃_i o carbocyclyl, 3-10 membered heterocyclyl, O₆_io aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^gg groups, or two geminal R^dd substituents can be joined to form =0 or =S;

each instance of R^ee is, independently, selected from Ci_₆ alkyl, Ci_₆ perhaloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C io carbocyclyl, CVio aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^gg groups;

each instance of R ff is, independently, selected from hydrogen, Ci_₆ alkyl, Ci_₆ perhaloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C₃_io carbocyclyl, 3-10 membered heterocyclyl, C₆-io aryl and 5-10 membered heteroaryl, or two R ff groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R⁸⁸ groups; and

each instance of R^gg is, independently, halogen, -CN, -N0₂, -N o -S0₂H, -SO₃H, -OH, — OCi_₆ alkyl, -ON(C_I-6 alkyl)₂, -N(C_I-6 alkyl)₂, -N(C_I-6 alkyl^X , -NH(C_I-6 alkyl)₂ ⁺X-, - NH₂(C_I-6 alkyl) ⁺X , -NH₃ ⁺X , -N(OC_I-6 alkyl)(Ci_₆ alkyl), -N(OH)(C_I-6 alkyl), -NH(OH), - SH,—SC i_₆ alkyl, -SS(C ,__ft alkyl), -C(=0)(Ci_₆ alkyl), -C0₂H, -C0₂(C_!-6 alkyl), -OC(=0)(Ci_₆ alkyl), -0C0₂( _₆ alkyl), -C(=0)NH₂, -C(=0)N(Ci^ alkyl)₂, -OC(=0)NH(C_!-6 alkyl), - NHC(=0)( Ci_₆ alkyl), -N(C_I-6 alkyl)C(=0)( C _₆ alkyl), -NHC0₂(Ci_₆ alkyl), -NHC(=0)N(C _ ₆ alkyl)₂, -NHC(=0)NH(Ci_₆ alkyl), -NHC(=0)NH₂, -C(=NH)0(Ci_₆ alkyl), -OC(=NH)(C_I-6 alkyl), -OC(=NH)OC_I-6 alkyl, -C(=NH)N(C_I-6 alkyl)₂, -C(=NH)NH(C_I-6 alkyl), -C(=NH)NH₂, -OC(=NH)N(C_I-6 alkyl)₂, -OC(NH)NH(C_I-6 alkyl), -OC(NH)NH₂, -NHC(NH)N(C_I-6 alkyl)₂, - NHC(=NH)NH₂, -NHS0₂(C_I-6 alkyl), -S0₂N(Ci_₆ alkyl)₂, -S0₂NH(Ci_₆ alkyl), -S0₂NH₂,- S0₂C _₆ alkyl, -S0₂0C _₆ alkyl, -0S0₂C _₆ alkyl, -S0C _₆ alkyl, -Si( _₆ alkyl)₃, -0Si(C_!-6 alkyl)₃ -C(=S)N(C_I-6 alkyl)₂, C(=S)NH(C_!-6 alkyl), C(=S)NH₂, -C(=0)S(Ci_₆ alkyl), - C(=S)SCi_₆ alkyl, -SC(=S)SC_!-6 alkyl, -P(=0)₂(Ci_₆ alkyl), -P(=0)(C« alkyl)_2> -0P(=0)(Ci_₆ alkyl)₂, -OP(=0)(OCi_₆ alkyl)₂, C ,__ri alkyl, C ,__fl perhaloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R^gg substituents can be joined to form =0 or =S; wherein X is a counterion.

Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms. Exemplary nitrogen atom substitutents include, but are not limited to, hydrogen, -OH, -OR^aa, -N(R^CC)₂, -CN, -C(=0)R^aa,

C_2-10 alkenyl, C_2-io alkynyl, C_3-io carbocyclyl, 3-14 membered heterocyclyl, CVi₄ aryl, and 5-14 membered heteroaryl, or two R^cc groups attached to a nitrogen atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups, and wherein R^aa, R^bb, R^cc and R^dd are as defined above.

“Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4— toluenesulfonic acid, camphorsulfonic acid, 4— methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N- methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term “pharmaceutically acceptable cation” refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, et at, J. Pharm. Sci. (1977) 66(1): 1-79.

Other features and advantages of the invention will be apparent from the Detailed Description, Examples, and Claims.

EQUIVALENTS

The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this disclosure has been described with reference to specific aspects, it is apparent that other aspects and variations may be devised by others skilled in the art without departing from the true spirit and scope of the disclosure. The appended claims are intended to be construed to include all such aspects and equivalent variations. Any patent, publication, or other disclosure material, in whole or in part, that is said to be incorporated by reference herein is incorporated herein only to the extent that the incorporated material does not conflict with existing definitions, statements, or other disclosure material set forth in this disclosure. As such, and to the extent necessary, the disclosure as explicitly set forth herein supersedes any conflicting material incorporated herein by reference.

While this disclosure has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the disclosure encompassed by the appended claims.

Claims

1. A compound of formula (I):

pharmaceutically acceptable salt thereof, wherein:

R is selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and halide, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more halides; each of R and R is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, and halide, wherein the alkyl, alkeynyl, alkynyl, or cycloalkyl is optionally substituted with one or more halides; or

R and R can be taken together to form a cycloalkyl or heterocyclyl;

R₄ is selected from the group consisting of: -N(R_a)₂, -ORj,, -SR_C, heterocyclyl, heteroaryl, and aryl, wherein the heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more substituents independently selected from the group consisting of: alkyl, -N(R_a)₂, -ORj,, and -SR_C; n is 0, 1, 2, or 3; each of R_a, R_b, and R_c is independently an alkyl or aryl, wherein the alkyl or aryl is optionally substituted with one or more substituents independently selected from the group consisting of: alkyl, -N(R_d)₂, -OR_e, and -SR_f; and each of R_c|, R_e, and R_f is alkyl or aryl; wherein the compound is not a compound selected from:

pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein the compound is a compound of formula (I-a):

pharmaceutically acceptable salt thereof, wherein:

R is selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and halide, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more halides; each of R and R3 is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, and halide, wherein the alkyl, alkeynyl, alkynyl, or cycloalkyl is optionally substituted with one or more halides; or

R₂ and R3 can be taken together to form a cycloalkyl;

R₄ is selected from the group consisting of: -N(R_a)₂, -OR_b, -SR_C, heterocyclyl, heteroaryl, and aryl, wherein the heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more substituents independently selected from the group consisting of: alkyl, -N(R_a)₂, -OR_b, and -SR_C; each of R_a, R_b, and R_c is independently an alkyl or aryl, wherein the alkyl or aryl is optionally substituted with one or more substituents independently selected from the group consisting of: alkyl, -N(R_C|)2, -OR_e, and -SR_f; each of R _|, R_e, and R_f is alkyl or aryl; and n is 0, 1, 2, or 3; wherein the compound is not a compound selected from:

pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, wherein R is alkyl or halogen, wherein the alkyl is substituted with 1, 2, or 3 halogens.

4. The compound of any one of claims 1-3, wherein R is selected from the group consisting of methyl, ethyl, F, CF₃, C1¾CF₃, and CF2CF3.

5. The compound of any one of claims 1-4, wherein R is selected from the group consisting of methyl, F, CF3, and C1¾CF₃.

6. The compound of any one of claims 1-5, wherein one of R₂ and R₃ is halide and the other is alkyl.

7. The compound of any one of claims 1-6, wherein one of R₂ and R₃ is fluoride.

8. The compound of any one of claims 1-7, wherein one of R₂ and R₃ is fluoride and the other is methyl.

9. The compound of any one of claims 1-8, wherein R₂ and R₃ are taken together to form a cycloalkyl.

10. The compound of any one of claims 1-9, wherein R₂ and R₃ are taken together to form a cyclopropyl or cyclobutyl.

11. The compound of any one of claims 1-10, wherein R₂ and R3 are alkyl.

12. The compound of any one of claims 1-11, wherein R₂ and R3 are methyl.

13. The compound of any one of claims 1-12, wherein R₄ is -N(R_a)₂ or heterocyclyl.

14. The compound of any one of claims 1-13, wherein R₄ is selected from the group consisting of:

15. The compound of any one of claims 1-14, wherein the compound is a compound of formula (I-b):

pharmaceutically acceptable salt thereof, wherein the variables as defined in any one of claims 1-14.

16. A compound of formula (II):

pharmaceutically acceptable salt thereof, wherein:

R is selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, and halogen, wherein alkyl, alkenyl, alkynyl, and cycloalkyl, are optionally substituted with one or more halogen;

R3 is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, and halogen, wherein the alkyl, alkeynyl, alkynyl, and cycloalkyl are optionally substituted with one or more halogen;

R₄ is selected from the group consisting of: -N(R_a)₂, -OR_b, -SR_C, and heterocyclyl; each of R_a, R_b, and R_c is independently an alkyl; and n is 0, 1, 2, or 3.

17. The compound of claim 16, wherein the compound is a compound of formula (Il-a):

pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 16.

18. The compound of claim 16 or 17, wherein R is alkyl or halogen, wherein the alkyl is substituted with 1, 2, or 3 halogens.

19. The compound of any one of claims 16-18, wherein R is selected from the group consisting of methyl, ethyl, F, CF₃, C1¾CF₃, and CF CF₃.

20. The compound of any one of claims 16-19, wherein R is selected from the group consisting of methyl, F, CF₃, and C1¾CF₃.

21. The compound of any one of claims 16-20, wherein R _¾ is alkyl.

22. The compound of any one of claims 16-21, wherein R is methyl.

23. The compound of any one of claims 14-22, wherein R is -N(R_a)₂ or heterocyclyl.

24. The compound of any one of claims 14-23, wherein R is selected from the group consisting of:

25. The compound of any one of claims 14-24, wherein n is 1.

26. A compound of formula (III):

pharmaceutically acceptable salt thereof, wherein:

R is selected from the group consisting of: -N(R_a)₂, -OR,, -SR_C, and heterocyclyl;

R is independently, for each occurrence, selected from the group consisting of: -CTT-, - NR_a-, -0-, and -S-; each of R_a, R_b, and R_c is independently an alkyl; m is 2, 3, 4, or 5; and n is 0, 1, 2, or 3.

27. The compound of claim 26, wherein the compound is a compound of formula (III- a):

pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 26.

28. The compound of claim 26, wherein the compound is a compound of formula (Ill-b):

pharmaceutically acceptable salt thereof, wherein:

R₄ is selected from the group consisting of: -N(R_a)₂, -ORj,, -SR_C, and heterocyclyl; each of R_a, R_b, and R_c is independently an alkyl; m is 2 or 3; and n is 0, 1, 2, or 3.

29. The compound of claim 28, wherein the compound is a compound of formula (III-c):

pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 28.

30. The compound of any one of claims 26-29, wherein Ri is alkyl or halogen, wherein the alkyl is substituted with 1 , 2, or 3 halogens.

31. The compound of any one of claims 26-30, wherein R is selected from the group consisting of methyl, ethyl, F, CF₃, CH CF₃, and CF CF₃.

32. The compound of any one of claims 26-31, wherein Ri is selected from the group consisting of methyl, F, CF₃, and CH CF₃.

33. The compound of any one of claims 26-32, wherein R is -N(R

or heterocyclyl.

34. The compound of any one of claims 26-33, wherein R is selected from the group consisting of:

35. The compound of any one of claims 26-34, wherein m is 2.

36. The compound of any one of claim 26-35, wherein m is 3.

37. The compound of any one of claims 26-36, wherein n is 1.

38. A compound of formula (IV):

R is selected from the group consisting of: alkyl, alkenyl, alkynyl, and cycloalkyl;

wherein the alkyl is substituted with one or more halogen; wherein the alkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more halogen;

R₂ and R3 are independently alkyl;

39. The compound of claim 38, wherein the compound is a compound of formula (IV-a):

40. The compound of claim 38 or 39, wherein Ri is alkyl substituted with 1, 2, or 3 halogens.

41. The compound of any one of claims 38-40, wherein R is CF _¾ or CH2CF3.

42. The compound of any one of claims 38-41, wherein R₂ and R3 are methyl.

43. The compound of any one of claims 38-42, wherein R4 is -N(R_a)₂ or heterocyclyl.

44. The compound of any one of claims 38-43, wherein R4 is selected from the group consisting of:

45. The compound of any one of claims 38-44, wherein n is 1.

46. A compound of formula (V):

pharmaceutically acceptable salt thereof, wherein:

R₂ and R3 are independently alkyl;

R₄ is selected from the group consisting of: -N(R_a)₂, -OR_b, -SR_C, and heterocyclyl;

wherein the heterocyclyl is not piperidinyl or pyrrolidinyl; each of R_a, R , and R_c is independently an alkyl; and n is 0, 1, 2, or 3.

47. The compound of claim 46, wherein the compound is a compound of formula (V-a):

pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 46.

48. The compound of claim 46 or 47, wherein R is alkyl substituted with 1, 2, or 3 halogens.

49. The compound of any one of claims 46-48, wherein R is selected from the group consisting of: methyl, ethyl, F, CF3, C1¾CF3, and CF2CF3.

50. The compound of any one of claims 46-49, wherein R is selected from the group consisting of methyl, F, CF3, and C1¾CF3.

51. The compound of any one of claims 46-50, wherein R₂ and R3 are methyl.

52. The compound of any one of claims 46-51, wherein R4 is -N(R_a)₂ or heterocyclyl, wherein the heterocyclyl is not piperidinyl or pyrrolidinyl.

53. The compound of any one of claims 46-52, wherein R4 is selected from the group consisting of:

54. The compound of any one of clai s 46-53, wherein n is 1.

55. The compound of any one of claims 1-54, wherein the compound is selected from the group consisting of:

pharmaceutically acceptable salt thereof.

56. A pharmaceutical composition comprising a compound of any one of claims 1-55 and a pharmaceutically acceptable excipient.